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WO2010119877A1 - Process for production of amidine derivative - Google Patents

Process for production of amidine derivative Download PDF

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Publication number
WO2010119877A1
WO2010119877A1 PCT/JP2010/056624 JP2010056624W WO2010119877A1 WO 2010119877 A1 WO2010119877 A1 WO 2010119877A1 JP 2010056624 W JP2010056624 W JP 2010056624W WO 2010119877 A1 WO2010119877 A1 WO 2010119877A1
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WIPO (PCT)
Prior art keywords
group
hydroxyethoxy
compound
salt
acid
Prior art date
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PCT/JP2010/056624
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French (fr)
Japanese (ja)
Inventor
康太朗 岡戸
宣博 山中
さとみ 大塚
真 室野井
範康 片岡
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味の素株式会社
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Publication of WO2010119877A1 publication Critical patent/WO2010119877A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
    • C07C259/18—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings

Definitions

  • the present invention relates to a method for producing an amidine derivative having inhibitory activity on activated blood coagulation factor X (hereinafter sometimes abbreviated as FXa). Further, the present invention relates to a novel compound useful as a synthetic intermediate for a compound applied to the production method.
  • FXa activated blood coagulation factor X
  • the extracorporeal blood circulation is an artificial blood circulation that passes through a blood circuit built outside the living body.
  • blood extracorporeal circulation is a circulation circuit that retransmits blood into the living body from a living body through an artificial blood flow path outside the body, and further through a device that performs a certain treatment, for example, an artificial heart-lung machine, a blood purification device, etc. Is done by.
  • Extracorporeal blood treatment may be required during blood purification therapy such as hemodialysis, blood filtration, hemodialysis fluid excess, blood festival exchange, and cardiopulmonary bypass during open heart surgery.
  • a typical example of the blood purification apparatus is a dialyzer.
  • Blood extracorporeal circuit consisting of artificial blood flow path and various devices during extracorporeal blood circulation is a foreign substance, and blood coagulates when it comes in contact with it, so it is necessary to take measures to prevent blood coagulation in extracorporeal blood circulation circuit by some method is there.
  • anti-blood coagulants such as unfractionated heparin and low molecular weight heparin have been used for the purpose of preventing thrombus in this extracorporeal circuit.
  • unfractionated heparin has thrombin inhibitory activity in addition to FXa inhibitory activity, there is a known risk of bleeding tendency and it cannot be used for patients with high bleeding risk.
  • low molecular weight heparin is a drug that chemically treats heparin to more selectively inhibit FXa against thrombin and has no thrombin inhibitory activity, thus reducing the risk of bleeding tendency and bleeding tendency Used for patients with
  • low molecular weight heparin since low molecular weight heparin has a long elimination half-life, it is difficult to stop bleeding when bleeding symptoms are observed.
  • Some serine protease inhibitors also have anticoagulant activity, for example, naphthostat mesylate is used during some extracorporeal circulation such as hemodialysis.
  • Nahuamostat mesylate is also used for patients who already have bleeding lesions because of its short elimination half-life in vivo.
  • nahuamostat mesylate has a weak inhibitory activity against FXa and thrombin and has a weak anticoagulant effect.
  • all drugs still have problems, and more effective and safe drugs are required.
  • a patient with an extracorporeal circuit has a problem of blood coagulation only when the circuit is used, and the situation is often different from a patient who must always prevent blood coagulation.
  • a selective small molecule FXa inhibitor with a short blood half-life can be safely and conveniently used as an anticoagulant for preventing blood coagulation for the extracorporeal circulation circuit. In the past, it has never been expected to reduce the amount to a minimum.
  • amidine compounds described in Patent Documents 1 to 3 are known as amidine compounds exhibiting anticoagulant activity based on FXa selective inhibitory action.
  • A′-COO-B ′ having an ester bond in the molecule described in Patent Document 3 [A ′ and B ′ represent an organic group, at least one of which includes an amidino group or a guanidino group structure]
  • the amidine derivative has an excellent activated blood coagulation factor X inhibitory activity and a short blood half-life, and was useful as a blood coagulation inhibitor for blood extracorporeal circuits.
  • the amidine derivative is specifically a compound shown below.
  • Patent Document 3 discloses a synthesis method via an alkyl bond forming reaction (alkyl bond forming route). This method is, for example, as follows, and a final compound is synthesized from the main skeleton formation through a plurality of side chain modifications.
  • X is a halogen atom
  • R is an alkyl group which may have a substituent
  • the process leading from the formation of the main skeleton to the drug substance is generally carried out in a controlled manufacturing facility that complies with the standards (GMP) of the regulatory authorities in each country, and advanced quality control and process control are performed. It takes a lot of cost to make it necessary. Therefore, simplification of the manufacturing process after the formation of the main skeleton is extremely important because it not only facilitates manufacturing and quality control, but also shortens the production period and reduces manufacturing costs. Therefore, there is a demand for a production method that can form the main skeleton in a shorter process than the alkyl bond formation route and obtain the drug substance.
  • the present invention relates to a production method suitable for industrialization of an amidine derivative having an ester bond, which is a highly useful compound as a drug having an anticoagulant action.
  • the present invention relates to a method for producing an amidine derivative having a target ester bond in a simple and high yield.
  • the present inventors can easily convert the amidine derivative having the desired ester bond into a high yield. For the first time. As a result of further intensive studies based on these findings, the present inventors have completed the present invention.
  • Ring A is a C 6-14 aryl group, a heteroaryl group, a nitrogen-containing non-aromatic heterocyclic group or a C 3-10 cycloalkyl group
  • V represents a hydrogen atom, a halogen atom, a C 1-10 alkyl group which may have a substituent, a C 1-10 alkoxy group which may have a substituent, or a substituent.
  • a C 1-10 alkylamino group, an optionally substituted C 1-10 alkylthio group, a cyano group, a nitro group, or an optionally substituted carbamoyl group, W is a heteroaryl group, or the following formula (A), (B) or (C)
  • Q represents a C 1-6 alkyl group, an optionally substituted amino group or a nitrogen-containing heterocyclic group having a bond to the nitrogen atom
  • R represents a C 1-6 alkyl group
  • m represents an integer of 1 to 3
  • Ring C represents a nitrogen-containing heterocyclic group
  • Y represents any of a nitrogen atom, an oxygen atom, a sulfur atom or a methylene group
  • Z represents a hydrogen atom, an amidino group which may be substituted with C 1-6 alkyl, or a C 1-6 alkyl group which may have imino at the 1-position
  • X is a halogen atom
  • An acid halide represented by the formula hereinafter sometimes referred to as “compound (1)” or “acid halide (1)”) or a salt thereof;
  • Ring B is a C 6-14 aryl group, a heteroaryl group, a nitrogen-containing non-aromatic heterocyclic group or a C 3-10 cycloalkyl group
  • T represents a hydrogen atom, a halogen atom, a hydroxy group, a C 1-10 alkoxy group which may have a substituent, an acyloxy group which may have a substituent, or a carbamoyl which may have a substituent.
  • An oxy group, an optionally substituted thiocarbamoyloxy group, an amino group, a cyano group, a nitro group, an optionally substituted C 1-10 alkyl group, and an optionally substituted group A good C 1-10 alkylamino group, an optionally substituted C 1-10 alkylthio group, an optionally substituted acylamino group, a carboxyl group, an optionally substituted C 1-10 alkoxy-carbonyl group, an optionally substituted carbamoyl group, or an optionally substituted thiocarbamoyl group, U has a hydrogen atom, an optionally substituted C 1-10 alkyl group, a carboxyl group, an optionally substituted C 1-10 alkoxy-carbonyl group, or a substituent.
  • a carbamoyl group that may be L is a nitrogen atom, oxygen atom, sulfur atom or methylene group, and n is an integer of 1 to 3)
  • a compound represented by formula (4) (hereinafter, may be referred to as “compound (3)” or “amidine compound (3)”) or a salt thereof:
  • each symbol is the same as [1].
  • the compound (3) or a salt thereof is condensed with a condensing agent.
  • the compound (1) or a salt thereof obtained by reacting the compound (2) or a salt thereof with an acid halogenating agent is condensed with the compound (3) or a salt thereof without isolation.
  • R ′′ is an optionally substituted C 1-10 alkyl group, and other symbols are the same as those in [1]
  • a compound (4) or a salt thereof characterized by condensing an ester compound represented by the formula (hereinafter sometimes referred to as “compound (5)”) or a salt thereof with a compound (3) or a salt thereof.
  • Salt production method [7] Ring A and ring B are a C 6-14 aryl group, V and U are hydrogen atoms, W is the formula (A)
  • T is hydrogen atom, hydroxy group, C 1-10 alkoxy or optionally C 1-10 alkoxy group optionally substituted by cyano
  • T ' is a hydroxy group, a C 1-10 alkoxy group or C 1-10 alkoxy group optionally substituted by cyano
  • compound (3 ′) 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof; 4-hydroxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof; 3- (2-hydroxyethoxy) -4-methoxybenzamidine or a salt thereof; 4-ethoxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof; and a compound selected from 3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzamidine or a salt thereof; [10] 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine, or a hydrochloride thereof; 4-hydroxy-3- (2-hydroxyethoxy) benzamidine acetate and hydrochloride; 3- (2-hydroxyethoxy) -4
  • T ′′ is a sodium atom, a hydrogen atom, or a C 1-10 alkyl group which may be substituted with C 1-10 alkoxy; G is a cyano group or substituted with hydroxy; A good amidino group
  • compound (3 ′′) is a salt thereof (hereinafter sometimes referred to as “compound (3 ′′)”);
  • T ′ ′′ is a C 1-10 alkyl group substituted with C 1-10 alkoxy
  • R ′ ′′ is a hydrogen atom or a C 1-10 alkyl group.
  • a salt thereof hereinafter sometimes referred to as “compound (3 ′ ′′)”
  • R ′ is an alkoxy group which may have a substituent or a halogen atom
  • Q ′′ is a bond to a C 1-10 alkoxy group, an amino group which may have a substituent or a nitrogen atom.
  • an amidine derivative having an ester bond which is a highly useful compound as a drug having an anticoagulant action, easily and in high yield through fewer steps than the alkyl bond formation route.
  • the present invention has the following formula
  • a new method for producing an amidine derivative (4) having an ester bond, which is a highly useful compound as a drug having an anticoagulant action (hereinafter referred to as “the production method of the present invention”). And was completed based on the discovery that compound (4) can be produced by reacting compound (1), compound (2) or compound (5) with compound (3). . By this production method, the compound (4) can be produced simply and with high yield.
  • novel compound of compound (3) As will be described later, a novel compound of compound (3), a synthetic intermediate useful for obtaining compound (3), and compound (1) for producing compound (4) of the present invention. These novel compounds and the novel compound (5) are also included in the present invention.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom unless otherwise specified.
  • C 1-6 alkyl group means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethyl unless otherwise specified. It means propyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
  • examples of the “C 2-10 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3- Methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, etc. Is mentioned. Of these, a C 2-6 alkenyl group is preferable.
  • examples of the “C 2-10 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- Examples include pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like. Of these, a C 2-6 alkynyl group is preferable.
  • C 1-6 alkoxy group means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy and the like unless otherwise specified. To do.
  • the “C 6-14 aryl group” means a monocyclic or bicyclic aromatic hydrocarbon ring group having 6 to 14 carbon atoms, or a 5- to 8-membered cycloalkyl ring (for example, a phenyl group) , Cyclopentane ring, cyclohexane ring, cycloheptane ring, cyclooctane ring and the like).
  • the C 6-14 aryl group may have a substituent described later.
  • Specific examples of the “C 6-14 aryl group” include a phenyl group, a naphthyl group, an indanyl group, and a tetrahydronaphthalenyl group. Of these, a C 6-10 aryl group is preferable, a phenyl group and a naphthyl group are more preferable, and a phenyl group is particularly preferable.
  • the “heteroaryl group” is a 4- to 7-membered monocyclic ring containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring-constituting atom.
  • an aromatic heterocyclic group having a formula and 8- to 12-membered fused aromatic heterocyclic group examples include a ring corresponding to these 4- to 7-membered monocyclic aromatic heterocyclic groups and a 5- or 6-membered aromatic heterocyclic ring containing 1 or 2 nitrogen atoms.
  • the heteroaryl group usually has 1 to 10 carbon atoms, preferably 1 to 9 carbon atoms.
  • Specific examples of such heteroaryl groups include pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (eg, 2-pyridinyl).
  • non-aromatic heterocyclic group that is, aliphatic heterocyclic group
  • the “non-aromatic heterocyclic group” includes 1 hetero atom selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to a carbon atom as a ring-constituting atom.
  • a 4- to 7-membered monocyclic non-aromatic heterocyclic group and an 8- to 12-membered condensed non-aromatic heterocyclic group containing ⁇ 4 are shown.
  • Examples of the fused non-aromatic heterocyclic group include, for example, a ring corresponding to the 4- to 7-membered monocyclic non-aromatic heterocyclic group, and a 5- or 6-membered aromatic group containing 1 or 2 nitrogen atoms.
  • 1 or 2 rings selected from a heterocycle eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine
  • a 5-membered aromatic heterocycle containing one sulfur atom eg, thiophene
  • a benzene ring examples thereof include a group derived from a condensed ring and a group obtained by partial saturation of the group.
  • the non-aromatic heterocyclic group preferably has 1 to 9 carbon atoms. Any carbon atom that is a ring-constituting atom may be substituted with an oxo group.
  • non-aromatic heterocyclic ring from which the non-aromatic heterocyclic group is derived include, for example, pyrrolidine ring, pyrazolidine ring, imidazolidine ring, pyrroline ring, pyrazoline ring, imidazoline ring, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydro Quinoline ring, tetrahydroisoquinoline ring, thiazolidine ring, piperidine ring, piperazine ring, quinuclidine ring, tetrahydropyran ring, morpholine ring, thiomorpholine ring, dioxolane ring, homopiperidine ring, homopiperazine ring, indoline ring, isoindoline ring, chroman ring And an isochroman ring.
  • Such non-aromatic heterocyclic groups include pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl), piperidinyl (eg, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), homopiperidinyl, morpholinyl (eg, Morpholino), thiomorpholinyl (eg, thiomorpholino), piperazinyl (eg, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl), homopiperazinyl, hexamethyleneiminyl (eg, hexamethyleneimine-1-yl), oxazolidinyl (eg, Oxazolidin-2-yl), thiazolidinyl (eg, thiazolidin-2-yl), dihydrothiopyranyl (eg, dihydrothiopyran-3-yl, dihydrothiopyran-4-yl), imi
  • a non-aromatic heterocyclic group having 2 to 8 carbon atoms is preferable, more preferably pyrrolidinyl, pyrrolinyl, tetrahydrofuryl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperidinyl, homopiperazinyl, particularly preferably pyrrolidinyl, Piperidinyl and homopiperidinyl.
  • nitrogen-containing non-aromatic heterocyclic group that is, nitrogen-containing aliphatic heterocyclic group
  • nitrogen-containing non-aromatic heterocyclic group refers to a non-aromatic heterocyclic group containing a nitrogen atom in the ring.
  • nitrogen-containing non-aromatic heterocyclic group generally include nitrogen-containing non-aromatic heterocyclic groups having 1 to 9 carbon atoms (preferably 2 to 9 carbon atoms, more preferably 2 to 8 carbon atoms).
  • the “C 3-10 cycloalkyl group” represents a saturated or unsaturated cyclic aliphatic hydrocarbon group having 3 to 10 carbon atoms, and partially has an unsaturated bond in the ring. May be included. Further, it may be monocyclic or polycyclic. Examples of the C 3-10 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl, cyclopentenyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.
  • C 1-10 alkyl group or “C 1-10 alkylthio group”, “C 1-10 alkylamino group”, “C 1-10 alkoxy group”, “C 1-10 alkoxy-”
  • the C 1-10 alkyl group moiety in the “carbonyl group” and the like is a linear or branched alkyl group having 1 to 10 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl.
  • a C 1-6 alkyl group is preferable, a methyl group, an ethyl group, an isopropyl group, and an isobutyl group are more preferable, and an alkyl group having 1 to 3 carbon atoms (a methyl group, an ethyl group, and an isopropyl group) is most preferable.
  • examples of the “C 1-10 alkylthio group” include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, a sec-butylthio group, a tert-butylthio group, and a pentylthio group.
  • Isopentylthio group Isopentylthio group, neopentylthio group, hexylthio group, heptylthio group, octylthio group, nonylthio group, decylthio group, 1,1-dimethyl-propylthio group and the like.
  • examples of the “C 1-10 alkylamino group” include a methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, sec-butylamino group, tert.
  • examples of the “C 1-10 alkylsulfonamide group” include a methylsulfonamide group, an ethylsulfonamide group, a propylsulfonamide group, an isopropylsulfonamide group, a butylsulfonamide group, an isobutylsulfonamide group, sec-butylsulfonamide group, tert-butylsulfonamide group, cyclopropylmethylsulfonamide group, pentylsulfonamide group, isopentylsulfonamide group, neopentylsulfonamide group, hexylsulfonamide group, heptylsulfonamide group, octylsulfone Amide group, nonylsulfonamide group, decylsulfonamide group, 1,1-dimethyl-propylsulfonamide group, cyclopropy
  • examples of the “C 1-10 alkoxy group” include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, and a pentyloxy group.
  • it is a C 1-6 alkoxy group.
  • examples of the “C 1-10 alkoxy-carbonyl group” include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, and a sec-butoxycarbonyl group.
  • acyl group in the “acyl group”, “acyloxy group”, “acylamino group” and the like in this specification includes a formyl group, a C 1-10 alkyl-carbonyl group (for example, an acetyl group, an ethylcarbonyl group, a propyl group).
  • Carbonyl group isopropylcarbonyl group, butylcarbonyl group, isobutylcarbonyl group, sec-butylcarbonyl group, tert-butylcarbonyl group, cyclopropylmethylcarbonyl group, pentylcarbonyl group, isopentylcarbonyl group, neopentylcarbonyl group, hexylcarbonyl group , Heptylcarbonyl group, octylcarbonyl group, nonylcarbonyl group, 1,1-dimethyl-propylcarbonyl group, cyclopropylcarbonyl group, cyclobutylcarbonyl group, cyclopentylcarbonyl group, cyclohexyl group, A silcarbonyl group, a cycloheptylcarbonyl group, a cyclooctylcarbonyl group, etc.), a C 6-10 aryl-carbonyl group (for example, a benzo
  • examples of the “acyloxy group” include a formyloxy group, an alkylcarbonyloxy group having 2 to 10 carbon atoms (for example, an acetyloxy group, an ethylcarbonyloxy group, a propylcarbonyloxy group, an isopropylcarbonyloxy group, Butylcarbonyloxy group, isobutylcarbonyloxy group, sec-butylcarbonyloxy group, tert-butylcarbonyloxy group, pentylcarbonyloxy group, isopentylcarbonyloxy group, neopentylcarbonyloxy group, hexylcarbonyloxy group, heptylcarbonyloxy group Octylcarbonyloxy group, nonylcarbonyloxy group, 1,1-dimethyl-propylcarbonyloxy group, etc.), C 6-10 aryl-carbonyloxy group (for example, benzoyloxy group) Etc.).
  • examples of the “acylamino group” include a formylamino group, a C 1-10 alkyl-carbonylamino group (for example, acetylamino group, ethylcarbonylamino group, propylcarbonylamino group, isopropylcarbonylamino group, butyl Carbonylamino group, isobutylcarbonylamino group, sec-butylcarbonylamino group, tert-butylcarbonylamino group, pentylcarbonylamino group, isopentylcarbonylamino group, neopentylcarbonylamino group, hexylcarbonylamino group, heptylcarbonylamino group, octyl carbonylamino group, nonyl carbonylamino group, 1,1-dimethyl - propyl carbonylamino group, etc.), C 6-10 aryl - carbonyl amino group (e
  • the “nitrogen-containing heterocyclic group” refers to the “nitrogen-containing non-aromatic heterocyclic group” defined above and the “heteroaryl group” defined above having a nitrogen atom in the ring.
  • a nitrogen-containing heterocyclic group having 2 to 8 carbon atoms is preferred, more preferably a pyrrolidinyl group, piperidinyl group, homopiperidinyl group, morpholinyl group, thiomorpholinyl group, piperazinyl group, pyrrolinyl group, imidazolyl group, pyridyl group, pyrrolyl group, More preferred are pyrrolidinyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, and piperazinyl group.
  • alkylamino group in this specification, or “carbamoyl or thiocarbamoyl substituted with an alkyl group (which may have a substituent, carbamoyl group, thiocarbamoyl group, carbamoyloxy group, thiocarbamoyloxy group)
  • the alkylamino moiety as a component such as “in which the substituent is an alkyl group” includes a monoalkylamino group and a dialkylamino group.
  • the alkyl group may be bonded to form a ring (for example, a nitrogen-containing heterocycle of the nitrogen-containing heterocyclic group).
  • the “amidino group” in the present specification refers to a group represented by H 2 N—C ( ⁇ NH) —.
  • each substituent “which may have a substituent” for example, (1) a halogen atom, (2) a hydroxy group, (3) an amino group, (4) a C 1-10 alkyl group, (5) C 2-10 alkenyl group, (6) a C 2-10 alkynyl group, (7) a C 1-10 alkoxy group, (8) a C 1-10 alkylamino group, (9) a cyano group, (10) a guanidino group, (11) a carboxyl group, (12) a carbamoyl group, (13) a C 6-14 aryl group, (14) a heteroaryl group, (15) a C 3-10 cycloalkyl group, (16) a nitrogen-containing non-aromatic heterocyclic group, (17) a C 1-10 alkylthio group, (18) an acyloxy group, (19) an acylamino group, (20) a C 1-10 alkylsulfona
  • compound (1), compound (2), compound (3), compound (4) and compound (5) of the present invention include various stereoisomers such as geometric isomers, tautomers and optical isomers. And mixtures thereof and isolated ones.
  • X in the compound (1) is a halogen atom, preferably a chlorine atom.
  • Examples of the group represented by ring A in compound (1), compound (2), compound (4) and compound (5) include a C 6-14 aryl group, a heteroaryl group, a nitrogen-containing non-aromatic heterocyclic group or A C 3-10 cycloalkyl group, preferably a C 6-14 aryl group, and particularly preferably a phenyl group.
  • the positions of the substituents V and W on the ring A and the carbonyl group are not particularly limited as long as they are substitutable positions on the ring A. However, when the ring A is a phenyl group, the substitution position of the carbonyl group is 1 In the case of W, W is preferably 4th.
  • V in the compound (1), the compound (2), the compound (4) and the compound (5) is a hydrogen atom, a halogen atom, a C 1-10 alkyl group which may have a substituent, or a substituent.
  • compound (2) As W in compound (1), compound (2), compound (4) and compound (5), heteroaryl group, or the following formula (A), (B) or (C)
  • Q represents a C 1-6 alkyl group, an optionally substituted amino group or a nitrogen-containing heterocyclic group having a bond to the nitrogen atom
  • R represents a C 1-6 alkyl group
  • m represents an integer of 1 to 3
  • Ring C represents a nitrogen-containing heterocyclic group
  • Y represents any of a nitrogen atom, an oxygen atom, a sulfur atom or a methylene group
  • Z represents a hydrogen atom, an amidino group which may be substituted with C 1-6 alkyl, or a C 1-6 alkyl group which may have imino at the 1-position
  • W is preferably a formula (A)
  • Q is a nitrogen-containing non-aromatic heterocyclic group having a bond at the nitrogen atom), and more preferably an imino (pyrrolidin-1-yl) methyl group.
  • the group represented by ring B is a C 6-14 aryl group, a heteroaryl group, a nitrogen-containing non-aromatic heterocyclic group or a C 3-10 cycloalkyl group, A C 6-14 aryl group is preferred, and a phenyl group is particularly preferred.
  • the position of the substituents T, L and amidino group on ring B is not particularly limited as long as it is a substitutable position on ring B, but ring B is a phenyl group, and the position of substitution of the amidino group is In the first position, T is preferably the 4th position, and L is preferably the 3rd position.
  • a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted C 1-10 alkoxy group, and an optionally substituted acyloxy group A carbamoyloxy group which may have a substituent, a thiocarbamoyloxy group which may have a substituent, an amino group, a cyano group, a nitro group, or a C 1-10 which may have a substituent
  • An alkyl group, an optionally substituted C 1-10 alkylamino group, an optionally substituted C 1-10 alkylthio group, an optionally substituted acylamino group, a carboxyl group , which may have a substituent C 1-10 alkoxy - carbonyl group, which may have a substituent carbamoyl group or an optionally substituted thiocarbamoyl group Preferably, a hydrogen atom, hydroxy group, methoxy group, ethoxy group, prop
  • U in the compounds (3) and (4) is a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a carboxyl group, or a C 1-10 alkoxy which may have a substituent.
  • -A carbonyl group or an optionally substituted carbamoyl group preferably a hydrogen atom or a C 1-10 alkyl group, more preferably a hydrogen atom.
  • L in the compounds (3) and (4) is a nitrogen atom (—NH—), an oxygen atom (—O—), a sulfur atom (—S—) or a methylene group (—CH 2 —), preferably Is a nitrogen atom, an oxygen atom, or a sulfur atom, more preferably an oxygen atom or a sulfur atom, and particularly preferably an oxygen atom.
  • N in the compound (3) and the compound (4) is an integer of 1 to 3, preferably 1 or 2, and more preferably 1.
  • Compound (1) The compound (1) in the production method of the present invention has the formula (1)
  • Ring A represents a C 6-14 aryl group, a heteroaryl group, a nitrogen-containing non-aromatic heterocyclic group or a C 3-10 cycloalkyl group
  • V represents a hydrogen atom, a halogen atom, a C 1-10 alkyl group which may have a substituent, a C 1-10 alkoxy group which may have a substituent, or a substituent.
  • W is a heteroaryl group, or the following formula (A), (B) or (C)
  • Q represents a C 1-6 alkyl group, an optionally substituted amino group or a nitrogen-containing heterocyclic group having a bond to the nitrogen atom
  • R represents a C 1-6 alkyl group
  • m represents an integer of 1 to 3
  • Ring C represents a nitrogen-containing heterocyclic group
  • Y represents any of a nitrogen atom, an oxygen atom, a sulfur atom or a methylene group
  • Z represents a hydrogen atom, an amidino group which may be substituted with C 1-6 alkyl, or a C 1-6 alkyl group which may have imino at the 1-position
  • X represents a halogen atom
  • the positions of the substituents V, W and the carbonyl group on the ring A are not particularly limited as long as they are substitutable positions on the ring A.
  • W is preferably the 4th place where is the 1st place.
  • ring A is preferably a C 6-14 aryl group
  • V is a hydrogen atom
  • W is represented by the formula (A)
  • Q is a nitrogen-containing non-aromatic heterocyclic group having a bond to the nitrogen atom
  • X is a halogen atom, more preferably ring
  • Particularly preferred is 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid chloride.
  • the 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid chloride exemplified as the compound (1) is a novel compound.
  • the said compound can be preferably used as a compound (1) applied to the manufacturing method of this invention.
  • the salt may be a chemically acceptable salt.
  • Organic salts such as ammonium salts, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, aluminum salts, zinc salts, triethylamine, ethanolamine, morpholine, piperidine, dicyclohexylamine
  • salts with amines and salts with basic amino acids such as arginine and lysine.
  • a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, etc.
  • TFA trifluoroacetic acid
  • the compound (1) and a necessary acid or base are mixed in an appropriate amount ratio in a solvent or a dispersant, or cation exchange or anion exchange is carried out from other salt forms. It can also be obtained by doing.
  • compound (1) when W of compound (1) is a basic group, compound (1) is a salt with a strong acid (for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, etc.) Can be preferably formed.
  • a strong acid for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, etc.
  • hydrochloric acid is preferable as the strong acid.
  • Compound (1) includes a solvate of compound (1).
  • Compound (1) can be obtained by reacting compound (2) described later with an acid halogenating agent, or can be produced by applying a method known per se.
  • the acid halogenating agent to be applied is any commercially available reagent that can be used for the acid halogenation reaction.
  • the acid halogenating agent can be used, and as such an acid halogenating agent, thionyl chloride, oxalyl chloride, phosphorus pentachloride, phosphoryl chloride, dichlorotriphenylphosphorane, thionyl bromide, dibromotriphenylphosphorane, Examples include cyanuric fluoride (DAST).
  • a preferred acid halogenating agent is thionyl chloride.
  • the acid halogenation reaction proceeds without adding a catalyst, but according to a conventional method, an amide-based reagent such as N, N-dimethylformamide (DMF) or N-methyl-2-pyrrolidone (NMP), or 1, An imide-based reagent such as 3-dimethyl-2-imidazolidinone (DMI) can be added from a catalytic amount to a solvent amount.
  • an organic solvent that is generally commercially available and can be used for an acid halogenation reaction or the like can also be used as necessary.
  • the organic solvent can also contain the above amide or imide reagent.
  • the amount of the acid halogenating agent used is 1 mol to 7 mol, preferably 1.7 mol to 3.5 mol, per 1 mol of compound (2).
  • the reaction time is usually 1 to 10 hours, preferably 2 to 3 hours.
  • the reaction temperature is usually ⁇ 40 ° C. to 200 ° C., preferably 70 ° C. to 90 ° C.
  • the amount of the acid halogenating agent to be used is 1 to 3 mol, preferably 1.0 to 1.2 mol, per 1 mol of compound (2).
  • the reaction time is 10 minutes to 10 hours, preferably 1 to 2 hours.
  • the reaction temperature is usually ⁇ 40 ° C. to 200 ° C., preferably 0 to 20 ° C.
  • the compound (1) can be applied to the production method of the present invention without isolation as described later.
  • the acid halogenated reaction product of the compound (2) is used. By adding a poor solvent to the solution containing it, it precipitates as a solid and can be isolated by a general solid-liquid separation method.
  • compound (1 ') or a salt thereof among compound (1) or a salt thereof is a novel compound.
  • Compound (1 ') can be in the form of a salt as with Compound (1), but the salt in that case may be a chemically acceptable salt.
  • the chemically acceptable salt include those described above for the compound (1), among which strong acids (for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid) Etc.) are preferred.
  • strong acids for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid) Etc.
  • a strong acid is preferably hydrochloric acid.
  • Compound (2) reacts with the acid halogenating agent described above at the carboxyl group portion to form Compound (1).
  • the position of the substituents V, W and the carbonyl group on ring A is not particularly limited as long as it is a substitutable position on ring A, but when ring A is a phenyl group, the position of substitution of the carbonyl group is the 1st position.
  • W is preferably fourth.
  • ring A is preferably a C 6-14 aryl group
  • V is a hydrogen atom
  • W is represented by the formula (A)
  • Q is a nitrogen-containing non-aromatic heterocyclic group having a bond to the nitrogen atom
  • ring A is a phenyl group
  • V is A compound which is a hydrogen atom
  • W represents an imino (pyrrolidin-1-yl) methyl group
  • Q is a pyrrolidin-1-yl group
  • the salt may be a chemically acceptable salt.
  • Organic salts such as ammonium salts, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, aluminum salts, zinc salts, triethylamine, ethanolamine, morpholine, piperidine, dicyclohexylamine
  • salts with amines and salts with basic amino acids such as arginine and lysine.
  • a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, etc.
  • TFA trifluoroacetic acid
  • the compound (2) and a necessary acid or base are mixed in an appropriate amount ratio in a solvent or a dispersant, or cation exchange or anion exchange is carried out from other salt forms. It can also be obtained by doing.
  • compound (2) when W of compound (2) represents a basic group, compound (2) is a salt with a strong acid (for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, etc.) Can be preferably formed.
  • a strong acid for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, etc.
  • hydrochloric acid is preferable as the strong acid.
  • Compound (2) includes solvates of compound (2), such as hydrates and alcohol adducts.
  • Compound (2) can be produced by a method known per se.
  • a compound in which ring A is a C 6-14 aryl group and W is a group represented by formula (A) can be produced, for example, by the following method.
  • the amidine derivative can be synthesized from 4-cyanobenzoic acid with reference to International Publication WO1998 / 31661, International Publication WO1999 / 47503 and International Publication WO2006 / 083003.
  • R ′′ is an optionally substituted C 1-10 alkyl group, and other symbols are the same as those described for compound (1) above) It is an ester compound represented by these.
  • the positions of the substituents V and W on the ring A and the alkoxycarbonyl group are not particularly limited as long as they are substitutable positions on the ring A. However, when the ring A is a phenyl group, the position of the alkoxycarbonyl group is changed. In the case of 1st place, W is preferably 4th place.
  • R ′′ is a C 1-10 alkyl group
  • ring A is a C 6-14 aryl group
  • V is a hydrogen atom
  • W is a compound of the formula (A)
  • R ′′ is a C 1-6 alkyl group.
  • Ring A is a phenyl group
  • V is a hydrogen atom
  • W is an imino (pyrrolidin-1-yl) methyl group (where Q is a pyrrolidin-1-yl group)
  • a particularly preferred compound is methyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate.
  • the salt may be a chemically acceptable salt.
  • Organic salts such as ammonium salts, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, aluminum salts, zinc salts, triethylamine, ethanolamine, morpholine, piperidine, dicyclohexylamine
  • salts with amines and salts with basic amino acids such as arginine and lysine.
  • a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, etc.
  • TFA trifluoroacetic acid
  • the compound (5) and a necessary acid or base are mixed in an appropriate amount ratio in a solvent or a dispersant, or cation exchange or anion exchange is carried out from other salt forms. It can also be obtained by doing.
  • compound (5) when W of compound (5) represents a basic group, compound (5) is a salt with a strong acid (for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, etc.) Can be preferably formed.
  • a strong acid for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, etc.
  • hydrochloric acid is preferable as the strong acid.
  • Compound (5) includes solvates of compound (5), such as hydrates and alcohol adducts.
  • 4- [Imino (pyrrolidin-1-yl) methyl] benzoic acid methyl chloride is easily prepared by, for example, methyl esterification of 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride and methanol. Can be manufactured.
  • methyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate hydrochloride can also be produced by the following method.
  • Methyl 4-cyanobenzoate is derived into methyl 4-ethoxyiminomethylbenzoate hydrochloride in the presence of hydrogen chloride in ethanol. Next, toluene is added to carry out dehydrochlorination concentration, and then pyrrolidine is added to lead to methyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate hydrochloride.
  • the synthetic raw material used in this reaction can be prepared from commercially available raw materials by a general organic synthesis method.
  • the manufacturing method of the said compound (5) is an illustration, and is not necessarily limited to the said method, A person skilled in the art can design a synthetic route suitably and can manufacture a compound (5).
  • Ring B represents a C 6-14 aryl group, a heteroaryl group, a nitrogen-containing non-aromatic heterocyclic group or a C 3-10 cycloalkyl group
  • T represents a hydrogen atom, a halogen atom, a hydroxy group, a C 1-10 alkoxy group which may have a substituent, an acyloxy group which may have a substituent, or a carbamoyl which may have a substituent.
  • U has a hydrogen atom, an optionally substituted C 1-10 alkyl group, a carboxyl group, an optionally substituted C 1-10 alkoxy-carbonyl group, or a substituent.
  • Compound (3) easily condenses with compound (1) at the hydroxy group moiety to form compound (4).
  • Compound (3) is condensed with compound (2) by using a condensing agent to form compound (4). Further, compound (3) is condensed with compound (5) by transesterification to form compound (4).
  • the position of the substituents T, L and amidino group on ring B is not particularly limited as long as it is a substitutable position on ring B.
  • the position of substitution of the amidino group is the 1st position.
  • T is preferably in the 4th position
  • L is preferably in the 3rd position.
  • the preferred compound (3), ring B is a C 6-14 aryl group, T is a hydroxy group, C 1-10 alkoxy group or C 1-10 alkoxy group optionally substituted by cyano, L Is an oxygen atom and n is 1.
  • the salt of compound (3) is preferably hydrochloride or acetate.
  • the compound (3) is 4-hydroxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof (hydrochloride, acetate), 3- (2-hydroxyethoxy) -4-methoxybenzamidine or a salt thereof (Hydrochloride, acetate), 4-ethoxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof (hydrochloride, acetate), 3- (2-hydroxyethoxy) -4- (2-methylpropoxy)- Benzamidine or a salt thereof (hydrochloride, acetate), 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof (hydrochloride).
  • the salt may be a chemically acceptable salt.
  • Organic salts such as ammonium salts, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, aluminum salts, zinc salts, triethylamine, ethanolamine, morpholine, piperidine, dicyclohexylamine
  • salts with amines and salts with basic amino acids such as arginine and lysine.
  • a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, etc.
  • the compound (3) and a necessary acid or base are mixed in an appropriate amount ratio in a solvent or a dispersant, or cation exchange or anion exchange is performed from other salt forms. It can also be obtained by doing.
  • the compound (3) preferably forms a salt with a strong acid (for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid) or acetic acid among the above-mentioned salts.
  • a strong acid for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid
  • acetic acid among the above-mentioned salts.
  • hydrochloric acid is preferable as the strong acid.
  • Compound (3) includes solvates of compound (3), such as hydrates and alcohol adducts.
  • ring B represents a C 6-14 aryl group
  • T represents hydroxy group, C 1-10 alkoxy group or a cyano with an optionally substituted C 1-10 alkoxy group
  • L is An example of a method for producing a compound showing an oxygen atom, U showing a hydrogen atom, and n showing 1 or a salt thereof, such as 4-hydroxy-3- (2-hydroxyethoxy) benzamidine hydrochloride, will be described.
  • 4-Hydroxy-3- (2-hydroxyethoxy) benzamidine hydrochloride can be produced by the following method using isovanillin as a starting material.
  • hydrochloric acid chloride with methanol / hydrogen chloride led to 4-hydroxy-3- (2-hydroxyethoxy) benzamidine hydrochloride.
  • the synthetic raw material used in this reaction can be prepared from commercially available raw materials by a general organic synthesis method.
  • the compound (3) is exemplified by a method for producing 3- (2-hydroxyethoxy) -4-methoxybenzamidine hydrochloride.
  • 3- (2-Hydroxyethoxy) -4-methoxybenzamidine hydrochloride can be produced by the following method using isovanillin as a starting material.
  • formyl group was cyanated from commercially available isovanillin according to a conventional method, leading to 3-hydroxy-4-methoxybenzonitrile. It was then alkylated with 2-chloroethanol leading to 3- (2-hydroxyethoxy) -4-methoxybenzonitrile.
  • hydrochloric acid was salified with methanol / hydrogen chloride, leading to 3- (2-hydroxyethoxy) -4-methoxybenzamidine hydrochloride.
  • 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride among the compounds (3) will be exemplified.
  • 4-Cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride can be produced by the following method using isovanillin as a starting material.
  • 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride can also be produced by the following method using vanillin as a starting material.
  • Cyanation of the formyl group was performed from commercially available vanillin according to a conventional method, leading to 4-hydroxy-3-methoxybenzonitrile.
  • alkylation was performed using bromoacetaldehyde diethyl acetal and potassium carbonate in DMF to obtain 4- (2,2-diethoxyethoxy) -3-methoxybenzonitrile.
  • tetramethylone 59 (33) 2003 6363-6373 is demethylated and the resulting 4- (2,2-diethoxyethoxy) -3-hydroxybenzonitrile is isolated.
  • the reaction was carried out using ethylene carbonate and potassium carbonate, leading to 4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile.
  • 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride was introduced in the same manner as described above.
  • the manufacturing method of the said compound (3) is an illustration, It is not necessarily limited to the said method, A person skilled in the art can design a synthetic route suitably and can manufacture a compound (3).
  • T ' is a hydroxy group, a C 1-10 alkoxy group or C 1-10 alkoxy group optionally substituted by cyano
  • a salt thereof (hereinafter sometimes referred to as compound (3 ′)) is a novel compound.
  • Compound (3 ′) can be in the form of a salt in the same manner as compound (3).
  • the salt may be a chemically acceptable salt. Examples of the chemically acceptable salt include those described above for compound (3).
  • T ′′ is a sodium atom, a hydrogen atom, or a C 1-10 alkyl group which may be substituted with C 1-10 alkoxy; G is a cyano group or substituted with hydroxy; A good amidino group
  • a salt thereof is also a novel compound.
  • These compounds can be used as a synthetic intermediate for obtaining the compound (3 ′).
  • the compound represented by the formula (3 ′′) can be in the form of a salt similarly to the target compound (3), and the salt in that case may be a chemically acceptable salt. Examples of the chemically acceptable salt include those described above for compound (3). Of these, a salt with hydrochloric acid and a salt with acetic acid can be preferably formed.
  • T ′ ′′ is a C 1-10 alkyl group substituted with C 1-10 alkoxy, and R is a hydrogen atom or a C 1-10 alkyl group
  • a salt thereof is a novel compound and can be preferably used as a synthetic intermediate for obtaining the compound (3 ′).
  • the compound represented by the formula (3 ′ ′′) can be in the form of a salt in the same manner as the target compound (3), but the salt in that case may be a chemically acceptable salt. Examples of the chemically acceptable salt include those described above for compound (3).
  • Compound (4) is the target compound in the production method of the present invention, obtained by condensing compound (1), compound (2) or compound (5) and compound (3).
  • the compound (4) or a salt thereof is useful as a low molecular weight FXa inhibitor. Therefore, an agent containing the compound (4) or a salt thereof as an active ingredient is an anti- (blood) coagulant for an extracorporeal blood circuit ( (Refer to International Publication No. 2006/083003 pamphlet).
  • Compound (4) can also be produced by the method for forming an alkyl bond described in International Publication No. 2006/083003 pamphlet, but according to the production method of the present invention, compound (4) can be produced in a simpler and higher yield than the above method. ) Can be obtained. This will be described in detail below.
  • the manufacturing method of the present invention has the following formula:
  • compound (4) is obtained by reacting compound (1), compound (2) or compound (5) with compound (3) to form an ester bond.
  • the following four methods (I) A method in which compound (2) is led to compound (1) using an acid halogenating reagent and then condensed with compound (3) without isolating said compound (1); (II) A method in which compound (2) is led to compound (1) using an acid halogenating reagent, and this is isolated and then condensed with compound (3); (III) A method of condensing compound (2) and compound (3) using a condensing agent; and (IV) a method of condensing compound (5) and compound (3) using a transesterification reaction: It is divided into.
  • each method will be described in detail.
  • the compound (2) having a carboxyl group is dissolved or suspended in an organic solvent.
  • the organic solvent used in this case is not particularly limited as long as it is a commercially available organic solvent that is generally used for acid halogenation reaction, etc., but preferably N, N-dimethylformamide (DMF), N, N Amide solvents such as dimethylacetamide (DMAC) and N-methyl-2-pyrrolidone (NMP) and imide solvents such as 1,3-dimethyl-2-imidazolidinone (DMI), more preferably NMP is there.
  • DMAC dimethylacetamide
  • NMP N-methyl-2-pyrrolidone
  • imide solvents such as 1,3-dimethyl-2-imidazolidinone (DMI), more preferably NMP is there.
  • an acid halogenating agent used in this case is as described above.
  • the reaction temperature of the acid halogenation is preferably ⁇ 40 to 200 ° C., more preferably around 0 to 20 ° C.
  • the benzamidine derivative (3) having a hydroxy group is added to the reaction solution containing the acid halide (1) to lead to the target compound (4).
  • the reaction temperature at this time is desirably ⁇ 40 ° C. to 200 ° C., more preferably 0 ° C. to 20 ° C.
  • this reaction proceeds without particularly adding a base, but a base may be added if necessary. Examples of the base include, but are not limited to, pyridine and triethylamine.
  • the progress of the reaction is confirmed by HPLC, and the reaction is terminated with the formation of the condensate (compound (4)) or the consumption of raw materials.
  • the reaction time for this reaction is usually about 1 to 24 hours.
  • water or an alcohol solvent preferably an alcohol solvent
  • an alcohol solvent preferably an alcohol solvent
  • methanol, ethanol, isopropyl alcohol and the like can be preferably used, but the alcohol solvent is not limited thereto.
  • the obtained compound (4) can be isolated by, for example, a solid-liquid separation method in which a poor solvent is added.
  • HMPA hexamethylphosphonic acid triamide
  • the condensing agent used in the reaction include, but are not limited to, acetic anhydride, trifluoroacetic anhydride (TFAA), N, N-carboxydiimidazole (CDI), and dicyclohexylcarbodiimide (DCC). However, it is preferable to use dicyclohexylcarbodiimide.
  • the reaction temperature of the reaction is usually ⁇ 40 to 100 ° C., preferably 0 to 50 ° C.
  • this reaction proceeds without particularly adding a base, but a base may be added if necessary.
  • the base include N, N-dimethylaminopyridine (DMAP) and pyridine, but are not limited thereto.
  • DMAP N-dimethylaminopyridine
  • the progress of the reaction is confirmed by general HPLC, and is completed with the formation of condensate or the consumption of raw materials. After confirming the progress of the reaction, the resulting compound can be isolated as described in (I).
  • each symbol is as described above.
  • Compound (5) and compound (3) are dissolved or suspended in an organic solvent, and an acid is added to conduct a condensation reaction by transesterification.
  • organic solvent used in the reaction any commercially available organic solvent can be used as long as it does not affect the condensation reaction, but N-methyl-2-pyrrolidone (NMP) is preferable. is there.
  • NMP N-methyl-2-pyrrolidone
  • the acid used in the reaction include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid, but are not limited thereto.
  • hydrochloric acid is preferably used.
  • the reaction temperature of the reaction is usually 50 to 200 ° C., preferably 100 to 150 ° C.
  • the progress of the reaction is confirmed by general HPLC, and is completed with the formation of condensate or the consumption of raw materials. After confirming the progress of the reaction, the resulting compound can be isolated as described in (I).
  • the various analysis means and analyzers are as follows.
  • the system consisting of the following was mainly used for the HPLC analyzer.
  • Pump Shimadzu LC-10AT and LC-10ATvp
  • Autosampler Kyowa Precision KMT-100X (injection volume is 10 ⁇ l unless otherwise specified)
  • Column oven Shodex AO-30C and GL Science C0631, Sugai U-620
  • UV detector Shimadzu SPD-10A and SPD-10Avp
  • HPLC controller Shimadzu Corporation SCL-10A and SCL-10Avp.
  • HORIBA D-52 was used for the pH meter, and HORIBA 9678 was used for the electrode. A sample calibrated with a pH standard solution was used.
  • Example 1 Compound (2) was led to compound (1) using an acid halogenating reagent, and then condensed with compound (3) without isolation of compound (1) to give compound (4) How to get
  • reaction completion liquid was added dropwise to 1550.0 ml of acetone and stirred overnight, and then the suspension was filtered under reduced pressure, washed with 100 ml of acetone and dried under reduced pressure at room temperature overnight to obtain 11.3 g of the title compound. .
  • reaction mixture was cooled to 8 ° C., quenched by adding 5.6 L of methanol, added with 12.9 L of methyl acetate, and stirred at 8 ° C. overnight.
  • Example 2 Method (1): Compound (2) is led to Compound (1) using an acid halogenating reagent, isolated and then condensed with Compound (3) to obtain Compound (4): Synthesis of 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride from 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride
  • NMP N-methyl-2-pyrrolidone
  • This reaction-terminated liquid was slowly added dropwise to another container in which 750 ml of ethyl acetate and 50 ml of ethanol had been added in advance, washed with 5 ml of ethanol, and then stirred at 15 ° C. overnight. Thereafter, the reaction mixture was filtered under reduced pressure, washed with 100 ml of ethyl acetate, and then dried under reduced pressure at room temperature for 4 hours to obtain 41.4 g of the title compound (net amount 36.5 g).
  • Example 3 Method of condensing compound (2) and compound (3) using a condensing agent to obtain compound (4) 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride and 4 2- [5-Amidino-2- (cyanomethoxy) phenoxy] ethyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate from cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride Synthesis of dihydrochloride
  • Example 4 Method of obtaining compound (4) by condensing compound (5) and compound (3) using transesterification (1): 4- [imino (pyrrolidin-1-yl) methyl] Synthesis of methyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate hydrochloride from benzoic acid chloride hydrochloride
  • Example 5 Synthesis of 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride from 3-hydroxy-4-methoxybenzaldehyde (isovanillin) (1): Synthesis of 3-hydroxy-4-methoxybenzonitrile from isovanillin Composition
  • the reaction mixture was filtered under reduced pressure to remove Pd / C and washed with 30 ml of methanol. At room temperature, 23.3 ml of 2M HCl / methanol was added to the filtrate to adjust the pH to around 3, and then concentrated to 38.5 g. After 90 ml of toluene was added dropwise at room temperature, the mixture was stirred at 10 ° C. for 3 hours or more. The suspension was filtered under reduced pressure, washed with toluene, and dried under reduced pressure at 60 ° C. for 2 hours to obtain 10.3 g of the title compound.
  • Example 6 Synthesis of 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride from isovanillin (alternative method) (1): Synthesis of sodium 4-cyano-2- (2-hydroxyethoxy) phenoxide from 3-hydroxy-4-methoxybenzonitrile
  • the obtained organic layer mixture was washed / separated with 60 ml of water, 1.5 g of activated carbon was added, and the mixture was stirred for 1 hour or more.
  • the reaction mixture was filtered under reduced pressure, and washed with 15 ml of toluene. While adding 64.7 ml of toluene little by little to the obtained filtrate, the solution was concentrated under reduced pressure to 90.3 g at 50 ° C. and then cooled to 35 ° C. 300 ml of n-heptane was added dropwise over 1 hour, cooled to 10 ° C. and stirred overnight.
  • the reaction mixture was separated by filtration under reduced pressure, washed with 60 ml of n-heptane, and then dried under reduced pressure at 60 ° C.
  • reaction solution was filtered under reduced pressure to remove Pd / C, and washed with 22.5 ml of methanol. 137 ml of 2M hydrogen chloride methanol solution was added to the filtrate and stirred at 40 ° C. for 16.5 hours or more. After confirming the completion of the reaction by HPLC, the mixture was concentrated to 135 g, and 90 ml of acetone was added to form a suspension. At 25 ° C., 180 ml of toluene was added dropwise over 5 minutes, cooled to 10 ° C. over 1.5 hours, and further stirred for 2 hours or more. The reaction mixture was filtered under reduced pressure, washed with 90 ml of toluene, and then dried under reduced pressure at 60 ° C. overnight to obtain 40.7 g of the title compound.
  • Example 7 Synthesis of 4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile from 4-hydroxy-3-methoxybenzaldehyde (vanillin) (1): 4-hydroxy-from vanillin Synthesis of 3-methoxybenzonitrile
  • Example 8 Synthesis of 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride from 4-cyanobenzoic acid (1): Synthesis of 4-ethoxyiminomethylbenzoic acid hydrochloride from 4-cyanobenzoic acid
  • Example 11 (1): Synthesis of 4-hydroxy-3- (2-hydroxyethoxy) benzamidine acetate from 4-hydroxy-3- (2-hydroxyethoxy) benzonitrile
  • the filtrate was concentrated. After raising the temperature to 60 ° C., the mixture was cooled to 50 ° C., and 245.0 ml of ethyl acetate was added. The suspension was cooled to 10 ° C., filtered under reduced pressure, and washed with 35 ml of ethyl acetate. The filtrate was dried under reduced pressure at 60 ° C. overnight to obtain 17.2 g of the title compound.
  • Example 12 (1): Synthesis of 3- (2-hydroxyethoxy) -4-methoxybenzamidine acetate from 3- (2-hydroxyethoxy) -4-methoxybenzonitrile
  • Example 13 (1): Synthesis of 4-ethoxy-3- (2-hydroxyethoxy) benzonitrile from sodium 4-cyano-2- (2-hydroxyethoxy) phenoxide
  • Example 14 (1): Synthesis of 3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzonitrile from sodium 4-cyano-2- (2-hydroxyethoxy) phenoxide
  • an amidine derivative having an ester bond which is a highly useful compound as a drug having an anticoagulant action, can be easily obtained in a high yield.

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Abstract

Disclosed is a process for producing an amidine derivative having an ester bond, which is a compound highly useful as a substance having an anti-coagulation activity, on an industrial scale. Specifically disclosed is a process for producing an amidine compound (4), which comprises reacting an acid halide (1), either one of a compound (2) or a compound (5) and an amidine compound (3) with one another to form an ester bond, wherein the compounds (1) to (5) are represented by formulae (wherein each symbol is as defined in the description).

Description

アミジン誘導体の製造方法Method for producing amidine derivative
　本発明は、活性化血液凝固第Ｘ因子（以下、ＦＸａと略記する場合もある）阻害活性を有するアミジン誘導体の製造方法に関する。また当該製法に適用する化合物の合成中間体として有用な新規化合物に関する。 The present invention relates to a method for producing an amidine derivative having inhibitory activity on activated blood coagulation factor X (hereinafter sometimes abbreviated as FXa). Further, the present invention relates to a novel compound useful as a synthetic intermediate for a compound applied to the production method.
　血液体外循環とは、生体外に造設された血液回路を通ずる人工的血液循環である。通常、血液体外循環は、血液を生体内から体外の人工血流路を経て、さらに一定の処置を行う装置、例えば、人工心肺装置、血液浄化装置等を経て、生体内に再送入する循環回路によって行われるものである。血液透析、血液漉過、血液透析液過、血祭交換などの血液浄化療法の際、開心術時における心肺バイパスの際などにおいて、血液体外循環処置が必要とされることがある。血液浄化装置としては、典型的には透析器などが挙げられる。血液は、異物と接触すると、通常、内因系の血液凝固カスケードが活性化され、最終的には凝固し、流動性を失う。血液体外循環時における人工血流路や各種装置からなる血液体外循環回路は異物であり、血液はそれらに接触すると凝固することから、何らかの方法により血液体外循環回路における血液凝固を防ぐ処置が必要である。 The extracorporeal blood circulation is an artificial blood circulation that passes through a blood circuit built outside the living body. Usually, blood extracorporeal circulation is a circulation circuit that retransmits blood into the living body from a living body through an artificial blood flow path outside the body, and further through a device that performs a certain treatment, for example, an artificial heart-lung machine, a blood purification device, etc. Is done by. Extracorporeal blood treatment may be required during blood purification therapy such as hemodialysis, blood filtration, hemodialysis fluid excess, blood festival exchange, and cardiopulmonary bypass during open heart surgery. A typical example of the blood purification apparatus is a dialyzer. When blood comes into contact with a foreign substance, the intrinsic blood coagulation cascade is usually activated, eventually coagulating and losing fluidity. Blood extracorporeal circuit consisting of artificial blood flow path and various devices during extracorporeal blood circulation is a foreign substance, and blood coagulates when it comes in contact with it, so it is necessary to take measures to prevent blood coagulation in extracorporeal blood circulation circuit by some method is there.
　従来、この血液体外循環回路における血栓予防を目的として、未分画ヘパリンや低分子ヘパリンなどの抗（血液）凝固薬（剤）が使用されている。しかしながら、未分画ヘパリンは、ＦＸａ阻害活性に加えてトロンビン阻害活性を有することから、出血傾向をきたす危険性が知られており、出血リスクの高い患者に使用することはできない。また、低分子ヘパリンはヘパリンに化学的な処理を施して、トロンビンに対しＦＸａをより選択的に阻害する薬剤であり、トロンビン阻害活性を持たないため、出血傾向の危険性が低下し、出血傾向を有する患者に対して使用されている。しかしながら、低分子ヘパリンは、消失半減期が長いため、出血症状が見られた際に、止血が困難である。 Conventionally, anti-blood coagulants (agents) such as unfractionated heparin and low molecular weight heparin have been used for the purpose of preventing thrombus in this extracorporeal circuit. However, since unfractionated heparin has thrombin inhibitory activity in addition to FXa inhibitory activity, there is a known risk of bleeding tendency and it cannot be used for patients with high bleeding risk. In addition, low molecular weight heparin is a drug that chemically treats heparin to more selectively inhibit FXa against thrombin and has no thrombin inhibitory activity, thus reducing the risk of bleeding tendency and bleeding tendency Used for patients with However, since low molecular weight heparin has a long elimination half-life, it is difficult to stop bleeding when bleeding symptoms are observed.
　また、いくつかのセリンプロテアーゼ阻害剤もまた抗凝固作用を有しており、例えば、メシル酸ナフアモスタットは、血液透析などの一部の血液体外循環時に使用されている。メシル酸ナフアモスタットは、生体内における消失半減期が短いために、すでに出血病変を有する患者に対しても使用されている。しかしながら、メシル酸ナフアモスタットは、ＦＸａやトロンビンに対する阻害活性が強力でなく、抗凝固効果が弱い。
　以上のように、いずれの薬剤もまだ課題を抱えており、より有効かつ安全な薬剤が求められている。なお、体外循環回路を設置された患者は、その回路を用いる場合にのみ血液凝固の問題を抱くのであって、常時、血液凝固を防止しなければならない患者とは事情が異なることが多い。血中半減期の短い選択的低分子ＦＸａ阻害剤が血液体外循環回路用の血液凝固防止のための抗凝固薬として安全に都合よく使用でき、血液体外循環終了後の止血の処置や注意が明らかに少なくてすむことは、従来、全く予想されていなかった。 Some serine protease inhibitors also have anticoagulant activity, for example, naphthostat mesylate is used during some extracorporeal circulation such as hemodialysis. Nahuamostat mesylate is also used for patients who already have bleeding lesions because of its short elimination half-life in vivo. However, nahuamostat mesylate has a weak inhibitory activity against FXa and thrombin and has a weak anticoagulant effect.
As described above, all drugs still have problems, and more effective and safe drugs are required. A patient with an extracorporeal circuit has a problem of blood coagulation only when the circuit is used, and the situation is often different from a patient who must always prevent blood coagulation. A selective small molecule FXa inhibitor with a short blood half-life can be safely and conveniently used as an anticoagulant for preventing blood coagulation for the extracorporeal circulation circuit. In the past, it has never been expected to reduce the amount to a minimum.
　一方、ＦＸａ選択的阻害作用に基づく抗凝固活性を発揮するアミジン化合物として、例えば特許文献１～３に記載された化合物が知られている。特に、特許文献３記載の分子内にエステル結合を有する、Ａ’－ＣＯＯ－Ｂ’［Ａ’およびＢ’は有機基を表し、少なくとも一方はアミジノ基あるいはグアニジノ基構造を含む］で表されるアミジン誘導体が、優れた活性化血液凝固第Ｘ因子阻害活性を有し、かつ血中半減期が短く、血液体外循環回路用の血液凝固防止剤として有用であった。当該アミジン誘導体は、具体的には以下に示す化合物である。 On the other hand, for example, compounds described in Patent Documents 1 to 3 are known as amidine compounds exhibiting anticoagulant activity based on FXa selective inhibitory action. In particular, A′-COO-B ′ having an ester bond in the molecule described in Patent Document 3 [A ′ and B ′ represent an organic group, at least one of which includes an amidino group or a guanidino group structure] The amidine derivative has an excellent activated blood coagulation factor X inhibitory activity and a short blood half-life, and was useful as a blood coagulation inhibitor for blood extracorporeal circuits. The amidine derivative is specifically a compound shown below.
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
　（式中、各記号は、特許文献３に記載のとおりである） (In the formula, each symbol is as described in Patent Document 3)
　当該アミジン誘導体の製造方法としては、特許文献３には、アルキル結合形成反応を経由する合成方法が示されている（アルキル結合形成ルート）。この方法は例えば以下の通りであり、主骨格形成から複数の側鎖修飾を経て最終化合物を合成するものである。（Ｘはハロゲン原子、Ｒは、置換基を有していてもよいアルキル基） As a method for producing the amidine derivative, Patent Document 3 discloses a synthesis method via an alkyl bond forming reaction (alkyl bond forming route). This method is, for example, as follows, and a final compound is synthesized from the main skeleton formation through a plurality of side chain modifications. (X is a halogen atom, R is an alkyl group which may have a substituent)
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
　一方、一般的に合成医薬品の製造において、主骨格形成から原薬へ導く工程は各国の規制当局の基準（ＧＭＰ）に適合した管理された製造設備で行われ、高度な品質管理と工程管理を必要とするために多大なコストが必要である。したがって主骨格形成以降の製造工程の簡略化は、製造と品質管理を容易にするだけでなく生産期間の短縮化や製造コストの低減化につながるため、極めて重要である。このため、アルキル結合形成ルートよりもより短い工程で主骨格を形成し、原薬を取得できる製造方法が求められている。 On the other hand, in the production of synthetic drugs, the process leading from the formation of the main skeleton to the drug substance is generally carried out in a controlled manufacturing facility that complies with the standards (GMP) of the regulatory authorities in each country, and advanced quality control and process control are performed. It takes a lot of cost to make it necessary. Therefore, simplification of the manufacturing process after the formation of the main skeleton is extremely important because it not only facilitates manufacturing and quality control, but also shortens the production period and reduces manufacturing costs. Therefore, there is a demand for a production method that can form the main skeleton in a shorter process than the alkyl bond formation route and obtain the drug substance.
国際公開１９９８／３１６６１号パンフレットInternational Publication No. 1998/31661 Pamphlet 国際公開１９９９／６４３９２号パンフレットInternational Publication No. 1999/64392 Pamphlet 国際公開２００６／８３００３号パンフレットInternational Publication No. 2006/83003 Pamphlet
　本発明は、抗凝固作用を有する薬剤として有用性の高い化合物である、エステル結合を有するアミジン誘導体の工業化に適した製造方法に関する。特に、目的のエステル結合を有するアミジン誘導体を、簡便かつ高収率で製造する方法に関する。 The present invention relates to a production method suitable for industrialization of an amidine derivative having an ester bond, which is a highly useful compound as a drug having an anticoagulant action. In particular, the present invention relates to a method for producing an amidine derivative having a target ester bond in a simple and high yield.
　本発明者らは、側鎖にアルコールを有する特定のアミジン誘導体と、特定のカルボン酸化合物あるいはその酸ハロゲン化物などを反応させることで、簡便かつ高収率に目的のエステル結合を有するアミジン誘導体へと導く製造方法を初めて見出した。本発明者らはこれらの知見に基づいてさらに鋭意研究を行った結果、本発明を完成するに至った。 By reacting a specific amidine derivative having an alcohol in the side chain with a specific carboxylic acid compound or an acid halide thereof, the present inventors can easily convert the amidine derivative having the desired ester bond into a high yield. For the first time. As a result of further intensive studies based on these findings, the present inventors have completed the present invention.
　即ち、本発明は以下のとおりである。
［１］式（１） That is, the present invention is as follows.
[1] Formula (1)
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
（式中、
　環Ａは、Ｃ６－１４アリール基、ヘテロアリール基、含窒素非芳香族複素環基またはＣ３－１０シクロアルキル基であり、
　Ｖは、水素原子、ハロゲン原子、置換基を有していてもよいＣ１－１０アルキル基、置換基を有していてもよいＣ１－１０アルコキシ基、置換基を有していてもよいＣ１－１０アルキルアミノ基、置換基を有していてもよいＣ１－１０アルキルチオ基、シアノ基、ニトロ基または置換基を有していてもよいカルバモイル基であり、
　Ｗは、へテロアリール基、あるいは下記式（Ａ）、（Ｂ）または（Ｃ） (Where
Ring A is a C 6-14 aryl group, a heteroaryl group, a nitrogen-containing non-aromatic heterocyclic group or a C 3-10 cycloalkyl group,
V represents a hydrogen atom, a halogen atom, a C 1-10 alkyl group which may have a substituent, a C 1-10 alkoxy group which may have a substituent, or a substituent. A C 1-10 alkylamino group, an optionally substituted C 1-10 alkylthio group, a cyano group, a nitro group, or an optionally substituted carbamoyl group,
W is a heteroaryl group, or the following formula (A), (B) or (C)
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
［式中、
　Ｑは、Ｃ１－６アルキル基、置換基を有していてもよいアミノ基または窒素原子に結合手を有する含窒素複素環基を表し、
　Ｒは、Ｃ１－６アルキル基を表し、
　ｍは、１～３の整数を表し、
　環Ｃは、含窒素複素環基を表し、
　Ｙは、窒素原子、酸素原子、硫黄原子またはメチレン基のいずれかを表し、
　Ｚは、水素原子、Ｃ１－６アルキルで置換されていてもよいアミジノ基、あるいは１位にイミノを有してもよいＣ１－６アルキル基を表す］
で表される基であり、そして
　Ｘは、ハロゲン原子である）
で表される酸ハロゲン化物（以下、「化合物（１）」または「酸ハロゲン化物（１）」と記載する場合がある）またはその塩と、式（３） [Where:
Q represents a C 1-6 alkyl group, an optionally substituted amino group or a nitrogen-containing heterocyclic group having a bond to the nitrogen atom,
R represents a C 1-6 alkyl group,
m represents an integer of 1 to 3,
Ring C represents a nitrogen-containing heterocyclic group,
Y represents any of a nitrogen atom, an oxygen atom, a sulfur atom or a methylene group,
Z represents a hydrogen atom, an amidino group which may be substituted with C 1-6 alkyl, or a C 1-6 alkyl group which may have imino at the 1-position]
And X is a halogen atom)
An acid halide represented by the formula (hereinafter sometimes referred to as “compound (1)” or “acid halide (1)”) or a salt thereof;
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
（式中、
　環Ｂは、Ｃ６－１４アリール基、ヘテロアリール基、含窒素非芳香族複素環基またはＣ３－１０シクロアルキル基であり、
　Ｔは、水素原子、ハロゲン原子、ヒドロキシ基、置換基を有していてもよいＣ１－１０アルコキシ基、置換基を有していてもよいアシルオキシ基、置換基を有していてもよいカルバモイルオキシ基、置換基を有していてもよいチオカルバモイルオキシ基、アミノ基、シアノ基、ニトロ基、置換基を有していてもよいＣ１－１０アルキル基、置換基を有していてもよいＣ１－１０アルキルアミノ基、置換基を有していてもよいＣ１－１０アルキルチオ基、置換基を有していてもよいアシルアミノ基、カルボキシル基、置換基を有していてもよいＣ１－１０アルコキシ－カルボニル基、置換基を有していてもよいカルバモイル基、または置換基を有していてもよいチオカルバモイル基であり、
　Ｕは、水素原子、置換基を有していてもよいＣ１－１０アルキル基、カルボキシル基、置換基を有していてもよいＣ１－１０アルコキシ－カルボニル基、または置換基を有していてもよいカルバモイル基であり、
　Ｌは、窒素原子、酸素原子、硫黄原子またはメチレン基であり、そして
　ｎは、１～３の整数である）
で表される化合物（以下、「化合物（３）」または「アミジン化合物（３）」と記載する場合がある）またはその塩とを縮合させることを特徴とする、式（４） (Where
Ring B is a C 6-14 aryl group, a heteroaryl group, a nitrogen-containing non-aromatic heterocyclic group or a C 3-10 cycloalkyl group,
T represents a hydrogen atom, a halogen atom, a hydroxy group, a C 1-10 alkoxy group which may have a substituent, an acyloxy group which may have a substituent, or a carbamoyl which may have a substituent. An oxy group, an optionally substituted thiocarbamoyloxy group, an amino group, a cyano group, a nitro group, an optionally substituted C 1-10 alkyl group, and an optionally substituted group A good C 1-10 alkylamino group, an optionally substituted C 1-10 alkylthio group, an optionally substituted acylamino group, a carboxyl group, an optionally substituted C 1-10 alkoxy-carbonyl group, an optionally substituted carbamoyl group, or an optionally substituted thiocarbamoyl group,
U has a hydrogen atom, an optionally substituted C 1-10 alkyl group, a carboxyl group, an optionally substituted C 1-10 alkoxy-carbonyl group, or a substituent. A carbamoyl group that may be
L is a nitrogen atom, oxygen atom, sulfur atom or methylene group, and n is an integer of 1 to 3)
A compound represented by formula (4) (hereinafter, may be referred to as “compound (3)” or “amidine compound (3)”) or a salt thereof:
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
（式中、各記号は、前記と同じである）
で表されるアミジン誘導体（以下、「化合物（４）」または「アミジン化合物（４）」と記載する場合がある）またはその塩の製造方法；
［２］式（２） (Wherein each symbol is the same as above)
A method for producing an amidine derivative represented by the formula (hereinafter sometimes referred to as “compound (4)” or “amidine compound (4)”) or a salt thereof;
[2] Formula (2)
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
（式中、各記号は、［１］と同じである）
で表されるカルボン酸化合物（以下、「化合物（２）」と記載する場合がある）またはその塩と、化合物（３）またはその塩とを、縮合剤を用いて縮合させることを特徴とする、化合物（４）またはその塩の製造方法；
［３］縮合剤が、Ｎ，Ｎ’－ジシクロヘキシルカルボジイミドである、［２］に記載の方法；
［４］化合物（２）またはその塩に、酸ハロゲン化剤を反応させて得られた化合物（１）またはその塩を、単離することなく化合物（３）またはその塩と縮合させることを特徴とする、化合物（４）またはその塩の製造方法；
［５］酸ハロゲン化剤が、塩化チオニルである、［４］に記載の方法；
［６］式（５） (In the formula, each symbol is the same as [1].)
Wherein the compound (3) or a salt thereof is condensed with a condensing agent. The carboxylic acid compound represented by the formula (hereinafter sometimes referred to as “compound (2)”) or a salt thereof And a method for producing compound (4) or a salt thereof;
[3] The method according to [2], wherein the condensing agent is N, N′-dicyclohexylcarbodiimide;
[4] The compound (1) or a salt thereof obtained by reacting the compound (2) or a salt thereof with an acid halogenating agent is condensed with the compound (3) or a salt thereof without isolation. A process for producing compound (4) or a salt thereof;
[5] The method according to [4], wherein the acid halogenating agent is thionyl chloride;
[6] Formula (5)
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
（式中、Ｒ’’は、置換基を有していてもよいＣ１－１０アルキル基であり、その他の各記号は、［１］と同じである）
で表されるエステル化合物（以下、「化合物（５）」と記載する場合がある）またはその塩と、化合物（３）またはその塩とを縮合させることを特徴とする、化合物（４）またはその塩の製造方法；
［７］環Ａおよび環Ｂが、Ｃ６－１４アリール基であり、
　ＶおよびＵが、水素原子であり、
　Ｗが、式（Ａ） (Wherein R ″ is an optionally substituted C 1-10 alkyl group, and other symbols are the same as those in [1])
A compound (4) or a salt thereof, characterized by condensing an ester compound represented by the formula (hereinafter sometimes referred to as “compound (5)”) or a salt thereof with a compound (3) or a salt thereof. Salt production method;
[7] Ring A and ring B are a C 6-14 aryl group,
V and U are hydrogen atoms,
W is the formula (A)
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
（式中、Ｑは、窒素原子に結合手を有する含窒素非芳香族複素環基である）で表される基であり、
　Ｔが、水素原子、ヒドロキシ基、Ｃ１－１０アルコキシまたはシアノで置換されていてもよいＣ１－１０アルコキシ基であり、
　Ｌが、酸素原子であり、そして
　ｎが、１である、［１］～［６］のいずれか一に記載の方法；
［８］式（３’） (Wherein Q is a nitrogen-containing non-aromatic heterocyclic group having a bond to the nitrogen atom),
T is hydrogen atom, hydroxy group, C 1-10 alkoxy or optionally C 1-10 alkoxy group optionally substituted by cyano,
The method according to any one of [1] to [6], wherein L is an oxygen atom, and n is 1.
[8] Formula (3 ′)
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
（式中、Ｔ’は、ヒドロキシ基、Ｃ１－１０アルコキシ基またはシアノで置換されていてもよいＣ１－１０アルコキシ基である）
で表される化合物（以下、「化合物（３’）」と記載する場合がある）またはその塩；
［９］４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジンまたはその塩；
４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンズアミジンまたはその塩；
３－（２－ヒドロキシエトキシ）－４－メトキシベンズアミジンまたはその塩；
４－エトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジンまたはその塩；ならびに
３－（２－ヒドロキシエトキシ）－４－（２－メチルプロポキシ）ベンズアミジンまたはその塩
から選択される化合物；
［１０］４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン、またはその塩酸塩；
４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　酢酸塩および塩酸塩；
３－（２－ヒドロキシエトキシ）－４－メトキシベンズアミジン　酢酸塩および塩酸塩；
４－エトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン、またはその酢酸塩および塩酸塩；ならびに
３－（２－ヒドロキシエトキシ）－４－（２－メチルプロポキシ）ベンズアミジン　酢酸塩および塩酸塩
から選択される化合物；
［１１］化合物（３’）またはその塩を合成するための合成中間体である、式（３’’） (Wherein, T 'is a hydroxy group, a C 1-10 alkoxy group or C 1-10 alkoxy group optionally substituted by cyano)
Or a salt thereof (hereinafter sometimes referred to as “compound (3 ′)”);
[9] 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof;
4-hydroxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof;
3- (2-hydroxyethoxy) -4-methoxybenzamidine or a salt thereof;
4-ethoxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof; and a compound selected from 3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzamidine or a salt thereof;
[10] 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine, or a hydrochloride thereof;
4-hydroxy-3- (2-hydroxyethoxy) benzamidine acetate and hydrochloride;
3- (2-hydroxyethoxy) -4-methoxybenzamidine acetate and hydrochloride;
Selected from 4-ethoxy-3- (2-hydroxyethoxy) benzamidine, or acetates and hydrochlorides thereof; and 3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzamidine acetates and hydrochlorides Compound;
[11] Formula (3 ″), which is a synthetic intermediate for synthesizing compound (3 ′) or a salt thereof
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
（式中、Ｔ’’は、ナトリウム原子、水素原子、またはＣ１－１０アルコキシで置換されていてもよいＣ１－１０アルキル基であり、Ｇは、シアノ基、またはヒドロキシで置換されていてもよいアミジノ基である）
で表される化合物（以下、「化合物（３’’）」と記載する場合がある）またはその塩；
［１２］化合物（３’）またはその塩を合成するための合成中間体である、式（３’’’） (Wherein T ″ is a sodium atom, a hydrogen atom, or a C 1-10 alkyl group which may be substituted with C 1-10 alkoxy; G is a cyano group or substituted with hydroxy; A good amidino group)
Or a salt thereof (hereinafter sometimes referred to as “compound (3 ″)”);
[12] Formula (3 ′ ″), which is a synthetic intermediate for synthesizing compound (3 ′) or a salt thereof
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
（式中、Ｔ’’’は、Ｃ１－１０アルコキシで置換されるＣ１－１０アルキル基であり、Ｒ’’’は、水素原子またはＣ１－１０アルキル基である）
で表される化合物（以下、「化合物（３’’’）」と記載する場合がある）またはその塩；
［１３］３－（２－ヒドロキシエトキシ）－４－メトキシベンゾニトリル；
ナトリウム　４－シアノ－２－（２－ヒドロキシエトキシ）フェノキシド；
４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンゾニトリル；
４－（２，２－ジメトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンゾニトリル；
４－（２，２－ジメトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミド＝オキシム；
４－（２，２－ジメトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩；
４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンゾニトリル；
４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミド＝オキシム；
４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミジン　酢酸塩；
４－（２，２－ジエトキシエトキシ）－３－メトキシベンゾニトリル；
４－エトキシ－３－（２－ヒドロキシエトキシ）ベンゾニトリル；および
３－（２－ヒドロキシエトキシ）－４－（２－メチルプロポキシ）ベンゾニトリル
から選択される化合物；
［１４］式（１’） Wherein T ′ ″ is a C 1-10 alkyl group substituted with C 1-10 alkoxy, and R ′ ″ is a hydrogen atom or a C 1-10 alkyl group.
Or a salt thereof (hereinafter sometimes referred to as “compound (3 ′ ″)”);
[13] 3- (2-hydroxyethoxy) -4-methoxybenzonitrile;
Sodium 4-cyano-2- (2-hydroxyethoxy) phenoxide;
4-hydroxy-3- (2-hydroxyethoxy) benzonitrile;
4- (2,2-dimethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile;
4- (2,2-dimethoxyethoxy) -3- (2-hydroxyethoxy) benzamide oxime;
4- (2,2-dimethoxyethoxy) -3- (2-hydroxyethoxy) benzamidine hydrochloride;
4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile;
4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzamide oxime;
4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzamidine acetate;
4- (2,2-diethoxyethoxy) -3-methoxybenzonitrile;
A compound selected from 4-ethoxy-3- (2-hydroxyethoxy) benzonitrile; and 3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzonitrile;
[14] Formula (1 ′)
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
（式中、
　Ｒ’は、置換基を有しても良いアルコキシ基またはハロゲン原子であり、そして
　Ｑ’’は、Ｃ１－１０アルコキシ基、置換基を有していてもよいアミノ基または窒素原子に結合手を有する含窒素複素環基を表す）
で表される化合物（以下、「化合物（１’）」と記載する場合がある）またはその塩；
［１５］４－［イミノ（ピロリジン－１－イル）メチル］安息香酸ハライドまたはその塩；
［１６］４－［イミノ（ピロリジン－１－イル）メチル］安息香酸メチルまたはその塩；
［１７］４－［イミノ（ピロリジン－１－イル）メチル］安息香酸クロリドまたはその塩酸塩；ならびに
［１８］４－［イミノ（ピロリジン－１－イル）メチル］安息香酸メチル　塩酸塩。 (Where
R ′ is an alkoxy group which may have a substituent or a halogen atom, and Q ″ is a bond to a C 1-10 alkoxy group, an amino group which may have a substituent or a nitrogen atom. Represents a nitrogen-containing heterocyclic group having
Or a salt thereof (hereinafter sometimes referred to as “compound (1 ′)”);
[15] 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid halide or a salt thereof;
[16] Methyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate or a salt thereof;
[17] 4- [Imino (pyrrolidin-1-yl) methyl] benzoic acid chloride or a hydrochloride thereof; and [18] 4- [Imino (pyrrolidin-1-yl) methyl] benzoic acid methyl hydrochloride.
　本発明によれば、抗凝固作用を有する薬剤として有用性の高い化合物であるエステル結合を有するアミジン誘導体を、アルキル結合形成ルートよりも少ない工程を経て、簡便かつ高収率に得ることが可能となる。 According to the present invention, it is possible to obtain an amidine derivative having an ester bond, which is a highly useful compound as a drug having an anticoagulant action, easily and in high yield through fewer steps than the alkyl bond formation route. Become.
　本発明は、下記式 The present invention has the following formula
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
で示されるような、抗凝固作用を有する薬剤として有用性の高い化合物である、エステル結合を有するアミジン誘導体（４）の新たな製造方法（以下、「本発明の製造方法」と記載する場合がある）であり、化合物（１）、化合物（２）または化合物（５）と、化合物（３）とを反応させることにより、化合物（４）を製造できることを発見したことに基づき完成したものである。本製造方法により、簡便かつ高収率に化合物（４）を製造することができる。 A new method for producing an amidine derivative (4) having an ester bond, which is a highly useful compound as a drug having an anticoagulant action (hereinafter referred to as “the production method of the present invention”). And was completed based on the discovery that compound (4) can be produced by reacting compound (1), compound (2) or compound (5) with compound (3). . By this production method, the compound (4) can be produced simply and with high yield.
　より詳細には、本発明の化合物（４）の製造方法としては、
（Ｉ）化合物（２）を、酸ハロゲン化試薬を用いて化合物（１）へ導いた後、当該化合物（１）を単離することなく、化合物（３）と縮合する方法；
（ＩＩ）化合物（２）を、酸ハロゲン化試薬を用いて化合物（１）へと導き、これを単離したのち化合物（３）と縮合させる方法； 
（ＩＩＩ）化合物（２）と化合物（３）とを、縮合剤を用いて縮合する方法；および
（ＩＶ）化合物（５）と化合物（３）とを、エステル交換反応を利用して縮合する方法：
を挙げることができる。これらの本発明の製造方法は、エステル結合の形成反応に基づくものであり、直接的に目的化合物である化合物（４）の基本骨格が構築できるので、工業的に有用な製造方法である。 In more detail, as a manufacturing method of the compound (4) of this invention,
(I) A method in which compound (2) is led to compound (1) using an acid halogenating reagent and then condensed with compound (3) without isolating said compound (1);
(II) A method in which compound (2) is led to compound (1) using an acid halogenating reagent, and this is isolated and then condensed with compound (3);
(III) a method of condensing compound (2) and compound (3) using a condensing agent; and (IV) a method of condensing compound (5) and compound (3) using a transesterification reaction. :
Can be mentioned. These production methods of the present invention are based on an ester bond formation reaction and are industrially useful production methods because the basic skeleton of the compound (4) which is the target compound can be directly constructed.
　また後述するように、本発明の化合物（４）を製造するための、化合物（３）の新規化合物、化合物（３）を得るために有用な合成中間体（新規化合物）、および化合物（１）の新規化合物、化合物（５）の新規化合物も、本発明に含まれる。 As will be described later, a novel compound of compound (3), a synthetic intermediate useful for obtaining compound (3), and compound (1) for producing compound (4) of the present invention. These novel compounds and the novel compound (5) are also included in the present invention.
　以下、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
　本明細書において使用する用語を以下に定義する。 The terms used in this specification are defined below.
　本明細書中、「ハロゲン原子」は、特に断りのない限り、フッ素原子、塩素原子、臭素原子、ヨウ素原子を意味する。 In the present specification, “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom unless otherwise specified.
　本明細書中、「Ｃ１－６アルキル基」は、特に断りのない限り、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、イソペンチル、ネオペンチル、１－エチルプロピル、ヘキシル、イソヘキシル、１，１－ジメチルブチル、２，２－ジメチルブチル、３，３－ジメチルブチル、２－エチルブチル等を意味する。 In this specification, “C 1-6 alkyl group” means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethyl unless otherwise specified. It means propyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
　本明細書中、「Ｃ２－１０アルケニル基」としては、例えば、エテニル、１－プロペニル、２－プロペニル、２－メチル－１－プロペニル、１－ブテニル、２－ブテニル、３－ブテニル、３－メチル－２－ブテニル、１－ペンテニル、２－ペンテニル、３－ペンテニル、４－ペンテニル、４－メチル－３－ペンテニル、１－ヘキセニル、３－ヘキセニル、５－ヘキセニル、１－ヘプテニル、１－オクテニル等が挙げられる。なかでも、Ｃ２－６アルケニル基が好ましい。 In the present specification, examples of the “C 2-10 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3- Methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, etc. Is mentioned. Of these, a C 2-6 alkenyl group is preferable.
　本明細書中、「Ｃ２－１０アルキニル基」としては、例えば、エチニル、１－プロピニル、２－プロピニル、１－ブチニル、２－ブチニル、３－ブチニル、１－ペンチニル、２－ペンチニル、３－ペンチニル、４－ペンチニル、１－ヘキシニル、２－ヘキシニル、３－ヘキシニル、４－ヘキシニル、５－ヘキシニル、１－ヘプチニル、１－オクチニル等が挙げられる。なかでも、Ｃ２－６アルキニル基が好ましい。 In the present specification, examples of the “C 2-10 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- Examples include pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like. Of these, a C 2-6 alkynyl group is preferable.
　本明細書中、「Ｃ１－６アルコキシ基」は、特に断りのない限り、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ、ペントキシ、イソペントキシ、ヘキソキシ等を意味する。 In the present specification, “C 1-6 alkoxy group” means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy and the like unless otherwise specified. To do.
　本明細書中、「Ｃ６－１４アリール基」とは、炭素数６～１４の単環または２環式の芳香族炭化水素環基、あるいはフェニル基に５～８員のシクロアルキル環（例えば、シクロペンタン環、シクロヘキサン環、シクロヘプタン環およびシクロオクタン環等）が縮環したものを示す。Ｃ６－１４アリール基は、後述する置換基を有していてもよい。Ｃ６－１４アリール基」として具体的には、例えば、フェニル基、ナフチル基、インダニル基及びテトラヒドロナフタレニル基が挙げられる。なかでもＣ６－１０アリール基が好ましく、フェニル基、ナフチル基がより好ましく、特に好ましくはフェニル基である。 In the present specification, the “C 6-14 aryl group” means a monocyclic or bicyclic aromatic hydrocarbon ring group having 6 to 14 carbon atoms, or a 5- to 8-membered cycloalkyl ring (for example, a phenyl group) , Cyclopentane ring, cyclohexane ring, cycloheptane ring, cyclooctane ring and the like). The C 6-14 aryl group may have a substituent described later. Specific examples of the “C 6-14 aryl group” include a phenyl group, a naphthyl group, an indanyl group, and a tetrahydronaphthalenyl group. Of these, a C 6-10 aryl group is preferable, a phenyl group and a naphthyl group are more preferable, and a phenyl group is particularly preferable.
　本明細書中、「ヘテロアリール基」としては、環構成原子として炭素原子以外に酸素原子、硫黄原子及び窒素原子から選択されるヘテロ原子を１～４個含有する、４～７員の単環式芳香族複素環基、および８～１２員の縮合芳香族複素環基が挙げられる。該縮合芳香族複素環基としては、例えば、これら４～７員の単環式芳香族複素環基に対応する環と、１または２個の窒素原子を含む５または６員の芳香族複素環（例、ピロール、イミダゾール、ピラゾール、ピラジン、ピリジン、ピリミジン）、１個の硫黄原子を含む５員の芳香族複素環（例、チオフェン）およびベンゼン環から選ばれる１または２個が縮合した環から誘導される基等が挙げられる。当該ヘテロアリール基は、後述する置換基を有していてもよい。 In the present specification, the “heteroaryl group” is a 4- to 7-membered monocyclic ring containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring-constituting atom. And an aromatic heterocyclic group having a formula and 8- to 12-membered fused aromatic heterocyclic group. Examples of the condensed aromatic heterocyclic group include a ring corresponding to these 4- to 7-membered monocyclic aromatic heterocyclic groups and a 5- or 6-membered aromatic heterocyclic ring containing 1 or 2 nitrogen atoms. (Eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine) From a ring in which 1 or 2 selected from a 5-membered aromatic heterocycle containing one sulfur atom (eg, thiophene) and a benzene ring are condensed Examples include groups to be derived. The heteroaryl group may have a substituent described later.
　該ヘテロアリール基が誘導される芳香族へテロ環として具体的には、例えば、ピリジン環、ピリダジン環、ピリミジン環、ピラジン環、フラン環、チオフェン環、ピロール環、イソオキサゾール環、オキサゾール環、イソチアゾール環、チアゾール環、ピラゾール環、イミダゾール環、オキサジアゾール環、チアジアゾール環、トリアゾール環、テトラゾール環、ベンゾフラン環、ベンゾチオフェン環、インドール環、イソインドール環、ベンゾオキサゾール環、ベンゾチアゾール環、ベンズイミダゾール環（＝ベンゾイミダゾール環）、インダゾール環、ベンズイソオキサゾール環、ベンズイソチアゾール環、ベンゾフラザン環、ベンゾチアジアゾール環、プリン環、キノリン環、イソキノリン環、シンノリン環、フタラジン環、キナゾリン環、キノキサリン環、プテリジン環、イミダゾオキサゾール環、イミダゾチアゾール環、イミダゾイミダゾール環等が挙げられる。 Specific examples of the aromatic heterocycle from which the heteroaryl group is derived include pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, furan ring, thiophene ring, pyrrole ring, isoxazole ring, oxazole ring, Thiazole ring, thiazole ring, pyrazole ring, imidazole ring, oxadiazole ring, thiadiazole ring, triazole ring, tetrazole ring, benzofuran ring, benzothiophene ring, indole ring, isoindole ring, benzoxazole ring, benzothiazole ring, benzimidazole Ring (= benzimidazole ring), indazole ring, benzisoxazole ring, benzisothiazole ring, benzofurazan ring, benzothiadiazole ring, purine ring, quinoline ring, isoquinoline ring, cinnoline ring, phthalazine ring, quinazo Down ring, quinoxaline ring, pteridine ring, imidazo benzoxazole ring, imidazothiazole ring, imidazo imidazole ring, and the like.
　ヘテロアリール基の炭素数は通常１～１０であり、好ましくは１～９である。
　このようなヘテロアリール基の例として具体的には、ピリジル（例、２－ピリジル、３－ピリジル、４－ピリジル）、ピリダジニル（例、３－ピリダジニル、４－ピリダジニル）、ピリミジニル（例、２－ピリミジニル、４－ピリミジニル、５－ピリミジニル）、ピラジニル（例、２－ピラジニル）、フリル（例、２－フリル、３－フリル）、チエニル（例、２－チエニル、３－チエニル）、ピロリル（例、１－ピロリル、２－ピロリル、３－ピロリル）、イソオキサゾリル（例、３－イソオキサゾリル、４－イソオキサゾリル、５－イソオキサゾリル）、オキサゾリル（例、２－オキサゾリル、４－オキサゾリル、５－オキサゾリル）、イソチアゾリル（例、３－イソチアゾリル、４－イソチアゾリル、５－イソチアゾリル）、チアゾリル（例、２－チアゾリル、４－チアゾリル、５－チアゾリル）、ピラゾリル（例、１－ピラゾリル、３－ピラゾリル、４－ピラゾリル）、イミダゾリル（例、１－イミダゾリル、２－イミダゾリル、４－イミダゾリル、５－イミダゾリル）、オキサジアゾリル（例、１，２，４－オキサジアゾール－５－イル、１，３，４－オキサジアゾール－２－イル）、チアジアゾリル（例、１，３，４－チアジアゾール－２－イル）、トリアゾリル（例、１，２，４－トリアゾール－１－イル、１，２，４－トリアゾール－３－イル、１，２，３－トリアゾール－１－イル、１，２，３－トリアゾール－２－イル、１，２，３－トリアゾール－４－イル）、テトラゾリル（例、テトラゾール－１－イル、テトラゾール－５－イル）等の単環式芳香族複素環基、キノリル（例、２－キノリル、３－キノリル、４－キノリル、６－キノリル）、イソキノリル（例、３－イソキノリル）、キナゾリル（例、２－キナゾリル、４－キナゾリル）、キノキサリル（例、２－キノキサリル、６－キノキサリル）、ベンゾフラニル（例、２－ベンゾフラニル、３－ベンゾフラニル）、ベンゾチエニル（例、２－ベンゾチエニル、３－ベンゾチエニル）、ベンズオキサゾリル（例、２－ベンズオキサゾリル）、ベンズイソオキサゾリル（例、７－ベンズイソオキサゾリル）、ベンゾチアゾリル（例、２－ベンゾチアゾリル）、ベンズイミダゾリル（例、ベンズイミダゾール－１－イル、ベンズイミダゾール－２－イル、ベンズイミダゾール－５－イル）、ベンゾトリアゾリル（例、１Ｈ－１，２，３－ベンゾトリアゾール－５－イル）、インドリル（例、インドール－１－イル、インドール－２－イル、インドール－３－イル、インドール－５－イル）、インダゾリル（例、１Ｈ－インダゾール－３－イル）、ピロロピラジニル（例、１Ｈ－ピロロ［２，３－ｂ］ピラジン－２－イル、１Ｈ－ピロロ［２，３－ｂ］ピラジン－６－イル）、イミダゾピリジニル（例、１Ｈ－イミダゾ［４，５－ｂ］ピリジン－２－イル、１Ｈ－イミダゾ［４，５－ｃ］ピリジン－２－イル、２Ｈ－イミダゾ［１，２－ａ］ピリジン－３－イル）、チエノピリジニル（例、チエノ［２，３－ｂ］ピリジン－３－イル）、イミダゾピラジニル（例、１Ｈ－イミダゾ［４，５－ｂ］ピラジン－２－イル）、ピラゾロピリジニル（例、１Ｈ－ピラゾロ［４，３－ｃ］ピリジン－３－イル）、ピラゾロチエニル（例、２Ｈ－ピラゾロ［３，４－ｂ］チオフェン－２－イル）、ピラゾロトリアジニル（例、ピラゾロ［５，１－ｃ］［１，２，４］トリアジン－３－イル）等の縮合芳香族複素環基であり、好ましくは単環式芳香族複素環基であり、特に好ましくはピリジル、チエニルである。 The heteroaryl group usually has 1 to 10 carbon atoms, preferably 1 to 9 carbon atoms.
Specific examples of such heteroaryl groups include pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (eg, 2-pyridinyl). Pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (eg, 2-pyrazinyl), furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), isoxazolyl (eg, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (eg, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isothiazolyl (eg, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), thiazolyl Examples, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl), oxadiazolyl (eg, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (eg, 1,3,4-thiadiazole-2- Yl), triazolyl (eg, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazole Monocyclic aromatic heterocycles such as -2-yl, 1,2,3-triazol-4-yl), tetrazolyl (eg, tetrazol-1-yl, tetrazol-5-yl) Quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolyl), isoquinolyl (eg, 3-isoquinolyl), quinazolyl (eg, 2-quinazolyl, 4-quinazolyl), quinoxalyl (eg, 2-quinolyl) Quinoxalyl, 6-quinoxalyl), benzofuranyl (eg, 2-benzofuranyl, 3-benzofuranyl), benzothienyl (eg, 2-benzothienyl, 3-benzothienyl), benzoxazolyl (eg, 2-benzoxazolyl) Benzisoxazolyl (eg, 7-benzisoxazolyl), benzothiazolyl (eg, 2-benzothiazolyl), benzimidazolyl (eg, benzimidazol-1-yl, benzimidazol-2-yl, benzimidazole-5) -Yl), benzotriazolyl (eg, 1H-1,2,3-benzotria) Zol-5-yl), indolyl (eg, indol-1-yl, indol-2-yl, indol-3-yl, indol-5-yl), indazolyl (eg, 1H-indazol-3-yl), pyrrolopyrazinyl (Eg, 1H-pyrrolo [2,3-b] pyrazin-2-yl, 1H-pyrrolo [2,3-b] pyrazin-6-yl), imidazopyridinyl (eg, 1H-imidazo [4,5 -B] pyridin-2-yl, 1H-imidazo [4,5-c] pyridin-2-yl, 2H-imidazo [1,2-a] pyridin-3-yl), thienopyridinyl (eg, thieno [2, 3-b] pyridin-3-yl), imidazopyrazinyl (eg, 1H-imidazo [4,5-b] pyrazin-2-yl), pyrazolopyridinyl (eg, 1H-pyrazolo [4,3 -C] pyridine-3- ), Pyrazolothienyl (eg, 2H-pyrazolo [3,4-b] thiophen-2-yl), pyrazolotriazinyl (eg, pyrazolo [5,1-c] [1,2,4] triazine-3 A fused aromatic heterocyclic group such as -yl), preferably a monocyclic aromatic heterocyclic group, particularly preferably pyridyl or thienyl.
　本明細書中、「非芳香族複素環基（即ち、脂肪族複素環基）」としては、環構成原子として、炭素原子以外に酸素原子、硫黄原子及び窒素原子から選択されるヘテロ原子を１～４個含有する、４～７員の単環式非芳香族複素環基、および８～１２員の縮合非芳香族複素環基を示す。該縮合非芳香族複素環基としては、例えば、これら４～７員の単環式非芳香族複素環基に対応する環と、１または２個の窒素原子を含む５または６員の芳香族複素環（例、ピロール、イミダゾール、ピラゾール、ピラジン、ピリジン、ピリミジン）、１個の硫黄原子を含む５員の芳香族複素環（例、チオフェン）およびベンゼン環から選ばれる１または２個の環が縮合した環から誘導される基、ならびに該基の部分飽和により得られる基等が挙げられる。当該非芳香族複素環基の好ましい炭素原子は１～９個である。なお、環構成原子である任意の炭素原子はオキソ基で置換されていてもよい。 In the present specification, the “non-aromatic heterocyclic group (that is, aliphatic heterocyclic group)” includes 1 hetero atom selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to a carbon atom as a ring-constituting atom. A 4- to 7-membered monocyclic non-aromatic heterocyclic group and an 8- to 12-membered condensed non-aromatic heterocyclic group containing ˜4 are shown. Examples of the fused non-aromatic heterocyclic group include, for example, a ring corresponding to the 4- to 7-membered monocyclic non-aromatic heterocyclic group, and a 5- or 6-membered aromatic group containing 1 or 2 nitrogen atoms. 1 or 2 rings selected from a heterocycle (eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine), a 5-membered aromatic heterocycle containing one sulfur atom (eg, thiophene) and a benzene ring Examples thereof include a group derived from a condensed ring and a group obtained by partial saturation of the group. The non-aromatic heterocyclic group preferably has 1 to 9 carbon atoms. Any carbon atom that is a ring-constituting atom may be substituted with an oxo group.
　該非芳香族複素環基が誘導される非芳香族複素環として具体的には、例えば、ピロリジン環、ピラゾリジン環、イミダゾリジン環、ピロリン環、ピラゾリン環、イミダゾリン環、テトラヒドロフラン環、テトラヒドロチオフェン環、テトラヒドロキノリン環、テトラヒドロイソキノリン環、チアゾリジン環、ピペリジン環、ピペラジン環、キヌクリジン環、テトラヒドロピラン環、モルホリン環、チオモルホリン環、ジオキソラン環、ホモピペリジン環、ホモピペラジン環、インドリン環、イソインドリン環、クロマン環、イソクロマン環等が挙げられる。このような非芳香族複素環基としては、ピロリジニル（例、１－ピロリジニル、２－ピロリジニル）、ピペリジニル（例、ピペリジノ、２－ピペリジニル、３－ピペリジニル、４－ピペリジニル）、ホモピペリジニル、モルホリニル（例、モルホリノ）、チオモルホリニル（例、チオモルホリノ）、ピペラジニル（例、１－ピペラジニル、２－ピペラジニル、３－ピペラジニル）、ホモピペラジニル、ヘキサメチレンイミニル（例、ヘキサメチレンイミン－１－イル）、オキサゾリジニル（例、オキサゾリジン－２－イル）、チアゾリジニル（例、チアゾリジン－２－イル）、ジヒドロチオピラニル（例、ジヒドロチオピラン－３－イル、ジヒドロチオピラン－４－イル）、イミダゾリジニル（例、イミダゾリジン－２－イル、イミダゾリジン－３－イル）、オキサゾリニル（例、オキサゾリン－２－イル）、チアゾリニル（例、チアゾリン－２－イル）、イミダゾリニル（例、イミダゾリン－２－イル、イミダゾリン－３－イル）、ジオキソリル（例、１，３－ジオキソール－４－イル）、ジオキソラニル（例、１，３－ジオキソラン－４－イル）、ジヒドロオキサジアゾリル（例、４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）、ピラニル（例、４－ピラニル）、テトラヒドロピラニル（例、２－テトラヒドロピラニル、３－テトラヒドロピラニル、４－テトラヒドロピラニル）、チオピラニル（例、４－チオピラニル）、テトラヒドロチオピラニル（例、２－テトラヒドロチオピラニル、３－テトラヒドロチオピラニル、４－テトラヒドロチオピラニル）、１－オキシドテトラヒドロチオピラニル（例、１－オキシドテトラヒドロチオピラン－４－イル）、１，１－ジオキシドテトラヒドロチオピラニル（例、１，１－ジオキシドテトラヒドロチオピラン－４－イル）、テトラヒドロフリル（例、テトラヒドロフラン－３－イル、テトラヒドロフラン－２－イル）、ピラゾリジニル（例、ピラゾリジン－１－イル、ピラゾリジン－３－イル）、ピラゾリニル（例、ピラゾリン－１－イル）、テトラヒドロピリミジニル（例、テトラヒドロピリミジン－１－イル）、ジヒドロトリアゾリル（例、２，３－ジヒドロ－１Ｈ－１，２，３－トリアゾール－１－イル）、テトラヒドロトリアゾリル（例、２，３，４，５－テトラヒドロ－１Ｈ－１，２，３－トリアゾール－１－イル）等の単環式非芳香族複素環基；ジヒドロインドリル（例、２，３－ジヒドロ－１Ｈ－インドール－１－イル）、ジヒドロイソインドリル（例、１，３－ジヒドロ－２Ｈ－イソインドール－２－イル）、ジヒドロベンゾフラニル（例、２，３－ジヒドロ－１－ベンゾフラン－５－イル）、ジヒドロベンゾジオキシニル（例、２，３－ジヒドロ－１，４－ベンゾジオキシニル）、ジヒドロベンゾジオキセピニル（例、３，４－ジヒドロ－２Ｈ－１，５－ベンゾジオキセピニル）、テトラヒドロベンゾフラニル（例、４，５，６，７－テトラヒドロ－１－ベンゾフラン－３－イル）、クロメニル（例、４Ｈ－クロメン－２－イル、２Ｈ－クロメン－３－イル）、ジヒドロクロメニル（例、３，４－ジヒドロ－２Ｈ－クロメン－２－イル）、ジヒドロキノリニル（例、１，２－ジヒドロキノリン－４－イル）、テトラヒドロキノリニル（例、１，２，３，４－テトラヒドロキノリン－４－イル）、ジヒドロイソキノリニル（例、１，２－ジヒドロイソキノリン－４－イル）、テトラヒドロイソキノリニル（例、１，２，３，４－テトラヒドロイソキノリン－４－イル）、ジヒドロフタラジニル（例、１，４－ジヒドロフタラジン－４－イル）等の縮合非芳香族複素環基；等が挙げられる。 Specific examples of the non-aromatic heterocyclic ring from which the non-aromatic heterocyclic group is derived include, for example, pyrrolidine ring, pyrazolidine ring, imidazolidine ring, pyrroline ring, pyrazoline ring, imidazoline ring, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydro Quinoline ring, tetrahydroisoquinoline ring, thiazolidine ring, piperidine ring, piperazine ring, quinuclidine ring, tetrahydropyran ring, morpholine ring, thiomorpholine ring, dioxolane ring, homopiperidine ring, homopiperazine ring, indoline ring, isoindoline ring, chroman ring And an isochroman ring. Such non-aromatic heterocyclic groups include pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl), piperidinyl (eg, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), homopiperidinyl, morpholinyl (eg, Morpholino), thiomorpholinyl (eg, thiomorpholino), piperazinyl (eg, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl), homopiperazinyl, hexamethyleneiminyl (eg, hexamethyleneimine-1-yl), oxazolidinyl (eg, Oxazolidin-2-yl), thiazolidinyl (eg, thiazolidin-2-yl), dihydrothiopyranyl (eg, dihydrothiopyran-3-yl, dihydrothiopyran-4-yl), imidazolidinyl (eg, imidazolidine-2) -Ill, imidazolide -3-yl), oxazolinyl (eg, oxazolin-2-yl), thiazolinyl (eg, thiazoline-2-yl), imidazolinyl (eg, imidazolin-2-yl, imidazolin-3-yl), dioxolyl (eg, 1 , 3-dioxol-4-yl), dioxolanyl (eg, 1,3-dioxolan-4-yl), dihydrooxadiazolyl (eg, 4,5-dihydro-1,2,4-oxadiazole-3- Yl), pyranyl (eg, 4-pyranyl), tetrahydropyranyl (eg, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl), thiopyranyl (eg, 4-thiopyranyl), tetrahydrothiopyranyl (Eg, 2-tetrahydrothiopyranyl, 3-tetrahydrothiopyranyl, 4-tetrahydrothiopyranyl), -Oxide tetrahydrothiopyranyl (eg, 1-oxidetetrahydrothiopyran-4-yl), 1,1-dioxidetetrahydrothiopyranyl (eg, 1,1-dioxidetetrahydrothiopyran-4-yl), tetrahydro Furyl (eg, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl), pyrazolidinyl (eg, pyrazolidin-1-yl, pyrazolidin-3-yl), pyrazolinyl (eg, pyrazolin-1-yl), tetrahydropyrimidinyl (eg, Tetrahydropyrimidin-1-yl), dihydrotriazolyl (eg, 2,3-dihydro-1H-1,2,3-triazol-1-yl), tetrahydrotriazolyl (eg, 2,3,4,5) -Tetrahydro-1H-1,2,3-triazol-1-yl) and other monocyclic non-aromatic heterocycles Ring group: dihydroindolyl (eg, 2,3-dihydro-1H-indol-1-yl), dihydroisoindolyl (eg, 1,3-dihydro-2H-isoindol-2-yl), dihydrobenzofura Nil (eg, 2,3-dihydro-1-benzofuran-5-yl), dihydrobenzodioxinyl (eg, 2,3-dihydro-1,4-benzodioxinyl), dihydrobenzodioxepinyl ( Examples, 3,4-dihydro-2H-1,5-benzodioxepinyl), tetrahydrobenzofuranyl (eg, 4,5,6,7-tetrahydro-1-benzofuran-3-yl), chromenyl (eg 4H-chromen-2-yl, 2H-chromen-3-yl), dihydrochromenyl (eg, 3,4-dihydro-2H-chromen-2-yl), dihydroquinolinyl (eg, 1,2 Dihydroquinolin-4-yl), tetrahydroquinolinyl (eg, 1,2,3,4-tetrahydroquinolin-4-yl), dihydroisoquinolinyl (eg, 1,2-dihydroisoquinolin-4-yl) , Tetrahydroisoquinolinyl (eg, 1,2,3,4-tetrahydroisoquinolin-4-yl), dihydrophthalazinyl (eg, 1,4-dihydrophthalazin-4-yl), etc. A heterocyclic group; and the like.
　なかでも、炭素数２～８の非芳香族複素環基が好ましく、さらに好ましくはピロリジニル、ピロリニル、テトラヒドロフリル、テトラヒドロチエニル、ピペリジニル、ピペラジニル、モルホリニル、チオモルホリニル、ホモピペリジニル、ホモピペラジニルであり、特に好ましくはピロリジニル、ピペリジニル、ホモピペリジニルである。 Among them, a non-aromatic heterocyclic group having 2 to 8 carbon atoms is preferable, more preferably pyrrolidinyl, pyrrolinyl, tetrahydrofuryl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperidinyl, homopiperazinyl, particularly preferably pyrrolidinyl, Piperidinyl and homopiperidinyl.
　本明細書中、「含窒素非芳香族複素環基（即ち、含窒素脂肪族複素環基）」とは、上記非芳香族複素環基のうち環中に窒素原子を含むもののことをいう。該含窒素非芳香族複素環基としては、通常、炭素数１～９（好ましくは炭素数２～９、より好ましくは炭素数２～８）の含窒素非芳香族複素環基が挙げられ、好ましくは、ピロリジニル、ピペリジニル、ホモピペリジニル、ピペラジニル、テトラヒドロキノリニル、テトラヒドロイソキノリニル、ピロリニルであり、特に好ましくは、ピロリジニル、ピペリジニル、ピペラジニルである。 In the present specification, the “nitrogen-containing non-aromatic heterocyclic group (that is, nitrogen-containing aliphatic heterocyclic group)” refers to a non-aromatic heterocyclic group containing a nitrogen atom in the ring. Examples of the nitrogen-containing non-aromatic heterocyclic group generally include nitrogen-containing non-aromatic heterocyclic groups having 1 to 9 carbon atoms (preferably 2 to 9 carbon atoms, more preferably 2 to 8 carbon atoms). Preferred are pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrrolinyl, and particularly preferred are pyrrolidinyl, piperidinyl and piperazinyl.
　本明細書中、「Ｃ３－１０シクロアルキル基」としては、飽和または不飽和の炭素数３～１０の環状脂肪族炭化水素基を示すものであり、部分的に不飽和結合をその環内に含んでいてもよい。また単環式であっても多環式であってもよい。当該Ｃ３－１０シクロアルキル基としては、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、シクロヘキセニル、シクロペンテニル、ビシクロ［２．２．１］ヘプチル、ビシクロ［２．２．２］オクチル、ビシクロ［３．２．１］オクチル、ビシクロ［３．２．２］ノニル、ビシクロ［３．３．１］ノニル、ビシクロ［４．２．１］ノニル、ビシクロ［４．３．１］デシル、アダマンチル等が挙げられる。好ましくは、Ｃ３－８シクロアルキル基であり、より好ましくは、シクロヘキシルである。
　該Ｃ３－１０シクロアルキル基は、ベンゼン環と縮合環基を形成していてもよく、このような縮合環基としては、例えば、インダニル等が挙げられる。 In the present specification, the “C 3-10 cycloalkyl group” represents a saturated or unsaturated cyclic aliphatic hydrocarbon group having 3 to 10 carbon atoms, and partially has an unsaturated bond in the ring. May be included. Further, it may be monocyclic or polycyclic. Examples of the C 3-10 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl, cyclopentenyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2. 2] Octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3. 1] Examples include decyl and adamantyl. A C 3-8 cycloalkyl group is preferred, and cyclohexyl is more preferred.
The C 3-10 cycloalkyl group may form a condensed ring group with a benzene ring, and examples of such a condensed ring group include indanyl and the like.
　本明細書中の「Ｃ１－１０アルキル基」、あるいは「Ｃ１－１０アルキルチオ基」、「Ｃ１－１０アルキルアミノ基」、「Ｃ１－１０アルコキシ基」、「Ｃ１－１０アルコキシ－カルボニル基」等におけるＣ１－１０アルキル基部分は、直鎖もしくは分岐鎖状の炭素数１～１０のアルキル基であり、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、シクロプロピルメチル基、ペンチル基、イソペンチル基、ネオペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基、１，１－ジメチル－プロピル基、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基、シクロオクチル基等が挙げられる。
　なかでも、Ｃ１－６アルキル基が好ましく、メチル基、エチル基、イソプロピル基、イソブチル基がより好ましく、炭素数１～３のアルキル基（メチル基、エチル基、イソプロピル基）が最も好ましい。 In the present specification, “C 1-10 alkyl group”, or “C 1-10 alkylthio group”, “C 1-10 alkylamino group”, “C 1-10 alkoxy group”, “C 1-10 alkoxy-” The C 1-10 alkyl group moiety in the “carbonyl group” and the like is a linear or branched alkyl group having 1 to 10 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl. Group, sec-butyl group, tert-butyl group, cyclopropylmethyl group, pentyl group, isopentyl group, neopentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, 1,1-dimethyl-propyl group, A cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, etc. are mentioned.
Of these, a C 1-6 alkyl group is preferable, a methyl group, an ethyl group, an isopropyl group, and an isobutyl group are more preferable, and an alkyl group having 1 to 3 carbon atoms (a methyl group, an ethyl group, and an isopropyl group) is most preferable.
　本明細書中、「Ｃ１－１０アルキルチオ基」としては、例えば、メチルチオ基、エチルチオ基、プロピルチオ基、イソプロピルチオ基、ブチルチオ基、イソブチルチオ基、ｓｅｃ－ブチルチオ基、ｔｅｒｔ－ブチルチオ基、ペンチルチオ基、イソペンチルチオ基、ネオペンチルチオ基、ヘキシルチオ基、ヘプチルチオ基、オクチルチオ基、ノニルチオ基、デシルチオ基、１，１－ジメチル－プロピルチオ基等が挙げられる。 In the present specification, examples of the “C 1-10 alkylthio group” include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, a sec-butylthio group, a tert-butylthio group, and a pentylthio group. , Isopentylthio group, neopentylthio group, hexylthio group, heptylthio group, octylthio group, nonylthio group, decylthio group, 1,1-dimethyl-propylthio group and the like.
　本明細書中、「Ｃ１－１０アルキルアミノ基」としては、例えば、メチルアミノ基、エチルアミノ基、プロピルアミノ基、イソプロピルアミノ基、ブチルアミノ基、イソブチルアミノ基、ｓｅｃ－ブチルアミノ基、ｔｅｒｔ－ブチルアミノ基、ペンチルアミノ基、イソペンチルアミノ基、ネオペンチルアミノ基、ヘキシルアミノ基、ヘプチルアミノ基、オクチルアミノ基、ノニルアミノ基、デシルアミノ基、１，１－ジメチル－プロピルアミノ基；ジメチルアミノ基、ジエチルアミノ基、ジプロピルアミノ基、ジイソプロピルアミノ基、ジブチルアミノ基、ジイソブチルアミノ基、ジ－ｓｅｃ－ブチルアミノ基、ジ－ｔｅｒｔ－ブチルアミノ基、ジペンチルアミノ基、ジイソペンチルアミノ基、ジネオペンチルアミノ基、ジヘキシルアミノ基；Ｎ－メチル－Ｎ－エチルアミノ基、Ｎ－メチル－Ｎ－プロピルアミノ基、Ｎ－メチル－Ｎ－イソプロピルアミノ基、Ｎ－メチル－Ｎ－ブチルアミノ基、Ｎ－メチル－Ｎ－イソブチルアミノ基、Ｎ－メチル－Ｎ－ｓｅｃ－ブチルアミノ基、Ｎ－メチル－Ｎ－ｔｅｒｔ－ブチルアミノ基、Ｎ－エチル－Ｎ－プロピルアミノ基、Ｎ－エチル－Ｎ－イソプロピルアミノ基、Ｎ－エチル－Ｎ－ブチルアミノ基、Ｎ－エチル－Ｎ－イソブチルアミノ基、Ｎ－エチル－Ｎ－ｓｅｃ－ブチルアミノ基、Ｎ－エチル－Ｎ－ｔｅｒｔ－ブチルアミノ基等が挙げられる。 In the present specification, examples of the “C 1-10 alkylamino group” include a methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, sec-butylamino group, tert. -Butylamino group, pentylamino group, isopentylamino group, neopentylamino group, hexylamino group, heptylamino group, octylamino group, nonylamino group, decylamino group, 1,1-dimethyl-propylamino group; dimethylamino group , Diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di-sec-butylamino group, di-tert-butylamino group, dipentylamino group, diisopentylamino group, dineopentyl Amino group, dihexylamino group N-methyl-N-ethylamino group, N-methyl-N-propylamino group, N-methyl-N-isopropylamino group, N-methyl-N-butylamino group, N-methyl-N-isobutylamino group; N-methyl-N-sec-butylamino group, N-methyl-N-tert-butylamino group, N-ethyl-N-propylamino group, N-ethyl-N-isopropylamino group, N-ethyl-N -Butylamino group, N-ethyl-N-isobutylamino group, N-ethyl-N-sec-butylamino group, N-ethyl-N-tert-butylamino group and the like.
　本明細書中、「Ｃ１－１０アルキルスルホンアミド基」としては、例えば、メチルスルホンアミド基、エチルスルホンアミド基、プロピルスルホンアミド基、イソプロピルスルホンアミド基、ブチルスルホンアミド基、イソブチルスルホンアミド基、ｓｅｃ－ブチルスルホンアミド基、ｔｅｒｔ－ブチルスルホンアミド基、シクロプロピルメチルスルホンアミド基、ペンチルスルホンアミド基、イソペンチルスルホンアミド基、ネオペンチルスルホンアミド基、ヘキシルスルホンアミド基、ヘプチルスルホンアミド基、オクチルスルホンアミド基、ノニルスルホンアミド基、デシルスルホンアミド基、１，１－ジメチル－プロピルスルホンアミド基、シクロプロピルスルホンアミド基、シクロブチルスルホンアミド基、シクロペンチルスルホンアミド基、シクロヘキシルスルホンアミド基、シクロヘプチルスルホンアミド基、シクロオクチルスルホンアミド基等が挙げられる。 In the present specification, examples of the “C 1-10 alkylsulfonamide group” include a methylsulfonamide group, an ethylsulfonamide group, a propylsulfonamide group, an isopropylsulfonamide group, a butylsulfonamide group, an isobutylsulfonamide group, sec-butylsulfonamide group, tert-butylsulfonamide group, cyclopropylmethylsulfonamide group, pentylsulfonamide group, isopentylsulfonamide group, neopentylsulfonamide group, hexylsulfonamide group, heptylsulfonamide group, octylsulfone Amide group, nonylsulfonamide group, decylsulfonamide group, 1,1-dimethyl-propylsulfonamide group, cyclopropylsulfonamide group, cyclobutylsulfonamide group, cyclopentylsulfone Amide group, cyclohexylsulfonamide group, cycloheptylsulfonamide group, cyclooctylsulfonamide group and the like.
　本明細書中、「Ｃ１－１０アルコキシ基」としては、例えば、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、イソブトキシ基、ｓｅｃ－ブトキシ基、ｔｅｒｔ－ブトキシ基、ペンチルオキシ基、イソペンチルオキシ基、ネオペンチルオキシ基、ヘキシルオキシ基、ヘプチルオキシ基、オクチルオキシ基、ノニルオキシ基、デシルオキシ基、１，１－ジメチル－プロポキシ基等が挙げられる。好ましくは、Ｃ１－６アルコキシ基である。 In the present specification, examples of the “C 1-10 alkoxy group” include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, and a pentyloxy group. And isopentyloxy group, neopentyloxy group, hexyloxy group, heptyloxy group, octyloxy group, nonyloxy group, decyloxy group, 1,1-dimethyl-propoxy group and the like. Preferably, it is a C 1-6 alkoxy group.
　本明細書中、「Ｃ１－１０アルコキシ－カルボニル基」としては、例えば、メトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基、イソプロポキシカルボニル基、ブトキシカルボニル基、イソブトキシカルボニル基、ｓｅｃ－ブトキシカルボニル基、ｔｅｒｔ－ブトキシカルボニル基、ペンチルオキシカルボニル基、イソペンチルオキシカルボニル基、ネオペンチルオキシカルボニル基、ヘキシルオキシカルボニル基、ヘプチルオキシカルボニル基、オクチルオキシカルボニル基、ノニルオキシカルボニル基、１，１－ジメチル－プロポキシカルボニル基等が挙げられる。 In the present specification, examples of the “C 1-10 alkoxy-carbonyl group” include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, and a sec-butoxycarbonyl group. Group, tert-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, hexyloxycarbonyl group, heptyloxycarbonyl group, octyloxycarbonyl group, nonyloxycarbonyl group, 1,1-dimethyl -Propoxycarbonyl group and the like.
　本明細書中の「アシル基」、あるいは「アシルオキシ基」、「アシルアミノ基」等におけるアシル基部分としては、ホルミル基、Ｃ１－１０アルキル－カルボニル基（例えば、アセチル基、エチルカルボニル基、プロピルカルボニル基、イソプロピルカルボニル基、ブチルカルボニル基、イソブチルカルボニル基、ｓｅｃ－ブチルカルボニル基、ｔｅｒｔ－ブチルカルボニル基、シクロプロピルメチルカルボニル基、ペンチルカルボニル基、イソペンチルカルボニル基、ネオペンチルカルボニル基、ヘキシルカルボニル基、ヘプチルカルボニル基、オクチルカルボニル基、ノニルカルボニル基、１，１－ジメチル－プロピルカルボニル基、シクロプロピルカルボニル基、シクロブチルカルボニル基、シクロペンチルカルボニル基、シクロヘキシルカルボニル基、シクロヘプチルカルボニル基、シクロオクチルカルボニル基等）、Ｃ６－１０アリール－カルボニル基（例えば、ベンゾイル基、１－ナフチルカルボニル基、２－ナフチルカルボニル基等）等が挙げられる。 The acyl group in the “acyl group”, “acyloxy group”, “acylamino group” and the like in this specification includes a formyl group, a C 1-10 alkyl-carbonyl group (for example, an acetyl group, an ethylcarbonyl group, a propyl group). Carbonyl group, isopropylcarbonyl group, butylcarbonyl group, isobutylcarbonyl group, sec-butylcarbonyl group, tert-butylcarbonyl group, cyclopropylmethylcarbonyl group, pentylcarbonyl group, isopentylcarbonyl group, neopentylcarbonyl group, hexylcarbonyl group , Heptylcarbonyl group, octylcarbonyl group, nonylcarbonyl group, 1,1-dimethyl-propylcarbonyl group, cyclopropylcarbonyl group, cyclobutylcarbonyl group, cyclopentylcarbonyl group, cyclohexyl group, A silcarbonyl group, a cycloheptylcarbonyl group, a cyclooctylcarbonyl group, etc.), a C 6-10 aryl-carbonyl group (for example, a benzoyl group, a 1-naphthylcarbonyl group, a 2-naphthylcarbonyl group, etc.) and the like.
　本明細書中、「アシルオキシ基」としては、例えば、ホルミルオキシ基、炭素数２～１０のアルキルカルボニルオキシ基（例えば、アセチルオキシ基、エチルカルボニルオキシ基、プロピルカルボニルオキシ基、イソプロピルカルボニルオキシ基、ブチルカルボニルオキシ基、イソブチルカルボニルオキシ基、ｓｅｃ－ブチルカルボニルオキシ基、ｔｅｒｔ－ブチルカルボニルオキシ基、ペンチルカルボニルオキシ基、イソペンチルカルボニルオキシ基、ネオペンチルカルボニルオキシ基、ヘキシルカルボニルオキシ基、ヘプチルカルボニルオキシ基、オクチルカルボニルオキシ基、ノニルカルボニルオキシ基、１，１－ジメチル－プロピルカルボニルオキシ基等）、Ｃ６－１０アリール－カルボニルオキシ基（例えば、ベンゾイルオキシ基等）等が挙げられる。 In the present specification, examples of the “acyloxy group” include a formyloxy group, an alkylcarbonyloxy group having 2 to 10 carbon atoms (for example, an acetyloxy group, an ethylcarbonyloxy group, a propylcarbonyloxy group, an isopropylcarbonyloxy group, Butylcarbonyloxy group, isobutylcarbonyloxy group, sec-butylcarbonyloxy group, tert-butylcarbonyloxy group, pentylcarbonyloxy group, isopentylcarbonyloxy group, neopentylcarbonyloxy group, hexylcarbonyloxy group, heptylcarbonyloxy group Octylcarbonyloxy group, nonylcarbonyloxy group, 1,1-dimethyl-propylcarbonyloxy group, etc.), C 6-10 aryl-carbonyloxy group (for example, benzoyloxy group) Etc.).
　本明細書中、「アシルアミノ基」としては、例えば、ホルミルアミノ基、Ｃ１－１０アルキル－カルボニルアミノ基（例えば、アセチルアミノ基、エチルカルボニルアミノ基、プロピルカルボニルアミノ基、イソプロピルカルボニルアミノ基、ブチルカルボニルアミノ基、イソブチルカルボニルアミノ基、ｓｅｃ－ブチルカルボニルアミノ基、ｔｅｒｔ－ブチルカルボニルアミノ基、ペンチルカルボニルアミノ基、イソペンチルカルボニルアミノ基、ネオペンチルカルボニルアミノ基、ヘキシルカルボニルアミノ基、ヘプチルカルボニルアミノ基、オクチルカルボニルアミノ基、ノニルカルボニルアミノ基、１，１－ジメチル－プロピルカルボニルアミノ基等）、Ｃ６－１０アリール－カルボニルアミノ基（例えば、ベンゾイルアミノ基等）等が挙げられる。 In the present specification, examples of the “acylamino group” include a formylamino group, a C 1-10 alkyl-carbonylamino group (for example, acetylamino group, ethylcarbonylamino group, propylcarbonylamino group, isopropylcarbonylamino group, butyl Carbonylamino group, isobutylcarbonylamino group, sec-butylcarbonylamino group, tert-butylcarbonylamino group, pentylcarbonylamino group, isopentylcarbonylamino group, neopentylcarbonylamino group, hexylcarbonylamino group, heptylcarbonylamino group, octyl carbonylamino group, nonyl carbonylamino group, 1,1-dimethyl - propyl carbonylamino group, etc.), C 6-10 aryl - carbonyl amino group (e.g., benzoylamino group, etc. Etc. The.
　本明細書中、「含窒素複素環基」とは、上記で定義した「含窒素非芳香族複素環基」、および環中に窒素原子を有する上記で定義した「ヘテロアリール基」のことをいう。炭素数２～８の含窒素複素環基が好ましく、より好ましくは、ピロリジニル基、ピペリジニル基、ホモピペリジニル基、モルホリニル基、チオモルホリニル基、ピペラジニル基、ピロリニル基、イミダゾリル基、ピリジル基、ピロリル基であり、より好ましくはピロリジニル基、ピペリジニル基、モルホリニル基、チオモルホリニル基、ピペラジニル基である。 In the present specification, the “nitrogen-containing heterocyclic group” refers to the “nitrogen-containing non-aromatic heterocyclic group” defined above and the “heteroaryl group” defined above having a nitrogen atom in the ring. Say. A nitrogen-containing heterocyclic group having 2 to 8 carbon atoms is preferred, more preferably a pyrrolidinyl group, piperidinyl group, homopiperidinyl group, morpholinyl group, thiomorpholinyl group, piperazinyl group, pyrrolinyl group, imidazolyl group, pyridyl group, pyrrolyl group, More preferred are pyrrolidinyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, and piperazinyl group.
　本明細書中の「アルキルアミノ基」、あるいは「アルキル基で置換された、カルバモイルまたはチオカルバモイル（置換基を有していてもよい、カルバモイル基、チオカルバモイル基、カルバモイルオキシ基、チオカルバモイルオキシ基などにおいて、置換基がアルキル基である場合も含む）」等の成分としてのアルキルアミノ部分には、モノアルキルアミノ基もジアルキルアミノ基も含まれる。ジアルキルアミノ基においては、該アルキル基は結合して環（例えば、上記含窒素複素環基の含窒素複素環等）を形成していてもよい。 The “alkylamino group” in this specification, or “carbamoyl or thiocarbamoyl substituted with an alkyl group (which may have a substituent, carbamoyl group, thiocarbamoyl group, carbamoyloxy group, thiocarbamoyloxy group) The alkylamino moiety as a component such as “in which the substituent is an alkyl group” includes a monoalkylamino group and a dialkylamino group. In the dialkylamino group, the alkyl group may be bonded to form a ring (for example, a nitrogen-containing heterocycle of the nitrogen-containing heterocyclic group).
　本明細書中の「アミジノ基」とは、Ｈ２Ｎ－Ｃ（＝ＮＨ）－で表される基のことをいう。 The “amidino group” in the present specification refers to a group represented by H 2 N—C (═NH) —.
　本明細書中、「置換基を有してもよい」各置換基における「置換基」としては、例えば、
（１）ハロゲン原子、
（２）ヒドロキシ基、
（３）アミノ基、
（４）Ｃ１－１０アルキル基、
（５）Ｃ２－１０アルケニル基、
（６）Ｃ２－１０アルキニル基、
（７）Ｃ１－１０アルコキシ基、
（８）Ｃ１－１０アルキルアミノ基、
（９）シアノ基、
（１０）グアニジノ基、
（１１）カルボキシル基、
（１２）カルバモイル基、
（１３）Ｃ６－１４アリール基、
（１４）ヘテロアリール基、
（１５）Ｃ３－１０シクロアルキル基、
（１６）含窒素非芳香族複素環基、
（１７）Ｃ１－１０アルキルチオ基、
（１８）アシルオキシ基、
（１９）アシルアミノ基、
（２０）Ｃ１－１０アルキルスルホンアミド基、
（２１）Ｃ１－１０アルコキシ－カルボニル基、
等が挙げられる。 In the present specification, as the “substituent” in each substituent “which may have a substituent”, for example,
(1) a halogen atom,
(2) a hydroxy group,
(3) an amino group,
(4) a C 1-10 alkyl group,
(5) C 2-10 alkenyl group,
(6) a C 2-10 alkynyl group,
(7) a C 1-10 alkoxy group,
(8) a C 1-10 alkylamino group,
(9) a cyano group,
(10) a guanidino group,
(11) a carboxyl group,
(12) a carbamoyl group,
(13) a C 6-14 aryl group,
(14) a heteroaryl group,
(15) a C 3-10 cycloalkyl group,
(16) a nitrogen-containing non-aromatic heterocyclic group,
(17) a C 1-10 alkylthio group,
(18) an acyloxy group,
(19) an acylamino group,
(20) a C 1-10 alkylsulfonamido group,
(21) a C 1-10 alkoxy-carbonyl group,
Etc.
　当該「置換基」として、好ましくは、
（１）ハロゲン原子、
（２）ヒドロキシ基、
（３）アミノ基、
（４）Ｃ１－６アルキル基、
（５）Ｃ２－６アルケニル基、
（６）Ｃ２－６アルキニル基、
（７）Ｃ１－６アルコキシ基、
（８）Ｃ１－６アルキルアミノ基、
（９）シアノ基、
（１０）グアニジノ基、
（１１）カルボキシル基、
（１２）カルバモイル基、
（１３）アシルアミノ基、
（１４）Ｃ３－８シクロアルキル基、
（１５）Ｃ１－６アルキルチオ基、
（１６）アシルオキシ基、
（１７）Ｃ１－６アルキルスルホンアミド基、
（１８）Ｃ１－１０アルコキシ－カルボニル基である。 As the “substituent”, preferably
(1) a halogen atom,
(2) a hydroxy group,
(3) an amino group,
(4) a C 1-6 alkyl group,
(5) a C 2-6 alkenyl group,
(6) a C 2-6 alkynyl group,
(7) a C 1-6 alkoxy group,
(8) a C 1-6 alkylamino group,
(9) a cyano group,
(10) a guanidino group,
(11) a carboxyl group,
(12) a carbamoyl group,
(13) an acylamino group,
(14) a C 3-8 cycloalkyl group,
(15) a C 1-6 alkylthio group,
(16) an acyloxy group,
(17) a C 1-6 alkylsulfonamido group,
(18) a C 1-10 alkoxy-carbonyl group.
　置換基の数および位置に特に限定はない。 There is no particular limitation on the number and position of substituents.
　また、本発明の化合物（１）、化合物（２）、化合物（３）、化合物（４）および化合物（５）には、幾何異性体、互変異性体、光学異性体などの各種立体異性体およびその混合物や単離されたものが含まれる。 In addition, compound (1), compound (2), compound (3), compound (4) and compound (5) of the present invention include various stereoisomers such as geometric isomers, tautomers and optical isomers. And mixtures thereof and isolated ones.
　化合物（１）におけるＸとしては、ハロゲン原子であり、好ましくは塩素原子である。 X in the compound (1) is a halogen atom, preferably a chlorine atom.
　化合物（１）、化合物（２）、化合物（４）および化合物（５）における環Ａで表される基としては、Ｃ６－１４アリール基、ヘテロアリール基、含窒素非芳香族複素環基またはＣ３－１０シクロアルキル基であり、好ましくはＣ６－１４アリール基であり、フェニル基が特に好ましい。また環Ａ上の置換基Ｖ、Ｗおよびカルボニル基の位置は、環Ａ上の置換可能な位置であれば、特に限定はないが、環Ａがフェニル基の場合、カルボニル基の置換位置を１位とした場合に、Ｗは４位であることが望ましい。 Examples of the group represented by ring A in compound (1), compound (2), compound (4) and compound (5) include a C 6-14 aryl group, a heteroaryl group, a nitrogen-containing non-aromatic heterocyclic group or A C 3-10 cycloalkyl group, preferably a C 6-14 aryl group, and particularly preferably a phenyl group. The positions of the substituents V and W on the ring A and the carbonyl group are not particularly limited as long as they are substitutable positions on the ring A. However, when the ring A is a phenyl group, the substitution position of the carbonyl group is 1 In the case of W, W is preferably 4th.
　化合物（１）、化合物（２）、化合物（４）および化合物（５）におけるＶとしては、水素原子、ハロゲン原子、置換基を有していてもよいＣ１－１０アルキル基、置換基を有していてもよいＣ１－１０アルコキシ基、置換基を有していてもよいＣ１－１０アルキルアミノ基、置換基を有していてもよいＣ１－１０アルキルチオ基、シアノ基、ニトロ基、または置換基を有していてもよいカルバモイル基であり、好ましくは水素原子である。 V in the compound (1), the compound (2), the compound (4) and the compound (5) is a hydrogen atom, a halogen atom, a C 1-10 alkyl group which may have a substituent, or a substituent. An optionally substituted C 1-10 alkoxy group, an optionally substituted C 1-10 alkylamino group, an optionally substituted C 1-10 alkylthio group, a cyano group, a nitro group Or a carbamoyl group optionally having a substituent, preferably a hydrogen atom.
　化合物（１）、化合物（２）、化合物（４）および化合物（５）におけるＷとしては、へテロアリール基、あるいは下記式（Ａ）、（Ｂ）または（Ｃ） As W in compound (1), compound (2), compound (4) and compound (5), heteroaryl group, or the following formula (A), (B) or (C)
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
［式中、
　Ｑは、Ｃ１－６アルキル基、置換基を有していてもよいアミノ基または窒素原子に結合手を有する含窒素複素環基を表し、
　Ｒは、Ｃ１－６アルキル基を表し、
　ｍは、１～３の整数を表し、
　環Ｃは、含窒素複素環基を表し、
　Ｙは、窒素原子、酸素原子、硫黄原子またはメチレン基のいずれかを表し、
　Ｚは、水素原子、Ｃ１－６アルキルで置換されていてもよいアミジノ基、あるいは１位にイミノを有してもよいＣ１－６アルキル基を表す］
で表される基である。環Ｃ上の置換基ＺおよびＹの位置は、環Ｃ上の置換可能な位置であれば、特に限定はない。Ｗとして好ましくは式（Ａ） [Where:
Q represents a C 1-6 alkyl group, an optionally substituted amino group or a nitrogen-containing heterocyclic group having a bond to the nitrogen atom,
R represents a C 1-6 alkyl group,
m represents an integer of 1 to 3,
Ring C represents a nitrogen-containing heterocyclic group,
Y represents any of a nitrogen atom, an oxygen atom, a sulfur atom or a methylene group,
Z represents a hydrogen atom, an amidino group which may be substituted with C 1-6 alkyl, or a C 1-6 alkyl group which may have imino at the 1-position]
It is group represented by these. The positions of the substituents Z and Y on the ring C are not particularly limited as long as they can be substituted on the ring C. W is preferably a formula (A)
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
（式中、Ｑは、窒素原子に結合手を有する含窒素非芳香族複素環基である）で表される基であり、より好ましくはイミノ（ピロリジン－１－イル）メチル基である。 (Wherein Q is a nitrogen-containing non-aromatic heterocyclic group having a bond at the nitrogen atom), and more preferably an imino (pyrrolidin-1-yl) methyl group.
　化合物（３）および化合物（４）における環Ｂで表される基としては、Ｃ６－１４アリール基、ヘテロアリール基、含窒素非芳香族複素環基またはＣ３－１０シクロアルキル基であり、好ましくはＣ６－１４アリール基であり、特に好ましくはフェニル基である。環Ｂ上の置換基Ｔ、Ｌおよびアミジノ基の位置は、環Ｂ上の置換可能な位置であれば特に限定はないが、環Ｂがフェニル基の場合であって、アミジノ基の置換位置を１位とした場合に、Ｔは４位であることが望ましく、またＬが３位であることが望ましい。 In the compounds (3) and (4), the group represented by ring B is a C 6-14 aryl group, a heteroaryl group, a nitrogen-containing non-aromatic heterocyclic group or a C 3-10 cycloalkyl group, A C 6-14 aryl group is preferred, and a phenyl group is particularly preferred. The position of the substituents T, L and amidino group on ring B is not particularly limited as long as it is a substitutable position on ring B, but ring B is a phenyl group, and the position of substitution of the amidino group is In the first position, T is preferably the 4th position, and L is preferably the 3rd position.
　化合物（３）および化合物（４）におけるＴとしては、水素原子、ハロゲン原子、ヒドロキシ基、置換基を有していてもよいＣ１－１０アルコキシ基、置換基を有していてもよいアシルオキシ基、置換基を有していてもよいカルバモイルオキシ基、置換基を有していてもよいチオカルバモイルオキシ基、アミノ基、シアノ基、ニトロ基、置換基を有していてもよいＣ１－１０アルキル基、置換基を有していてもよいＣ１－１０アルキルアミノ基、置換基を有していてもよいＣ１－１０アルキルチオ基、置換基を有していてもよいアシルアミノ基、カルボキシル基、置換基を有していてもよいＣ１－１０アルコキシ－カルボニル基、置換基を有していてもよいカルバモイル基、または置換基を有していてもよいチオカルバモイル基であり、好ましくは水素原子、ヒドロキシ基、メトキシ基、エトキシ基、プロポキシ基、イソブトキシ基、２－ヒドロキシエトキシ基、シアノメトキシ基、カルボキシメトキシ基、２－シアノエチル基、２－カルボキシエチル基、ジメチルチオカルバモイル基、シクロプロピルメトキシ基、１－ピロリジニルエトキシ基、アミノエチル基、アセチルアミノエチル基、アシルオキシ基、ジメチルカルバモイル基、１－ピロリジニルカルボニル基であり、より好ましくは水素原子、ヒドロキシ基、メトキシ基、エトキシ基、プロポキシ基、イソブトキシ基、２－ヒドロキシエトキシ基、シアノメトキシ基、カルボキシメトキシ基、２－シアノエチル基、２－カルボキシエチル基であり、特に好ましくは、水素原子、ヒドロキシ基、メトキシ基、エトキシ基、イソブトキシ基、シアノメトキシ基である。 As T in the compound (3) and the compound (4), a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted C 1-10 alkoxy group, and an optionally substituted acyloxy group A carbamoyloxy group which may have a substituent, a thiocarbamoyloxy group which may have a substituent, an amino group, a cyano group, a nitro group, or a C 1-10 which may have a substituent An alkyl group, an optionally substituted C 1-10 alkylamino group, an optionally substituted C 1-10 alkylthio group, an optionally substituted acylamino group, a carboxyl group , which may have a substituent C 1-10 alkoxy - carbonyl group, which may have a substituent carbamoyl group or an optionally substituted thiocarbamoyl group, Preferably, a hydrogen atom, hydroxy group, methoxy group, ethoxy group, propoxy group, isobutoxy group, 2-hydroxyethoxy group, cyanomethoxy group, carboxymethoxy group, 2-cyanoethyl group, 2-carboxyethyl group, dimethylthiocarbamoyl group , Cyclopropylmethoxy group, 1-pyrrolidinylethoxy group, aminoethyl group, acetylaminoethyl group, acyloxy group, dimethylcarbamoyl group, 1-pyrrolidinylcarbonyl group, more preferably hydrogen atom, hydroxy group, methoxy group Group, ethoxy group, propoxy group, isobutoxy group, 2-hydroxyethoxy group, cyanomethoxy group, carboxymethoxy group, 2-cyanoethyl group, 2-carboxyethyl group, particularly preferably hydrogen atom, hydroxy group, methoxy group Ethoxy group, An isobutoxy group and a cyanomethoxy group.
　化合物（３）および化合物（４）におけるＵとしては、水素原子、置換基を有していてもよいＣ１－１０アルキル基、カルボキシル基、置換基を有していてもよいＣ１－１０アルコキシ－カルボニル基、または置換基を有していてもよいカルバモイル基であり、好ましくは、水素原子またはＣ１－１０アルキル基であり、より好ましくは水素原子である。 U in the compounds (3) and (4) is a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a carboxyl group, or a C 1-10 alkoxy which may have a substituent. -A carbonyl group or an optionally substituted carbamoyl group, preferably a hydrogen atom or a C 1-10 alkyl group, more preferably a hydrogen atom.
　化合物（３）および化合物（４）におけるＬとしては、窒素原子（－ＮＨ－）、酸素原子（－Ｏ－）、硫黄原子（－Ｓ－）またはメチレン基（－ＣＨ２－）であり、好ましくは窒素原子、酸素原子、硫黄原子であり、より好ましくは酸素原子、硫黄原子であり、特に好ましくは酸素原子である。 L in the compounds (3) and (4) is a nitrogen atom (—NH—), an oxygen atom (—O—), a sulfur atom (—S—) or a methylene group (—CH 2 —), preferably Is a nitrogen atom, an oxygen atom, or a sulfur atom, more preferably an oxygen atom or a sulfur atom, and particularly preferably an oxygen atom.
　化合物（３）および化合物（４）におけるｎとしては、１～３の整数であり、１または２が好ましく、１がより好ましい。 N in the compound (3) and the compound (4) is an integer of 1 to 3, preferably 1 or 2, and more preferably 1.
　本発明においては、上記各置換基の説明に記載されている、好ましい基の組み合わせからなる化合物（１）～（５）が好適である。以下、本発明の製造方法における各化合物（１）～（５）について具体的に説明する。 In the present invention, compounds (1) to (5) comprising a combination of preferable groups described in the description of each substituent are preferable. Hereinafter, each of the compounds (1) to (5) in the production method of the present invention will be specifically described.
１．化合物（１）
　本発明の製造方法における化合物（１）は、式（１） 1. Compound (1)
The compound (1) in the production method of the present invention has the formula (1)
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
（式中、
　環Ａは、Ｃ６－１４アリール基、ヘテロアリール基、含窒素非芳香族複素環基またはＣ３－１０シクロアルキル基を表し、
　Ｖは、水素原子、ハロゲン原子、置換基を有していてもよいＣ１－１０アルキル基、置換基を有していてもよいＣ１－１０アルコキシ基、置換基を有していてもよいＣ１－１０アルキルアミノ基、置換基を有していてもよいＣ１－１０アルキルチオ基、シアノ基、ニトロ基または置換基を有していてもよいカルバモイル基を表し、
　Ｗは、へテロアリール基、あるいは下記式（Ａ）、（Ｂ）または（Ｃ） (Where
Ring A represents a C 6-14 aryl group, a heteroaryl group, a nitrogen-containing non-aromatic heterocyclic group or a C 3-10 cycloalkyl group,
V represents a hydrogen atom, a halogen atom, a C 1-10 alkyl group which may have a substituent, a C 1-10 alkoxy group which may have a substituent, or a substituent. A C 1-10 alkylamino group, an optionally substituted C 1-10 alkylthio group, a cyano group, a nitro group or an optionally substituted carbamoyl group;
W is a heteroaryl group, or the following formula (A), (B) or (C)
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
［式中、
　Ｑは、Ｃ１－６アルキル基、置換基を有していてもよいアミノ基または窒素原子に結合手を有する含窒素複素環基を表し、
　Ｒは、Ｃ１－６アルキル基を表し、
　ｍは、１～３の整数を表し、
　環Ｃは、含窒素複素環基を表し、
　Ｙは、窒素原子、酸素原子、硫黄原子またはメチレン基のいずれかを表し、
　Ｚは、水素原子、Ｃ１－６アルキルで置換されていてもよいアミジノ基、あるいは１位にイミノを有してもよいＣ１－６アルキル基を表す］
で表される基を示し、そして
　Ｘは、ハロゲン原子を示す）
で表される酸ハロゲン化物である。 [Where:
Q represents a C 1-6 alkyl group, an optionally substituted amino group or a nitrogen-containing heterocyclic group having a bond to the nitrogen atom,
R represents a C 1-6 alkyl group,
m represents an integer of 1 to 3,
Ring C represents a nitrogen-containing heterocyclic group,
Y represents any of a nitrogen atom, an oxygen atom, a sulfur atom or a methylene group,
Z represents a hydrogen atom, an amidino group which may be substituted with C 1-6 alkyl, or a C 1-6 alkyl group which may have imino at the 1-position]
And X represents a halogen atom)
It is an acid halide represented by.
　化合物（１）は、後述する化合物（３）と容易に縮合して、後述する化合物（４）を形成せしめる。 Compound (1) easily condenses with compound (3) described later to form compound (4) described later.
　環Ａ上の置換基Ｖ、Ｗおよびカルボニル基の位置は、環Ａ上の置換可能な位置であれば、特に限定はないが、環Ａがフェニル基の場合であって、カルボニル基の置換位置を１位とした場合に、Ｗは４位であることが望ましい。
　化合物（１）として好ましくは、環ＡがＣ６－１４アリール基であり、Ｖが水素原子であり、Ｗが式（Ａ） The positions of the substituents V, W and the carbonyl group on the ring A are not particularly limited as long as they are substitutable positions on the ring A. However, when the ring A is a phenyl group, W is preferably the 4th place where is the 1st place.
As the compound (1), ring A is preferably a C 6-14 aryl group, V is a hydrogen atom, and W is represented by the formula (A)
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
（式中、Ｑは、窒素原子に結合手を有する含窒素非芳香族複素環基である）で表される基を示し、そしてＸがハロゲン原子である化合物であり、より好ましくは、環Ａがフェニル基であり、Ｖが水素原子であり、Ｗがイミノ（ピロリジン－１－イル）メチル基（Ｑがピロリジン－１－イル基を示す）であり、そしてＸが塩素原子である化合物であり、特に好ましくは、４－［イミノ（ピロリジン－１－イル）メチル］安息香酸クロリドである。
　なお化合物（１）として例示した上記４－［イミノ（ピロリジン－１－イル）メチル］安息香酸クロリドは、新規化合物である。当該化合物を、本発明の製造方法に適用する化合物（１）として好ましく用いることができる。 (Wherein Q is a nitrogen-containing non-aromatic heterocyclic group having a bond to the nitrogen atom), and X is a halogen atom, more preferably ring A A compound in which is a phenyl group, V is a hydrogen atom, W is an imino (pyrrolidin-1-yl) methyl group (Q represents a pyrrolidin-1-yl group), and X is a chlorine atom Particularly preferred is 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid chloride.
The 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid chloride exemplified as the compound (1) is a novel compound. The said compound can be preferably used as a compound (1) applied to the manufacturing method of this invention.
　化合物（１）が塩の形態を成し得る場合、その塩は化学的に許容しうる塩であればよく、例えば、式中にカルボキシル基等の酸性基が存在する場合の酸性基に対しては、アンモニウム塩、ナトリウム、カリウム等のアルカリ金属との塩、カルシウム、マグネシウム等のアルカリ土類金属との塩、アルミニウム塩、亜鉛塩、トリエチルアミン、エタノールアミン、モルホリン、ピペリジン、ジシクロへキシルアミン等の有機アミンとの塩、アルギニン、リジン等の塩基性アミノ酸との塩を挙げることができる。 When compound (1) can be in the form of a salt, the salt may be a chemically acceptable salt. For example, for an acidic group when an acidic group such as a carboxyl group is present in the formula, Organic salts such as ammonium salts, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, aluminum salts, zinc salts, triethylamine, ethanolamine, morpholine, piperidine, dicyclohexylamine Examples thereof include salts with amines and salts with basic amino acids such as arginine and lysine.
　また式中に塩基性基が存在する場合の塩基性基に対しては、塩酸、硫酸、リン酸、硝酸、臭化水素酸、フッ化水素酸、ヨウ化水素酸などの無機酸との塩、酢酸、トリフルオロ酢酸（ＴＦＡ）、クエン酸、安息香酸、マレイン酸、フマル酸、酒石酸、コハク酸、タンニン酸、酪酸、ヒベンズ酸、パモ酸、エナント酸、デカン酸、テオクル酸、サリチル酸、乳酸、シュウ酸、マンデル酸、リンゴ酸等の有機カルボン酸との塩、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸等の有機スルホン酸との塩を挙げることができる。塩を形成する方法としては、化合物（１）と必要な酸または塩基とを適当な量比で溶媒、分散剤中で混合することや、他の塩の形より陽イオン交換または陰イオン交換を行うことによっても得られる。 In addition, when a basic group is present in the formula, for a basic group, a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, etc. , Acetic acid, trifluoroacetic acid (TFA), citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, tannic acid, butyric acid, hibenzic acid, pamoic acid, enanthic acid, decanoic acid, teocric acid, salicylic acid, lactic acid And salts with organic carboxylic acids such as oxalic acid, mandelic acid and malic acid, and salts with organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. As a method of forming a salt, the compound (1) and a necessary acid or base are mixed in an appropriate amount ratio in a solvent or a dispersant, or cation exchange or anion exchange is carried out from other salt forms. It can also be obtained by doing.
　特に化合物（１）のＷが塩基性基である場合、化合物（１）は、強酸（例えば、フッ化水素酸、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸など）との塩を好ましく形成することができる。ここで強酸として好ましくは、塩酸である。 In particular, when W of compound (1) is a basic group, compound (1) is a salt with a strong acid (for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, etc.) Can be preferably formed. Here, hydrochloric acid is preferable as the strong acid.
　化合物（１）としては、化合物（１）の溶媒和物も含んでいる。 Compound (1) includes a solvate of compound (1).
　化合物（１）は、後述する化合物（２）に酸ハロゲン化剤を反応させることにより得られるほか、自体公知の方法を適用して製造することが可能である。 Compound (1) can be obtained by reacting compound (2) described later with an acid halogenating agent, or can be produced by applying a method known per se.
　化合物（２）に酸ハロゲン化剤を反応させて化合物（１）を製造する場合、適用する酸ハロゲン化剤としては、一般的に市販され、酸ハロゲン化反応に使用される試薬であればいずれの酸ハロゲン化剤でも用いることができ、このような酸ハロゲン化剤としては、塩化チオニル、塩化オキサリル、五塩化リン、塩化ホスホリル、ジクロロトリフェニルホスホラン、臭化チオニル、ジブロモトリフェニルホスホラン、フッ化シアヌル（ＤＡＳＴ）などが挙げられる。好ましい酸ハロゲン化剤は、塩化チオニルである。また酸ハロゲン化反応は特に触媒を加えなくても進行するが、定法に従って、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、Ｎ－メチル－２－ピロリドン（ＮＭＰ）などのアミド系試薬、或いは、１，３－ジメチル－２－イミダゾリジノン（ＤＭＩ）などのイミド系試薬を触媒量から溶媒量まで加えることもできる。また酸ハロゲン化反応は特に溶媒を加えなくても進行するが、必要に応じて一般的に市販され、かつ酸ハロゲン化反応などに使用することができる有機溶媒を用いることもできる。なお、この有機溶媒には上記のアミド或いはイミド系試薬も含むことができる。有機溶媒を使用しない場合、酸ハロゲン化剤の使用量は、化合物（２）１モルに対して１モル～７モル、好ましくは１．７モル～３．５モルである。反応時間は通常１～１０時間であり、好ましくは２～３時間である。また反応温度は通常－４０℃～２００℃であり、好ましくは７０℃～９０℃である。一方、有機溶媒を使用した場合、酸ハロゲン化剤の使用量は化合物（２）１モルに対して、１～３モル、好ましくは１．０～１．２モルである。反応時間は１０分～１０時間であり、好ましくは１～２時間である。また、反応温度は通常－４０℃から２００℃であり、好ましくは０～２０℃である。 When the compound (1) is produced by reacting the compound (2) with an acid halogenating agent, the acid halogenating agent to be applied is any commercially available reagent that can be used for the acid halogenation reaction. The acid halogenating agent can be used, and as such an acid halogenating agent, thionyl chloride, oxalyl chloride, phosphorus pentachloride, phosphoryl chloride, dichlorotriphenylphosphorane, thionyl bromide, dibromotriphenylphosphorane, Examples include cyanuric fluoride (DAST). A preferred acid halogenating agent is thionyl chloride. In addition, the acid halogenation reaction proceeds without adding a catalyst, but according to a conventional method, an amide-based reagent such as N, N-dimethylformamide (DMF) or N-methyl-2-pyrrolidone (NMP), or 1, An imide-based reagent such as 3-dimethyl-2-imidazolidinone (DMI) can be added from a catalytic amount to a solvent amount. The acid halogenation reaction proceeds even without adding a solvent, but an organic solvent that is generally commercially available and can be used for an acid halogenation reaction or the like can also be used as necessary. The organic solvent can also contain the above amide or imide reagent. When no organic solvent is used, the amount of the acid halogenating agent used is 1 mol to 7 mol, preferably 1.7 mol to 3.5 mol, per 1 mol of compound (2). The reaction time is usually 1 to 10 hours, preferably 2 to 3 hours. The reaction temperature is usually −40 ° C. to 200 ° C., preferably 70 ° C. to 90 ° C. On the other hand, when an organic solvent is used, the amount of the acid halogenating agent to be used is 1 to 3 mol, preferably 1.0 to 1.2 mol, per 1 mol of compound (2). The reaction time is 10 minutes to 10 hours, preferably 1 to 2 hours. The reaction temperature is usually −40 ° C. to 200 ° C., preferably 0 to 20 ° C.
　また化合物（１）は、後述するように単離しなくても本発明の製造方法に適用することが可能であるが、単離が必要な場合は、化合物（２）の酸ハロゲン化反応物を含む溶液に貧溶媒を加えることで固体として析出させ、一般的な固液分離方法によって単離することができる。 Further, the compound (1) can be applied to the production method of the present invention without isolation as described later. However, when isolation is necessary, the acid halogenated reaction product of the compound (2) is used. By adding a poor solvent to the solution containing it, it precipitates as a solid and can be isolated by a general solid-liquid separation method.
　また、化合物（１）またはその塩のうち、化合物（１’）またはその塩は、新規化合物である。 In addition, compound (1 ') or a salt thereof among compound (1) or a salt thereof is a novel compound.
　化合物（１’）は、化合物（１）と同様に塩の形態をなし得るが、その場合の塩としては、化学的に許容される塩であればよい。化学的に許容される塩としては、化合物（１）において上記した塩が例示されるが、なかでも強酸（例えば、フッ化水素酸、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸など）との塩が好ましい。強酸として好ましくは、塩酸である。 Compound (1 ') can be in the form of a salt as with Compound (1), but the salt in that case may be a chemically acceptable salt. Examples of the chemically acceptable salt include those described above for the compound (1), among which strong acids (for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid) Etc.) are preferred. A strong acid is preferably hydrochloric acid.
　化合物（１’）のなかでも、４－［イミノ（ピロリジン－１－イル）メチル］安息香酸ハライド（酸ハライドとしては、酸クロリド、酸ブロミド、酸ヨージドなどが挙げられる）またはその強酸との塩を、特に好ましい化合物として挙げることができる。すなわち化合物（１）の合成中間体として最も好ましいものは、４－［イミノ（ピロリジン－１－イル）メチル］安息香酸クロリドまたはその塩酸塩である。 Among the compounds (1 ′), 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid halide (acid halides include acid chloride, acid bromide, acid iodide, etc.) or a salt thereof with a strong acid Can be mentioned as particularly preferred compounds. That is, the most preferred synthetic intermediate for compound (1) is 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid chloride or its hydrochloride.
２．化合物（２）
　本発明の製造方法における化合物（２）は、式（２） 2. Compound (2)
The compound (2) in the production method of the present invention has the formula (2)
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
（式中、各記号は、上記化合物（１）で記載したものと同じである）
で表されるカルボキシル基を有する化合物である。 (In the formula, each symbol is the same as described in the above compound (1)).
It is a compound which has the carboxyl group represented by these.
　化合物（２）は、カルボキシル基部分で前記した酸ハロゲン化剤と反応して、化合物（１）を形成せしめる。 Compound (2) reacts with the acid halogenating agent described above at the carboxyl group portion to form Compound (1).
　環Ａ上の置換基Ｖ、Ｗおよびカルボニル基の位置は、環Ａ上の置換可能な位置であれば、特に限定はないが、環Ａがフェニル基の場合、カルボニル基の置換位置を１位とした場合に、Ｗは４位であることが望ましい。 The position of the substituents V, W and the carbonyl group on ring A is not particularly limited as long as it is a substitutable position on ring A, but when ring A is a phenyl group, the position of substitution of the carbonyl group is the 1st position. In this case, W is preferably fourth.
　化合物（２）として好ましくは、環ＡがＣ６－１４アリール基であり、Ｖが水素原子であり、Ｗが式（Ａ） As the compound (2), ring A is preferably a C 6-14 aryl group, V is a hydrogen atom, and W is represented by the formula (A)
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
（式中、Ｑは、窒素原子に結合手を有する含窒素非芳香族複素環基である）で表される基を示す化合物であり、より好ましくは、環Ａがフェニル基であり、Ｖが水素原子であり、そしてＷがイミノ（ピロリジン－１－イル）メチル基（この場合のＱは、ピロリジン－１－イル基である）を示すような化合物であり、特に好ましくは、４－［イミノ（ピロリジン－１－イル）メチル］安息香酸である。 (Wherein Q is a nitrogen-containing non-aromatic heterocyclic group having a bond to the nitrogen atom), more preferably, ring A is a phenyl group, and V is A compound which is a hydrogen atom and W represents an imino (pyrrolidin-1-yl) methyl group (in this case, Q is a pyrrolidin-1-yl group), particularly preferably 4- [imino (Pyrrolidin-1-yl) methyl] benzoic acid.
　化合物（２）が塩の形態を成し得る場合、その塩は化学的に許容しうる塩であればよく、例えば、式中にカルボキシル基等の酸性基が存在する場合の酸性基に対しては、アンモニウム塩、ナトリウム、カリウム等のアルカリ金属との塩、カルシウム、マグネシウム等のアルカリ土類金属との塩、アルミニウム塩、亜鉛塩、トリエチルアミン、エタノールアミン、モルホリン、ピペリジン、ジシクロへキシルアミン等の有機アミンとの塩、アルギニン、リジン等の塩基性アミノ酸との塩を挙げることができる。 When compound (2) can be in the form of a salt, the salt may be a chemically acceptable salt. For example, for an acidic group when an acidic group such as a carboxyl group is present in the formula, Organic salts such as ammonium salts, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, aluminum salts, zinc salts, triethylamine, ethanolamine, morpholine, piperidine, dicyclohexylamine Examples thereof include salts with amines and salts with basic amino acids such as arginine and lysine.
　また式中に塩基性基が存在する場合の塩基性基に対しては、塩酸、硫酸、リン酸、硝酸、臭化水素酸、フッ化水素酸、ヨウ化水素酸などの無機酸との塩、酢酸、トリフルオロ酢酸（ＴＦＡ）、クエン酸、安息香酸、マレイン酸、フマル酸、酒石酸、コハク酸、タンニン酸、酪酸、ヒベンズ酸、パモ酸、エナント酸、デカン酸、テオクル酸、サリチル酸、乳酸、シュウ酸、マンデル酸、リンゴ酸等の有機カルボン酸との塩、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸等の有機スルホン酸との塩を挙げることができる。塩を形成する方法としては、化合物（２）と必要な酸または塩基とを適当な量比で溶媒、分散剤中で混合することや、他の塩の形より陽イオン交換または陰イオン交換を行うことによっても得られる。 In addition, when a basic group is present in the formula, for a basic group, a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, etc. , Acetic acid, trifluoroacetic acid (TFA), citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, tannic acid, butyric acid, hibenzic acid, pamoic acid, enanthic acid, decanoic acid, teocric acid, salicylic acid, lactic acid And salts with organic carboxylic acids such as oxalic acid, mandelic acid and malic acid, and salts with organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. As a method of forming a salt, the compound (2) and a necessary acid or base are mixed in an appropriate amount ratio in a solvent or a dispersant, or cation exchange or anion exchange is carried out from other salt forms. It can also be obtained by doing.
　特に化合物（２）のＷが塩基性基を示す場合、化合物（２）は、強酸（例えば、フッ化水素酸、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸など）との塩を好ましく形成することができる。ここで強酸として好ましくは、塩酸である。 In particular, when W of compound (2) represents a basic group, compound (2) is a salt with a strong acid (for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, etc.) Can be preferably formed. Here, hydrochloric acid is preferable as the strong acid.
　化合物（２）としては、化合物（２）の溶媒和物、例えば水和物、アルコール付加物等も含んでいる。 Compound (2) includes solvates of compound (2), such as hydrates and alcohol adducts.
　化合物（２）は、自体公知の方法を適用して製造することが可能である。特に化合物（２）のうち、環ＡがＣ６－１４アリール基であり、Ｗが式（Ａ）で表される基である化合物は、例えば以下の方法で製造することができる。 Compound (2) can be produced by a method known per se. In particular, among compounds (2), a compound in which ring A is a C 6-14 aryl group and W is a group represented by formula (A) can be produced, for example, by the following method.
　当該化合物（２）の製造方法のうち、４－［イミノ（ピロリジン－１－イル）メチル］安息香酸の製造方法について例示する。当該アミジン誘導体の合成は、国際公開ＷＯ１９９８／３１６６１パンフレット、国際公開ＷＯ１９９９／４７５０３パンフレットおよび国際公開ＷＯ２００６／０８３００３パンフレットを参考に、４－シアノ安息香酸から合成することができる。 Among the methods for producing the compound (2), a method for producing 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid is exemplified. The amidine derivative can be synthesized from 4-cyanobenzoic acid with reference to International Publication WO1998 / 31661, International Publication WO1999 / 47503 and International Publication WO2006 / 083003.
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
　また、４－［イミノ（ピロリジン－１－イル）メチル］安息香酸は、４－シアノ安息香酸メチルから、以下の方法によっても合成することができる。 4- [Imino (pyrrolidin-1-yl) methyl] benzoic acid can also be synthesized from methyl 4-cyanobenzoate by the following method.
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
　この方法では、４－［イミノ（ピロリジン－１－イル）メチル］安息香酸を途中の中間体化合物を単離することなく合成することが可能である。なおこの方法で得られる中間体化合物である、４－［イミノ（ピロリジン－１－イル）メチル］安息香酸メチルは新規化合物である。この化合物は、化合物（５）としても取り扱うことができる。なお上記製造方法は例示であり、化合物（２）の製造方法はこれらの方法に限定されるわけではなく、当業者であれば適宜合成ルートを設計して化合物（２）を製造することが可能である。 In this method, 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid can be synthesized without isolating intermediate compounds on the way. The intermediate compound obtained by this method, methyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate, is a novel compound. This compound can also be handled as compound (5). In addition, the said manufacturing method is an illustration, The manufacturing method of a compound (2) is not necessarily limited to these methods, and those skilled in the art can design a synthetic route suitably and can manufacture a compound (2). It is.
３．化合物（５）
　本発明の製造方法における化合物（５）は、式（５） 3. Compound (5)
The compound (5) in the production method of the present invention has the formula (5)
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
（式中、Ｒ’’は、置換基を有していてもよいＣ１－１０アルキル基であり、その他の各記号は、上記化合物（１）で記載したものと同じである）
で表されるエステル化合物である。 (Wherein R ″ is an optionally substituted C 1-10 alkyl group, and other symbols are the same as those described for compound (1) above)
It is an ester compound represented by these.
　化合物（５）は、後述する化合物（３）とのエステル交換反応を経て、後述する化合物（４）を形成せしめる。 Compound (5) undergoes a transesterification reaction with Compound (3) described later to form Compound (4) described later.
　環Ａ上の置換基Ｖ、Ｗおよびアルコキシカルボニル基の位置は、環Ａ上の置換可能な位置であれば、特に限定はないが、環Ａがフェニル基の場合、アルコキシカルボニル基の置換位置を１位とした場合に、Ｗは４位であることが望ましい。 The positions of the substituents V and W on the ring A and the alkoxycarbonyl group are not particularly limited as long as they are substitutable positions on the ring A. However, when the ring A is a phenyl group, the position of the alkoxycarbonyl group is changed. In the case of 1st place, W is preferably 4th place.
　化合物（５）として好ましくは、Ｒ’’がＣ１－１０アルキル基であり、環ＡがＣ６－１４アリール基であり、Ｖが水素原子であり、Ｗが式（Ａ） Preferably, as compound (5), R ″ is a C 1-10 alkyl group, ring A is a C 6-14 aryl group, V is a hydrogen atom, and W is a compound of the formula (A)
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
（式中、Ｑは、窒素原子に結合手を有する含窒素非芳香族複素環基である）で表される基を示す化合物であり、より好ましくは、Ｒ’’がＣ１－６アルキル基であり、環Ａがフェニル基であり、Ｖが水素原子であり、そしてＷがイミノ（ピロリジン－１－イル）メチル基（この場合のＱは、ピロリジン－１－イル基である）を示すような化合物であり、特に好ましくは、４－［イミノ（ピロリジン－１－イル）メチル］安息香酸メチルである。 (Wherein Q is a nitrogen-containing non-aromatic heterocyclic group having a bond at the nitrogen atom), more preferably, R ″ is a C 1-6 alkyl group. Ring A is a phenyl group, V is a hydrogen atom, and W is an imino (pyrrolidin-1-yl) methyl group (where Q is a pyrrolidin-1-yl group) A particularly preferred compound is methyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate.
　化合物（５）が塩の形態を成し得る場合、その塩は化学的に許容しうる塩であればよく、例えば、式中にカルボキシル基等の酸性基が存在する場合の酸性基に対しては、アンモニウム塩、ナトリウム、カリウム等のアルカリ金属との塩、カルシウム、マグネシウム等のアルカリ土類金属との塩、アルミニウム塩、亜鉛塩、トリエチルアミン、エタノールアミン、モルホリン、ピペリジン、ジシクロへキシルアミン等の有機アミンとの塩、アルギニン、リジン等の塩基性アミノ酸との塩を挙げることができる。 When compound (5) can be in the form of a salt, the salt may be a chemically acceptable salt. For example, for an acidic group when an acidic group such as a carboxyl group is present in the formula, Organic salts such as ammonium salts, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, aluminum salts, zinc salts, triethylamine, ethanolamine, morpholine, piperidine, dicyclohexylamine Examples thereof include salts with amines and salts with basic amino acids such as arginine and lysine.
　また式中に塩基性基が存在する場合の塩基性基に対しては、塩酸、硫酸、リン酸、硝酸、臭化水素酸、フッ化水素酸、ヨウ化水素酸などの無機酸との塩、酢酸、トリフルオロ酢酸（ＴＦＡ）、クエン酸、安息香酸、マレイン酸、フマル酸、酒石酸、コハク酸、タンニン酸、酪酸、ヒベンズ酸、パモ酸、エナント酸、デカン酸、テオクル酸、サリチル酸、乳酸、シュウ酸、マンデル酸、リンゴ酸等の有機カルボン酸との塩、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸等の有機スルホン酸との塩を挙げることができる。塩を形成する方法としては、化合物（５）と必要な酸または塩基とを適当な量比で溶媒、分散剤中で混合することや、他の塩の形より陽イオン交換または陰イオン交換を行うことによっても得られる。 In addition, when a basic group is present in the formula, for a basic group, a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, etc. , Acetic acid, trifluoroacetic acid (TFA), citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, tannic acid, butyric acid, hibenzic acid, pamoic acid, enanthic acid, decanoic acid, teocric acid, salicylic acid, lactic acid And salts with organic carboxylic acids such as oxalic acid, mandelic acid and malic acid, and salts with organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. As a method for forming a salt, the compound (5) and a necessary acid or base are mixed in an appropriate amount ratio in a solvent or a dispersant, or cation exchange or anion exchange is carried out from other salt forms. It can also be obtained by doing.
　特に化合物（５）のＷが塩基性基を示す場合、化合物（５）は、強酸（例えば、フッ化水素酸、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸など）との塩を好ましく形成することができる。ここで強酸として好ましくは、塩酸である。 In particular, when W of compound (5) represents a basic group, compound (5) is a salt with a strong acid (for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, etc.) Can be preferably formed. Here, hydrochloric acid is preferable as the strong acid.
　化合物（５）としては、化合物（５）の溶媒和物、例えば水和物、アルコール付加物等も含んでいる。 Compound (5) includes solvates of compound (5), such as hydrates and alcohol adducts.
　化合物（５）のうち、環ＡがＣ６－１４アリール基であり、Ｗが式（Ａ）で表される基である化合物、例えば４－［イミノ（ピロリジン－１－イル）メチル］安息香酸メチル　塩酸塩の製造方法について例示する。
　４－［イミノ（ピロリジン－１－イル）メチル］安息香酸メチル　塩酸塩は、例えば、４－［イミノ（ピロリジン－１－イル）メチル］安息香酸クロリド　塩酸塩とメタノールとのメチルエステル化によって容易に製造することができる。 Of the compounds (5), a compound wherein ring A is a C 6-14 aryl group and W is a group represented by the formula (A), such as 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid It illustrates about the manufacturing method of methyl hydrochloride.
4- [Imino (pyrrolidin-1-yl) methyl] benzoic acid methyl chloride is easily prepared by, for example, methyl esterification of 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride and methanol. Can be manufactured.
　また、４－［イミノ（ピロリジン－１－イル）メチル］安息香酸メチル　塩酸塩は、次の方法によっても製造することができる。 Further, methyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate hydrochloride can also be produced by the following method.
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
　エタノール中、塩化水素存在下で４－シアノ安息香酸メチルを４－エトキシイミノメチル安息香酸メチル　塩酸塩に誘導する。次いでトルエンを加えて脱塩化水素濃縮を行った後、ピロリジンを加えて４－［イミノ（ピロリジン－１－イル）メチル］安息香酸メチル　塩酸塩へと導く。
　本反応で使用する合成原料は、市販で入手可能な原料から一般的な有機合成手法によって調製することができる。
　なお上記化合物（５）の製造方法は例示であり、当該方法に限定されるわけではなく、当業者であれば適宜合成ルートを設計して化合物（５）を製造することが可能である。 Methyl 4-cyanobenzoate is derived into methyl 4-ethoxyiminomethylbenzoate hydrochloride in the presence of hydrogen chloride in ethanol. Next, toluene is added to carry out dehydrochlorination concentration, and then pyrrolidine is added to lead to methyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate hydrochloride.
The synthetic raw material used in this reaction can be prepared from commercially available raw materials by a general organic synthesis method.
In addition, the manufacturing method of the said compound (5) is an illustration, and is not necessarily limited to the said method, A person skilled in the art can design a synthetic route suitably and can manufacture a compound (5).
４．化合物（３）
　本発明における化合物（３）は、式（３） 4). Compound (3)
The compound (3) in the present invention has the formula (3)
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
（式中、
　環Ｂは、Ｃ６－１４アリール基、ヘテロアリール基、含窒素非芳香族複素環基またはＣ３－１０シクロアルキル基を表し、
　Ｔは、水素原子、ハロゲン原子、ヒドロキシ基、置換基を有していてもよいＣ１－１０アルコキシ基、置換基を有していてもよいアシルオキシ基、置換基を有していてもよいカルバモイルオキシ基、置換基を有していてもよいチオカルバモイルオキシ基、アミノ基、シアノ基、ニトロ基、置換基を有していてもよいＣ１－１０アルキル基、置換基を有していてもよいＣ１－１０アルキルアミノ基、置換基を有していてもよいＣ１－１０アルキルチオ基、置換基を有していてもよいアシルアミノ基、カルボキシル基、置換基を有していてもよいＣ１－１０アルコキシ－カルボニル基、置換基を有していてもよいカルバモイル基、または置換基を有していてもよいチオカルバモイル基を表し、
　Ｕは、水素原子、置換基を有していてもよいＣ１－１０アルキル基、カルボキシル基、置換基を有していてもよいＣ１－１０アルコキシ－カルボニル基、または置換基を有していてもよいカルバモイル基を表し、
　Ｌは、窒素原子、酸素原子、硫黄原子またはメチレン基を表し、そして
　ｎは、１～３の整数を表す）
で表される、ヒドロキシ基を有する化合物である。 (Where
Ring B represents a C 6-14 aryl group, a heteroaryl group, a nitrogen-containing non-aromatic heterocyclic group or a C 3-10 cycloalkyl group,
T represents a hydrogen atom, a halogen atom, a hydroxy group, a C 1-10 alkoxy group which may have a substituent, an acyloxy group which may have a substituent, or a carbamoyl which may have a substituent. An oxy group, an optionally substituted thiocarbamoyloxy group, an amino group, a cyano group, a nitro group, an optionally substituted C 1-10 alkyl group, and an optionally substituted group A good C 1-10 alkylamino group, an optionally substituted C 1-10 alkylthio group, an optionally substituted acylamino group, a carboxyl group, an optionally substituted C 1-10 represents an alkoxy-carbonyl group, an optionally substituted carbamoyl group, or an optionally substituted thiocarbamoyl group,
U has a hydrogen atom, an optionally substituted C 1-10 alkyl group, a carboxyl group, an optionally substituted C 1-10 alkoxy-carbonyl group, or a substituent. Represents a carbamoyl group which may be
L represents a nitrogen atom, an oxygen atom, a sulfur atom or a methylene group, and n represents an integer of 1 to 3)
And a compound having a hydroxy group.
　化合物（３）は、ヒドロキシ基部分で前記化合物（１）と容易に縮合して、化合物（４）を形成せしめる。
　また化合物（３）は、縮合剤を用いることで化合物（２）と縮合して、化合物（４）を形成せしめる。
　さらに化合物（３）は、化合物（５）とエステル交換反応により縮合して、化合物（４）を形成せしめる。 Compound (3) easily condenses with compound (1) at the hydroxy group moiety to form compound (4).
Compound (3) is condensed with compound (2) by using a condensing agent to form compound (4).
Further, compound (3) is condensed with compound (5) by transesterification to form compound (4).
　環Ｂ上の置換基Ｔ、Ｌおよびアミジノ基の位置は、環Ｂ上の置換可能な位置であれば、特に限定はないが、環Ｂがフェニル基の場合、アミジノ基の置換位置を１位とした場合に、Ｔは４位であることが望ましく、またＬが３位であることが望ましい。
　化合物（３）として好ましくは、環ＢがＣ６－１４アリール基であり、Ｔがヒドロキシ基、Ｃ１－１０アルコキシ基またはシアノで置換されていてもよいＣ１－１０アルコキシ基であり、Ｌが酸素原子であり、ｎが１であるような化合物であり、化合物（３）の塩としては、塩酸塩、酢酸塩が望ましい。
　化合物（３）として特に好ましくは、４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンズアミジンまたはその塩（塩酸塩、酢酸塩）、３－（２－ヒドロキシエトキシ）－４－メトキシベンズアミジンまたはその塩（塩酸塩、酢酸塩）、４－エトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジンまたはその塩（塩酸塩、酢酸塩）、３－（２－ヒドロキシエトキシ）－４－（２－メチルプロポキシ）－ベンズアミジンまたはその塩（塩酸塩、酢酸塩）、４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジンまたはその塩（塩酸塩）である。 The position of the substituents T, L and amidino group on ring B is not particularly limited as long as it is a substitutable position on ring B. When ring B is a phenyl group, the position of substitution of the amidino group is the 1st position. In this case, T is preferably in the 4th position, and L is preferably in the 3rd position.
The preferred compound (3), ring B is a C 6-14 aryl group, T is a hydroxy group, C 1-10 alkoxy group or C 1-10 alkoxy group optionally substituted by cyano, L Is an oxygen atom and n is 1. The salt of compound (3) is preferably hydrochloride or acetate.
Particularly preferred as the compound (3) is 4-hydroxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof (hydrochloride, acetate), 3- (2-hydroxyethoxy) -4-methoxybenzamidine or a salt thereof (Hydrochloride, acetate), 4-ethoxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof (hydrochloride, acetate), 3- (2-hydroxyethoxy) -4- (2-methylpropoxy)- Benzamidine or a salt thereof (hydrochloride, acetate), 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof (hydrochloride).
　化合物（３）が塩の形態を成し得る場合、その塩は化学的に許容しうる塩であればよく、例えば、式中にカルボキシル基等の酸性基が存在する場合の酸性基に対しては、アンモニウム塩、ナトリウム、カリウム等のアルカリ金属との塩、カルシウム、マグネシウム等のアルカリ土類金属との塩、アルミニウム塩、亜鉛塩、トリエチルアミン、エタノールアミン、モルホリン、ピペリジン、ジシクロへキシルアミン等の有機アミンとの塩、アルギニン、リジン等の塩基性アミノ酸との塩を挙げることができる。 When compound (3) can be in the form of a salt, the salt may be a chemically acceptable salt. For example, for an acidic group in the case where an acidic group such as a carboxyl group is present in the formula, Organic salts such as ammonium salts, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, aluminum salts, zinc salts, triethylamine, ethanolamine, morpholine, piperidine, dicyclohexylamine Examples thereof include salts with amines and salts with basic amino acids such as arginine and lysine.
　また式中に塩基性基が存在する場合の塩基性基に対しては、塩酸、硫酸、リン酸、硝酸、臭化水素酸、フッ化水素酸、ヨウ化水素酸などの無機酸との塩、酢酸、トリフルオロ酢酸（ＴＦＡ）、クエン酸、安息香酸、マレイン酸、フマル酸、酒石酸、コハク酸、タンニン酸、酪酸、ヒベンズ酸、パモ酸、エナント酸、デカン酸、テオクル酸、サリチル酸、乳酸、シュウ酸、マンデル酸、リンゴ酸等の有機カルボン酸との塩、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸等の有機スルホン酸との塩を挙げることができる。化合物（３）は塩基性基（アミジノ基）を有するので、これらの塩を形成することが可能である。 In addition, when a basic group is present in the formula, for a basic group, a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, etc. , Acetic acid, trifluoroacetic acid (TFA), citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, tannic acid, butyric acid, hibenzic acid, pamoic acid, enanthic acid, decanoic acid, teocric acid, salicylic acid, lactic acid And salts with organic carboxylic acids such as oxalic acid, mandelic acid and malic acid, and salts with organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. Since compound (3) has a basic group (amidino group), these salts can be formed.
　塩を形成する方法としては、化合物（３）と必要な酸または塩基とを適当な量比で溶媒、分散剤中で混合することや、他の塩の形より陽イオン交換または陰イオン交換を行うことによっても得られる。 As a method of forming a salt, the compound (3) and a necessary acid or base are mixed in an appropriate amount ratio in a solvent or a dispersant, or cation exchange or anion exchange is performed from other salt forms. It can also be obtained by doing.
　特に化合物（３）は、上記の塩のなかでも、強酸（例えば、フッ化水素酸、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸など）や酢酸との塩を好ましく形成することができる。ここで強酸として好ましくは、塩酸である。 Particularly, the compound (3) preferably forms a salt with a strong acid (for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid) or acetic acid among the above-mentioned salts. Can do. Here, hydrochloric acid is preferable as the strong acid.
　化合物（３）としては、化合物（３）の溶媒和物、例えば水和物、アルコール付加物等も含んでいる。 Compound (3) includes solvates of compound (3), such as hydrates and alcohol adducts.
　化合物（３）のうち、環ＢがＣ６－１４アリール基を示し、Ｔがヒドロキシ基、Ｃ１－１０アルコキシ基またはシアノで置換されていてもよいＣ１－１０アルコキシ基を示し、Ｌが酸素原子を示し、Ｕが水素原子を示し、ｎが１を示す化合物またはその塩、例えば４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩の製造方法について例示する。
　４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩は、イソバニリンを出発原料として次の方法で製造することができる。 Among the compounds (3), ring B represents a C 6-14 aryl group, T represents hydroxy group, C 1-10 alkoxy group or a cyano with an optionally substituted C 1-10 alkoxy group, L is An example of a method for producing a compound showing an oxygen atom, U showing a hydrogen atom, and n showing 1 or a salt thereof, such as 4-hydroxy-3- (2-hydroxyethoxy) benzamidine hydrochloride, will be described.
4-Hydroxy-3- (2-hydroxyethoxy) benzamidine hydrochloride can be produced by the following method using isovanillin as a starting material.
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
　はじめに、市販で入手可能なイソバニリンから定法に従ってホルミル基のシアノ化を行い、３－ヒドロキシ－４－メトキシベンゾニトリルへと導いた。次にＤＭＦ中、炭酸エチレンと炭酸カリウムを用いて反応を行い、３－（２－ヒドロキシエトキシ）－４－メトキシベンゾニトリルへと導いた。これを単離することなく、テトラへドロン　５９巻（３３），２００３年，６３６３－６３７３頁に記載の方法により脱メチル化を行い、ナトリウム　４－シアノ－２－（２－ヒドロキシエトキシ）フェノキシドを得た。次に水中、塩酸を用いて中和し、４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンゾニトリルを得た。次にメタノール中、ヒドロキシルアミン塩酸塩とナトリウムメトキシドから得られるヒドロキシルアミンをｉｎ　ｓｉｔｕで調製してアミドオキシム化を行い、４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンズアミド＝オキシムへと導いた。これを単離することなく、無水酢酸とＰｄ／Ｃで水素添加反応を行い、４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　酢酸塩へと導いた。次にメタノール／塩化水素で塩酸塩化を行い、４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩へと導いた。
　本反応で使用する合成原料は、市販で入手可能な原料から一般的な有機合成手法によって調製することができる。 First, formyl group was cyanated from commercially available isovanillin according to a conventional method to lead to 3-hydroxy-4-methoxybenzonitrile. Next, the reaction was carried out using ethylene carbonate and potassium carbonate in DMF, leading to 3- (2-hydroxyethoxy) -4-methoxybenzonitrile. Without isolating this, demethylation was performed by the method described in Tetrahedron 59 (33), 2003, 6363-6373, and sodium 4-cyano-2- (2-hydroxyethoxy) phenoxide was obtained. Obtained. Next, it was neutralized with hydrochloric acid in water to obtain 4-hydroxy-3- (2-hydroxyethoxy) benzonitrile. Next, hydroxylamine obtained from hydroxylamine hydrochloride and sodium methoxide in methanol was prepared in situ and subjected to amide oximation, leading to 4-hydroxy-3- (2-hydroxyethoxy) benzamide = oxime. . Without isolation, this was hydrogenated with acetic anhydride and Pd / C, leading to 4-hydroxy-3- (2-hydroxyethoxy) benzamidine acetate. Next, hydrochloric acid chloride with methanol / hydrogen chloride led to 4-hydroxy-3- (2-hydroxyethoxy) benzamidine hydrochloride.
The synthetic raw material used in this reaction can be prepared from commercially available raw materials by a general organic synthesis method.
　また化合物（３）のうち、３－（２－ヒドロキシエトキシ）－４－メトキシベンズアミジン　塩酸塩の製造法について例示する。３－（２－ヒドロキシエトキシ）－４－メトキシベンズアミジン　塩酸塩は、イソバニリンを出発原料として次の方法で製造することができる。 In addition, the compound (3) is exemplified by a method for producing 3- (2-hydroxyethoxy) -4-methoxybenzamidine hydrochloride. 3- (2-Hydroxyethoxy) -4-methoxybenzamidine hydrochloride can be produced by the following method using isovanillin as a starting material.
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
　はじめに、市販で入手可能なイソバニリンから定法に従ってホルミル基のシアノ化を行い、３－ヒドロキシ－４－メトキシベンゾニトリルへと導いた。次に２－クロロエタノールとアルキル化を行い、３－（２－ヒドロキシエトキシ）－４－メトキシベンゾニトリルへと導いた。次にメタノール中、ヒドロキシルアミン塩酸塩と水酸化カリウムから得られるヒドロキシルアミンをｉｎ　ｓｉｔｕで調製してアミドオキシム化を行い、３－（２－ヒドロキシエトキシ）－４－メトキシベンズアミド＝オキシムへと導いた。これを単離することなく、無水酢酸とＰｄ／Ｃで水素添加反応を行い３－（２－ヒドロキシエトキシ）－４－メトキシベンズアミジン　酢酸塩へと導いた。次にメタノール／塩化水素で塩酸塩化を行い、３－（２－ヒドロキシエトキシ）－４－メトキシベンズアミジン　塩酸塩へと導いた。 First, formyl group was cyanated from commercially available isovanillin according to a conventional method, leading to 3-hydroxy-4-methoxybenzonitrile. It was then alkylated with 2-chloroethanol leading to 3- (2-hydroxyethoxy) -4-methoxybenzonitrile. Next, hydroxylamine obtained from hydroxylamine hydrochloride and potassium hydroxide in methanol was prepared in situ and subjected to amide oximation, leading to 3- (2-hydroxyethoxy) -4-methoxybenzamide = oxime. . Without isolation, this was hydrogenated with acetic anhydride and Pd / C to give 3- (2-hydroxyethoxy) -4-methoxybenzamidine acetate. Next, hydrochloric acid was salified with methanol / hydrogen chloride, leading to 3- (2-hydroxyethoxy) -4-methoxybenzamidine hydrochloride.
　さらに化合物（３）のうち、４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩の製造方法について例示する。４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩は、イソバニリンを出発原料として次の方法で製造することができる。 Further, a method for producing 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride among the compounds (3) will be exemplified. 4-Cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride can be produced by the following method using isovanillin as a starting material.
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
　はじめに、市販で入手可能なイソバニリンから定法に従ってホルミル基のシアノ化を行い、３－ヒドロキシ－４－メトキシベンゾニトリルへと導いた。次にＤＭＦ中、炭酸エチレンと炭酸カリウムを用いて反応を行い、３－（２－ヒドロキシエトキシ）－４－メトキシベンゾニトリルへと導いた。これを単離することなく、テトラへドロン　５９巻（３３），２００３年，６３６３－６３７３頁に記載の方法により脱メチル化を行い、ナトリウム　４－シアノ－２－（２－ヒドロキシエトキシ）フェノキシドを得た。次にＤＭＦ中、ブロモアセトアルデヒドジエチルアセタールと炭酸カリウムを用いてアルキル化し、４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンゾニトリルを得た。次にメタノール中、ヒドロキシルアミン塩酸塩と水酸化カリウムから得られるヒドロキシルアミンをｉｎ　ｓｉｔｕで調製してアミドオキシム化を行い、４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミド＝オキシムへと導いた。これを単離することなく、無水酢酸とＰｄ／Ｃで水素添加反応を行い、４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミジン　酢酸塩へと導いた。次に水中、ヒドロキシルアミン－Ｏ－スルホニルを用いてシアノ化を行い、４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジンへと導いた。次にメタノール／塩化水素で塩酸塩化を行い、４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩へと導いた。
　本反応で使用する合成原料は、市販で入手可能な原料から一般的な有機合成手法によって調製することができる。 First, formyl group was cyanated from commercially available isovanillin according to a conventional method to lead to 3-hydroxy-4-methoxybenzonitrile. Next, the reaction was carried out using ethylene carbonate and potassium carbonate in DMF, leading to 3- (2-hydroxyethoxy) -4-methoxybenzonitrile. Without isolating this, demethylation was performed by the method described in Tetrahedron 59 (33), 2003, 6363-6373, and sodium 4-cyano-2- (2-hydroxyethoxy) phenoxide was obtained. Obtained. Next, alkylation was performed using bromoacetaldehyde diethyl acetal and potassium carbonate in DMF to obtain 4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile. Next, hydroxylamine obtained from hydroxylamine hydrochloride and potassium hydroxide in methanol was prepared in situ and subjected to amide oximation to give 4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy). ) Led to benzamide-oxime. Without isolation, this was hydrogenated with acetic anhydride and Pd / C, leading to 4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzamidine acetate. Next, cyanation was performed using hydroxylamine-O-sulfonyl in water, leading to 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine. Next, hydrochloric acid salification with methanol / hydrogen chloride led to 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride.
The synthetic raw material used in this reaction can be prepared from commercially available raw materials by a general organic synthesis method.
　また化合物（３）のうち、４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩は、バニリンを出発原料として次の方法でも製造することができる。 Among the compounds (3), 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride can also be produced by the following method using vanillin as a starting material.
　市販入手可能なバニリンから定法に従ってホルミル基のシアノ化を行い、４－ヒドロキシ－３－メトキシベンゾニトリルへと導いた。次にＤＭＦ中、ブロモアセトアルデヒドジエチルアセタールと炭酸カリウムを用いてアルキル化し、４－（２，２－ジエトキシエトキシ）－３－メトキシベンゾニトリルを得た。次にテトラへドロン　５９巻（３３）　２００３年　６３６３－６３７３頁に記載の方法により脱メチル化を行い、生成した４－（２，２－ジエトキシエトキシ）－３－ヒドロキシベンゾニトリルを単離することなく、炭酸エチレンと炭酸カリウムを用いて反応を行い、４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンゾニトリルへと導いた。続いて前記と同様の手法で４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩へと導いた。 Cyanation of the formyl group was performed from commercially available vanillin according to a conventional method, leading to 4-hydroxy-3-methoxybenzonitrile. Next, alkylation was performed using bromoacetaldehyde diethyl acetal and potassium carbonate in DMF to obtain 4- (2,2-diethoxyethoxy) -3-methoxybenzonitrile. Next, tetramethylone 59 (33) 2003 6363-6373 is demethylated and the resulting 4- (2,2-diethoxyethoxy) -3-hydroxybenzonitrile is isolated. Instead, the reaction was carried out using ethylene carbonate and potassium carbonate, leading to 4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile. Subsequently, 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride was introduced in the same manner as described above.
　なお上記化合物（３）の製造方法は例示であり、当該方法に限定されるわけではなく、当業者であれば適宜合成ルートを設計して化合物（３）を製造することが可能である。 In addition, the manufacturing method of the said compound (3) is an illustration, It is not necessarily limited to the said method, A person skilled in the art can design a synthetic route suitably and can manufacture a compound (3).
　なお化合物（３）のうち、式（３’） Of the compound (3), the formula (3 ')
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
（式中、Ｔ’は、ヒドロキシ基、Ｃ１－１０アルコキシ基またはシアノで置換されていてもよいＣ１－１０アルコキシ基である）
で表される化合物またはその塩（以下、化合物（３’）と記載する場合がある）は新規化合物である。これらの化合物は、本発明の製造方法の合成中間体として用いることができる。化合物（３’）は、化合物（３）と同様に塩の形態をなし得るが、その場合の塩としては、化学的に許容される塩であればよい。化学的に許容される塩としては、化合物（３）において上記した塩が例示される。 (Wherein, T 'is a hydroxy group, a C 1-10 alkoxy group or C 1-10 alkoxy group optionally substituted by cyano)
Or a salt thereof (hereinafter sometimes referred to as compound (3 ′)) is a novel compound. These compounds can be used as a synthetic intermediate in the production method of the present invention. Compound (3 ′) can be in the form of a salt in the same manner as compound (3). In this case, the salt may be a chemically acceptable salt. Examples of the chemically acceptable salt include those described above for compound (3).
　化合物（３’）のなかでも、
４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジンまたはその塩、
４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンズアミジンまたはその塩；
３－（２－ヒドロキシエトキシ）－４－メトキシベンズアミジンまたはその塩；
４－エトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジンまたはその塩；ならびに
３－（２－ヒドロキシエトキシ）－４－（２－メチルプロポキシ）ベンズアミジンまたはその塩
を、好ましい例として挙げることができ、さらに、
４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン（実施例５（８））、またはその塩酸塩（実施例５（９））、
４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　酢酸塩（実施例１１（１））および塩酸塩（実施例１１（２））、
３－（２－ヒドロキシエトキシ）－４－メトキシベンズアミジン　酢酸塩（実施例１２（１））および塩酸塩（実施例１２（２））、
４－エトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン（実施例１３（３））、またはその酢酸塩（実施例１３（２））および塩酸塩（実施例１３（４））、
３－（２－ヒドロキシエトキシ）－４－（２－メチルプロポキシ）ベンズアミジン　酢酸塩（実施例１４（２））および塩酸塩（実施例１４（３））
を、特に好ましい例として挙げることができる。 Among the compounds (3 '),
4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof,
4-hydroxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof;
3- (2-hydroxyethoxy) -4-methoxybenzamidine or a salt thereof;
Preferred examples include 4-ethoxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof; and 3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzamidine or a salt thereof, ,
4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine (Example 5 (8)), or a hydrochloride thereof (Example 5 (9)),
4-hydroxy-3- (2-hydroxyethoxy) benzamidine acetate (Example 11 (1)) and hydrochloride (Example 11 (2)),
3- (2-hydroxyethoxy) -4-methoxybenzamidine acetate (Example 12 (1)) and hydrochloride (Example 12 (2)),
4-ethoxy-3- (2-hydroxyethoxy) benzamidine (Example 13 (3)), or its acetate (Example 13 (2)) and hydrochloride (Example 13 (4)),
3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzamidine acetate (Example 14 (2)) and hydrochloride (Example 14 (3))
Can be mentioned as a particularly preferred example.
　また、化合物（３）のうち、化合物（３’）を合成するための、イソバニリンを出発原料とする合成ルートにおける下記式（３’’） In addition, the following formula (3 ″) in a synthesis route using isovanillin as a starting material for synthesizing compound (3 ′) among compounds (3)
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
（式中、Ｔ’’は、ナトリウム原子、水素原子、またはＣ１－１０アルコキシで置換されていてもよいＣ１－１０アルキル基であり、Ｇは、シアノ基、またはヒドロキシで置換されていてもよいアミジノ基である）
で表される化合物またはその塩も新規化合物である。これらの化合物は、化合物（３’）を得るための合成中間体として用いることができる。式（３’’）で表される化合物は、目的化合物（３）と同様に塩の形態をなし得るが、その場合の塩としては、化学的に許容される塩であればよい。化学的に許容される塩としては、化合物（３）において上記した塩が例示される。なかでも、塩酸との塩、酢酸との塩を好ましく形成することができる。 (Wherein T ″ is a sodium atom, a hydrogen atom, or a C 1-10 alkyl group which may be substituted with C 1-10 alkoxy; G is a cyano group or substituted with hydroxy; A good amidino group)
Or a salt thereof is also a novel compound. These compounds can be used as a synthetic intermediate for obtaining the compound (3 ′). The compound represented by the formula (3 ″) can be in the form of a salt similarly to the target compound (3), and the salt in that case may be a chemically acceptable salt. Examples of the chemically acceptable salt include those described above for compound (3). Of these, a salt with hydrochloric acid and a salt with acetic acid can be preferably formed.
　式（３’’）で表される化合物のなかでも、
３－（２－ヒドロキシエトキシ）－４－メトキシベンゾニトリル、ナトリウム　４－シアノ－２－（２－ヒドロキシエトキシ）フェノキシド、４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンゾニトリル、４－（２，２－ジメトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンゾニトリル、４－（２，２－ジメトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミド＝オキシム、４－（２，２－ジメトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミジン、４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンゾニトリル、４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミド＝オキシム、４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミジン、４－エトキシ－３－（２－ヒドロキシエトキシ）ベンゾニトリル、および３－（２－ヒドロキシエトキシ）－４－（２－メチルプロポキシ）ベンゾニトリルから選択される化合物またはそれらの塩を好ましい例として挙げることができる。 Among the compounds represented by formula (3 ″),
3- (2-hydroxyethoxy) -4-methoxybenzonitrile, sodium 4-cyano-2- (2-hydroxyethoxy) phenoxide, 4-hydroxy-3- (2-hydroxyethoxy) benzonitrile, 4- (2, 2-dimethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile, 4- (2,2-dimethoxyethoxy) -3- (2-hydroxyethoxy) benzamide = oxime, 4- (2,2-dimethoxyethoxy) -3- (2-hydroxyethoxy) benzamidine, 4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile, 4- (2,2-diethoxyethoxy) -3- (2 -Hydroxyethoxy) benzamide = oxime, 4- (2,2-diethoxyethoxy) -3- (2-hydro Preferred are compounds selected from xoxyethoxy) benzamidine, 4-ethoxy-3- (2-hydroxyethoxy) benzonitrile, and 3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzonitrile, or salts thereof. As an example.
　さらに、式（３’’）で表される化合物のなかでも、
３－（２－ヒドロキシエトキシ）－４－メトキシベンゾニトリル（実施例５（２））、
ナトリウム　４－シアノ－２－（２－ヒドロキシエトキシ）フェノキシド（実施例５（３））、
４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンゾニトリル（実施例５（４））、
４－（２，２－ジメトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンゾニトリル（実施例５（５））、
４－（２，２－ジメトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミド＝オキシム（実施例５（６））、
４－（２，２－ジメトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩（実施例５（７））、
４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンゾニトリル（実施例６（２））、
４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミド＝オキシム（実施例６（３））、
４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミジン　酢酸塩（実施例６（５））
４－エトキシ－３－（２－ヒドロキシエトキシ）ベンゾニトリル（実施例１３（１））、および
３－（２－ヒドロキシエトキシ）－４－（２－メチルプロポキシ）ベンゾニトリル（実施例１４（１））
を、特に好ましい化合物として用いることができる。 Furthermore, among the compounds represented by the formula (3 ″),
3- (2-hydroxyethoxy) -4-methoxybenzonitrile (Example 5 (2)),
Sodium 4-cyano-2- (2-hydroxyethoxy) phenoxide (Example 5 (3)),
4-hydroxy-3- (2-hydroxyethoxy) benzonitrile (Example 5 (4)),
4- (2,2-dimethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile (Example 5 (5)),
4- (2,2-dimethoxyethoxy) -3- (2-hydroxyethoxy) benzamide oxime (Example 5 (6)),
4- (2,2-dimethoxyethoxy) -3- (2-hydroxyethoxy) benzamidine hydrochloride (Example 5 (7)),
4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile (Example 6 (2)),
4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzamide oxime (Example 6 (3)),
4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzamidine acetate (Example 6 (5))
4-Ethoxy-3- (2-hydroxyethoxy) benzonitrile (Example 13 (1)) and 3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzonitrile (Example 14 (1)) )
Can be used as particularly preferred compounds.
　また、化合物（３）のうち、化合物（３’）を合成するための、バニリンを出発原料とする合成ルートにおける下記式（３’’’） In addition, in the synthesis route using vanillin as a starting material for synthesizing the compound (3 ′) among the compounds (3), the following formula (3 ′ ″)
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055
（式中、Ｔ’’’は、Ｃ１－１０アルコキシで置換されるＣ１－１０アルキル基であり、Ｒは、水素原子またはＣ１－１０アルキル基である）
で表される化合物またはその塩は新規化合物であり、化合物（３’）を得るための合成中間体として好ましく用いることができる。式（３’’’）で表される化合物は、目的化合物（３）と同様に塩の形態をなし得るが、その場合の塩としては、化学的に許容される塩であればよい。化学的に許容される塩としては、化合物（３）において上記した塩が例示される。 (Wherein T ′ ″ is a C 1-10 alkyl group substituted with C 1-10 alkoxy, and R is a hydrogen atom or a C 1-10 alkyl group)
Or a salt thereof is a novel compound and can be preferably used as a synthetic intermediate for obtaining the compound (3 ′). The compound represented by the formula (3 ′ ″) can be in the form of a salt in the same manner as the target compound (3), but the salt in that case may be a chemically acceptable salt. Examples of the chemically acceptable salt include those described above for compound (3).
　式（３’’’）で表される化合物のなかでも、
４－（２，２－ジエトキシエトキシ）－３－メトキシベンゾニトリル（実施例７（２））
を、特に好ましい化合物として用いることができる。 Among the compounds represented by the formula (3 ′ ″),
4- (2,2-diethoxyethoxy) -3-methoxybenzonitrile (Example 7 (2))
Can be used as particularly preferred compounds.
５．化合物（４）
　化合物（４）は、化合物（１）、化合物（２）または化合物（５）と、化合物（３）とを縮合して得られる、本発明の製造方法における目的化合物である。化合物（４）またはその塩は、低分子ＦＸａ阻害剤として有用であり、このため化合物（４）またはその塩を有効成分として含有する剤は、血液体外循環回路用の抗（血液）凝固薬（剤）として有用である（国際公開２００６／０８３００３号パンフレット参照）。化合物（４）は国際公開２００６／０８３００３号パンフレットに記載されているアルキル結合を形成する方法でも製造しうるが、本発明の製造方法によれば、当該用法より簡便かつ高収率に化合物（４）を得ることができる。以下詳細に説明する。 5). Compound (4)
Compound (4) is the target compound in the production method of the present invention, obtained by condensing compound (1), compound (2) or compound (5) and compound (3). The compound (4) or a salt thereof is useful as a low molecular weight FXa inhibitor. Therefore, an agent containing the compound (4) or a salt thereof as an active ingredient is an anti- (blood) coagulant for an extracorporeal blood circuit ( (Refer to International Publication No. 2006/083003 pamphlet). Compound (4) can also be produced by the method for forming an alkyl bond described in International Publication No. 2006/083003 pamphlet, but according to the production method of the present invention, compound (4) can be produced in a simpler and higher yield than the above method. ) Can be obtained. This will be described in detail below.
　本発明の製造方法は、下記式 The manufacturing method of the present invention has the following formula:
Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056
で示されるように、化合物（１）、化合物（２）または化合物（５）と、化合物（３）とを反応させてエステル結合を形成することにより、化合物（４）を得るものであるが、詳細には以下の４通りの方法：
（Ｉ）化合物（２）を、酸ハロゲン化試薬を用いて化合物（１）へ導いた後、当該化合物（１）を単離することなく、化合物（３）と縮合する方法；
（ＩＩ）化合物（２）を、酸ハロゲン化試薬を用いて化合物（１）へと導き、これを単離したのち化合物（３）と縮合させる方法；
（ＩＩＩ）化合物（２）と化合物（３）を、縮合剤を用いて縮合する方法；および
（ＩＶ）化合物（５）と化合物（３）とを、エステル交換反応を利用して縮合する方法：
に分けられる。以下、各方法について詳細に説明する。 As shown in the above, compound (4) is obtained by reacting compound (1), compound (2) or compound (5) with compound (3) to form an ester bond. In detail, the following four methods:
(I) A method in which compound (2) is led to compound (1) using an acid halogenating reagent and then condensed with compound (3) without isolating said compound (1);
(II) A method in which compound (2) is led to compound (1) using an acid halogenating reagent, and this is isolated and then condensed with compound (3);
(III) A method of condensing compound (2) and compound (3) using a condensing agent; and (IV) a method of condensing compound (5) and compound (3) using a transesterification reaction:
It is divided into. Hereinafter, each method will be described in detail.
（Ｉ）化合物（２）を、酸ハロゲン化試薬を用いて化合物（１）へ導いた後、当該化合物（１）を単離することなく、化合物（３）と縮合する方法（酸ハロゲン化～縮合連結法）：
　本方法は、以下の式 (I) A method in which compound (2) is led to compound (1) using an acid halogenating reagent and then condensed with compound (3) without isolation of the compound (1) (acid halogenation to Condensation method):
This method uses the following formula:
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057
（式中、各記号は、前記のとおりである）で示される。まずカルボキシル基を有する化合物（２）を有機溶媒に溶解あるいは懸濁させる。この際に用いられる有機溶媒としては、一般的に市販され、酸ハロゲン化反応などに使用される有機溶媒であれば特に限定されないが、好ましくはＮ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、Ｎ，Ｎ－ジメチルアセトアミド（ＤＭＡＣ）、Ｎ－メチル－２－ピロリドン（ＮＭＰ）などのアミド系溶媒や１，３－ジメチル－２－イミダゾリジノン（ＤＭＩ）などのイミド系溶媒であり、より好ましくはＮＭＰである。次に酸ハロゲン化剤と反応させて、酸ハロゲン化物（１）へと導く。この際に用いられる酸ハロゲン化剤としては、前記したとおりである。酸ハロゲン化の反応温度は－４０～２００℃、より好ましくは０～２０℃付近が望ましい。 (Wherein each symbol is as described above). First, the compound (2) having a carboxyl group is dissolved or suspended in an organic solvent. The organic solvent used in this case is not particularly limited as long as it is a commercially available organic solvent that is generally used for acid halogenation reaction, etc., but preferably N, N-dimethylformamide (DMF), N, N Amide solvents such as dimethylacetamide (DMAC) and N-methyl-2-pyrrolidone (NMP) and imide solvents such as 1,3-dimethyl-2-imidazolidinone (DMI), more preferably NMP is there. Next, it is reacted with an acid halogenating agent to lead to an acid halide (1). The acid halogenating agent used in this case is as described above. The reaction temperature of the acid halogenation is preferably −40 to 200 ° C., more preferably around 0 to 20 ° C.
　次いで酸ハロゲン化物（１）を含む反応液にヒドロキシ基を有するベンズアミジン誘導体（３）を加えて、目的の化合物（４）へと導く。この際の反応温度は－４０℃～２００℃、より好ましくは０℃～２０℃が望ましい。また、本反応は特に塩基を加えなくとも進行するが、必要に応じて塩基を加えても良い。塩基としては、例えばピリジンやトリエチルアミンなどが挙げられるが、これらに限定されない。反応の進捗はＨＰＬＣにより確認し、縮合体（化合物（４））の生成あるいは原料の消費をもって終了させる。本反応の反応時間は通常１～２４時間程度である。反応の進捗を確認した後、化合物（４）を含む反応液に水またはアルコール溶媒、好ましくはアルコール溶媒を加えて、過剰量の酸ハロゲン化剤と酸ハロゲン化物（１）とを分解させる。アルコール溶媒としては、メタノール、エタノール、イソプロピルアルコール等を好ましく用いることができるが、これに限定されるわけではない。得られた化合物（４）は、例えば、貧溶媒を加える固液分離手法によって単離することができる。 Subsequently, the benzamidine derivative (3) having a hydroxy group is added to the reaction solution containing the acid halide (1) to lead to the target compound (4). The reaction temperature at this time is desirably −40 ° C. to 200 ° C., more preferably 0 ° C. to 20 ° C. In addition, this reaction proceeds without particularly adding a base, but a base may be added if necessary. Examples of the base include, but are not limited to, pyridine and triethylamine. The progress of the reaction is confirmed by HPLC, and the reaction is terminated with the formation of the condensate (compound (4)) or the consumption of raw materials. The reaction time for this reaction is usually about 1 to 24 hours. After confirming the progress of the reaction, water or an alcohol solvent, preferably an alcohol solvent, is added to the reaction solution containing the compound (4) to decompose an excess amount of the acid halogenating agent and the acid halide (1). As the alcohol solvent, methanol, ethanol, isopropyl alcohol and the like can be preferably used, but the alcohol solvent is not limited thereto. The obtained compound (4) can be isolated by, for example, a solid-liquid separation method in which a poor solvent is added.
（ＩＩ）化合物（２）を、酸ハロゲン化試薬を用いて化合物（１）へと導き、これを単離したのち化合物（３）と縮合させる方法：
　化合物（１）を単離してから化合物（３）と反応させる場合には、前記したように、化合物（２）の酸ハロゲン化反応で生じた化合物（１）を含む溶液に、貧溶媒を加えることで化合物（２）を固体として析出させ、一般的な固液分離手法によって化合物（２）を単離する。ここで単離して得られた化合物（１）を、前記（Ｉ）に記載した縮合条件に従い、化合物（３）と反応させて化合物（４）へと導く。 (II) A method in which compound (2) is led to compound (1) using an acid halogenating reagent, and this is isolated and then condensed with compound (3):
When the compound (1) is isolated and then reacted with the compound (3), as described above, a poor solvent is added to the solution containing the compound (1) generated by the acid halogenation reaction of the compound (2). Thus, the compound (2) is precipitated as a solid, and the compound (2) is isolated by a general solid-liquid separation technique. The compound (1) obtained by isolation here is reacted with the compound (3) according to the condensation conditions described in the above (I) to lead to the compound (4).
（ＩＩＩ）化合物（２）と化合物（３）を、縮合剤を用いて縮合する方法：
　本方法は、以下の式 (III) Method of condensing compound (2) and compound (3) using a condensing agent:
This method uses the following formula:
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058
（式中、各記号は、前記のとおりである）によって示される。化合物（２）と化合物（３）とを有機溶媒に溶解あるいは懸濁させ、縮合剤を加えて縮合反応を行う。当該反応に用いる有機溶媒としては、縮合反応に影響しない限り、一般的に市販される有機溶媒であればいずれのものも用いることができるが、好ましくはヘキサメチルホスホン酸トリアミド（ＨＭＰＡ）である。また当該反応に用いる縮合剤としては、例えば無水酢酸、トリフルオロ無水酢酸（ＴＦＡＡ）、Ｎ，Ｎ－カルボキシジイミダゾール（ＣＤＩ）、ジシクロヘキシルカルボジイミド（ＤＣＣ）が挙げられ、これらに限定されるものではないが、ジシクロヘキシルカルボジイミドを用いることが好ましい。当該反応の反応温度は、通常－４０～１００℃であり、好ましくは０～５０℃である。また本反応は特に塩基を加えなくとも進行するが、必要に応じて塩基を加えても良い。塩基としては、例えばＮ，Ｎ－ジメチルアミノピリジン（ＤＭＡＰ）やピリジンなどが挙げられるが、これに限定されない。反応の進捗は一般的なＨＰＬＣによって確認し、縮合体の生成あるいは原料の消費をもって終了させる。反応の進捗を確認した後、得られた化合物は（Ｉ）で記載したように単離することができる。 Where each symbol is as described above. Compound (2) and compound (3) are dissolved or suspended in an organic solvent, and a condensation agent is added to carry out a condensation reaction. As the organic solvent used in the reaction, any commercially available organic solvent can be used as long as it does not affect the condensation reaction, but hexamethylphosphonic acid triamide (HMPA) is preferable. Examples of the condensing agent used in the reaction include, but are not limited to, acetic anhydride, trifluoroacetic anhydride (TFAA), N, N-carboxydiimidazole (CDI), and dicyclohexylcarbodiimide (DCC). However, it is preferable to use dicyclohexylcarbodiimide. The reaction temperature of the reaction is usually −40 to 100 ° C., preferably 0 to 50 ° C. In addition, this reaction proceeds without particularly adding a base, but a base may be added if necessary. Examples of the base include N, N-dimethylaminopyridine (DMAP) and pyridine, but are not limited thereto. The progress of the reaction is confirmed by general HPLC, and is completed with the formation of condensate or the consumption of raw materials. After confirming the progress of the reaction, the resulting compound can be isolated as described in (I).
（ＩＶ）化合物（５）と化合物（３）とを、エステル交換反応により縮合する方法：
　本方法は、以下の式 (IV) Method of condensing compound (5) and compound (3) by transesterification:
This method uses the following formula:
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000059
（式中、各記号は、前記のとおりである）によって示される。化合物（５）と化合物（３）とを有機溶媒に溶解あるいは懸濁させ、酸を加えてエステル交換による縮合反応を行う。当該反応に用いる有機溶媒としては、縮合反応に影響しない限り、一般的に市販される有機溶媒であればいずれのものも用いることができるが、好ましくはＮ－メチル－２－ピロリドン（ＮＭＰ）である。また当該反応に用いる酸としては、例えば塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、トリフルオロ酢酸、メタンスルホン酸、ｐ－トルエンスルホン酸が挙げられ、これに限定されるものではないが、塩酸を用いることが好ましい。当該反応の反応温度は、通常５０～２００℃であり、好ましくは１００～１５０℃である。反応の進捗は一般的なＨＰＬＣによって確認し、縮合体の生成あるいは原料の消費をもって終了させる。反応の進捗を確認した後、得られた化合物は（Ｉ）で記載したように単離することができる。 Where each symbol is as described above. Compound (5) and compound (3) are dissolved or suspended in an organic solvent, and an acid is added to conduct a condensation reaction by transesterification. As the organic solvent used in the reaction, any commercially available organic solvent can be used as long as it does not affect the condensation reaction, but N-methyl-2-pyrrolidone (NMP) is preferable. is there. Examples of the acid used in the reaction include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid, but are not limited thereto. Although not preferred, hydrochloric acid is preferably used. The reaction temperature of the reaction is usually 50 to 200 ° C., preferably 100 to 150 ° C. The progress of the reaction is confirmed by general HPLC, and is completed with the formation of condensate or the consumption of raw materials. After confirming the progress of the reaction, the resulting compound can be isolated as described in (I).
　以下に実施例を挙げて本発明をさらに具体的に説明する。但し、本発明がこれらの実施例のみに限定されるものではない。 The present invention will be described more specifically with reference to the following examples. However, the present invention is not limited only to these examples.
　各種分析手段および分析装置は、以下の通りである。 The various analysis means and analyzers are as follows.
　１Ｈ及び１３Ｃ　ＮＭＲは、ＴＭＳを内部標準物質として、ブルッカー社製アバンス４００ＭＨｚ核磁気共鳴装置で測定を実施した。ＣＤＣｌ３、ＤＭＳＯ－ｄ６、重水は市販品をそのまま使用した。 1 H and 13 C NMR were measured with a Bruker Avance 400 MHz nuclear magnetic resonance apparatus using TMS as an internal standard substance. Commercially available CDCl 3 , DMSO-d 6 and heavy water were used as they were.
　ＨＰＬＣ分析装置には、以下からなるシステムを主に使用した。
ポンプ：島津製作所ＬＣ－１０ＡＴ及びＬＣ－１０ＡＴｖｐ、
オートサンプラー：協和精密ＫＭＴ－１００Ｘ（注入量は特に記載のない限り１０μｌ）、
カラムオーブン：Ｓｈｏｄｅｘ　ＡＯ－３０Ｃ及びＧＬサイエンスＣ０６３１、スガイ製Ｕ－６２０、
ＵＶ検出器：島津ＳＰＤ－１０Ａ及びＳＰＤ－１０Ａｖｐ、
ＨＰＬＣコントローラー：島津製作所ＳＣＬ－１０Ａ及びＳＣＬ－１０Ａｖｐ。 The system consisting of the following was mainly used for the HPLC analyzer.
Pump: Shimadzu LC-10AT and LC-10ATvp,
Autosampler: Kyowa Precision KMT-100X (injection volume is 10 μl unless otherwise specified),
Column oven: Shodex AO-30C and GL Science C0631, Sugai U-620,
UV detector: Shimadzu SPD-10A and SPD-10Avp,
HPLC controller: Shimadzu Corporation SCL-10A and SCL-10Avp.
　ＨＰＬＣデータ解析処理装置には、ＧＬサイエンス製ＥＺ　ＣｈｒｏｍＥｌｉｔｅ　（Ｖｅｒ．　２．８．３、ビルド２２４９）と島津製作所製Ｃｌａｓｓ－ＶＰ　（バージョン６．１０）及び（株）島津製作所のＣＲ－７Ａｐｌｕｓとを使用した。 For the HPLC data analysis processor, GL Science's EZ ChromElite (Ver. 2.8.3, Build 2249), Shimadzu Class-VP (version 6.10), and Shimadzu Corporation CR-7Aplus were used. used.
　イオンクロマト（Ｃｌアニオン）には、米国ダイオネクス社製装置（ＤＩＯＮＥＸ、ＤＸ－１２０）を使用し、データ解析装置は島津製作所製ＣＲ－７Ａｐｌｕｓを用いた。
　イオンクロマト分析の溶離液には、１Ｍ　Ｎａ２ＣＯ３／１Ｍ　ＮａＨＣＯ３＝９／１を使用し、分析サンプルはイオンフリーの水に溶解させて分析した。塩化物イオン（Ｃｌ－）の標準品は塩化カリウムを使用した。 For ion chromatography (Cl anion), an apparatus (DIONEX, DX-120) manufactured by Dionex, Inc., USA was used, and CR-7 Plus manufactured by Shimadzu Corporation was used as a data analysis apparatus.
As an eluent for ion chromatography analysis, 1M Na 2 CO 3 / 1M NaHCO 3 = 9/1 was used, and an analysis sample was dissolved in ion-free water for analysis. Potassium chloride was used as a standard product of chloride ion (Cl − ).
　ＬＣ／ＭＳスペクトルには、ＵＰＬＣ／ＳＱＤシステム、ＭＳ検出器：ＳＱＤを使用した。 For LC / MS spectrum, UPLC / SQD system, MS detector: SQD was used.
　精密質量分析（ＨＲＭＳ）には、日本電子製ＭＳ７００Ｖ、ＦＡＢマトリックスはＹＯＫＵＥＤＬ－ＦＡＢ－Ｍａｔｒｉｘ（ｍ－ＮＢＡ／ＤＴＴの混合物）を使用した。 For accurate mass spectrometry (HRMS), MS700V manufactured by JEOL Ltd., and YOKUEDL-FAB-Matrix (mixture of m-NBA / DTT) was used as the FAB matrix.
　ｐＨ計には、ＨＯＲＩＢＡ製Ｄ－５２、電極には、ＨＯＲＩＢＡ製９６７８を使用した。ｐＨ標準液で校正を行ったものを使用した。 HORIBA D-52 was used for the pH meter, and HORIBA 9678 was used for the electrode. A sample calibrated with a pH standard solution was used.
　本実施例において、使用した原料及び試薬類はいずれも市販品を特に精製することなくそのまま使用した。 In this example, all the raw materials and reagents used were used as they were without purifying commercially available products.
　ＨＰＬＣ分析条件は、以下のとおりである。
溶離液組成：Ａ液－０．１％トリフルオロ酢酸水溶液、Ｂ液－０．１％トリフルオロ酢酸含有アセトニトリル、流速：１．０ｍＬ／ｍｉｎ
検出器：ＵＶ（２５４ｎｍ）、
使用カラム：逆相ＯＤＳシリカゲルカラム（資生堂製　ＣＡＰＣＥＬＬ　ＰＡＣ　ｔｙｐｅＭＧＩＩ、カラムサイズ：内径φ４．６ｍｍ×長１５０ｍｍ、５μｍ、或いは島津製　ＸＲ－ＯＤＳ　カラムサイズ：内径φ３．０ｍｍ×長７５ｍｍ　２．２μｍ）
カラム温度：４０℃
グラジエント分析条件：
（Ａ液／Ｂ液）＝初期（９９／１）～２５分後（１０／９０）～３０分後（１０／９０）、或いは
（Ａ液／Ｂ液）＝初期（９９／１）～１２分後（１０／９０）
、或いは
（Ａ液／Ｂ液）＝初期（９９／１）～２０分後（７０／３０）～３０分後（１０／９０）
サンプル注入量：１０μｌ The HPLC analysis conditions are as follows.
Eluent composition: A solution—0.1% trifluoroacetic acid aqueous solution, B solution—0.1% trifluoroacetic acid-containing acetonitrile, flow rate: 1.0 mL / min
Detector: UV (254 nm),
Column used: Reversed phase ODS silica gel column (Capsule PAC type MGII manufactured by Shiseido, column size: inner diameter φ4.6 mm × length 150 mm, 5 μm, or Shimadzu XR-ODS column size: inner diameter φ3.0 mm × length 75 mm 2.2 μm)
Column temperature: 40 ° C
Gradient analysis conditions:
(A liquid / B liquid) = initial (99/1) to 25 minutes later (10/90) to 30 minutes later (10/90), or (A liquid / B liquid) = initial (99/1) to 12 Minutes later (10/90)
Or (liquid A / liquid B) = initial (99/1) to 20 minutes later (70/30) to 30 minutes later (10/90)
Sample injection volume: 10 μl
実施例１：化合物（２）を、酸ハロゲン化試薬を用いて化合物（１）へと導いた後、化合物（１）を単離することなく、化合物（３）と縮合して化合物（４）を得る方法 Example 1: Compound (2) was led to compound (1) using an acid halogenating reagent, and then condensed with compound (3) without isolation of compound (1) to give compound (4) How to get
（１）：４－［イミノ（ピロリジン－１－イル）メチル］安息香酸　塩酸塩と３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩からの、２－（３－アミジノフェノキシ）エチル　４－［イミノ（ピロリジン－１－イル）メチル］ベンゾアート　二塩酸塩の合成 (1): 4- [Imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride and 3- (2-hydroxyethoxy) benzamidine hydrochloride, 2- (3-amidinophenoxy) ethyl 4- [imino ( Synthesis of pyrrolidin-1-yl) methyl] benzoate dihydrochloride
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060
　４－［イミノ（ピロリジン－１－イル）メチル］安息香酸　塩酸塩２４．７ｇに対しＮ－メチル－２－ピロリドン７０．０ｍｌを加えて８℃で攪拌した。次に、塩化チオニル７．４ｍｌを滴下して３０分以上攪拌した。ＨＰＬＣで反応終了を確認後、３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩２０．０ｇを二回に分けて加え、Ｎ－メチル－２－ピロリドン１０．０ｍｌで洗いこみ、１５℃に昇温して一晩攪拌した。反応終了をＨＰＬＣにて確認し、８℃に冷却した後、メタノール８０．０ｍｌを加えて反応を停止した。貧溶媒として酢酸メチルのかわりにアセトンを使用し、実施例１と同様に固体を取得した。室温で一晩減圧乾燥し表題化合物４１．４ｇ（正味量３６．４ｇ）を得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　９．６５－９．２６（ｍ，６Ｈ），８．１５－８．１０（ｍ，２Ｈ），７．８４－７．７９（ｍ，２Ｈ），７．６３－７．６０（ｍ，１Ｈ），７．５６－７．５０（ｍ，２Ｈ），７．３９－７．３３（ｍ，１Ｈ），４．７３－４．６７（ｍ，２Ｈ），４．５５－４．５０（ｍ，２Ｈ），３．６１（ｔ，２Ｈ，Ｊ＝６．９Ｈｚ），３．３５（ｔ，２Ｈ，Ｊ＝６．７Ｈｚ），２．１０－２．００（ｍ，２Ｈ），１．９０－１．８０（ｍ，２Ｈ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１６５．５０，１６４．９９，１６１．０６，１５８．４５，１３４．５７，１３２．３２，１３０．４９，１２９．７７，１２９．２１，１２８．６３，１２０．７４，１２０．６６，１１４．１５，６６．４７，６４．０５，５１．６１，４９．４４，２５．２６，２４．５９ 70.0 ml of N-methyl-2-pyrrolidone was added to 24.7 g of 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride and stirred at 8 ° C. Next, 7.4 ml of thionyl chloride was added dropwise and stirred for 30 minutes or more. After confirming the completion of the reaction by HPLC, 20.0 g of 3- (2-hydroxyethoxy) benzamidine hydrochloride was added in two portions, washed with 10.0 ml of N-methyl-2-pyrrolidone, and heated to 15 ° C. And stirred overnight. After completion of the reaction was confirmed by HPLC and cooled to 8 ° C., 80.0 ml of methanol was added to stop the reaction. Acetone was used in place of methyl acetate as a poor solvent, and a solid was obtained in the same manner as in Example 1. The residue was dried overnight at room temperature under reduced pressure to obtain 41.4 g (net amount 36.4 g) of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 9.65-9.26 (m, 6H), 8.15-8.10 (m, 2H), 7.84-7.79 (m, 2H), 7.63-7.60 (m, 1H), 7.56-7.50 (m, 2H), 7.39-7.33 (m, 1H), 4.73-4.67 ( m, 2H), 4.55-4.50 (m, 2H), 3.61 (t, 2H, J = 6.9 Hz), 3.35 (t, 2H, J = 6.7 Hz), 2. 10-2.00 (m, 2H), 1.90-1.80 (m, 2H)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 165.50, 164.99, 161.06, 158.45, 134.57, 132.32, 130.49, 129.77, 129.21, 128.63, 120.74, 120.66, 114.15, 66.47, 64.05, 51.61, 49.44, 25.26, 24.59
（２）：４－［イミノ（ピロリジン－１－イル）メチル］安息香酸　塩酸塩と４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩からの、２－［５－アミジノ－２－ヒドロキシフェノキシ］エチル　４－［イミノ（ピロリジン－１－イル）メチル］ベンゾアート　二塩酸塩の合成 (2): 2- [5-Amidino-2-hydroxy from 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride and 4-hydroxy-3- (2-hydroxyethoxy) benzamidine hydrochloride Synthesis of phenoxy] ethyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate dihydrochloride
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061
　４－［イミノ（ピロリジン－１－イル）メチル］安息香酸　塩酸塩１１．５ｇに対しＮ－メチル－２－ピロリドン３５．０ｍｌを加えて８℃で攪拌した。次に、塩化チオニル３．５ｍｌを徐々に加えた後、３０分以上攪拌した。ＨＰＬＣで反応終了確認後、４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩１０．０ｇを二回に分けて加えて、Ｎ－メチル－２－ピロリドン５．０ｍｌで洗いこみ、１５℃に昇温して一晩攪拌した。反応終了をＨＰＬＣにて確認し、８℃に冷却した後、メタノール１２０．０ｍｌで反応を停止した。アセトン１５５０．０ｍｌに対して反応終了液を滴下して一晩攪拌した後、懸濁液を減圧濾過し、アセトン１００ｍｌで洗浄して室温で一晩減圧乾燥し、表題化合物１１．３ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１０．６２（ｂｒ－ｓ，１Ｈ），９．６０－９．１０（ｍ，６Ｈ），８．１２－８．０７（ｍ，２Ｈ），７．８３－７．７８（ｍ，２Ｈ），７．７４（ｄ，１Ｈ，Ｊ＝２．１Ｈｚ），７．５４－７．４８（ｍ，１Ｈ），７．１０（ｄ，１Ｈ，Ｊ＝８．４Ｈｚ），４．７０－４．６５（ｍ，２Ｈ），４．５５－４．４５（ｍ，２Ｈ），３．６１（ｔ，２Ｈ，Ｊ＝６．９Ｈｚ），３．３５（ｔ，２Ｈ，Ｊ＝６．７Ｈｚ），２．１０－２．００（ｍ，２Ｈ），１．９１－１．８１（ｍ，２Ｈ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１６５．０６，１６４．８５，１６１．０９，１５３．０６，１４６．６７，１３４．５３，１３２．４５，１２９．７９，１２８．６２，１２２．９５，１１７．４８，１１５．９８，１１４．７０，６７．２８，６４．４２，５１．７０，４９．５８，２５．３１，２４．６３ To 11.5 g of 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride, 35.0 ml of N-methyl-2-pyrrolidone was added and stirred at 8 ° C. Next, 3.5 ml of thionyl chloride was gradually added, followed by stirring for 30 minutes or more. After confirming the completion of the reaction by HPLC, 10.0 g of 4-hydroxy-3- (2-hydroxyethoxy) benzamidine hydrochloride was added in two portions, washed with 5.0 ml of N-methyl-2-pyrrolidone, and 15 ° C. The mixture was warmed to rt and stirred overnight. After the completion of the reaction was confirmed by HPLC and cooled to 8 ° C., the reaction was stopped with 120.0 ml of methanol. The reaction completion liquid was added dropwise to 1550.0 ml of acetone and stirred overnight, and then the suspension was filtered under reduced pressure, washed with 100 ml of acetone and dried under reduced pressure at room temperature overnight to obtain 11.3 g of the title compound. .
1 H-NMR (400 MHz, DMSO-d 6 ): δ 10.62 (br-s, 1H), 9.60-9.10 (m, 6H), 8.12-8.07 (m, 2H) 7.83-7.78 (m, 2H), 7.74 (d, 1H, J = 2.1 Hz), 7.54-7.48 (m, 1H), 7.10 (d, 1H, J = 8.4 Hz), 4.70-4.65 (m, 2H), 4.55-4.45 (m, 2H), 3.61 (t, 2H, J = 6.9 Hz), 3. 35 (t, 2H, J = 6.7 Hz), 2.10-2.00 (m, 2H), 1.91-1.81 (m, 2H)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 165.06, 164.85, 161.09, 153.06, 146.67, 134.53, 132.45, 129.79, 128.62, 122.95, 117.48, 115.98, 114.70, 67.28, 64.42, 51.70, 49.58, 25.31, 24.63
（３）：４－［イミノ（ピロリジン－１－イル）メチル］安息香酸　塩酸塩と３－（２－ヒドロキシエトキシ）－４－メトキシベンズアミジン　塩酸塩からの、２－（５－アミジノ－２－メトキシフェノキシ）エチル　４－［イミノ（ピロリジン－１－イル）メチル］ベンゾアート　二塩酸塩の合成 (3): 2- [5-Amidino-2- from 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride and 3- (2-hydroxyethoxy) -4-methoxybenzamidine hydrochloride Synthesis of methoxyphenoxy) ethyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate dihydrochloride
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062
　４－［イミノ（ピロリジン－１－イル）メチル］安息香酸　塩酸塩２１．７ｇに対し、Ｎ－メチル－２－ピロリドン７０．０ｍｌを加えて８℃で攪拌した。次に、塩化チオニル６．５ｍｌを徐々に加えた後、３０分以上攪拌した。ＨＰＬＣで反応終了を確認した後、３－（２－ヒドロキシエトキシ）－４－メトキシベンズアミジン　塩酸塩２０．０ｇを二回に分けて加え、Ｎ－メチル－２－ピロリドン１０．０ｍｌで洗いこみ、１５℃に昇温して一晩攪拌した。反応終了をＨＰＬＣにて確認し、８℃に冷却した後、メタノール８０．０ｍｌを加えて反応を停止した。酢酸メチルを１８４．０ｍｌ加えて６時間以上攪拌し、懸濁液を減圧濾過して、メタノール／酢酸メチル＝１／４（ボリューム比）の混合液８０ｍｌで洗浄した。濾過物を８０℃で一晩減圧乾燥し、表題化合物３８．２ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　９．６０－９．１０（ｍ，６Ｈ），８．１３－８．０８（ｍ，２Ｈ），７．８４－７．７８（ｍ，２Ｈ），７．７３（ｄ，１Ｈ，Ｊ＝２．２Ｈｚ），７．６６－７．６１（ｍ，１Ｈ），７．１９（ｄ，１Ｈ，Ｊ＝８．７Ｈｚ），４．７１－４．６６（ｍ，２Ｈ），４．５５－４．５０（ｍ，２Ｈ），３．８５（ｓ，３Ｈ），３．６０（ｔ，２Ｈ，Ｊ＝７．０Ｈｚ），３．３５（ｔ，２Ｈ，Ｊ＝６．７Ｈｚ），２．１０－２．００（ｍ，２Ｈ），１．９１－１．８１（ｍ，２Ｈ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１６４．９８，１６４．７２，１６１．０８，１５３．８２，１４７．５８，１３４．５４，１３２．３９，１２９．７７，１２８．５９，１２２．７５，１１９．３１，１１３．６０，１１２．０６，６７．２５，６４．１９，５６．１９，５１．６３，４９．３９，２５．２７，２４．５９ To 21.7 g of 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride, 70.0 ml of N-methyl-2-pyrrolidone was added and stirred at 8 ° C. Next, after gradually adding 6.5 ml of thionyl chloride, the mixture was stirred for 30 minutes or more. After confirming the completion of the reaction by HPLC, 20.0 g of 3- (2-hydroxyethoxy) -4-methoxybenzamidine hydrochloride was added in two portions and washed with 10.0 ml of N-methyl-2-pyrrolidone. The temperature was raised to 15 ° C. and stirred overnight. After completion of the reaction was confirmed by HPLC and cooled to 8 ° C., 80.0 ml of methanol was added to stop the reaction. 184.0 ml of methyl acetate was added and stirred for 6 hours or more. The suspension was filtered under reduced pressure and washed with 80 ml of a mixed solution of methanol / methyl acetate = 1/4 (volume ratio). The filtrate was dried under reduced pressure at 80 ° C. overnight to obtain 38.2 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 9.60-9.10 (m, 6H), 8.13-8.08 (m, 2H), 7.84-7.78 (m, 2H), 7.73 (d, 1H, J = 2.2 Hz), 7.66-7.61 (m, 1H), 7.19 (d, 1H, J = 8.7 Hz), 4.71- 4.66 (m, 2H), 4.55-4.50 (m, 2H), 3.85 (s, 3H), 3.60 (t, 2H, J = 7.0 Hz), 3.35 ( t, 2H, J = 6.7 Hz), 2.10-2.00 (m, 2H), 1.91-1.81 (m, 2H)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 164.98, 164.72, 161.08, 153.82, 147.58, 134.54, 132.39, 129.77, 128.59, 122.75, 119.31, 113.60, 112.06, 67.25, 64.19, 56.19, 51.63, 49.39, 25.27, 24.59
（４）：４－［イミノ（ピロリジン－１－イル）メチル］安息香酸　塩酸塩と４－エトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩からの、２－（５－アミジノ－２－エトキシフェノキシ）エチル　４－［イミノ（ピロリジン－１－イル）メチル］ベンゾアート　二塩酸塩の合成 (4): 2- [5-Amidino-2-ethoxy from 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride and 4-ethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride Synthesis of phenoxy) ethyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate dihydrochloride
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063
　４－［イミノ（ピロリジン－１－イル）メチル］安息香酸　塩酸塩１８．７９ｇ、Ｎ－メチル－２－ピロリドン７０ｍｌを加え、８℃で攪拌した。塩化チオニル５．６４ｍｌを４０分かけて滴下し、８℃で１時間攪拌した。ＨＰＬＣで反応終了を確認した後、４－エトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩２０．０ｇを２分割して投入した後、Ｎ－メチル－２－ピロリドン５ｍｌで洗い込みを行い、１５℃で１８時間攪拌した。ＨＰＬＣで反応終了確認後、８℃に冷却し、８０．０ｍｌ、酢酸メチル１８４ｍｌを加えて２時間熟成させた。スラリーを減圧濾過し、メタノール／ＡｃＯＭｅ＝１／４（ボリューム比）１００ｍｌで洗浄した後、８０℃で１８時間減圧乾燥して表題化合物３５．４ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　９．７０－９．２０（ｍ，６Ｈ），８．１１－８．０７（ｍ，２Ｈ），７．８３－７．８０（ｍ，３Ｈ），７．６７－７．６４（ｍ，１Ｈ），７．１７（ｄ，１Ｈ，Ｊ＝８．７Ｈｚ），４．７５－４．５０（ｍ，４Ｈ），４．１２　（ｑ，２Ｈ，Ｊ＝７．０Ｈｚ），３．６２（ｔ，２Ｈ，Ｊ＝６．９Ｈｚ），３　．３６（ｔ，２Ｈ，Ｊ＝６．７Ｈｚ），２．０８－２．０２（ｍ，２Ｈ），１．９３－１．８５（ｍ，２Ｈ），１．２９（ｔ，３Ｈ，Ｊ＝７．０Ｈｚ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１６４．９２，１６４．７３，１６１．０５，１５３．２５，１４７．７０，１３４．５４，１３２．４０，１２９．７２，１２８．５８，１２２．８９，１１９．１３，１１４．３５，１１３．０２，６７．３９，６４．４２，６４．１８，５１．６２，４９．４９，２５．２７，２４．５９，１４．６２ 4- [Imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride (18.79 g) and N-methyl-2-pyrrolidone (70 ml) were added, and the mixture was stirred at 8 ° C. 5.64 ml of thionyl chloride was added dropwise over 40 minutes and stirred at 8 ° C. for 1 hour. After confirming the completion of the reaction by HPLC, 20.0 g of 4-ethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride was added in two portions, followed by washing with 5 ml of N-methyl-2-pyrrolidone. Stir at 15 ° C. for 18 hours. After confirming the completion of the reaction by HPLC, the mixture was cooled to 8 ° C., 80.0 ml and 184 ml of methyl acetate were added and aged for 2 hours. The slurry was filtered under reduced pressure, washed with 100 ml of methanol / AcOMe = 1/4 (volume ratio), and then dried under reduced pressure at 80 ° C. for 18 hours to obtain 35.4 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 9.70-9.20 (m, 6H), 8.11-8.07 (m, 2H), 7.83-7.80 (m, 3H), 7.67-7.64 (m, 1H), 7.17 (d, 1H, J = 8.7 Hz), 4.75-4.50 (m, 4H), 4.12 (q, 2H, J = 7.0 Hz), 3.62 (t, 2H, J = 6.9 Hz), 3. 36 (t, 2H, J = 6.7 Hz), 2.08-2.02 (m, 2H), 1.93-1.85 (m, 2H), 1.29 (t, 3H, J = 7 .0Hz)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 164.92, 164.73, 161.05, 153.25, 147.70, 134.54, 132.40, 129.72, 128.58, 122.89, 119.13, 114.35, 113.02, 67.39, 64.42, 64.18, 51.62, 49.49, 25.27, 24.59, 14.62
（５）：４－［イミノ（ピロリジン－１－イル）メチル］安息香酸　塩酸塩と３－（２－ヒドロキシエトキシ）－４－（２－メチルプロポキシ）ベンズアミジン　塩酸塩からの、２－［５－アミジノ－２－（２－メチルプロポキシ）フェノキシ］エチル　４－［イミノ（ピロリジン－１－イル）メチル］ベンゾアート　二塩酸塩の合成 (5): 2- [5- [Imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride and 3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzamidine hydrochloride Synthesis of amidino-2- (2-methylpropoxy) phenoxy] ethyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate dihydrochloride
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064
　４－［イミノ（ピロリジン－１－イル）メチル］安息香酸　塩酸塩１．９ｇに対しＮ－メチル－２－ピロリドン７．０ｍｌを加えて８℃で攪拌した。次に、塩化チオニル０．６ｍｌを徐々に加えた後、３０分以上攪拌した。ＨＰＬＣで反応終了確認後、３－（２－ヒドロキシエトキシ）－４－（２－メチルプロポキシ）ベンズアミジン　塩酸塩２．０ｇを二回に分けて加え、Ｎ－メチル－２－ピロリドン１．０ｍｌで洗いこみ、１５℃に昇温して一晩攪拌した。反応終了をＨＰＬＣにて確認し、８℃に冷却した後、メタノール８．０ｍｌ、酢酸メチル１８．４ｍｌを加えて６時間以上攪拌した。懸濁液を減圧濾過し、メタノール／酢酸エチル＝１／４（ボリューム比）混合液８ｍｌで洗浄し、８０℃で一晩減圧乾燥して表題化合物３．５ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　９．５５－９．１０（ｍ，６Ｈ），８．１２－８．０６（ｍ，２Ｈ），７．８３－７．７７（ｍ，２Ｈ），７．７２（ｄ，１Ｈ，Ｊ＝２．２Ｈｚ），７．６３－７．５７（ｍ，１Ｈ），７．１７（ｄ，１Ｈ，Ｊ＝８．７Ｈｚ），４．７４－４．６６（ｍ，２Ｈ），４．５６－４．４８（ｍ，２Ｈ），３．８３（ｄ，２Ｈ，Ｊ＝６．６Ｈｚ），３．６０（ｔ，２Ｈ，Ｊ＝６．９Ｈｚ），３．３４（ｔ，２Ｈ，Ｊ＝６．７Ｈｚ），２．１０－１．８２（ｍ，５Ｈ），０．９１（ｄ，６Ｈ，Ｊ＝６．７Ｈｚ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１６４．８７，１６４．７１，１６１．０７，１５３．５３，１４７．８２，１３４．５３，１３２．４０，１２９．７２，１２８．５０，１２２．８４，１１９．２４，１１４．２５，１１３．２３，７４．７８，６７．３７，６４．０７，５１．６０，４９．３８，２７．７９，２５．２４，２４．５９，１９．００ 7.0 ml of N-methyl-2-pyrrolidone was added to 1.9 g of 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride and stirred at 8 ° C. Next, 0.6 ml of thionyl chloride was gradually added, followed by stirring for 30 minutes or more. After confirming the completion of the reaction by HPLC, 2.0 g of 3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzamidine hydrochloride was added in two portions and washed with 1.0 ml of N-methyl-2-pyrrolidone. The mixture was heated to 15 ° C. and stirred overnight. After completion of the reaction was confirmed by HPLC and cooled to 8 ° C., 8.0 ml of methanol and 18.4 ml of methyl acetate were added and stirred for 6 hours or more. The suspension was filtered under reduced pressure, washed with 8 ml of a methanol / ethyl acetate = 1/4 (volume ratio) mixture, and dried under reduced pressure at 80 ° C. overnight to obtain 3.5 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 9.55-9.10 (m, 6H), 8.12-8.06 (m, 2H), 7.83-7.77 (m, 2H), 7.72 (d, 1H, J = 2.2 Hz), 7.63-7.57 (m, 1H), 7.17 (d, 1H, J = 8.7 Hz), 4.74- 4.66 (m, 2H), 4.56-4.48 (m, 2H), 3.83 (d, 2H, J = 6.6 Hz), 3.60 (t, 2H, J = 6.9 Hz) ), 3.34 (t, 2H, J = 6.7 Hz), 2.10-1.82 (m, 5H), 0.91 (d, 6H, J = 6.7 Hz)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 164.87, 164.71, 161.07, 153.53, 147.82, 134.53, 132.40, 129.72, 128.50, 122.84, 119.24, 114.25, 113.23, 74.78, 67.37, 64.07, 51.60, 49.38, 27.79, 25.24, 24.59, 19. 00
（６）：４－［イミノ（ピロリジン－１－イル）メチル］安息香酸　塩酸塩と４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩とから、２－［５－アミジノ－２－（シアノメトキシ）フェノキシ］エチル　４－［イミノ（ピロリジン－１－イル）メチル］ベンゾアート　二塩酸塩を合成する方法 (6): 4- [Imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride and 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride are converted into 2- [5-amidino-2- (Cyanomethoxy) phenoxy] ethyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate dihydrochloride
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065
　４－［イミノ（ピロリジン－１－イル）メチル］安息香酸　塩酸塩　１．４０ｋｇ（正味量１．３８ｋｇ）に対し、Ｎ－メチル－２－ピロリドン（ＮＭＰ）４．９Ｌを加えて８℃で攪拌した。得られたスラリーに対して塩化チオニル０．４４Ｌを１時間かけて滴下し、さらに３時間攪拌した。次に４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩１．４７ｋｇ（正味量１．４０ｋｇ）を加え、１５℃で１８時間攪拌した。ＨＰＬＣで反応終了を確認した後、８℃に冷却し、メタノール５．６Ｌを加えてクエンチを行った後、酢酸メチル１２．９Ｌを加えて８℃で一晩攪拌した。反応混合液を遠心分離機でろ過した後、メタノール／酢酸メチル＝１／４の混合液５．６Ｌで洗浄し、８０℃で一晩減圧乾燥して、２－［５－アミジノ－２－（シアノメトキシ）フェノキシ］エチル　４－［イミノ（ピロリジン－１－イル）メチル］ベンゾアート　二塩酸塩を２．２９ｋｇ（正味量２．１６ｋｇ）得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　９．６０－８．９０（ｍ，６Ｈ），８．１１（ｄ，２Ｈ，Ｊ＝８．３Ｈｚ），７．８９（ｄ，１Ｈ，Ｊ＝２．０Ｈｚ），７．８２（ｄ，２Ｈ，Ｊ＝８．６Ｈｚ），７．６９（ｄｄ，１Ｈ，Ｊ＝８．６および２．３Ｈｚ），７．３８（ｄ，１Ｈ，Ｊ＝８．６Ｈｚ），５．３０（ｓ，２Ｈ），４．７５－４．６８（ｍ，２Ｈ），４．６５－４．５８（ｍ，２Ｈ），３．６７－３．５７（ｍ，２Ｈ），３．４０－３．３２（ｍ，２Ｈ），２．１０－２．００（ｍ，２Ｈ），１．９２－１．８１（ｍ，２Ｈ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１６４．９７，１６４．６７，１６１．０６，１５０．２０，１４８．０８，１３４．５４，１３２．３７，１２９．７６，１２８．６０，１２２．２７，１２１．８９，１１６．４２，１１４．３９，６７．４３，６４．０５，５４．５５，５１．６４，４９．４８，２５．２７，２４．６０
ＭＳ　（ＦＡＢ＋）：　ｍ／ｚ　４３６（Ｍ＋Ｈ＋）
ＨＲＭＳ（ＦＡＢ＋）：ｃａｌｃｄ　ｆｏｒ　Ｃ２３Ｈ２５Ｎ５Ｏ４　ｍ／ｚ　４３６．１９８５（Ｍ＋Ｈ＋），ｆｏｕｎｄ　ｍ／ｚ　４３６．１９９４（Ｍ＋Ｈ＋） 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride 1.40 kg (net amount 1.38 kg) was added with 4.9 L of N-methyl-2-pyrrolidone (NMP) and stirred at 8 ° C. did. To the resulting slurry, 0.44 L of thionyl chloride was added dropwise over 1 hour, and the mixture was further stirred for 3 hours. Next, 1.47 kg (net amount 1.40 kg) of 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride was added, and the mixture was stirred at 15 ° C. for 18 hours. After confirming the completion of the reaction by HPLC, the reaction mixture was cooled to 8 ° C., quenched by adding 5.6 L of methanol, added with 12.9 L of methyl acetate, and stirred at 8 ° C. overnight. The reaction mixture was filtered with a centrifuge, washed with 5.6 L of a mixture of methanol / methyl acetate = 1/4, dried under reduced pressure at 80 ° C. overnight, and 2- [5-amidino-2- ( There were obtained 2.29 kg (net amount 2.16 kg) of cyanomethoxy) phenoxy] ethyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate dihydrochloride.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 9.60-8.90 (m, 6H), 8.11 (d, 2H, J = 8.3 Hz), 7.89 (d, 1H, J = 2.0 Hz), 7.82 (d, 2H, J = 8.6 Hz), 7.69 (dd, 1H, J = 8.6 and 2.3 Hz), 7.38 (d, 1H, J = 8.6 Hz), 5.30 (s, 2H), 4.75-4.68 (m, 2H), 4.65-4.58 (m, 2H), 3.67-3.57 (m) , 2H), 3.40-3.32 (m, 2H), 2.10-2.00 (m, 2H), 1.92-1.81 (m, 2H)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 164.97, 164.67, 161.06, 150.20, 148.08, 134.54, 132.37, 129.76, 128.60, 122.27, 121.89, 116.42, 114.39, 67.43, 64.05, 54.55, 51.64, 49.48, 25.27, 24.60
MS (FAB +): m / z 436 (M + H + )
HRMS (FAB +): calcd for C 23 H 25 N 5 O 4 m / z 436.1985 (M + H +), found m / z 436.1994 (M + H +)
実施例２：化合物（２）を、酸ハロゲン化試薬を用いて化合物（１）へと導き、これを単離したのち化合物（３）と縮合させて化合物（４）を得る方法
（１）：４－［イミノ（ピロリジン－１－イル）メチル］安息香酸　塩酸塩からの、４－［イミノ（ピロリジン－１－イル）メチル］安息香酸クロリド　塩酸塩の合成 Example 2: Method (1): Compound (2) is led to Compound (1) using an acid halogenating reagent, isolated and then condensed with Compound (3) to obtain Compound (4): Synthesis of 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride from 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066
　４－［イミノ（ピロリジン－１－イル）メチル］安息香酸　塩酸塩　２０．０ｇに対し、塩化チオニル１０．０ｍｌを加えて８０℃に加熱し、攪拌した。次に１，３－ジメチル－２－イミダゾリジノン（ＤＭＩ）を１～２滴加えて１時間以上攪拌した。ＨＰＬＣで反応終了を確認した後、酢酸エチル２００ｍｌを加えた。さらに酢酸エチルを１００ｍｌ加えた後、室温に冷却して１時間以上攪拌した。反応混合液を減圧濾過し、酢酸エチル４０ｍｌで洗浄した後、４０℃で一晩乾燥して表題化合物を２０．０７ｇ得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）：δ　１０．５０－１０．００（ｍ，２Ｈ），８．２５（ｄ，２Ｈ，Ｊ＝８．０Ｈｚ），７．７８（ｄ，２Ｈ，Ｊ＝８．２Ｈｚ），４．１０－３．９０（ｍ，２Ｈ），３．５０－３．３０（ｍ，２Ｈ），２．３０－２．１０（ｍ，２Ｈ），２．００－１．８０（ｍ，２Ｈ） To 20.0 g of 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride, 10.0 ml of thionyl chloride was added and heated to 80 ° C. and stirred. Next, 1 or 2 drops of 1,3-dimethyl-2-imidazolidinone (DMI) was added and stirred for 1 hour or longer. After confirming the completion of the reaction by HPLC, 200 ml of ethyl acetate was added. Furthermore, after adding 100 ml of ethyl acetate, it cooled to room temperature and stirred for 1 hour or more. The reaction mixture was filtered under reduced pressure, washed with 40 ml of ethyl acetate, and then dried overnight at 40 ° C. to obtain 20.07 g of the title compound.
1 H-NMR (400MHz, CDCl 3): δ 10.50-10.00 (m, 2H), 8.25 (d, 2H, J = 8.0Hz), 7.78 (d, 2H, J = 8.2 Hz), 4.10-3.90 (m, 2H), 3.50-3.30 (m, 2H), 2.30-2.10 (m, 2H), 2.00-1. 80 (m, 2H)
（２）：４－［イミノ（ピロリジン－１－イル）メチル］安息香酸クロリド　塩酸塩と４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩とからの、２－［５－アミジノ－２－（シアノメトキシ）フェノキシ］エチル　４－［イミノ（ピロリジン－１－イル）メチル］ベンゾアート　二塩酸塩の合成 (2): 2- [5-Amidino- from 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride and 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride Synthesis of 2- (cyanomethoxy) phenoxy] ethyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate dihydrochloride
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000067
　４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩　２０．０ｇに対しＮ－メチル－２－ピロリドン（ＮＭＰ）６０ｍｌを加え、１５℃で攪拌した。次に、合計２２．１ｇの４－［イミノ（ピロリジン－１－イル）メチル］安息香酸クロリド　塩酸塩を３分割で加えて、１５℃で一晩攪拌した。ＨＰＬＣで反応終了を確認した後、エタノール５０ｍｌを加えてクエンチを行った。この反応終了液を酢酸エチル７５０ｍｌ、エタノール５０ｍｌをあらかじめ加えた別の容器にゆっくりと滴下し、エタノール５ｍｌで洗浄した後、１５℃で一晩攪拌した。その後、反応混合液を減圧濾過し、酢酸エチル１００ｍｌで洗浄した後、室温で４時間減圧乾燥し、表題化合物を４１．４ｇ得た（正味量３６．５ｇ）。 60 ml of N-methyl-2-pyrrolidone (NMP) was added to 20.0 g of 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride and stirred at 15 ° C. Next, a total of 22.1 g of 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride was added in three portions and stirred at 15 ° C. overnight. After confirming the completion of the reaction by HPLC, 50 ml of ethanol was added to quench the reaction. This reaction-terminated liquid was slowly added dropwise to another container in which 750 ml of ethyl acetate and 50 ml of ethanol had been added in advance, washed with 5 ml of ethanol, and then stirred at 15 ° C. overnight. Thereafter, the reaction mixture was filtered under reduced pressure, washed with 100 ml of ethyl acetate, and then dried under reduced pressure at room temperature for 4 hours to obtain 41.4 g of the title compound (net amount 36.5 g).
実施例３：化合物（２）と化合物（３）を、縮合剤を用いて縮合し、化合物（４）を得る方法
　４－［イミノ（ピロリジン－１－イル）メチル］安息香酸　塩酸塩と、４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩とからの、２－［５－アミジノ－２－（シアノメトキシ）フェノキシ］エチル　４－［イミノ（ピロリジン－１－イル）メチル］ベンゾアート　二塩酸塩の合成 Example 3: Method of condensing compound (2) and compound (3) using a condensing agent to obtain compound (4) 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride and 4 2- [5-Amidino-2- (cyanomethoxy) phenoxy] ethyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate from cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride Synthesis of dihydrochloride
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068
　４－［イミノ（ピロリジン－１－イル）メチル］安息香酸　塩酸塩　１２７．４ｍｇに対し、ジシクロヘキシルカルボジイミド　１１３．６ｍｇとヘキサメチルリン酸トリアミド（ＨＭＰＡ）２ｍｌを加えて２５℃で攪拌した。次に、４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩１３５．９ｍｇと４－ジメチルアミノピリジン（ＤＭＡＰ）７ｍｇとを加えて、二晩攪拌した。ＬＣ／ＭＳにて縮合剤を用いた２－［５－アミジノ－２－（シアノメトキシ）フェノキシ］エチル　４－［イミノ（ピロリジン－１－イル）メチル］ベンゾアート　二塩酸塩の生成を確認した。 To 117.4 mg of 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride, 113.6 mg of dicyclohexylcarbodiimide and 2 ml of hexamethylphosphoric triamide (HMPA) were added and stirred at 25 ° C. Next, 135.9 mg of 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride and 7 mg of 4-dimethylaminopyridine (DMAP) were added, and the mixture was stirred overnight. The formation of 2- [5-amidino-2- (cyanomethoxy) phenoxy] ethyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate dihydrochloride using a condensing agent was confirmed by LC / MS.
実施例４：化合物（５）と化合物（３）とを、エステル交換反応を利用して縮合させ、化合物（４）を得る方法
（１）：４－［イミノ（ピロリジン－１－イル）メチル］安息香酸クロリド　塩酸塩からの、４－［イミノ（ピロリジン－１－イル）メチル］安息香酸メチル　塩酸塩の合成 Example 4: Method of obtaining compound (4) by condensing compound (5) and compound (3) using transesterification (1): 4- [imino (pyrrolidin-1-yl) methyl] Synthesis of methyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate hydrochloride from benzoic acid chloride hydrochloride
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069
　４－［イミノ（ピロリジン－１－イル）メチル］安息香酸クロリド　塩酸塩１．０ｇに対し、メタノール２０ｍｌを加えて１５℃で１時間攪拌した。メタノールが飛びきるまで濃縮し、アセトン１０ｍｌと種晶を加えて１５℃で１時間攪拌した。スラリーを減圧濾過し、アセトン２ｍｌで洗浄した後、８０℃で減圧乾燥して表題化合物０．５５ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　９．７０－９．００（ｍ，２Ｈ），８．１８－８．１０（ｍ，２Ｈ），７．８５－７．７５（ｍ，２Ｈ），３．９１（ｓ，３Ｈ），３．６５－３．５５（ｍ，２Ｈ），３．４０－３．３０（ｍ，２Ｈ），２．１０－２．００（ｍ，２Ｈ），１．９２－１．８０（ｍ，２Ｈ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１６５．５６，１６１．１０，１３４．４４，１３２．５０，１２９．７１，１２８．５５，５２．７８，５１．５９，４９．３７，２５．２３，２４．５８ To 1.0 g of 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride, 20 ml of methanol was added and stirred at 15 ° C. for 1 hour. The mixture was concentrated until the methanol was released, 10 ml of acetone and seed crystals were added, and the mixture was stirred at 15 ° C. for 1 hour. The slurry was filtered under reduced pressure, washed with 2 ml of acetone, and then dried under reduced pressure at 80 ° C. to obtain 0.55 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 9.70-9.00 (m, 2H), 8.18-8.10 (m, 2H), 7.85-7.75 (m, 2H), 3.91 (s, 3H), 3.65-3.55 (m, 2H), 3.40-3.30 (m, 2H), 2.10-2.00 (m, 2H) , 1.92-1.80 (m, 2H)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 165.56, 161.10, 134.44, 132.50, 129.71, 128.55, 52.78, 51.59, 49.37, 25.23, 24.58
（２）：４－［イミノ（ピロリジン－１－イル）メチル］安息香酸メチル　塩酸塩と４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩とからの、２－［５－アミジノ－２－（シアノメトキシ）フェノキシ］エチル　４－［イミノ（ピロリジン－１－イル）メチル］ベンゾアート　二塩酸塩の合成 (2): 2- [5-Amidino- from methyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate hydrochloride and 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride Synthesis of 2- (cyanomethoxy) phenoxy] ethyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate dihydrochloride
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070
　４－［イミノ（ピロリジン－１－イル）メチル］安息香酸メチル　塩酸塩１．０ｇ、４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩１．２ｇに対し、Ｎ－メチル－２－ピロリドン４．０ｍｌ、４Ｍ　ＨＣｌ／シクロペンチルメチルエーテル２．０ｍｌを加えて８０℃で１時間攪拌した。その後、１２０℃に昇温し、４Ｍ　ＨＣｌ／シクロペンチルメチルエーテル４．０ｍｌを加えて1時間攪拌し、ＨＰＬＣ及びＬＣ／ＭＳにて表題化合物の生成を確認した。 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride 1.0 g, 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride 1.2 g, N-methyl-2- Pyrrolidone 4.0 ml, 4 M HCl / cyclopentyl methyl ether 2.0 ml was added and stirred at 80 ° C. for 1 hour. Thereafter, the temperature was raised to 120 ° C., 4.0 ml of 4M HCl / cyclopentyl methyl ether was added, and the mixture was stirred for 1 hour, and production of the title compound was confirmed by HPLC and LC / MS.
実施例５：
３－ヒドロキシ－４－メトキシベンズアルデヒド（イソバニリン）からの、４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩の合成
（１）：イソバニリンからの、３－ヒドロキシ－４－メトキシベンゾニトリルの合成 Example 5:
Synthesis of 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride from 3-hydroxy-4-methoxybenzaldehyde (isovanillin) (1): Synthesis of 3-hydroxy-4-methoxybenzonitrile from isovanillin Composition
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000071
　イソバニリン１００ｇに対し、ギ酸ナトリウム８３．１ｇ、ギ酸４５０ｍｌを加えて８５℃付近まで加熱した。次に約１０分間隔でヒドロキシルアミン硫酸塩５９．２ｇを３分割して投入した。３時間後、ＨＰＬＣで反応終了を確認し、１０℃まで冷却した。ここに塩化ナトリウム３８４．１ｇを水１９００ｍｌに溶解させた塩化ナトリウム水溶液を１時間かけて滴下し、さらに５時間以上攪拌した。反応混合液を減圧濾過で分離し、水３００ｍｌで洗浄を行い、表題化合物を１１５．４ｇ得た（正味量９１．３ｇ）。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　９．８１（ｓ，１Ｈ），７．２７（ｄｄ，１Ｈ，Ｊ＝２．０および８．４Ｈｚ），７．１２（ｄ，１Ｈ，Ｊ＝２．０Ｈｚ），７．０８（ｄ，１Ｈ，Ｊ＝８．４Ｈｚ），３．８６（ｓ，３Ｈ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１５２．１６，１４７．２０，１２４．９０，１１９．４４，１１８．０１，１１２．７２，１０２．８１，５５．９６
ＭＳ（ＦＡＢ＋）：ｍ／ｚ　１５０（Ｍ＋Ｈ＋）
ＨＲＭＳ（ＦＡＢ＋）：ｃａｌｃｄ　ｆｏｒ　Ｃ８Ｈ７ＮＯ２　ｍ／ｚ　１５０．０５５５（Ｍ＋Ｈ＋），ｆｏｕｎｄ　ｍ／ｚ　１５０．０５４９（Ｍ＋Ｈ＋） To 100 g of isovanillin, 83.1 g of sodium formate and 450 ml of formic acid were added and heated to around 85 ° C. Next, 59.2 g of hydroxylamine sulfate was added in three divided portions at intervals of about 10 minutes. After 3 hours, the completion of the reaction was confirmed by HPLC, and cooled to 10 ° C. A sodium chloride aqueous solution in which 384.1 g of sodium chloride was dissolved in 1900 ml of water was added dropwise over 1 hour, and the mixture was further stirred for 5 hours or more. The reaction mixture was separated by filtration under reduced pressure and washed with 300 ml of water to obtain 115.4 g of the title compound (net amount: 91.3 g).
1 H-NMR (400 MHz, DMSO-d 6 ): δ 9.81 (s, 1H), 7.27 (dd, 1H, J = 2.0 and 8.4 Hz), 7.12 (d, 1H, J = 2.0 Hz), 7.08 (d, 1H, J = 8.4 Hz), 3.86 (s, 3H)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 152.16, 147.20, 124.90, 119.44, 118.01, 112.72, 102.81, 55.96
MS (FAB +): m / z 150 (M + H + )
HRMS (FAB +): calcd for C 8 H 7 NO 2 m / z 150.0555 (M + H + ), found m / z 150.0549 (M + H + )
（２）：３－ヒドロキシ－４－メトキシベンゾニトリルからの、３－（２－ヒドロキシエトキシ）－４－メトキシベンゾニトリルの合成 (2): Synthesis of 3- (2-hydroxyethoxy) -4-methoxybenzonitrile from 3-hydroxy-4-methoxybenzonitrile
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000072
　３－ヒドロキシ－４－メトキシベンゾニトリル５６．２ｇ（正味量４６．５ｇ）に対し、水２２３ｍｌ、２－クロロエタノール４１．８ｍｌ、水酸化ナトリウム２１．０ｇを加え、６０℃付近にまで加熱して５時間以上攪拌した。ＨＰＬＣで反応終了を確認した後、１０℃まで冷却し、一晩攪拌を行った。反応混合液を減圧濾過で分離し、水９３ｍｌで洗浄した後、６０℃で一晩減圧乾燥して表題化合物５８．１ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　７．４４－７．３８（ｍ，２Ｈ），７．１２（ｄ，１Ｈ，Ｊ＝８．１Ｈｚ），４．８８（ｔ，１Ｈ，Ｊ＝５．４Ｈｚ），４．０５－４．０２（ｍ，２Ｈ），３．８５（ｓ，３Ｈ），３．７６－３．６８（ｍ，２Ｈ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１５３．１１，１４８．５０，１２６．５５，１１９．４４，１１５．６２，１１２．４２，１０２．７３，７０．７０，５９．５５，５５．９３
ＭＳ（ＦＡＢ＋）：ｍ／ｚ　１９４（Ｍ＋Ｈ＋）
ＨＲＭＳ（ＦＡＢ＋）：ｃａｌｃｄ　ｆｏｒ　Ｃ１０Ｈ１１ＮＯ３　ｍ／ｚ　１９４．０８１７（Ｍ＋Ｈ＋），ｆｏｕｎｄ　ｍ／ｚ　１９４．０８０１（Ｍ＋Ｈ＋） To 56.2 g of 3-hydroxy-4-methoxybenzonitrile (net amount 46.5 g), add 223 ml of water, 41.8 ml of 2-chloroethanol and 21.0 g of sodium hydroxide, and heat to around 60 ° C. Stir for 5 hours or more. After confirming the completion of the reaction by HPLC, the mixture was cooled to 10 ° C. and stirred overnight. The reaction mixture was separated by filtration under reduced pressure, washed with 93 ml of water, and then dried under reduced pressure at 60 ° C. overnight to obtain 58.1 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 7.44-7.38 (m, 2H), 7.12 (d, 1H, J = 8.1 Hz), 4.88 (t, 1H, J = 5.4 Hz), 4.05-4.02 (m, 2H), 3.85 (s, 3H), 3.76-3.68 (m, 2H)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 153.11, 148.50, 126.55, 119.44, 115.62, 112.42, 102.73, 70.70, 59.55, 55.93
MS (FAB +): m / z 194 (M + H < + > )
HRMS (FAB +): calcd for C 10 H 11 NO 3 m / z 194.0817 (M + H +), found m / z 194.0801 (M + H +)
（３）：３－（２－ヒドロキシエトキシ）－４－メトキシベンゾニトリルからの、ナトリウム　４－シアノ－２－（２－ヒドロキシエトキシ）フェノキシドの合成 (3): Synthesis of sodium 4-cyano-2- (2-hydroxyethoxy) phenoxide from 3- (2-hydroxyethoxy) -4-methoxybenzonitrile
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000073
　３－（２－ヒドロキシエトキシ）－４－メトキシベンゾニトリル２７．９ｇに対し、ＤＭＦ１６８ｍｌ、ｎ－ドデシルメルカプタン５５．２ｍｌ、ナトリウムメトキシド１２．５ｇを加え、１００℃付近にまで加熱して１時間以上攪拌した。ＨＰＬＣで反応終了を確認した後、２５℃まで冷却して、その後５０℃に加熱した。この溶液に対し、酢酸エチル３３６ｍｌを１時間かけて滴下して１．５時間攪拌した後、２５℃に冷却して一晩攪拌した。反応混合液を減圧濾過で分離し、酢酸エチル８４ｍｌで洗浄した後、６０℃で３時間減圧乾燥して表題化合物を３７．１ｇ得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　７．０８（ｂｓ，１Ｈ），６．９２（ｄｄ，１Ｈ，Ｊ＝８．３および２．２Ｈｚ），６．８２（ｄ，１Ｈ，Ｊ＝２．２Ｈｚ），６．１８（ｄ，１Ｈ，Ｊ＝８．４Ｈｚ），３．８４－３．８１（ｍ，２Ｈ），３．７０－３．５０（ｍ，２Ｈ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１６８．０６，１５０．０９，１２８．９９，１２２．９６，１１９．２５，１１７．５２，８５．８０，７２．２８，５９．９０ To 27.9 g of 3- (2-hydroxyethoxy) -4-methoxybenzonitrile, add 168 ml of DMF, 55.2 ml of n-dodecyl mercaptan, and 12.5 g of sodium methoxide, and heat to around 100 ° C. for over 1 hour Stir. After confirming the completion of the reaction by HPLC, it was cooled to 25 ° C. and then heated to 50 ° C. To this solution, 336 ml of ethyl acetate was added dropwise over 1 hour and stirred for 1.5 hours, then cooled to 25 ° C. and stirred overnight. The reaction mixture was separated by filtration under reduced pressure, washed with 84 ml of ethyl acetate, and then dried under reduced pressure at 60 ° C. for 3 hours to obtain 37.1 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 7.08 (bs, 1H), 6.92 (dd, 1H, J = 8.3 and 2.2 Hz), 6.82 (d, 1H, J = 2.2 Hz), 6.18 (d, 1H, J = 8.4 Hz), 3.84-3.81 (m, 2H), 3.70-3.50 (m, 2H)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 168.06, 150.09, 128.99, 122.96, 119.25, 117.52, 85.80, 72.28, 59.90
（４）：ナトリウム　４－シアノ－２－（２－ヒドロキシエトキシ）フェノキシドからの、４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンゾニトリルの合成 (4): Synthesis of 4-hydroxy-3- (2-hydroxyethoxy) benzonitrile from sodium 4-cyano-2- (2-hydroxyethoxy) phenoxide
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000074
　ナトリウム　４－シアノ－２－（２－ヒドロキシエトキシ）フェノキシド３７．１ｇを水１４０ｍｌに懸濁させ、濃塩酸１７．６ｍｌを滴下してｐＨ＝４．０に調整した（２５℃）。５時間以上攪拌した後、１０℃に冷却してさらに一晩攪拌を行った。反応混合液を減圧濾過で分離し、水５６ｍｌ、ｎ－ヘプタン５６ｍｌで洗浄した後、６０℃で３時間減圧乾燥して表題化合物２５．０ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６：δ　７．３７（ｄ，１Ｈ，Ｊ＝１．９Ｈｚ），７．２７（ｄｄ，１Ｈ，Ｊ＝８．１および１．９Ｈｚ），６．９３（ｄ，１Ｈ，Ｊ＝８．２Ｈｚ），４．０４（ｔ，２Ｈ，Ｊ＝４．８Ｈｚ），３．７４（ｔ，２Ｈ，Ｊ＝４．９Ｈｚ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６：δ　１５１．７２，１４７．２９，１２６．７７，１１９．７１，１１６．５４，１１６．３３，１０１．２２，７０．８３，５９．６９
ＭＳ（ＦＡＢ＋）：ｍ／ｚ　１８０（Ｍ＋Ｈ＋）
ＨＲＭＳ（ＦＡＢ＋）：ｃａｌｃｄ　ｆｏｒ　Ｃ９Ｈ９ＮＯ３　ｍ／ｚ　１８０．０６６１（Ｍ＋Ｈ＋），ｆｏｕｎｄ　ｍ／ｚ　１８０．０６５４（Ｍ＋Ｈ＋） 37.1 g of sodium 4-cyano-2- (2-hydroxyethoxy) phenoxide was suspended in 140 ml of water, and 17.6 ml of concentrated hydrochloric acid was added dropwise to adjust pH = 4.0 (25 ° C.). After stirring for 5 hours or more, the mixture was cooled to 10 ° C. and further stirred overnight. The reaction mixture was separated by filtration under reduced pressure, washed with 56 ml of water and 56 ml of n-heptane, and then dried under reduced pressure at 60 ° C. for 3 hours to obtain 25.0 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 : δ 7.37 (d, 1H, J = 1.9 Hz), 7.27 (dd, 1H, J = 8.1 and 1.9 Hz), 6.93 (D, 1H, J = 8.2 Hz), 4.04 (t, 2H, J = 4.8 Hz), 3.74 (t, 2H, J = 4.9 Hz)
13 C-NMR (100 MHz, DMSO-d 6 : δ 151.72, 147.29, 126.77, 119.71, 116.54, 116.33, 101.22, 70.83, 59.69
MS (FAB +): m / z 180 (M + H + )
HRMS (FAB +): calcd for C 9 H 9 NO 3 m / z 180.0661 (M + H + ), found m / z 180.0654 (M + H + )
（５）：４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンゾニトリルからの、４－（２，２－ジメトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンゾニトリルの合成 (5): Synthesis of 4- (2,2-dimethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile from 4-hydroxy-3- (2-hydroxyethoxy) benzonitrile
Figure JPOXMLDOC01-appb-C000075
Figure JPOXMLDOC01-appb-C000075
　４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンゾニトリル１５．０ｇに対し、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）４５ｍｌ、ブロモアセトアルデヒドジメチルアセタール２５．３ｍｌを加え５０℃に加熱した。さらに炭酸カリウム１２．７ｇを加え、１００℃に加熱して１８時間以上攪拌した。ＨＰＬＣで反応終了を確認した後、２５℃まで冷却して飽和塩化ナトリウム水溶液を７５ｍｌ、ｎ－ヘプタン１５ｍｌを加えて抽出した。次に分離した水層に対して、酢酸エチル７５ｍｌ×３回で抽出を行った。得られた有機層を水３０ｍｌで洗浄した後、有機溶媒を濃縮して目的物の油状物を得た。これをシリカゲルクロマトグラフィー（シリカ：Ｋ－６０、直径：６ｃｍ、高さ：１４ｃｍ、展開液：酢酸エチル／ヘキサン＝１／１→酢酸エチル）で精製し、表題化合物２１．８ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　７．４３（ｄ，１Ｈ，Ｊ＝１．９Ｈｚ），７．３９（ｄｄ，１Ｈ，Ｊ＝８．４および１．９Ｈｚ），７．１６（ｄ，１Ｈ，Ｊ＝８．３Ｈｚ），４．８８（ｔ，１Ｈ，Ｊ＝５．４Ｈｚ），４．７０（ｔ，１Ｈ，Ｊ＝５．１Ｈｚ），４．１０－４．０２（ｍ，４Ｈ），３．７５－３．６７（ｍ，２Ｈ），３．３６（ｓ，６Ｈ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１５２．２９，１４８．７９，１２６．６４，１１９．４０，１１６．７８，１１４．２９，１０３．４２，１０１．９１，７１．０２，６８．６５，５９．６９，５４．２７ To 15.0 g of 4-hydroxy-3- (2-hydroxyethoxy) benzonitrile, 45 ml of N, N-dimethylformamide (DMF) and 25.3 ml of bromoacetaldehyde dimethylacetal were added and heated to 50 ° C. Further, 12.7 g of potassium carbonate was added, heated to 100 ° C. and stirred for 18 hours or more. After confirming the completion of the reaction by HPLC, the mixture was cooled to 25 ° C. and extracted with 75 ml of a saturated sodium chloride aqueous solution and 15 ml of n-heptane. Next, the separated aqueous layer was extracted with 75 ml of ethyl acetate three times. The obtained organic layer was washed with 30 ml of water, and then the organic solvent was concentrated to obtain the desired oily product. This was purified by silica gel chromatography (silica: K-60, diameter: 6 cm, height: 14 cm, developing solution: ethyl acetate / hexane = 1/1 → ethyl acetate) to obtain 21.8 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 7.43 (d, 1H, J = 1.9 Hz), 7.39 (dd, 1H, J = 8.4 and 1.9 Hz), 7. 16 (d, 1H, J = 8.3 Hz), 4.88 (t, 1H, J = 5.4 Hz), 4.70 (t, 1H, J = 5.1 Hz), 4.10-4.02 (M, 4H), 3.75-3.67 (m, 2H), 3.36 (s, 6H)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 152.29, 148.79, 126.64, 119.40, 116.78, 114.29, 103.42, 101.91, 71.02 68.65, 59.69, 54.27
（６）：４－（２，２－ジメトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンゾニトリルからの、４－（２，２－ジメトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミド＝オキシムの合成 (6): 4- (2,2-dimethoxyethoxy) -3- (2-hydroxyethoxy) benzamide = oxime from 4- (2,2-dimethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile Synthesis of
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000076
　４－（２，２－ジメトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンゾニトリル　２０．０ｇに対してメタノール１００ｍｌ、ヒドロキシルアミン塩酸塩７．８ｇおよび水酸化カリウム６．０３ｇを加えて４０℃に加熱し、１２時間以上攪拌した。ＨＰＬＣで反応終了を確認した後、６０℃に昇温後、脱塩ろ過を行い、メタノール６０ｍｌで洗浄した。ろ液１４４ｇを１０３ｇまで濃縮し、トルエン１００ｍｌを滴下した。６０℃から１０℃に冷却し、トルエン３０ｍｌを追加して一晩攪拌を行った。反応混合液を減圧濾過し、トルエンで洗浄した後、６０℃で一晩乾燥して表題化合物１７．５ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　９．４９（ｓ，１Ｈ），７．２８（ｄ，１Ｈ，Ｊ＝２．０Ｈｚ），７．２１（ｄｄ，１Ｈ，Ｊ＝８．２および２．１Ｈｚ），６．９８（ｄ，１Ｈ，Ｊ＝８．４Ｈｚ），５．７４（ｂｓ，２Ｈ），４．８５（ｔ，１Ｈ，Ｊ＝５．４Ｈｚ），４．６８（ｔ，１Ｈ，Ｊ＝５．２Ｈｚ），４．０５－３．９５（ｍ，４Ｈ），３．７５－３．６５（ｍ，２Ｈ），３．３５（ｓ，６Ｈ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１５０．６７，１４８．９０，１４８．１９，１２６．９４，１１８．４２，１１４．０８，１１１．５７，１０２．０４，７０．６１，６８．７４，５９．７４，５３．９９ 100 ml of methanol, 7.8 g of hydroxylamine hydrochloride and 6.03 g of potassium hydroxide were added to 20.0 g of 4- (2,2-dimethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile, and the mixture was heated to 40 ° C. Heated and stirred for 12 hours or more. After confirming the completion of the reaction by HPLC, the temperature was raised to 60 ° C., followed by desalting filtration, and washing with 60 ml of methanol. 144 g of the filtrate was concentrated to 103 g, and 100 ml of toluene was added dropwise. The mixture was cooled from 60 ° C. to 10 ° C., 30 ml of toluene was added, and the mixture was stirred overnight. The reaction mixture was filtered under reduced pressure, washed with toluene, and dried at 60 ° C. overnight to obtain 17.5 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 9.49 (s, 1H), 7.28 (d, 1H, J = 2.0 Hz), 7.21 (dd, 1H, J = 8. 2 and 2.1 Hz), 6.98 (d, 1 H, J = 8.4 Hz), 5.74 (bs, 2 H), 4.85 (t, 1 H, J = 5.4 Hz), 4.68 ( t, 1H, J = 5.2 Hz), 4.05-3.95 (m, 4H), 3.75-3.65 (m, 2H), 3.35 (s, 6H)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 150.67, 148.90, 148.19, 126.94, 118.42, 114.08, 111.57, 102.04, 70.61 68.74, 59.74, 53.99
（７）：４－（２，２－ジメトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミド＝オキシムからの、４－（２，２－ジメトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩の合成 (7): 4- (2,2-dimethoxyethoxy) -3- (2-hydroxyethoxy) benzamide = oxime, 4- (2,2-dimethoxyethoxy) -3- (2-hydroxyethoxy) benzamidine hydrochloride Salt synthesis
Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000077
　４－（２，２－ジメトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミド＝オキシム１０．０ｇに対し、メタノール１５０ｍｌを加え２５℃で攪拌した。この溶液に対して無水酢酸３．１５ｍｌを滴下し、ＨＰＬＣで反応終了を確認した後、アルゴン雰囲気下で１０％Ｐｄ／Ｃ（ｄｒｙ、ＴｙｐｅＭ、川研ファインケミカル社製）を１７７．３ｍｇ加えた。次いで水素雰囲気下で一晩攪拌した後、アルゴン雰囲気下とし、ＨＰＬＣで反応終了を確認した。反応混合液を減圧濾過してＰｄ／Ｃを除き、メタノール３０ｍｌで洗浄した。室温下、ろ液に対して２Ｍ ＨＣｌ/メタノールを２３．３ｍｌ加え、ｐＨ３付近とした後、３８．５ｇまで濃縮した。室温でトルエン９０ｍｌを滴下した後、１０℃で３時間以上攪拌した。懸濁液を減圧濾過し、トルエンで洗浄を行い、６０℃で２時間減圧乾燥して表題化合物１０．３ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　９．４０－８．９０（ｍ，４Ｈ），７．５６（ｄ，１Ｈ，Ｊ＝２．２Ｈｚ），７．５２（ｄｄ，１Ｈ，Ｊ＝８．４および２．２Ｈｚ），７．２３（ｄ，１Ｈ，Ｊ＝８．６Ｈｚ），４．７２（ｔ，１Ｈ，Ｊ＝５．１Ｈｚ），４．１６－４．０５（ｍ，４Ｈ），３．７４（ｔ，２Ｈ，Ｊ＝５．２Ｈｚ），３．３７（ｓ，６Ｈ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１６４．７７，１５２．７２，１４８．３４，１２２．０９，１１９．９７，１１３．５３，１１３．４５，１０１．８９，７０．８３，６８．６７，５９．５７，５４．２０
ＭＳ（ＦＡＢ＋）：ｍ／ｚ　２８５（Ｍ＋Ｈ＋）
ＨＲＭＳ（ＦＡＢ＋）：ｃａｌｃｄ　ｆｏｒ　Ｃ１３Ｈ２０Ｎ２Ｏ５　ｍ／ｚ　２８５．１４５０（Ｍ＋Ｈ＋），ｆｏｕｎｄ　ｍ／ｚ　２８５．１４６１（Ｍ＋Ｈ＋） To 10.0 g of 4- (2,2-dimethoxyethoxy) -3- (2-hydroxyethoxy) benzamide = oxime, 150 ml of methanol was added and stirred at 25 ° C. To this solution, 3.15 ml of acetic anhydride was added dropwise, and after completion of the reaction was confirmed by HPLC, 177.3 mg of 10% Pd / C (dry, TypeM, manufactured by Kawaken Fine Chemical Co., Ltd.) was added under an argon atmosphere. Subsequently, after stirring overnight under a hydrogen atmosphere, the reaction was completed under an argon atmosphere, and the completion of the reaction was confirmed by HPLC. The reaction mixture was filtered under reduced pressure to remove Pd / C and washed with 30 ml of methanol. At room temperature, 23.3 ml of 2M HCl / methanol was added to the filtrate to adjust the pH to around 3, and then concentrated to 38.5 g. After 90 ml of toluene was added dropwise at room temperature, the mixture was stirred at 10 ° C. for 3 hours or more. The suspension was filtered under reduced pressure, washed with toluene, and dried under reduced pressure at 60 ° C. for 2 hours to obtain 10.3 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 9.40-8.90 (m, 4H), 7.56 (d, 1H, J = 2.2 Hz), 7.52 (dd, 1H, J = 8.4 and 2.2 Hz), 7.23 (d, 1H, J = 8.6 Hz), 4.72 (t, 1H, J = 5.1 Hz), 4.16-4.05 (m , 4H), 3.74 (t, 2H, J = 5.2 Hz), 3.37 (s, 6H)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 164.77, 152.72, 148.34, 122.09, 119.97, 113.53, 113.45, 101.89, 70.83 68.67, 59.57, 54.20
MS (FAB +): m / z 285 (M + H + )
HRMS (FAB +): calcd for C 13 H 20 N 2 O 5 m / z 285.1450 (M + H +), found m / z 285.1461 (M + H +)
（８）：４－（２，２－ジメトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩からの、４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジンの合成 (8): 4- (2,2-dimethoxyethoxy) -3- (2-hydroxyethoxy) benzamidine Synthesis of 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine from hydrochloride
Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000078
　４－（２，２－ジメトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩　５３ｇに対し、水１０６０ｍｌ、ヒドロキシルアミン－Ｏ－スルホニル（９５％）２５．５７ｇ（正味量２４．２９ｇ）を加えて６５℃で２時間以上攪拌した。ＨＰＬＣで反応終了を確認後、１０℃に冷却し、６Ｍ水酸化ナトリウム水溶液６３．５ｍｌを滴下してｐＨを２～３に調整した。次に無水酢酸９．３７ｍｌを滴下し、３０分間以上攪拌した後、６Ｍ水酸化ナトリウム水溶液６６ｍｌを滴下して、ｐＨを１０付近に調整し、３時間攪拌した。反応混合液を減圧濾過し、１０℃に冷却した水１０６ｍｌで洗浄した後、室温で一晩減圧乾燥して表題化合物３４．１ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　７．４６（ｄ，１Ｈ，Ｊ＝１．９Ｈｚ），７．３７（ｄｄ，１Ｈ，Ｊ＝８．４および１．９Ｈｚ），７．１２（ｄ，１Ｈ，Ｊ＝８．４Ｈｚ），６．５５（ｂｓ，２Ｈ），５．２０（ｓ，２Ｈ），４．０６（ｔ，２Ｈ，Ｊ＝４．９Ｈｚ），３．７４（ｔ，２Ｈ，Ｊ＝５．１Ｈｚ） To 53 g of 4- (2,2-dimethoxyethoxy) -3- (2-hydroxyethoxy) benzamidine hydrochloride, 1060 ml of water, 25.57 g of hydroxylamine-O-sulfonyl (95%) (net amount 24.29 g) In addition, the mixture was stirred at 65 ° C. for 2 hours or more. After confirming the completion of the reaction by HPLC, the mixture was cooled to 10 ° C., and 63.5 ml of 6M aqueous sodium hydroxide solution was added dropwise to adjust the pH to 2 to 3. Next, 9.37 ml of acetic anhydride was added dropwise and stirred for 30 minutes or more, then 66 ml of 6M aqueous sodium hydroxide solution was added dropwise to adjust the pH to around 10 and stirred for 3 hours. The reaction mixture was filtered under reduced pressure, washed with 106 ml of water cooled to 10 ° C., and then dried under reduced pressure at room temperature overnight to obtain 34.1 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 7.46 (d, 1H, J = 1.9 Hz), 7.37 (dd, 1H, J = 8.4 and 1.9 Hz), 7. 12 (d, 1H, J = 8.4 Hz), 6.55 (bs, 2H), 5.20 (s, 2H), 4.06 (t, 2H, J = 4.9 Hz), 3.74 ( t, 2H, J = 5.1 Hz)
（９）：４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジンからの、４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩の合成 (9): Synthesis of 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride from 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine
Figure JPOXMLDOC01-appb-C000079
Figure JPOXMLDOC01-appb-C000079
　４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　５．０ｇに対し、ＩＰＡ２０ｍｌ加えて９℃で攪拌した。この懸濁液に対し、２Ｍ　ＨＣｌ／ＩＰＡ溶液９．４ｍｌを２５分間かけて滴下し、１時間以上攪拌した。反応混合液を減圧濾過で分離し、ＩＰＡ１０ｍｌで洗浄した後、８０℃で一晩減圧乾燥して表題化合物５．５９ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　９．６０－９．００（ｍ，４Ｈ），７．５７（ｄ，１Ｈ，Ｊ＝２．１Ｈｚ），７．５３（ｄｄ，１Ｈ，Ｊ＝８．４および２．１Ｈｚ），７．３４（ｄ，１Ｈ，Ｊ＝８．６Ｈｚ），５．３２（ｓ，２Ｈ），４．９８（ｔ，１Ｈ，Ｊ＝５．４Ｈｚ），４．１５（ｔ，２Ｈ，Ｊ＝５．０Ｈｚ），３．８０－３．７４（ｍ，２Ｈ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１６４．７８，１４９．９５，１４８．６７，１２２．１４，１２１．６０，１１６．４６，１１４．３２，１１３．３７，７０．８３，５９．４５，５４．４２
ＭＳ（ＥＳＩ＋）：ｍ／ｚ　２３６（Ｍ＋Ｈ＋）
ＨＲＭＳ（ＦＡＢ＋）：ｃａｌｃｄ　ｆｏｒ　Ｃ１１Ｈ１３Ｎ３Ｏ３　ｍ／ｚ　２３６．１０３５（Ｍ＋Ｈ＋），ｆｏｕｎｄ　ｍ／ｚ　２３６．１０１９（Ｍ＋Ｈ＋） To 5.0 g of 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine, 20 ml of IPA was added and stirred at 9 ° C. To this suspension, 9.4 ml of 2M HCl / IPA solution was added dropwise over 25 minutes and stirred for 1 hour or more. The reaction mixture was separated by filtration under reduced pressure, washed with 10 ml of IPA, and then dried under reduced pressure at 80 ° C. overnight to obtain 5.59 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 9.60-9.00 (m, 4H), 7.57 (d, 1H, J = 2.1 Hz), 7.53 (dd, 1H, J = 8.4 and 2.1 Hz), 7.34 (d, 1H, J = 8.6 Hz), 5.32 (s, 2H), 4.98 (t, 1H, J = 5.4 Hz), 4.15 (t, 2H, J = 5.0Hz), 3.80-3.74 (m, 2H)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 164.78, 149.95, 148.67, 122.14, 121.60, 116.46, 114.32, 113.37, 70.83 59.45, 54.42
MS (ESI +): m / z 236 (M + H < + > )
HRMS (FAB +): calcd for C 11 H 13 N 3 O 3 m / z 236.1035 (M + H +), found m / z 236.1019 (M + H +)
実施例６：
イソバニリンからの、４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩の合成（別法）
（１）：３－ヒドロキシ－４－メトキシベンゾニトリルからの、ナトリウム　４－シアノ－２－（２－ヒドロキシエトキシ）フェノキシドの合成 Example 6:
Synthesis of 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride from isovanillin (alternative method)
(1): Synthesis of sodium 4-cyano-2- (2-hydroxyethoxy) phenoxide from 3-hydroxy-4-methoxybenzonitrile
Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000080
　実施例５の工程（１）で得られた３－ヒドロキシ－４－メトキシベンゾニトリル５．０ｇに対し、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）２０ｍｌ、炭酸エチレン３．２５ｇ、炭酸カリウム５．１ｇを添加し、９５℃付近にまで加熱して１２時間以上攪拌した。ＨＰＬＣで反応終了を確認した後、１０℃まで冷却して、２Ｍ　ＨＣｌ／メタノール　４０．５ｍｌを滴下し、ｐＨ＝６～７に合わせた。溶液５０℃でメタノールを５％以下になるまで減圧濃縮した後、脱塩濾過を行い、ＤＭＦ　１０ｍｌで洗浄した。ろ過液にｎ－ドデシルメルカプタン１２．８ｍｌ、ナトリウムメトキシド２．９ｇを加え、１００℃まで加熱して０．５時間以上攪拌した。さらにｎ－ドデシルメルカプタン０．８ｍｌ、ナトリウムメトキシド０．１８ｇを加え、１００℃で０．５時間以上攪拌した。ＨＰＬＣで反応終了を確認した後、２５℃まで冷却した。この溶液に対し、２－プロパノール６０ｍｌを滴下後、一晩攪拌した。反応混合液を減圧濾過で分離し、２－プロパノール１０ｍｌで洗浄した後、６０℃で４時間乾燥して表題化合物７．６３ｇを得た。 To 5.0 g of 3-hydroxy-4-methoxybenzonitrile obtained in step (1) of Example 5, 20 ml of N, N-dimethylformamide (DMF), 3.25 g of ethylene carbonate, and 5.1 g of potassium carbonate were added. The mixture was added, heated to around 95 ° C. and stirred for 12 hours or more. After confirming the completion of the reaction by HPLC, the mixture was cooled to 10 ° C., 40.5 ml of 2M HCl / methanol was added dropwise, and the pH was adjusted to 6-7. The solution was concentrated under reduced pressure at 50 ° C. to 5% or less, then desalted and filtered, and washed with 10 ml of DMF. To the filtrate, 12.8 ml of n-dodecyl mercaptan and 2.9 g of sodium methoxide were added, heated to 100 ° C. and stirred for 0.5 hours or more. Further, 0.8 ml of n-dodecyl mercaptan and 0.18 g of sodium methoxide were added and stirred at 100 ° C. for 0.5 hours or more. After confirming the completion of the reaction by HPLC, it was cooled to 25 ° C. To this solution, 60 ml of 2-propanol was added dropwise and stirred overnight. The reaction mixture was separated by filtration under reduced pressure, washed with 10 ml of 2-propanol, and then dried at 60 ° C. for 4 hours to obtain 7.63 g of the title compound.
（２）：ナトリウム　４－シアノ－２－（２－ヒドロキシエトキシ）フェノキシドからの、４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンゾニトリルの合成 (2): Synthesis of 4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile from sodium 4-cyano-2- (2-hydroxyethoxy) phenoxide
Figure JPOXMLDOC01-appb-C000081
Figure JPOXMLDOC01-appb-C000081
　ナトリウム　４－シアノ－２－（２－ヒドロキシエトキシ）フェノキシド３５．８ｇ（正味量３０．０ｇ）に対し、ＤＭＦ９０ｍｌ、ブロモアセトアルデヒドジエチルアセタール４５．９ｍｌ、炭酸カリウム４．１２ｇを加え、１００℃付近に加熱して１８時間以上攪拌した。ＨＰＬＣで反応終了を確認した後、４０℃まで冷却して水２２５ｍｌ、トルエン１５０ｍｌを加えて抽出した。次に分離した水層に対して、トルエン１２０ｍｌで抽出を行った。得られた有機層の混合液を水６０ｍｌで洗浄・分離した後、活性炭１．５ｇを添加し、１時間以上攪拌後、反応混合液の減圧濾過を行い、トルエン１５ｍｌで洗浄した。得られた濾過液に対してトルエン６４．７ｍｌを少しずつ加えながら、５０℃で９０．３ｇまで減圧濃縮を実施した後、３５℃に冷却した。ｎ－ヘプタン３００ｍｌを１時間以上かけて滴下し、１０℃に冷却し、一晩攪拌した。反応混合液を減圧濾過で分離し、ｎ－ヘプタン６０ｍｌで洗浄した後、６０℃で一晩減圧乾燥して表題化合物３８．９ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　７．４２（ｄ，１Ｈ，Ｊ＝１．９Ｈｚ），７．３８（ｄｄ，１Ｈ，Ｊ＝８．２および１．９Ｈｚ），７．１６（ｄ，１Ｈ，Ｊ＝８．４Ｈｚ），４．８２（ｍ，２Ｈ），４．０４（ｍ，４Ｈ），３．７４－３．５４（ｍ，６Ｈ），１．１３（ｔ，６Ｈ，Ｊ＝７．０Ｈｚ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１５２．３３，１４８．７３，１２６．５５，１１９．３１，１１６．８０，１１４．２５，１０３．２６，１００．０１，７０．９４，６９．３６，６２．４４，５９．６４，１５．４２
ＨＲＭＳ（ＦＡＢ＋）：ｃａｌｃｄ　ｆｏｒ　Ｃ１５Ｈ２２ＮＯ５　ｍ／ｚ　２９６．１４９８（Ｍ＋Ｈ＋），ｆｏｕｎｄ　ｍ／ｚ　２９６．１４９１（Ｍ＋Ｈ＋） To 35.8 g (net amount 30.0 g) of sodium 4-cyano-2- (2-hydroxyethoxy) phenoxide, add 90 ml of DMF, 45.9 ml of bromoacetaldehyde diethyl acetal, and 4.12 g of potassium carbonate, and heat to around 100 ° C. And stirred for 18 hours or more. After confirming the completion of the reaction by HPLC, the mixture was cooled to 40 ° C. and extracted by adding 225 ml of water and 150 ml of toluene. Next, the separated aqueous layer was extracted with 120 ml of toluene. The obtained organic layer mixture was washed / separated with 60 ml of water, 1.5 g of activated carbon was added, and the mixture was stirred for 1 hour or more. The reaction mixture was filtered under reduced pressure, and washed with 15 ml of toluene. While adding 64.7 ml of toluene little by little to the obtained filtrate, the solution was concentrated under reduced pressure to 90.3 g at 50 ° C. and then cooled to 35 ° C. 300 ml of n-heptane was added dropwise over 1 hour, cooled to 10 ° C. and stirred overnight. The reaction mixture was separated by filtration under reduced pressure, washed with 60 ml of n-heptane, and then dried under reduced pressure at 60 ° C. overnight to obtain 38.9 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 7.42 (d, 1H, J = 1.9 Hz), 7.38 (dd, 1H, J = 8.2 and 1.9 Hz), 7. 16 (d, 1H, J = 8.4 Hz), 4.82 (m, 2H), 4.04 (m, 4H), 3.74-3.54 (m, 6H), 1.13 (t, 6H, J = 7.0Hz)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 152.33, 148.73, 126.55, 119.31, 116.80, 114.25, 103.26, 100.01, 70.94 69.36, 62.44, 59.64, 15.42
HRMS (FAB +): calcd for C 15 H 22 NO 5 m / z 296.1498 (M + H +), found m / z 296.1491 (M + H +)
（３）：４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンゾニトリルからの、４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミド＝オキシムの合成 (3): 4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzamide from 4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile = Synthesis of oximes
Figure JPOXMLDOC01-appb-C000082
Figure JPOXMLDOC01-appb-C000082
　４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンゾニトリル　４５．８ｇ（正味量４５．０ｇ）に対してメタノール１８０ｍｌ、ヒドロキシルアミン塩酸塩１５．９ｇ、水酸化カリウム１３．３ｇを加えて４０℃に加熱し，１８時間以上攪拌した。ＨＰＬＣで反応終了を確認した後、脱塩ろ過を行い、メタノール２２．５ｍｌで洗浄した。ろ液を約９０ｍｌまで濃縮し、トルエン７６５ｍｌを滴下した。次に５０℃で約６０６ｇまで濃縮し、トルエン４０ｍｌを加えた後、１０℃に冷却し、さらにメタノール２．２５ｍｌを添加し、一晩攪拌を行った。反応混合液を減圧濾過し、トルエン９０ｍｌで洗浄した後、６０℃で３時間乾燥して表題化合物５１．１ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　９．４６（ｓ，１Ｈ），７．２８（ｄ，１Ｈ，Ｊ＝２．０Ｈｚ），７．２１（ｄｄ，１Ｈ，Ｊ＝８．４および２．０Ｈｚ），６．９７（ｄ，１Ｈ，Ｊ＝８．４Ｈｚ），５．７３（ｂｓ，２Ｈ），４．７９（ｍ，２Ｈ），４．００（ｔ，２Ｈ，Ｊ＝５．２Ｈｚ），３．９６（ｄ，２Ｈ，Ｊ＝５．２Ｈｚ），３．７４－３．５３（ｍ，６Ｈ），１．１４（ｔ，６Ｈ，Ｊ＝７．２Ｈｚ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１５０．６５，１４９．０３，１４８．１６，１２６．８３，１１８．４６，１１４．０１，１１１．７０，１００．２２，７０．６５，６９．５５，６２．２０，５９．７７，１５．４５
ＨＲＭＳ（ＦＡＢ＋）：ｃａｌｃｄ　ｆｏｒ　Ｃ１５Ｈ２５Ｎ２Ｏ６　ｍ／ｚ　３２９．１７１３（Ｍ＋Ｈ＋），ｆｏｕｎｄ　ｍ／ｚ　３２９．１６９６（Ｍ＋Ｈ＋） 4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile (45.8 g, net amount 45.0 g), methanol 180 ml, hydroxylamine hydrochloride 15.9 g, potassium hydroxide 13 .3 g was added and heated to 40 ° C. and stirred for 18 hours or more. After confirming the completion of the reaction by HPLC, desalting filtration was carried out, followed by washing with 22.5 ml of methanol. The filtrate was concentrated to about 90 ml, and 765 ml of toluene was added dropwise. Next, the mixture was concentrated to about 606 g at 50 ° C., 40 ml of toluene was added, and the mixture was cooled to 10 ° C., and 2.25 ml of methanol was further added, followed by stirring overnight. The reaction mixture was filtered under reduced pressure, washed with 90 ml of toluene, and then dried at 60 ° C. for 3 hours to obtain 51.1 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 9.46 (s, 1H), 7.28 (d, 1H, J = 2.0 Hz), 7.21 (dd, 1H, J = 8. 4 and 2.0 Hz), 6.97 (d, 1H, J = 8.4 Hz), 5.73 (bs, 2H), 4.79 (m, 2H), 4.00 (t, 2H, J = 5.2 Hz), 3.96 (d, 2H, J = 5.2 Hz), 3.74-3.53 (m, 6H), 1.14 (t, 6H, J = 7.2 Hz)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 150.65, 149.03, 148.16, 126.83, 118.46, 114.01, 111.70, 100.22, 70.65 69.55, 62.20, 59.77, 15.45
HRMS (FAB +): calcd for C 15 H 25 N 2 O 6 m / z 329.1713 (M + H + ), found m / z 329.1696 (M + H + )
（４）：４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミド＝オキシムからの、４－（２，２－ジメトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩の合成 (4): 4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzamide = oxime, 4- (2,2-dimethoxyethoxy) -3- (2-hydroxyethoxy) benzamidine Synthesis of hydrochloride
Figure JPOXMLDOC01-appb-C000083
Figure JPOXMLDOC01-appb-C000083
　４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミド＝オキシム４５．０ｇに対し、メタノール４５０ｍｌを加え２５℃で攪拌した。この溶液に対して無水酢酸１３．６ｍｌを１０分間で滴下し、ＨＰＬＣで反応終了を確認した後、アルゴン雰囲気下として１０％Ｐｄ／Ｃ（ｗｅｔ、ＴｙｐｅＭ、川研ファインケミカル社製）を６０４ｍｇ加えた。次に水素雰囲気下として２５℃で一晩攪拌した後、アルゴン雰囲気下にしてＨＰＬＣで反応終了を確認した。反応液を減圧濾過してＰｄ／Ｃを除き、メタノール２２．５ｍｌで洗浄した。ろ液に２Ｍ　塩化水素メタノール溶液を１３７ｍｌ添加し、４０℃で１６．５時間以上攪拌した。ＨＰＬＣで反応終了を確認した後、１３５ｇまで濃縮し、アセトン９０ｍｌを加えて懸濁液とした。２５℃で、トルエン１８０ｍｌを５分間以上かけて滴下後、１．５時間かけて１０℃に冷却し、さらに２時間以上攪拌した。反応混合液を減圧濾過し、トルエン９０ｍｌで洗浄した後、６０℃で一晩減圧乾燥して表題化合物４０．７ｇを得た。 450 ml of methanol was added to 45.0 g of 4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzamide = oxime, and the mixture was stirred at 25 ° C. To this solution, 13.6 ml of acetic anhydride was added dropwise over 10 minutes, and after completion of the reaction was confirmed by HPLC, 604 mg of 10% Pd / C (wet, TypeM, manufactured by Kawaken Fine Chemical Co., Ltd.) was added under an argon atmosphere. . Next, after stirring overnight at 25 ° C. under a hydrogen atmosphere, completion of the reaction was confirmed by HPLC under an argon atmosphere. The reaction solution was filtered under reduced pressure to remove Pd / C, and washed with 22.5 ml of methanol. 137 ml of 2M hydrogen chloride methanol solution was added to the filtrate and stirred at 40 ° C. for 16.5 hours or more. After confirming the completion of the reaction by HPLC, the mixture was concentrated to 135 g, and 90 ml of acetone was added to form a suspension. At 25 ° C., 180 ml of toluene was added dropwise over 5 minutes, cooled to 10 ° C. over 1.5 hours, and further stirred for 2 hours or more. The reaction mixture was filtered under reduced pressure, washed with 90 ml of toluene, and then dried under reduced pressure at 60 ° C. overnight to obtain 40.7 g of the title compound.
（５）：４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンゾニトリルからの、４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミジン　酢酸塩の合成 (5): 4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzamidine from 4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile Synthesis of acetate
Figure JPOXMLDOC01-appb-C000084
Figure JPOXMLDOC01-appb-C000084
　４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンゾニトリル１０．０ｇに対して、メタノール５０ｍｌ、ヒドロキシルアミン塩酸塩３．５３ｇおよび水酸化カリウム２．９７ｇを加えて４０℃に加熱し、１８時間以上攪拌した。ＨＰＬＣで反応終了を確認した後、２５℃に冷却し、無水酢酸５．４ｍｌを滴下した。同温で１時間以上攪拌し、ＨＰＬＣで反応終了を確認した後、アルゴン雰囲気下で１０％Ｐｄ／Ｃ（ｗｅｔ、タイプＭ、川研ファインケミカル社製）を０．３ｇ加えた。次いで水素雰囲気下、同温で一晩攪拌した後、アルゴン雰囲気下にしてＨＰＬＣで反応終了を確認した。減圧濾過でＰｄ／Ｃを除き、メタノールで洗浄した。ろ液を約２５ｍｌまで濃縮した後、同温で酢酸エチル１８０ｍｌを３０分間以上かけて滴下した。混合液を１０℃まで冷却し、さらに２時間以上熟成した後、減圧濾過し、酢酸エチル２０ｍｌで洗浄した後、６０℃で一晩減圧乾燥して表題化合物１２．０ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　７．４６（ｄ，１Ｈ，Ｊ＝２．２Ｈｚ），７．４３（ｄｄ，１Ｈ，Ｊ＝８．４および２．２Ｈｚ），７．１９（ｄ，１Ｈ，Ｊ＝８．６Ｈｚ），４．８３（ｔ，１Ｈ，Ｊ＝５．２Ｈｚ），４．０９（ｔ，２Ｈ，Ｊ＝５．２Ｈｚ），４．０５（ｄ，２Ｈ，Ｊ＝５．２Ｈｚ），３．７５－３．５５（ｍ，６Ｈ），１．７０（ｓ，３Ｈ），１．１４（ｔ，６Ｈ，Ｊ＝７．０Ｈｚ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１７６．７３，１６５．１９，１５２．２３，１４８．３３，１２１．７２，１２１．３９，１１３．５６，１１３．１５，１００．０７，７０．７７，６９．４４，６２．４１，５９．６４，２５．１１，１５．４５
ＨＲＭＳ（ＦＡＢ＋）：ｃａｌｃｄ　ｆｏｒ　Ｃ１５Ｈ２４Ｎ２Ｏ５　ｍ／ｚ　３１３．１７６３（Ｍ＋Ｈ＋），ｆｏｕｎｄ　ｍ／ｚ　３１３．１７７１（Ｍ＋Ｈ＋） To 10.0 g of 4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile, 50 ml of methanol, 3.53 g of hydroxylamine hydrochloride and 2.97 g of potassium hydroxide were added to add 40 The mixture was heated to 0 ° C. and stirred for 18 hours or more. After confirming the completion of the reaction by HPLC, the mixture was cooled to 25 ° C., and 5.4 ml of acetic anhydride was added dropwise. After stirring for 1 hour or more at the same temperature and confirming the completion of the reaction by HPLC, 0.3 g of 10% Pd / C (wet, type M, manufactured by Kawaken Fine Chemical Co., Ltd.) was added under an argon atmosphere. Subsequently, after stirring overnight at the same temperature in a hydrogen atmosphere, the reaction was completed by HPLC under an argon atmosphere. Pd / C was removed by vacuum filtration and washed with methanol. After the filtrate was concentrated to about 25 ml, 180 ml of ethyl acetate was added dropwise at the same temperature over 30 minutes. The mixture was cooled to 10 ° C. and further aged for 2 hours or more, then filtered under reduced pressure, washed with 20 ml of ethyl acetate, and then dried under reduced pressure at 60 ° C. overnight to obtain 12.0 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 7.46 (d, 1H, J = 2.2 Hz), 7.43 (dd, 1H, J = 8.4 and 2.2 Hz), 7. 19 (d, 1H, J = 8.6 Hz), 4.83 (t, 1H, J = 5.2 Hz), 4.09 (t, 2H, J = 5.2 Hz), 4.05 (d, 2H) , J = 5.2 Hz), 3.75-3.55 (m, 6H), 1.70 (s, 3H), 1.14 (t, 6H, J = 7.0 Hz)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 176.73, 165.19, 152.23, 148.33, 121.72, 121.39, 113.56, 113.15, 100.07, 70.77, 69.44, 62.41, 59.64, 25.11, 15.45
HRMS (FAB +): calcd for C 15 H 24 N 2 O 5 m / z 313.1763 (M + H +), found m / z 313.1771 (M + H +)
（６）：４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミジン　酢酸塩からの、４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジンの合成 (6): 4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzamidine Synthesis of 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine from acetate
Figure JPOXMLDOC01-appb-C000085
Figure JPOXMLDOC01-appb-C000085
　４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミジン　酢酸塩２２．４ｇ（正味量２０．０ｇ）に対し、水３４０ｍｌおよびヒドロキシルアミン－Ｏ－スルホニル（９５％）７．６７ｇを加え、１０℃以下に冷却した。その後６Ｍ塩酸９．５ｍｌを添加し、ｐＨを１．０に合わせた。次に６５℃に昇温し、２時間以上攪拌した。ＨＰＬＣで反応終了を確認後、８℃に冷却し、３Ｍ　水酸化ナトリウム水溶液４１．５ｍｌを滴下してｐＨを２～３に調整した。次に無水酢酸２．５４ｍｌを滴下し、３０分間以上攪拌した後、３Ｍ　水酸化ナトリウム水溶液約５１．０ｍｌを滴下してｐＨを１０～１１に調整し、一晩攪拌した。反応混合液を減圧濾過し、１０℃に冷却した水４４．８ｍｌで洗浄後、さらに１０℃に冷却したエタノール４４．８ｍｌで洗浄し、表題化合物１３．９ｇを得た。 4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzamidine acetate 22.4 g (net amount 20.0 g), water 340 ml and hydroxylamine-O-sulfonyl (95%) 7 .67 g was added and cooled to 10 ° C or lower. Thereafter, 9.5 ml of 6M hydrochloric acid was added to adjust the pH to 1.0. Next, it heated up at 65 degreeC and stirred for 2 hours or more. After confirming the completion of the reaction by HPLC, the mixture was cooled to 8 ° C., and 41.5 ml of 3M aqueous sodium hydroxide solution was added dropwise to adjust the pH to 2 to 3. Next, 2.54 ml of acetic anhydride was added dropwise and stirred for 30 minutes or more, and then about 51.0 ml of 3M aqueous sodium hydroxide solution was added dropwise to adjust the pH to 10-11 and stirred overnight. The reaction mixture was filtered under reduced pressure, washed with 44.8 ml of water cooled to 10 ° C., and further washed with 44.8 ml of ethanol cooled to 10 ° C. to obtain 13.9 g of the title compound.
（７）：４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジンからの、４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩の合成 (7): Synthesis of 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride from 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine
Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000086
　４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン１６．３ｇ（正味量１５．０ｇ）に対し、メタノール６０．０ｍｌを加えて１０℃で攪拌した。この懸濁液に対し、２Ｍ　ＨＣｌ／メタノール溶液３７．１ｍｌを３０分間以上かけて滴下し、ｐＨ２．０以下とした。３０分間以上攪拌した後、３５℃に昇温した。ｐＨ２付近で均一液となったことを確認後、２．５時間以上かけて１０℃に冷却し、酢酸メチル１６２ｍｌを１時間以上かけて滴下した。一晩攪拌後、反応混合液を減圧濾過で分離し、酢酸メチル３０．０ｍｌで洗浄した後、８０℃で一晩減圧乾燥して表題化合物１６．７ｇを得た。 60.0 ml of methanol was added to 16.3 g (net amount 15.0 g) of 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine, and the mixture was stirred at 10 ° C. To this suspension, 37.1 ml of 2M HCl / methanol solution was added dropwise over 30 minutes to a pH of 2.0 or less. After stirring for 30 minutes or more, the temperature was raised to 35 ° C. After confirming that it became a homogeneous liquid near pH 2, it was cooled to 10 ° C. over 2.5 hours, and 162 ml of methyl acetate was added dropwise over 1 hour. After stirring overnight, the reaction mixture was separated by filtration under reduced pressure, washed with 30.0 ml of methyl acetate, and then dried under reduced pressure at 80 ° C. overnight to obtain 16.7 g of the title compound.
（８）：４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジンからの、４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩の合成 (8): Synthesis of 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride from 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine
Figure JPOXMLDOC01-appb-C000087
Figure JPOXMLDOC01-appb-C000087
　４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン１９．９ｇ（正味量１５．９ｇ）に対し、メタノール５２ｍｌを加えて１０℃で攪拌した。この懸濁液に対し、２Ｍ　ＨＣｌ／メタノール溶液３７．６ｍｌを１時間かけて滴下し、ｐＨ２以下とした。３０分以上攪拌した後、３７℃に昇温した。ｐＨ１付近で均一液となったことを確認後、酢酸エチル３８ｍｌを１時間で滴下した。３０分間攪拌後、１．５時間以上かけて１０℃に冷却し、酢酸エチル２４５ｍｌを２時間以上かけて滴下した。一晩攪拌後、反応混合液を減圧濾過で分離し、酢酸エチル３２ｍｌで洗浄した後、８０℃で一晩減圧乾燥して、表題化合物１６．７ｇを得た。 To 19.9 g (net amount 15.9 g) of 4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine, 52 ml of methanol was added and stirred at 10 ° C. To this suspension, 37.6 ml of 2M HCl / methanol solution was added dropwise over 1 hour to adjust the pH to 2 or less. After stirring for 30 minutes or more, the temperature was raised to 37 ° C. After confirming that the solution became homogeneous near pH 1, 38 ml of ethyl acetate was added dropwise over 1 hour. After stirring for 30 minutes, the mixture was cooled to 10 ° C. over 1.5 hours, and 245 ml of ethyl acetate was added dropwise over 2 hours. After stirring overnight, the reaction mixture was separated by filtration under reduced pressure, washed with 32 ml of ethyl acetate, and then dried under reduced pressure at 80 ° C. overnight to give 16.7 g of the title compound.
実施例７：
４－ヒドロキシ－３－メトキシベンズアルデヒド（バニリン）からの、４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンゾニトリルの合成
（１）：バニリンからの、４－ヒドロキシ－３－メトキシベンゾニトリルの合成 Example 7:
Synthesis of 4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile from 4-hydroxy-3-methoxybenzaldehyde (vanillin) (1): 4-hydroxy-from vanillin Synthesis of 3-methoxybenzonitrile
Figure JPOXMLDOC01-appb-C000088
Figure JPOXMLDOC01-appb-C000088
　４－ヒドロキシ－３－メトキシベンズアルデヒド（バニリン）２５ｇに対し、ギ酸ナトリウム２０．８ｇ、ギ酸１１２．５ｍｌを加えて８５℃付近まで加熱した。次に約１０分間隔でヒドロキシルアミン硫酸塩１４．８ｇを３分割して投入した。３時間後、ＨＰＬＣで反応終了を確認し、１０℃まで冷却し、塩化ナトリウム９６．０ｇを水４７５ｍｌに溶解させた水溶液を滴下し、３時間攪拌した。反応混合液を減圧濾過で分離し、水６０ｍｌで洗浄を行い、減圧乾燥を実施して表題化合物２０．５ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１０．３３（ｂｓ，１Ｈ），７．３５（ｄ，１Ｈ，Ｊ＝１．９Ｈｚ），７．２６（ｄｄ，１Ｈ，Ｊ＝８．１および１．９Ｈｚ），６．９２（ｄ，１Ｈ，Ｊ＝８．１Ｈｚ），３．８２（ｓ，３Ｈ） To 25 g of 4-hydroxy-3-methoxybenzaldehyde (vanillin), 20.8 g of sodium formate and 112.5 ml of formic acid were added and heated to around 85 ° C. Next, 14.8 g of hydroxylamine sulfate was added in three portions at intervals of about 10 minutes. After 3 hours, the completion of the reaction was confirmed by HPLC, the solution was cooled to 10 ° C., an aqueous solution in which 96.0 g of sodium chloride was dissolved in 475 ml of water was dropped, and the mixture was stirred for 3 hours. The reaction mixture was separated by filtration under reduced pressure, washed with 60 ml of water, and dried under reduced pressure to obtain 20.5 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 10.33 (bs, 1H), 7.35 (d, 1H, J = 1.9 Hz), 7.26 (dd, 1H, J = 8. 1 and 1.9 Hz), 6.92 (d, 1 H, J = 8.1 Hz), 3.82 (s, 3 H)
（２）：４－ヒドロキシ－３－メトキシベンゾニトリルからの、４－（２，２－ジエトキシエトキシ）－３－メトキシベンゾニトリルの合成 (2): Synthesis of 4- (2,2-diethoxyethoxy) -3-methoxybenzonitrile from 4-hydroxy-3-methoxybenzonitrile
Figure JPOXMLDOC01-appb-C000089
Figure JPOXMLDOC01-appb-C000089
　４－ヒドロキシ－３－メトキシベンゾニトリル１．０ｇに対し、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）３ｍｌ、ブロモアセトアルデヒドジエチルアセタール１．９４ｍｌ、炭酸カリウム１．０５ｇを加え、１０５℃付近まで加熱して７時間以上攪拌した。ＨＰＬＣで反応終了を確認した後、水５ｍｌとトルエン５ｍｌを加えて抽出を行い、さらに水層をトルエン５ｍｌで再抽出した。２つの有機層を混合し、活性炭を５０ｍｇ加えて１時間以上室温で攪拌した後、ろ過した。ろ液を濃縮してトルエンを除去し、ヘプタン１０ｍｌを加えた。一晩攪拌した後、反応混合液を減圧濾過で分離し、ヘプタンで洗浄した後、室温で一晩減圧乾燥して表題化合物１．５１ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　７．４５－７．３５（ｍ，２Ｈ），７．１６（ｄ，１Ｈ，Ｊ＝８．２Ｈｚ），４．８２（ｔ，１Ｈ，Ｊ＝５．１Ｈｚ），４．０３（ｄ，２Ｈ，Ｊ＝５．２Ｈｚ），３．８１（ｓ，３Ｈ），３．７５－３．４５（ｍ，４Ｈ），１．１３（ｔ，６Ｈ，Ｊ＝７．０Ｈｚ） To 1.0 g of 4-hydroxy-3-methoxybenzonitrile, 3 ml of N, N-dimethylformamide (DMF), 1.94 ml of bromoacetaldehyde diethyl acetal and 1.05 g of potassium carbonate are added and heated to around 105 ° C. to 7 Stir for more than an hour. After confirming the completion of the reaction by HPLC, 5 ml of water and 5 ml of toluene were added for extraction, and the aqueous layer was re-extracted with 5 ml of toluene. The two organic layers were mixed, 50 mg of activated carbon was added, and the mixture was stirred for 1 hour or more at room temperature, followed by filtration. The filtrate was concentrated to remove toluene and 10 ml of heptane was added. After stirring overnight, the reaction mixture was separated by vacuum filtration, washed with heptane, and then dried overnight at room temperature under reduced pressure to give 1.51 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 7.45-7.35 (m, 2H), 7.16 (d, 1H, J = 8.2 Hz), 4.82 (t, 1H, J = 5.1 Hz), 4.03 (d, 2H, J = 5.2 Hz), 3.81 (s, 3H), 3.75-3.45 (m, 4H), 1.13 (t, 6H, J = 7.0Hz)
（３）：４－（２，２－ジエトキシエトキシ）－３－メトキシベンゾニトリルからの、４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンゾニトリルの合成 (3): Synthesis of 4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile from 4- (2,2-diethoxyethoxy) -3-methoxybenzonitrile
Figure JPOXMLDOC01-appb-C000090
Figure JPOXMLDOC01-appb-C000090
　４－（２，２－ジエトキシエトキシ）－３－メトキシベンゾニトリル０．２ｇに対し、Ｎ，Ｎ－ジメチルホルムアミド０．８ｍｌ、ｎ－ドデシルメルカプタン０．３ｍｌ、ナトリウムメトキシド６９ｍｇを加え、１００℃付近にまで加熱して１時間以上攪拌した。その後、さらにｎ－ドデシルメルカプタン０．０５ｍｌ、ナトリウムメトキシド１２ｍｇを追加して１時間以上攪拌した。ＨＰＬＣで反応終了を確認した後、２５℃まで冷却してｐＨが６～７まで塩酸を加えた。この溶液に対し、ｎ－ヘプタン１ｍｌ×２回で抽出した後、水層をトルエン１ｍｌ×２回で再抽出を行った。２つの有機層を混合し、濃縮乾固させた後、Ｎ，Ｎ－ジメチルホルムアミド０．８ｍｌ、炭酸カリウム１０４ｍｇ、炭酸エチレン６６ｍｇを加えて９５℃まで加熱させ、１６時間以上攪拌した。その後、さらに炭酸エチレン２６ｍｇを追加して４時間以上攪拌した。ＨＰＬＣで反応終了を確認後、水１ｍｌを加えた後、ｐＨが２～３まで塩酸を加えた。この溶液に対し、トルエン１ｍｌ×２で抽出を行った後、有機層を濃縮乾固させた。その後、トルエン０．２ｍｌで溶解させ、ヘプタン０．８ｍｌを加え、上澄み液を除去し、再度濃縮乾固させ、表題化合物を得た。 To 0.2 g of 4- (2,2-diethoxyethoxy) -3-methoxybenzonitrile, 0.8 ml of N, N-dimethylformamide, 0.3 ml of n-dodecyl mercaptan and 69 mg of sodium methoxide were added, and 100 ° C. The mixture was heated to near and stirred for 1 hour or more. Thereafter, 0.05 ml of n-dodecyl mercaptan and 12 mg of sodium methoxide were further added and stirred for 1 hour or more. After confirming the completion of the reaction by HPLC, the mixture was cooled to 25 ° C. and hydrochloric acid was added until the pH was 6-7. This solution was extracted with 1 ml × 2 times of n-heptane, and then the aqueous layer was re-extracted with 2 × 1 ml of toluene. After the two organic layers were mixed and concentrated to dryness, 0.8 ml of N, N-dimethylformamide, 104 mg of potassium carbonate and 66 mg of ethylene carbonate were added and heated to 95 ° C. and stirred for 16 hours or more. Thereafter, 26 mg of ethylene carbonate was further added and stirred for 4 hours or more. After confirming the completion of the reaction by HPLC, 1 ml of water was added, and hydrochloric acid was added until the pH reached 2-3. This solution was extracted with toluene 1 ml × 2, and then the organic layer was concentrated to dryness. Thereafter, the residue was dissolved in 0.2 ml of toluene, 0.8 ml of heptane was added, the supernatant was removed, and the mixture was concentrated and dried again to obtain the title compound.
実施例８：
４－シアノ安息香酸からの、４－［イミノ（ピロリジン－１－イル）メチル］安息香酸　塩酸塩の合成
（１）：４－シアノ安息香酸からの、４－エトキシイミノメチル安息香酸　塩酸塩の合成 Example 8:
Synthesis of 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride from 4-cyanobenzoic acid (1): Synthesis of 4-ethoxyiminomethylbenzoic acid hydrochloride from 4-cyanobenzoic acid
Figure JPOXMLDOC01-appb-C000091
Figure JPOXMLDOC01-appb-C000091
　５℃に冷却した、酢酸エチル２３４ｍｌ、エタノール２６０ｍｌ及び４－シアノ安息香酸５０．１ｇの混合液に、塩化アセチル２５６ｍｌを５時間かけて滴下した。２０℃で４７時間攪拌した後、反応混合液を減圧濾過し、酢酸エチル１５０ｍｌで洗浄した後、室温で減圧乾燥して表題化合物６４．９ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　８．２３（ｍ，２Ｈ），８．１３（ｍ，２Ｈ），４．６７（ｍ，２Ｈ），１．５０（ｔ，３Ｈ，Ｊ＝７．０Ｈｚ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１７０．３０，１６６．３２，１３６．４１，１２９．７８，１２９．５８，１２７．８６，７０．０４，１３．６７
ＭＳ（ＥＳＩ＋）：ｍ／ｚ　１９４．１（Ｍ＋Ｈ＋） To a mixed liquid of 234 ml of ethyl acetate, 260 ml of ethanol and 50.1 g of 4-cyanobenzoic acid cooled to 5 ° C., 256 ml of acetyl chloride was added dropwise over 5 hours. After stirring at 20 ° C. for 47 hours, the reaction mixture was filtered under reduced pressure, washed with 150 ml of ethyl acetate, and dried under reduced pressure at room temperature to obtain 64.9 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 8.23 (m, 2H), 8.13 (m, 2H), 4.67 (m, 2H), 1.50 (t, 3H, J = 7.0 Hz)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 170.30, 166.32, 136.41, 129.78, 129.58, 127.86, 70.04, 13.67
MS (ESI +): m / z 194.1 (M + H < + > )
（２）：４－エトキシイミノメチル安息香酸　塩酸塩からの、４－［イミノ（ピロリジン－１－イル）メチル］安息香酸の合成 (2): 4-Ethoxyiminomethylbenzoic acid Synthesis of 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid from hydrochloride
Figure JPOXMLDOC01-appb-C000092
Figure JPOXMLDOC01-appb-C000092
　１５℃に冷却した、ピロリジン４９．１ｍｌ、エタノール１００ｍｌの混合液に、４－エトキシイミノメチル安息香酸　塩酸塩５１．８ｇを１時間かけて投入した。３０分間攪拌後、１０℃に冷却し、１．５時間攪拌後、水１５ｍｌを添加した。３０分間攪拌後、アセトン８５０ｍｌを１．５時間かけて滴下した。一晩攪拌した後、反応混合液を減圧濾過し、アセトン１００ｍｌで洗浄した後、６０℃で一晩減圧乾燥して表題化合物４４．３ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，Ｄ２Ｏ）：δ　７．７９（ｍ，２Ｈ），７．４５（ｍ，２Ｈ），３．４９（ｔ，２Ｈ，Ｊ＝７．０Ｈｚ），３．２９（ｔ，２Ｈ，Ｊ＝６．８Ｈｚ），２．０１（ｍ，２Ｈ），１．７８（ｍ，２Ｈ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，Ｄ２Ｏ））：δ　１７４．２２，１６２．４１，１４０．１１，１３１．９１，１２９．５７，１２７．７２，５２．２９，４８．９３，２５．４９，２４．８７
ＨＲＭＳ（ＦＡＢ＋）：ｃａｌｃｄ　ｆｏｒ　Ｃ１２Ｈ１５Ｎ２Ｏ２　ｍ／ｚ　２１９．１１３４（Ｍ＋Ｈ＋），ｆｏｕｎｄ　ｍ／ｚ　２１９．１１３８（Ｍ＋Ｈ＋） To a mixed solution of 49.1 ml of pyrrolidine and 100 ml of ethanol cooled to 15 ° C., 51.8 g of 4-ethoxyiminomethylbenzoic acid hydrochloride was added over 1 hour. After stirring for 30 minutes, it was cooled to 10 ° C., and after stirring for 1.5 hours, 15 ml of water was added. After stirring for 30 minutes, 850 ml of acetone was added dropwise over 1.5 hours. After stirring overnight, the reaction mixture was filtered under reduced pressure, washed with 100 ml of acetone, and then dried under reduced pressure at 60 ° C. overnight to obtain 44.3 g of the title compound.
1 H-NMR (400 MHz, D 2 O): δ 7.79 (m, 2H), 7.45 (m, 2H), 3.49 (t, 2H, J = 7.0 Hz), 3.29 ( t, 2H, J = 6.8 Hz), 2.01 (m, 2H), 1.78 (m, 2H)
13 C-NMR (100 MHz, D 2 O)): δ 174.22, 162.41, 140.11, 131.91, 129.57, 127.72, 52.29, 48.93, 25.49, 24.87
HRMS (FAB +): calcd for C 12 H 15 N 2 O 2 m / z 219.1134 (M + H +), found m / z 219.1138 (M + H +)
（３）：４－［イミノ（ピロリジン－１－イル）メチル］安息香酸からの、４－［イミノ（ピロリジン－１－イル）メチル］安息香酸　塩酸塩の合成 (3): Synthesis of 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride from 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid
Figure JPOXMLDOC01-appb-C000093
Figure JPOXMLDOC01-appb-C000093
　酢酸エチル１２０ｍｌおよび４－［イミノ（ピロリジン－１－イル）メチル］安息香酸４１．４ｇの混合液に、４Ｍ　ＨＣｌ／ＥｔＯＡｃ　５５ｍｌを２０℃で１時間かけて滴下した。１時間攪拌した後、反応混合液を減圧濾過し、酢酸エチル８０ｍｌで洗浄した後、６０℃で減圧乾燥して表題化合物４７．９ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　９．５３（ｓ，１Ｈ），９．２６（ｓ，１Ｈ），８．１１（ｍ，２Ｈ），７．７７（ｍ，２Ｈ），３．６２（ｔ，２Ｈ，Ｊ＝７．０Ｈｚ），３．３７（ｔ，２Ｈ，Ｊ＝６．７Ｈｚ），２．０５（ｍ，２Ｈ），１．８６（ｍ，２Ｈ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１６６．５１，１６１．２６，１３４．０５，１３３．８３，１２９．８０，１２８．３７，５１．６２，４９．４４，２５．２５，２４．５９ To a mixture of 120 ml of ethyl acetate and 41.4 g of 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid, 55 ml of 4M HCl / EtOAc was added dropwise at 20 ° C. over 1 hour. After stirring for 1 hour, the reaction mixture was filtered under reduced pressure, washed with 80 ml of ethyl acetate, and then dried under reduced pressure at 60 ° C. to obtain 47.9 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 9.53 (s, 1H), 9.26 (s, 1H), 8.11 (m, 2H), 7.77 (m, 2H), 3.62 (t, 2H, J = 7.0 Hz), 3.37 (t, 2H, J = 6.7 Hz), 2.05 (m, 2H), 1.86 (m, 2H)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 166.51, 161.26, 134.05, 133.83, 129.80, 128.37, 51.62, 49.44, 25.25, 24.59
実施例９：
４－シアノ安息香酸メチルからの、４－［イミノ（ピロリジン－１－イル）メチル］安息香酸　塩酸塩の合成 Example 9:
Synthesis of 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride from methyl 4-cyanobenzoate
Figure JPOXMLDOC01-appb-C000094
Figure JPOXMLDOC01-appb-C000094
　エタノール１０５ｍｌ及び４－シアノ安息香酸メチル３５．０ｇの混合液を１０℃に冷却した後、塩化アセチル９２．３ｍｌを２時間３０分かけて滴下して４２時間攪拌した。ＨＰＬＣで４－エトキシイミノメチル安息香酸メチル　塩酸塩が生成していることを確認後、トルエン７０ｍｌを加えて濃縮し、再度トルエン７０ｍｌを加えて溶液量が２００ｍｌになるまで減圧濃縮した。トルエン１００ｍｌを追加後、１５℃に冷却し、ピロリジン２１．７ｍｌを１５分かけて滴下した。４０℃に昇温後、２時間１０分攪拌し、ＨＰＬＣで４－［イミノ（ピロリジン－１－イル）メチル］安息香酸メチル　塩酸塩が生成していることを確認後、濃塩酸２２．０ｍｌ及び水８６．９ｍｌを添加した。４０℃で１５分攪拌後、抽出分層を行い、得られた水層を微減圧下、９５℃で６時間攪拌した後、ＨＰＬＣで反応終了を確認した。溶液量が１００ｍｌになるまで濃縮した後、５０℃に冷却し、溶液量が９０ｍｌになるまで濃縮した。その後、アセトン８３７ｍｌを３０分かけて添加し、２５℃で２時間攪拌した。反応混合液を減圧濾過し、アセトン７５ｍｌで洗浄した後、６０℃で減圧乾燥して表題化合物５０．７ｇを得た。 A mixture of 105 ml of ethanol and 35.0 g of methyl 4-cyanobenzoate was cooled to 10 ° C., and 92.3 ml of acetyl chloride was added dropwise over 2 hours and 30 minutes, followed by stirring for 42 hours. After confirming the formation of methyl 4-ethoxyiminomethylbenzoate hydrochloride by HPLC, 70 ml of toluene was added and concentrated, and then 70 ml of toluene was added again and concentrated under reduced pressure until the amount of the solution reached 200 ml. After adding 100 ml of toluene, the mixture was cooled to 15 ° C., and 21.7 ml of pyrrolidine was added dropwise over 15 minutes. After the temperature was raised to 40 ° C., the mixture was stirred for 2 hours and 10 minutes. After confirming that methyl 4- [imino (pyrrolidin-1-yl) methyl] benzoate hydrochloride was formed by HPLC, 22.0 ml of concentrated hydrochloric acid and 86.9 ml of water was added. After stirring at 40 ° C. for 15 minutes, an extraction layer was formed, and the obtained aqueous layer was stirred at 95 ° C. for 6 hours under slightly reduced pressure, and then the completion of the reaction was confirmed by HPLC. After concentrating until the amount of the solution reached 100 ml, the solution was cooled to 50 ° C. and concentrated until the amount of the solution reached 90 ml. Thereafter, 837 ml of acetone was added over 30 minutes, and the mixture was stirred at 25 ° C. for 2 hours. The reaction mixture was filtered under reduced pressure, washed with 75 ml of acetone, and dried under reduced pressure at 60 ° C. to obtain 50.7 g of the title compound.
製造例１：
３－ヒドロキシベンゾニトリルからの、３－（２－ヒドロキシエトキシ）ベンゾニトリルの合成 Production Example 1:
Synthesis of 3- (2-hydroxyethoxy) benzonitrile from 3-hydroxybenzonitrile
Figure JPOXMLDOC01-appb-C000095
Figure JPOXMLDOC01-appb-C000095
　市販の３－ヒドロキシベンゾニトリル２５．５ｇに対して水１２０．０ｍｌ、及び、２－クロロエタノール２８．７ｍｌを加え２５℃で攪拌した。次に、水酸化ナトリウム１４．２ｇを加え、６０℃で一晩攪拌した。反応液を８℃に冷却し、１．５時間攪拌した後、懸濁液を減圧濾過し、水５０ｍｌで洗浄した。濾過物を６０℃に加熱して減圧乾燥したところ、融解したので、メタノールで全て回収した後、水２００ｍｌで再結晶させた。減圧濾過し、水５０ｍｌで洗浄した後、室温で一晩減圧乾燥して表題化合物３２．０ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　７．５１－７．４５（ｍ，１Ｈ），７．４２－７．３７（ｍ，２Ｈ），７．３２－７．２８（ｍ，１Ｈ），４．９１（ｔ，１Ｈ，Ｊ＝５．５Ｈｚ），４．０６（ｔ，２Ｈ，Ｊ＝４．８Ｈｚ），３．７４－３．７０（ｍ，２Ｈ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１５９．０５，１３１．００，１２４．５８，１２０．５９，１１８．８８，１１７．５０，１１２．３７，７０．２６，５９．５６ To 25.5 g of commercially available 3-hydroxybenzonitrile, 120.0 ml of water and 28.7 ml of 2-chloroethanol were added and stirred at 25 ° C. Next, 14.2 g of sodium hydroxide was added and stirred at 60 ° C. overnight. The reaction solution was cooled to 8 ° C. and stirred for 1.5 hours, and then the suspension was filtered under reduced pressure and washed with 50 ml of water. When the filtrate was heated to 60 ° C. and dried under reduced pressure, it melted. All of the filtrate was recovered with methanol, and then recrystallized with 200 ml of water. After filtration under reduced pressure, washing with 50 ml of water and drying under reduced pressure at room temperature overnight, 32.0 g of the title compound was obtained.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 7.51-7.45 (m, 1H), 7.42-7.37 (m, 2H), 7.32-7.28 (m, 1H), 4.91 (t, 1H, J = 5.5 Hz), 4.06 (t, 2H, J = 4.8 Hz), 3.74-3.70 (m, 2H)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 159.05, 131.00, 122.58, 120.59, 118.88, 117.50, 112.37, 70.26, 59.56
実施例１０：
３－（２－ヒドロキシエトキシ）ベンゾニトリルからの、３－（２－ヒドロキシエトキシ）ベンズアミジン　酢酸塩の合成 Example 10:
Synthesis of 3- (2-hydroxyethoxy) benzamidine acetate from 3- (2-hydroxyethoxy) benzonitrile
Figure JPOXMLDOC01-appb-C000096
Figure JPOXMLDOC01-appb-C000096
　３－（２－ヒドロキシエトキシ）ベンゾニトリル２５．０ｇに対して、メタノール１２５．０ｍｌ、ヒドロキシルアミン塩酸塩１６．０ｇを加えて１０℃で攪拌した。ｐＨ計が９．４を示すまでナトリウムメトキシドを加え、６７℃で還流した後、１５時間攪拌した。ＨＰＬＣで反応終了を確認し、１０℃以下に冷却した後、無水酢酸２３．２ｍｌを加えて１時間程攪拌した。反応終了をＨＰＬＣで確認した後、アルゴン雰囲気下で１０％Ｐｄ／Ｃ（ｗｅｔ、ＴｙｐｅＭ、川研ファインケミカル製）３．４ｇ加えて、水素雰囲気下で一晩以上攪拌した後、アルゴン雰囲気下とし、ＨＰＬＣで反応終了を確認した。反応混合液を減圧ろ過して、Ｐｄ／Ｃを除き、メタノール１２．５ｍｌで洗浄した後、ろ液を濃縮した。６０℃に昇温した後、５０℃に冷却して固体を析出させ、酢酸エチル３５０．０ｍｌを加えて攪拌した。懸濁液を８℃に冷却し、減圧濾過した後、酢酸エチル５０ｍｌで洗浄した。濾過物を４０℃で一晩減圧乾燥して表題化合物３２．６ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　７．５１－７．４６（ｍ，１Ｈ），７．３８－７．３４（ｍ，２Ｈ），７．２７－７．２３（ｍ，１Ｈ），４．０８（ｔ，２Ｈ，Ｊ＝４．８Ｈｚ），３．７４（ｔ，２Ｈ，Ｊ＝５．１Ｈｚ），１．７１（ｓ，３Ｈ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１７６．６９，１６５．９７，１５８．９３，１３０．９７，１３０．３２，１１９．７２，１１９．４６，１１３．５９，７０．０５，５９．６０，２４．９２ To 25.0 g of 3- (2-hydroxyethoxy) benzonitrile, 125.0 ml of methanol and 16.0 g of hydroxylamine hydrochloride were added and stirred at 10 ° C. Sodium methoxide was added until the pH meter showed 9.4, and the mixture was refluxed at 67 ° C. and stirred for 15 hours. After confirming the completion of the reaction by HPLC and cooling to 10 ° C. or lower, 23.2 ml of acetic anhydride was added and stirred for about 1 hour. After confirming the completion of the reaction by HPLC, 3.4 g of 10% Pd / C (wet, TypeM, manufactured by Kawaken Fine Chemical Co., Ltd.) was added under an argon atmosphere, and the mixture was stirred overnight or more under a hydrogen atmosphere. Completion of the reaction was confirmed by HPLC. The reaction mixture was filtered under reduced pressure to remove Pd / C, washed with 12.5 ml of methanol, and the filtrate was concentrated. After heating up to 60 degreeC, it cooled to 50 degreeC and solid was deposited, 350.0 ml of ethyl acetate was added and stirred. The suspension was cooled to 8 ° C., filtered under reduced pressure, and washed with 50 ml of ethyl acetate. The filtrate was dried under reduced pressure at 40 ° C. overnight to obtain 32.6 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 7.51-7.46 (m, 1H), 7.38-7.34 (m, 2H), 7.27-7.23 (m, 1H), 4.08 (t, 2H, J = 4.8 Hz), 3.74 (t, 2H, J = 5.1 Hz), 1.71 (s, 3H)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 176.69, 165.97, 158.93, 130.97, 130.32, 119.72, 119.46, 113.59, 70.05, 59.60, 24.92
製造例２：
３－（２－ヒドロキシエトキシ）ベンズアミジン　酢酸塩からの、３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩の合成 Production Example 2:
Synthesis of 3- (2-hydroxyethoxy) benzamidine hydrochloride from 3- (2-hydroxyethoxy) benzamidine acetate
Figure JPOXMLDOC01-appb-C000097
Figure JPOXMLDOC01-appb-C000097
　３－（２－ヒドロキシエトキシ）ベンズアミジン　酢酸塩　３０．０ｇに対し、１０℃で２Ｍ　塩酸／メタノールを加えてｐＨを２以下とした。６０℃に昇温した後、１０℃に冷却して酢酸エチル８００ｍｌを滴下した。４時間以上攪拌し、懸濁液を減圧濾過した後、酢酸エチル６０ｍｌで洗浄した。濾過物を８０℃で一晩減圧乾燥し、表題化合物２３．４ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　９．６０－９．２０（ｍ，４Ｈ），７．５５－７．４９（ｍ，１Ｈ），７．４５－７．４０（ｍ，２Ｈ），７．３２－７．２８（ｍ，１Ｈ），４．９８（ｂｒ－ｓ，１Ｈ），４．１０（ｔ，２Ｈ，Ｊ＝４．８Ｈｚ），３．７４（ｔ，２Ｈ，Ｊ＝５．０Ｈｚ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１６５．６４，１５８．９３，１３０．４４，１２９．３２，１２０．３６，１２０．２１，１１３．９４，７０．１３，５９．５６ To 30.0 g of 3- (2-hydroxyethoxy) benzamidine acetate, 2 M hydrochloric acid / methanol was added at 10 ° C. to adjust the pH to 2 or less. After raising the temperature to 60 ° C., the mixture was cooled to 10 ° C. and 800 ml of ethyl acetate was added dropwise. After stirring for 4 hours or more, the suspension was filtered under reduced pressure, and then washed with 60 ml of ethyl acetate. The filtrate was dried under reduced pressure at 80 ° C. overnight to obtain 23.4 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 9.60-9.20 (m, 4H), 7.55-7.49 (m, 1H), 7.45-7.40 (m, 2H), 7.32-7.28 (m, 1H), 4.98 (br-s, 1H), 4.10 (t, 2H, J = 4.8 Hz), 3.74 (t, 2H, J = 5.0Hz)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 165.64, 158.93, 130.44, 129.32, 120.36, 120.21, 113.94, 70.13, 59.56
実施例１１：
（１）：４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンゾニトリルからの、４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　酢酸塩の合成 Example 11:
(1): Synthesis of 4-hydroxy-3- (2-hydroxyethoxy) benzamidine acetate from 4-hydroxy-3- (2-hydroxyethoxy) benzonitrile
Figure JPOXMLDOC01-appb-C000098
Figure JPOXMLDOC01-appb-C000098
　メタノール８７．５ｍｌに対し、ヒドロキシルアミン塩酸塩１０．２ｇ、ナトリウムメトキシド７．９ｇ、４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンゾニトリル１７．５ｇを加えて１０℃で攪拌した。３０℃に昇温した後、ｐＨ計が９．０を示すまでナトリウムメトキシドを追加した。６７℃で還流し、一晩攪拌した後、３０℃に冷却してヒドロキシルアミン塩酸塩６．８ｇ、ナトリウムメトキシド１．２ｇを追加し、再度６７℃で２時間還流した。ＨＰＬＣにて反応終了を確認し、３０℃に冷却して、酢酸をｐＨ計が６．８を示すまで加えた。この反応液を１０℃に冷却し、無水酢酸２４．０ｍｌを加え、反応終了をＨＰＬＣで確認した。続いて、アルゴン雰囲気下で１０％Ｐｄ／Ｃ（ｗｅｔ、ＴｙｐｅＭ、川研ファインケミカル製）２．２ｇ、メタノール１７５ｍｌを加えて、水素雰囲気下で一晩攪拌した後、２５℃に昇温して一晩以上攪拌した。アルゴン雰囲気下とし、ＨＰＬＣで反応終了を確認した。反応混合液を減圧ろ過して、Ｐｄ／Ｃを除き、メタノール１７．５ｍｌで洗浄した。ろ液を濃縮した。６０℃に昇温した後、５０℃に冷却し、酢酸エチル２４５．０ｍｌを加えた。懸濁液を１０℃に冷却し、減圧濾過した後、酢酸エチル３５ｍｌで洗浄した。濾過物を６０℃で一晩減圧乾燥して表題化合物１７．２ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　７．３８－７．３１（ｍ，２Ｈ），６．７３（ｄ，１Ｈ，Ｊ＝８．３Ｈｚ），３．９９（ｔ，２Ｈ，Ｊ＝４．７Ｈｚ），３．７０（ｔ，２Ｈ，Ｊ＝５．０Ｈｚ），１．７３（ｓ，３Ｈ）　
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１７５．３５，１６６．３０，１６４．９１，１４８．０１，１２３．０２，１１６．６７，１１３．４５，７１．１２，５９．８２，１９．６６ To 87.5 ml of methanol, 10.2 g of hydroxylamine hydrochloride, 7.9 g of sodium methoxide, and 17.5 g of 4-hydroxy-3- (2-hydroxyethoxy) benzonitrile were added and stirred at 10 ° C. After raising the temperature to 30 ° C., sodium methoxide was added until the pH meter showed 9.0. After refluxing at 67 ° C. and stirring overnight, the mixture was cooled to 30 ° C., 6.8 g of hydroxylamine hydrochloride and 1.2 g of sodium methoxide were added, and the mixture was refluxed again at 67 ° C. for 2 hours. The completion of the reaction was confirmed by HPLC, cooled to 30 ° C., and acetic acid was added until the pH meter showed 6.8. The reaction solution was cooled to 10 ° C., 24.0 ml of acetic anhydride was added, and the completion of the reaction was confirmed by HPLC. Subsequently, 2.2 g of 10% Pd / C (wet, TypeM, manufactured by Kawaken Fine Chemicals) and 175 ml of methanol were added under an argon atmosphere, and the mixture was stirred overnight under a hydrogen atmosphere. Stir over night. The reaction was completed by HPLC under an argon atmosphere. The reaction mixture was filtered under reduced pressure to remove Pd / C and washed with 17.5 ml of methanol. The filtrate was concentrated. After raising the temperature to 60 ° C., the mixture was cooled to 50 ° C., and 245.0 ml of ethyl acetate was added. The suspension was cooled to 10 ° C., filtered under reduced pressure, and washed with 35 ml of ethyl acetate. The filtrate was dried under reduced pressure at 60 ° C. overnight to obtain 17.2 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 7.38-7.31 (m, 2H), 6.73 (d, 1H, J = 8.3 Hz), 3.99 (t, 2H, J = 4.7 Hz), 3.70 (t, 2H, J = 5.0 Hz), 1.73 (s, 3H)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 175.35, 166.30, 164.91, 148.01, 123.02, 116.67, 113.45, 71.12, 59.82, 19.66
（２）：４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　酢酸塩からの、４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩の合成 (2): Synthesis of 4-hydroxy-3- (2-hydroxyethoxy) benzamidine hydrochloride from 4-hydroxy-3- (2-hydroxyethoxy) benzamidine acetate
Figure JPOXMLDOC01-appb-C000099
Figure JPOXMLDOC01-appb-C000099
　４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　酢酸塩１６．０ｇに１０℃冷却下で２Ｍ　塩酸／メタノールを加えて、ｐＨを２以下とした。６０℃以上に昇温した後、１０℃に冷却し、酢酸エチル１４０．０ｍｌを滴下した。２時間以上攪拌し、懸濁液を減圧濾過した後、酢酸エチル２３ｍｌで洗浄した。濾過物を８０℃で一晩減圧乾燥して、表題化合物１１．１ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１０．１８（ｓ，１Ｈ），９．４０－９．１０（ｍ，４Ｈ），７．５６（ｄ，１Ｈ，Ｊ＝２．０Ｈｚ），７．４８－７．４３（ｍ，１Ｈ），７．０２（ｄ，１Ｈ，Ｊ＝８．４Ｈｚ），５．１０－５．００（ｍ，１Ｈ），４．１０（ｔ，２Ｈ，Ｊ＝４．９Ｈｚ），３．７９－３．７０（ｍ，２Ｈ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１６４．９１，１５２．５０，１４６．９６，１２２．３６，１１７．７５，１１５．６０，１１３．１７，７０．７３，５９．６０ To 16.0 g of 4-hydroxy-3- (2-hydroxyethoxy) benzamidine acetate, 2M hydrochloric acid / methanol was added under cooling at 10 ° C. to adjust the pH to 2 or less. After raising the temperature to 60 ° C. or higher, the mixture was cooled to 10 ° C., and 140.0 ml of ethyl acetate was added dropwise. The mixture was stirred for 2 hours or more, and the suspension was filtered under reduced pressure, and then washed with 23 ml of ethyl acetate. The filtrate was dried under reduced pressure at 80 ° C. overnight to obtain 11.1 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 10.18 (s, 1H), 9.40-9.10 (m, 4H), 7.56 (d, 1H, J = 2.0 Hz) 7.48-7.43 (m, 1H), 7.02 (d, 1H, J = 8.4 Hz), 5.10-5.00 (m, 1H), 4.10 (t, 2H, J = 4.9 Hz), 3.79-3.70 (m, 2H)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 164.91, 152.50, 146.96, 122.36, 117.75, 115.60, 113.17, 70.73, 59.60
実施例１２：
（１）：３－（２－ヒドロキシエトキシ）－４－メトキシベンゾニトリルからの、３－（２－ヒドロキシエトキシ）－４－メトキシベンズアミジン　酢酸塩の合成 Example 12:
(1): Synthesis of 3- (2-hydroxyethoxy) -4-methoxybenzamidine acetate from 3- (2-hydroxyethoxy) -4-methoxybenzonitrile
Figure JPOXMLDOC01-appb-C000100
Figure JPOXMLDOC01-appb-C000100
　３－（２－ヒドロキシエトキシ）－４－メトキシベンゾニトリル３０．０ｇに対して、メタノール１５０．０ｍｌ、ヒドロキシルアミン塩酸塩１６．２ｇ、ナトリウムメトキシド１３．１ｇを加えて、８℃で攪拌した。ｐＨ計が９．２を示すまでナトリウムメトキシドを追加した後、６７℃で還流し、１２時間以上攪拌した後、ＨＰＬＣで反応終了を確認し、８℃以下に冷却して無水酢酸２３．５ｍｌを加えた。１時間攪拌し、反応終了をＨＰＬＣで確認した。アルゴン雰囲気下で１０％Ｐｄ／Ｃ（ｗｅｔ、ＴｙｐｅＭ、川研ファインケミカル製）３．４ｇを加え、水素雰囲気下で一晩攪拌した後、アルゴン雰囲気下としてＨＰＬＣで反応終了を確認した。反応混合液を減圧ろ過して、Ｐｄ／Ｃを除き、メタノール　１５ｍｌで洗浄した後、ろ液を濃縮した。この反応液を６０℃に昇温し、溶液がほぼ均一になるまでメタノールを加えた後、５０℃に冷却して酢酸エチル４２０．０ｍｌを加えた。８℃に冷却した懸濁液を減圧濾過した後、酢酸エチル６０ｍｌで洗浄し、４０℃で一晩乾燥して表題化合物４０．４ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　７．５２－７．４６（ｍ，２Ｈ），７．１４（ｄ，１Ｈ，Ｊ＝８．４Ｈｚ），４．０９（ｔ，２Ｈ，Ｊ＝５．１Ｈｚ），３．８５（ｓ，３Ｈ），３．７５（ｔ，２Ｈ，Ｊ＝５．２Ｈｚ），１．７１（ｓ，３Ｈ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１７６．８１，１６５．２６，１５３．１１，１４８．１３，１２１．４５，１２０．８８，１１２．０４，１１１．７０，７０．５０，５９．５６，５５．９９，２５．２０ To 30.0 g of 3- (2-hydroxyethoxy) -4-methoxybenzonitrile, 150.0 ml of methanol, 16.2 g of hydroxylamine hydrochloride and 13.1 g of sodium methoxide were added and stirred at 8 ° C. After adding sodium methoxide until the pH meter shows 9.2, the mixture was refluxed at 67 ° C. and stirred for 12 hours or longer. After completion of the reaction was confirmed by HPLC, cooled to 8 ° C. or lower and acetic anhydride 23.5 ml. Was added. The mixture was stirred for 1 hour, and the completion of the reaction was confirmed by HPLC. 3.4 g of 10% Pd / C (wet, TypeM, manufactured by Kawaken Fine Chemicals) was added under an argon atmosphere and stirred overnight under a hydrogen atmosphere, and then the completion of the reaction was confirmed by HPLC under an argon atmosphere. The reaction mixture was filtered under reduced pressure to remove Pd / C, washed with 15 ml of methanol, and then the filtrate was concentrated. The temperature of the reaction solution was raised to 60 ° C., methanol was added until the solution became almost uniform, then cooled to 50 ° C., and 420.0 ml of ethyl acetate was added. The suspension cooled to 8 ° C. was filtered under reduced pressure, washed with 60 ml of ethyl acetate, and dried at 40 ° C. overnight to obtain 40.4 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 7.52-7.46 (m, 2H), 7.14 (d, 1H, J = 8.4 Hz), 4.09 (t, 2H, J = 5.1 Hz), 3.85 (s, 3H), 3.75 (t, 2H, J = 5.2 Hz), 1.71 (s, 3H)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 176.81, 165.26, 153.11, 148.13, 121.45, 120.88, 112.04, 111.70, 70.50, 59.56, 55.99, 25.20
（２）：３－（２－ヒドロキシエトキシ）－４－メトキシベンズアミジン　酢酸塩からの、３－（２－ヒドロキシエトキシ）－４－メトキシベンズアミジン　塩酸塩の合成 (2): Synthesis of 3- (2-hydroxyethoxy) -4-methoxybenzamidine hydrochloride from 3- (2-hydroxyethoxy) -4-methoxybenzamidine acetate
Figure JPOXMLDOC01-appb-C000101
Figure JPOXMLDOC01-appb-C000101
　３－（２－ヒドロキシエトキシ）－４－メトキシベンズアミジン　酢酸塩３５．０ｇに水５９５．０ｍｌを加えて１０℃に冷却し、６Ｍ　水酸化ナトリウム水溶液２１．６ｍｌを滴下してｐＨを１２～１３に調整した。１時間程攪拌した後、懸濁液を減圧濾過し、水７０ｍｌで洗浄し、３－（２－ヒドロキシエトキシ）－４－メトキシベンズアミジンのｗｅｔ固体を得た。この固体に対し、メタノール１１２．６ｍｌを加え、２Ｍ　塩酸－メタノールをｐＨ計が２以下となるまで１０℃で加えた。４０℃以上に昇温し、均一液であることを確認後、１０℃に冷却し、酢酸エチル７２１．４ｍｌを滴下した後、１時間攪拌した。懸濁液を減圧濾過した後、酢酸エチル７０ｍｌで洗浄し、８０℃で１８時間減圧乾燥して表題化合物２６．５ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　９．４０－９．００（ｍ，４Ｈ），７．５７－７．５１（ｍ，２Ｈ），７．１８（ｄ，１Ｈ，Ｊ＝８．６Ｈｚ），５．０１－４．９４（ｍ，１Ｈ），４．１０（ｔ，２Ｈ，Ｊ＝５．０Ｈｚ），３．８７（ｓ，３Ｈ），３．７８－３．７２（ｍ，２Ｈ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１６４．８２，１５３．６３，１４８．１３，１２２．０８，１１９．３３，１１２．３２，１１１．７３，７０．５５，５９．５２，５６．０５ 3- (2-Hydroxyethoxy) -4-methoxybenzamidine 595.0 ml of water was added to 35.0 g of acetate and cooled to 10 ° C., and 21.6 ml of 6M aqueous sodium hydroxide solution was added dropwise to adjust the pH to 12-13. Adjusted. After stirring for about 1 hour, the suspension was filtered under reduced pressure and washed with 70 ml of water to obtain a wet solid of 3- (2-hydroxyethoxy) -4-methoxybenzamidine. To this solid, 112.6 ml of methanol was added, and 2M hydrochloric acid-methanol was added at 10 ° C. until the pH meter was 2 or less. The temperature was raised to 40 ° C. or higher, and after confirming that the solution was homogeneous, the solution was cooled to 10 ° C., 721.4 ml of ethyl acetate was added dropwise, and the mixture was stirred for 1 hour. The suspension was filtered under reduced pressure, washed with 70 ml of ethyl acetate, and dried under reduced pressure at 80 ° C. for 18 hours to obtain 26.5 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 9.40-9.00 (m, 4H), 7.57-7.51 (m, 2H), 7.18 (d, 1H, J = 8.6 Hz), 5.01-4.94 (m, 1H), 4.10 (t, 2H, J = 5.0 Hz), 3.87 (s, 3H), 3.78-3.72 ( m, 2H)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 164.82, 153.63, 148.13, 122.08, 119.33, 112.32, 111.73, 70.55, 59.52, 56.05
実施例１３：
（１）：ナトリウム　４－シアノ－２－（２－ヒドロキシエトキシ）フェノキシドからの、４－エトキシ－３－（２－ヒドロキシエトキシ）ベンゾニトリルの合成 Example 13:
(1): Synthesis of 4-ethoxy-3- (2-hydroxyethoxy) benzonitrile from sodium 4-cyano-2- (2-hydroxyethoxy) phenoxide
Figure JPOXMLDOC01-appb-C000102
Figure JPOXMLDOC01-appb-C000102
　ナトリウム　４－シアノ－２－（２－ヒドロキシエトキシ）フェノキシド２６．９ｇに対し、炭酸カリウム３．４３ｇ、ＤＭＦ７５ｍｌ、ブロモエタン１６ｍｌを加え、室温で４時間、６０℃で１時間攪拌した。ＨＰＬＣで反応終了を確認した後、室温下、水１２５ｍｌを滴下して目的物を起晶させた。さらに水１５０ｍｌを滴下した後、１０℃に冷却して１時間熟成させた。このスラリーを減圧濾過し、水５０ｍｌで洗浄した後、４０℃で１８時間減圧乾燥して表題化合物２５．１ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　７．４１－７．３７（ｍ，２Ｈ），７．１０（ｄ，１Ｈ，Ｊ＝８．１Ｈｚ），４．８７（ｔ，１Ｈ，Ｊ＝５．４Ｈｚ），４．１４　（ｑ，２Ｈ，Ｊ＝７．０Ｈｚ），４．０４（ｔ，２Ｈ，Ｊ＝４．８Ｈｚ），３．７２　（ｑ，２Ｈ，Ｊ＝５．２Ｈｚ），１．３５（ｔ，３Ｈ，Ｊ＝７．０Ｈｚ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１５２．４５，１４８．５７，１２６．５９，１１９．４７，１１６．１４，１１３．３２，１０２．５９，７０．７８，６４．２７，５９．５６，１４．６２ To 26.9 g of sodium 4-cyano-2- (2-hydroxyethoxy) phenoxide, 3.43 g of potassium carbonate, 75 ml of DMF and 16 ml of bromoethane were added, followed by stirring at room temperature for 4 hours and at 60 ° C. for 1 hour. After confirming the completion of the reaction by HPLC, 125 ml of water was added dropwise at room temperature to crystallize the desired product. Further, 150 ml of water was added dropwise, followed by cooling to 10 ° C. and aging for 1 hour. The slurry was filtered under reduced pressure, washed with 50 ml of water, and dried under reduced pressure at 40 ° C. for 18 hours to obtain 25.1 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 7.41-7.37 (m, 2H), 7.10 (d, 1H, J = 8.1 Hz), 4.87 (t, 1H, J = 5.4 Hz), 4.14 (q, 2H, J = 7.0 Hz), 4.04 (t, 2H, J = 4.8 Hz), 3.72 (q, 2H, J = 5.2 Hz) ), 1.35 (t, 3H, J = 7.0 Hz)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 152.45, 148.57, 126.59, 119.47, 116.14, 113.32, 102.59, 70.78, 64.27, 59.56, 14.62
（２）：４－エトキシ－３－（２－ヒドロキシエトキシ）ベンゾニトリルからの、４－エトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　酢酸塩の合成 (2): Synthesis of 4-ethoxy-3- (2-hydroxyethoxy) benzamidine acetate from 4-ethoxy-3- (2-hydroxyethoxy) benzonitrile
Figure JPOXMLDOC01-appb-C000103
Figure JPOXMLDOC01-appb-C000103
　ヒドロキシルアミン塩酸塩１２．５７ｇ、メタノール　１２５ｍｌ、ナトリウムメトキシド９．７８ｇを加えて２０℃で攪拌した。この液に対し、４－エトキシ－３－（２－ヒドロキシエトキシ）ベンゾニトリル２５．０ｇを加え、さらにｐＨ計が９．３を示すまでナトリウムメトキシドを追加した後、６７℃（Ｒｅｆｌｕｘ）で３．５時間攪拌した。ＨＰＬＣで反応終了を確認した後、メタノール７５ｍｌを加えて１０℃に冷却した後、無水酢酸１８．３ｍｌを１０分間で滴下した。ＨＰＬＣで反応終了確認後、系をＡｒで置換した後、１０％Ｐｄ／Ｃ（ｗｅｔ、タイプＭ、川研ファインケミカル製）２．５３ｇを加えて水素で置換した。一晩攪拌後、Ａｒで置換した後、ＨＰＬＣで反応終了を確認し、４０℃に加熱して減圧濾過でＰｄ／Ｃを除去した。メタノール２５ｍｌで洗浄後、ろ液を４８．６ｇまで減圧濃縮し、メタノール５０ｍｌを加えて６０℃に加熱した。この液を４０℃に冷却して起晶させ、再度６０℃に加熱して酢酸エチル５００ｍｌを滴下した後、１０℃に冷却して１時間熟成させた。このスラリーを減圧濾過し、酢酸エチル５０ｍｌで洗浄して６０℃で１８時間減圧乾燥し、表題化合物３４．１ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　７．４８－７．４５（ｍ，２Ｈ），７．１３（ｄ，１Ｈ，Ｊ＝８．３Ｈｚ），４．１６－４．０７（ｍ，４Ｈ），３．７４（ｔ，２Ｈ，Ｊ＝５．２Ｈｚ），１．７０（ｓ，３Ｈ），１．３５（ｔ，３Ｈ，Ｊ＝６．９Ｈｚ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１７６．６１，１６５．１７，１５２．４１，１４８．２０，１２１．４８，１２０．７８，１１２．６６，１１２．５６，７０．５７，６４．２５，５９．５４，２５．１８，１４．７０ Hydroxylamine hydrochloride (12.57 g), methanol (125 ml) and sodium methoxide (9.78 g) were added, and the mixture was stirred at 20 ° C. To this solution, 25.0 g of 4-ethoxy-3- (2-hydroxyethoxy) benzonitrile was added, and sodium methoxide was further added until the pH meter showed 9.3, and then 3 hours at 67 ° C. (Reflux). Stir for 5 hours. After confirming the completion of the reaction by HPLC, 75 ml of methanol was added and cooled to 10 ° C., and then 18.3 ml of acetic anhydride was added dropwise over 10 minutes. After confirming the completion of the reaction by HPLC, the system was replaced with Ar, and 2.53 g of 10% Pd / C (wet, type M, manufactured by Kawaken Fine Chemicals) was added and replaced with hydrogen. After stirring overnight and replacing with Ar, the completion of the reaction was confirmed by HPLC, heating to 40 ° C., and Pd / C was removed by filtration under reduced pressure. After washing with 25 ml of methanol, the filtrate was concentrated to 48.6 g under reduced pressure, 50 ml of methanol was added, and the mixture was heated to 60 ° C. This liquid was cooled to 40 ° C. for crystallization, heated again to 60 ° C., 500 ml of ethyl acetate was added dropwise, then cooled to 10 ° C. and aged for 1 hour. This slurry was filtered under reduced pressure, washed with 50 ml of ethyl acetate, and dried under reduced pressure at 60 ° C. for 18 hours to obtain 34.1 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 7.48-7.45 (m, 2H), 7.13 (d, 1H, J = 8.3 Hz), 4.16-4.07 ( m, 4H), 3.74 (t, 2H, J = 5.2 Hz), 1.70 (s, 3H), 1.35 (t, 3H, J = 6.9 Hz)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 176.61, 165.17, 152.41, 148.20, 121.48, 120.78, 112.66, 112.56, 70.57, 64.25, 59.54, 25.18, 14.70
（３）：４－エトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　酢酸塩からの、４－エトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジンの合成 (3): 4-Ethoxy-3- (2-hydroxyethoxy) benzamidine Synthesis of 4-ethoxy-3- (2-hydroxyethoxy) benzamidine from acetate
Figure JPOXMLDOC01-appb-C000104
Figure JPOXMLDOC01-appb-C000104
　４－エトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　酢酸塩３２．０ｇに対し、水３２０ｍｌを加えて５０℃に加熱した。８℃に冷却して６Ｍ水酸化ナトリウム水溶液をｐＨ計が１１．５に安定するまで滴下した。生じた結晶を減圧濾過し、水６４ｍｌ、ＥｔＯＨ６４ｍｌで洗浄し、表題化合物のｗｅｔ固体２７．０ｇを得た（正味量１８．９ｇ）。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　７．３９（ｄ，１Ｈ，Ｊ＝１．９Ｈｚ），７．３４－７．３０（ｍ，１Ｈ），６．９３（ｄ，１Ｈ，Ｊ＝８．４Ｈｚ），５．９５　（ｂｒｏａｄ－ｓ，４Ｈ），４．０８－４．００（ｍ，４Ｈ），３．７２（ｔ，２Ｈ，Ｊ＝５．３Ｈｚ），１．３３（ｔ，３Ｈ，Ｊ＝７．０Ｈｚ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１６２．３８，１４９．７７，１４７．７９，１２８．９５，１１９．６２，１１２．５１，１１２．３１，７０．４７，６３．９７，５９．７１，１４．８９ To 32.0 g of 4-ethoxy-3- (2-hydroxyethoxy) benzamidine acetate, 320 ml of water was added and heated to 50 ° C. After cooling to 8 ° C., a 6M aqueous sodium hydroxide solution was added dropwise until the pH meter was stabilized at 11.5. The resulting crystals were filtered under reduced pressure and washed with water (64 ml) and EtOH (64 ml) to obtain 27.0 g of the title compound as a wet solid (net amount: 18.9 g).
1 H-NMR (400 MHz, DMSO-d 6 ): δ 7.39 (d, 1H, J = 1.9 Hz), 7.34-7.30 (m, 1H), 6.93 (d, 1H, J = 8.4 Hz), 5.95 (broad-s, 4H), 4.08-4.00 (m, 4H), 3.72 (t, 2H, J = 5.3 Hz), 1.33 ( t, 3H, J = 7.0Hz)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 162.38, 149.77, 147.79, 128.95, 119.62, 112.51, 112.31, 70.47, 63.97, 59.71, 14.89
（４）：４－エトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジンからの、４－エトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩の合成 (4): Synthesis of 4-ethoxy-3- (2-hydroxyethoxy) benzamidine hydrochloride from 4-ethoxy-3- (2-hydroxyethoxy) benzamidine
Figure JPOXMLDOC01-appb-C000105
Figure JPOXMLDOC01-appb-C000105
　４－エトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジンのｗｅｔ固体２６．５ｇ（正味量１８．６ｇ）に対し、メタノール７４．４ｍｌを加えて８℃で攪拌した。２Ｍ　ＨＣｌ／メタノールを４６ｍｌ加え、ｐＨ計が０．５であることを確認し、５０℃に昇温して酢酸エチル３３５ｍｌを滴下した。８℃に冷却して２時間熟成させ、スラリーを減圧濾過し、酢酸エチル３８ｍｌで洗浄した後、８０℃で１６時間減圧乾燥して表題化合物２１．５ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　９．５０－９．００（ｍ，４Ｈ），７．５８－７．５５（ｍ，２Ｈ），７．１７（ｄ，１Ｈ，Ｊ＝９．０Ｈｚ），５．００（ｓ，１Ｈ），４．２０－４．１０（ｍ，４Ｈ），３．７６（ｔ，２Ｈ，Ｊ＝４．９Ｈｚ），１．３６（ｔ，３Ｈ，Ｊ＝７．０Ｈｚ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１６４．８４，１５２．９９，１４８．２３，１２２．１９，１１９．１３，１１２．８５，１１２．６４，７０．６６，６４．３５，５９．５４，１４．６９ To 26.5 g of wet solid of 4-ethoxy-3- (2-hydroxyethoxy) benzamidine (net amount 18.6 g), 74.4 ml of methanol was added and stirred at 8 ° C. 46 ml of 2M HCl / methanol was added, it was confirmed that the pH meter was 0.5, the temperature was raised to 50 ° C., and 335 ml of ethyl acetate was added dropwise. After cooling to 8 ° C. and aging for 2 hours, the slurry was filtered under reduced pressure, washed with 38 ml of ethyl acetate, and then dried under reduced pressure at 80 ° C. for 16 hours to obtain 21.5 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 9.50-9.00 (m, 4H), 7.58-7.55 (m, 2H), 7.17 (d, 1H, J = 9.0 Hz), 5.00 (s, 1H), 4.20-4.10 (m, 4H), 3.76 (t, 2H, J = 4.9 Hz), 1.36 (t, 3H, J = 7.0Hz)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 164.84, 152.99, 148.23, 122.19, 119.13, 112.85, 112.64, 70.66, 64.35, 59.54, 14.69
実施例１４：
（１）：ナトリウム　４－シアノ－２－（２－ヒドロキシエトキシ）フェノキシドからの、３－（２－ヒドロキシエトキシ）－４－（２－メチルプロポキシ）ベンゾニトリルの合成 Example 14:
(1): Synthesis of 3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzonitrile from sodium 4-cyano-2- (2-hydroxyethoxy) phenoxide
Figure JPOXMLDOC01-appb-C000106
 　
Figure JPOXMLDOC01-appb-C000106
 　
　ナトリウム　４－シアノ－２－（２－ヒドロキシエトキシ）フェノキシド２６．９ｇに対し、ジメチルホルムアミド７５．０ｍｌ、イソブチルブロミド２０．０ｍｌ、炭酸カリウム３．４ｇを加え、１００℃に加熱して３０時間以上攪拌した。ＨＰＬＣで反応終了を確認した後、室温まで冷却して水１２５．０ｍｌ、トルエン１２５．０ｍｌを加えて抽出した。分離した水層に対して、トルエン６２．５ｍｌを加えて抽出を行った。得られた有機層の混合液を水６２．５ｍｌで洗浄・分離した後、有機層を減圧濃縮を実施して表題化合物３３．３ｇ（含量７０．１ｗｔ％）を得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　７．４２－７．３７（ｍ，２Ｈ），７．１１（ｄ，１Ｈ，Ｊ＝８．４Ｈｚ），４．８４（ｔ，１Ｈ，Ｊ＝５．４Ｈｚ），４．０５（ｔ，２Ｈ，Ｊ＝４．９Ｈｚ），３．８３（ｄ，２Ｈ，Ｊ＝６．６Ｈｚ），３．７４－３．６９（ｍ，２Ｈ），２．１０－１．９０（ｍ，１Ｈ），０．９８（ｄ，６Ｈ，Ｊ＝６．７Ｈｚ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１５２．９２，１４８．７２，１２６．７２，１１９．４４，１１６．７８，１１３．６９，１０２．６５，７４．７４，７１．０１，５９．６８，２７．７６，１９．１３ To 26.9 g of sodium 4-cyano-2- (2-hydroxyethoxy) phenoxide, add 75.0 ml of dimethylformamide, 20.0 ml of isobutyl bromide and 3.4 g of potassium carbonate, heat to 100 ° C. and stir for 30 hours or more did. After confirming the completion of the reaction by HPLC, the reaction mixture was cooled to room temperature and extracted by adding 125.0 ml of water and 125.0 ml of toluene. To the separated aqueous layer, 62.5 ml of toluene was added for extraction. The obtained mixture of organic layers was washed and separated with 62.5 ml of water, and then the organic layer was concentrated under reduced pressure to obtain 33.3 g (content 70.1 wt%) of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 7.42-7.37 (m, 2H), 7.11 (d, 1H, J = 8.4 Hz), 4.84 (t, 1H, J = 5.4 Hz), 4.05 (t, 2H, J = 4.9 Hz), 3.83 (d, 2H, J = 6.6 Hz), 3.74-3.69 (m, 2H), 2.10-1.90 (m, 1H), 0.98 (d, 6H, J = 6.7 Hz)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 152.92, 148.72, 126.72, 119.44, 116.78, 113.69, 102.65, 74.74, 71.01 59.68, 27.76, 19.13
（２）：３－（２－ヒドロキシエトキシ）－４－（２－メチルプロポキシ）ベンゾニトリルからの、３－（２－ヒドロキシエトキシ）－４－（２－メチルプロポキシ）ベンズアミジン　酢酸塩の合成 (2): Synthesis of 3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzamidine acetate from 3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzonitrile
Figure JPOXMLDOC01-appb-C000107
Figure JPOXMLDOC01-appb-C000107
　３－（２－ヒドロキシエトキシ）－４－（２－メチルプロポキシ）ベンゾニトリル３３．３ｇ（含量７０．１ｗｔ％）に対して、メタノール１１７．０ｍｌ、ヒドロキシルアミン塩酸塩１０．３ｇ、ナトリウムメトキシド８．４ｇを加えて１０℃で攪拌した。ｐＨ計が９．２を示すまでナトリウムメトキシドを追加した後、６７℃で還流し、一晩攪拌した。ＨＰＬＣで反応終了を確認し、１０℃以下に冷却して無水酢酸１５．０ｍｌを加え、１時間攪拌した。ＨＰＣＬで反応終了を確認した後、アルゴン雰囲気下とし、１０％Ｐｄ／Ｃ（ｗｅｔ、ＴｙｐｅＭ、川研ファインケミカル製）を２．２ｇ加えた。さらに水素雰囲気下で一晩以上攪拌した後、アルゴン雰囲気下としてＨＰＬＣで反応終了を確認した。反応混合液を減圧ろ過し、Ｐｄ／Ｃを除き、メタノール１２ｍｌで洗浄した。ろ液を濃縮した後、５０℃に昇温し、酢酸エチル３２７．０ｍｌを加えて攪拌した。懸濁液を減圧濾過した後、酢酸エチル４６．６ｍｌで洗浄した後、６０℃で一晩減圧乾燥して表題化合物６．１ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　７．５１－７．４５（ｍ，２Ｈ），７．１４（ｄ，１Ｈ，Ｊ＝８．４Ｈｚ），４．０９（ｔ，２Ｈ，Ｊ＝５．２Ｈｚ），３．８５（ｄ，２Ｈ，Ｊ＝６．６Ｈｚ），３．７３（ｔ，２Ｈ，Ｊ＝５．３Ｈｚ），２．１１－１．９９（ｍ，１Ｈ），１．７１（ｓ，３Ｈ），０．９９（ｄ，６Ｈ，Ｊ＝６．７Ｈｚ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１７６．３９，１６５．１５，１５３．０７，１４８．３７，１２１．８７，１２０．３９，１１３．３７，１１３．０６，７４．８４，７０．８６，５９．６６，２７．８３，２４．９２，１９．１９ 113.3 ml of methanol, 10.3 g of hydroxylamine hydrochloride, sodium methoxide 8 against 33.3 g (content 70.1 wt%) of 3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzonitrile .4 g was added and stirred at 10 ° C. Sodium methoxide was added until the pH meter showed 9.2, and then the mixture was refluxed at 67 ° C. and stirred overnight. After confirming the completion of the reaction by HPLC, the mixture was cooled to 10 ° C. or lower, 15.0 ml of acetic anhydride was added, and the mixture was stirred for 1 hour. After confirming the completion of the reaction by HPCL, under an argon atmosphere, 2.2 g of 10% Pd / C (wet, TypeM, manufactured by Kawaken Fine Chemicals) was added. Furthermore, after stirring overnight or more under a hydrogen atmosphere, the completion of the reaction was confirmed by HPLC under an argon atmosphere. The reaction mixture was filtered under reduced pressure to remove Pd / C and washed with 12 ml of methanol. After the filtrate was concentrated, the temperature was raised to 50 ° C., and 327.0 ml of ethyl acetate was added and stirred. The suspension was filtered under reduced pressure, washed with 46.6 ml of ethyl acetate, and then dried under reduced pressure at 60 ° C. overnight to obtain 6.1 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 7.51-7.45 (m, 2H), 7.14 (d, 1H, J = 8.4 Hz), 4.09 (t, 2H, J = 5.2 Hz), 3.85 (d, 2H, J = 6.6 Hz), 3.73 (t, 2H, J = 5.3 Hz), 2.11-1.99 (m, 1H), 1.71 (s, 3H), 0.99 (d, 6H, J = 6.7 Hz)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 176.39, 165.15, 153.07, 148.37, 121.87, 120.39, 113.37, 113.06, 74.84, 70.86, 59.66, 27.83, 24.92, 19.19
（３）：３－（２－ヒドロキシエトキシ）－４－（２－メチルプロポキシ）ベンズアミジン　酢酸塩からの、３－（２－ヒドロキシエトキシ）－４－（２－メチルプロポキシ）ベンズアミジン　塩酸塩の合成 (3): Synthesis of 3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzamidine hydrochloride from 3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzamidine acetate
Figure JPOXMLDOC01-appb-C000108
Figure JPOXMLDOC01-appb-C000108
　３－（２－ヒドロキシエトキシ）－４－（２－メチルプロポキシ）ベンズアミジン　酢酸塩５．５ｇに対し、水５５．０ｍｌ加えて８０℃に昇温した後、６Ｍ　水酸化ナトリウム水溶液２．９ｍｌを滴下してｐＨを１１～１２に調整した。８℃に冷却し、３０分程攪拌した後、懸濁液を減圧濾過し、水１１ｍｌで洗浄した。得られた３－（２－ヒドロキシエトキシ）－４－（２－メチルプロポキシ）ベンズアミジンのＷｅｔ固体に対し、８℃でメタノール２１．０ｍｌを加え、ｐＨが２以下となるまで２Ｍ　ＨＣｌ／メタノールを加えた。４０℃に昇温した後、８℃に冷却して酢酸エチル１０７．０ｍｌを滴下した後、２時間攪拌した。懸濁液を減圧濾過した後、酢酸エチル１１．０ｍｌで洗浄し、８０℃で一晩減圧乾燥して、表題化合物２．２ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　９．３５－８．９０（ｍ，４Ｈ），７．５５－７．４８（ｍ，２Ｈ），７．１８（ｄ，１Ｈ，Ｊ＝９．０Ｈｚ），４．９１（ｂｒ－ｓ，１Ｈ），４．１０（ｔ，２Ｈ，Ｊ＝５．２Ｈｚ），３．８６（ｄ，２Ｈ，Ｊ＝６．７Ｈｚ），３．７４（ｔ，２Ｈ，Ｊ＝５．２Ｈｚ），２．１３－１．９８（ｍ，１Ｈ），０．９９（ｄ，６Ｈ，Ｊ＝６．７Ｈｚ）
１３Ｃ－ＮＭＲ（１００ＭＨｚ，ＤＭＳＯ－ｄ６）：δ　１６４．８１，１５３．４６，１４８．３６，１２２．３２，１１９．２２，１１３．５２，１１３．０２，７４．８３，７０．８８，５９．６４，２７．８０，１９．１７ 3- (2-Hydroxyethoxy) -4- (2-methylpropoxy) benzamidine To 5.5 g of acetate, 55.0 ml of water was added and the temperature was raised to 80 ° C., followed by dropwise addition of 2.9 ml of 6M aqueous sodium hydroxide solution The pH was adjusted to 11-12. After cooling to 8 ° C. and stirring for about 30 minutes, the suspension was filtered under reduced pressure and washed with 11 ml of water. To the obtained wet solid of 3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzamidine, 21.0 ml of methanol was added at 8 ° C., and 2M HCl / methanol was added until the pH was 2 or less. It was. After raising the temperature to 40 ° C., the mixture was cooled to 8 ° C., 107.0 ml of ethyl acetate was added dropwise, and the mixture was stirred for 2 hours. The suspension was filtered under reduced pressure, washed with 11.0 ml of ethyl acetate, and dried under reduced pressure at 80 ° C. overnight to obtain 2.2 g of the title compound.
1 H-NMR (400 MHz, DMSO-d 6 ): δ 9.35-8.90 (m, 4H), 7.55-7.48 (m, 2H), 7.18 (d, 1H, J = 9.0 Hz), 4.91 (br-s, 1H), 4.10 (t, 2H, J = 5.2 Hz), 3.86 (d, 2H, J = 6.7 Hz), 3.74 ( t, 2H, J = 5.2 Hz), 2.13-1.98 (m, 1H), 0.99 (d, 6H, J = 6.7 Hz)
13 C-NMR (100 MHz, DMSO-d 6 ): δ 164.81, 153.46, 148.36, 122.32, 119.22, 113.52, 113.02, 74.83, 70.88, 59.64, 27.80, 19.17
　本発明を好ましい態様を強調して説明してきたが、好ましい態様が変更され得ることは当業者にとって自明であろう。本発明は、本発明が本明細書に詳細に記載された以外の方法で実施され得ることを意図している。したがって、本発明は添付の「請求の範囲」の精神および範囲に包含されるすべての変更を含むものである。
　ここで述べられた特許および特許出願明細書を含む全ての刊行物に記載された内容は、ここに引用されたことによって、その全てが明示されたと同程度に本明細書に組み込まれるものである。 While the invention has been described with emphasis on preferred embodiments, it will be apparent to those skilled in the art that the preferred embodiments can be modified. The present invention contemplates that the present invention may be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications encompassed within the spirit and scope of the appended claims.
The contents of all publications, including the patents and patent application specifications mentioned herein, are hereby incorporated by reference herein to the same extent as if all were expressly cited. .
　本発明によれば、抗凝固作用を有する薬剤として有用性の高い化合物であるエステル結合を有するアミジン誘導体を、簡便かつ高収率に得ることが可能となる。
　本出願は、日本で出願された特願２００９－０９７５０４（出願日：平成２１年４月１３日）を基礎としており、その内容は本明細書にすべて包含される。 According to the present invention, an amidine derivative having an ester bond, which is a highly useful compound as a drug having an anticoagulant action, can be easily obtained in a high yield.
This application is based on Japanese Patent Application No. 2009-097504 filed in Japan (filing date: April 13, 2009), the contents of which are incorporated in full herein.

Claims (18)

  1. 式（１）
    Figure JPOXMLDOC01-appb-C000001
     （式中、
    　環Ａは、Ｃ６－１４アリール基、ヘテロアリール基、含窒素非芳香族複素環基またはＣ３－１０シクロアルキル基であり、
    　Ｖは、水素原子、ハロゲン原子、置換基を有していてもよいＣ１－１０アルキル基、置換基を有していてもよいＣ１－１０アルコキシ基、置換基を有していてもよいＣ１－１０アルキルアミノ基、置換基を有していてもよいＣ１－１０アルキルチオ基、シアノ基、ニトロ基または置換基を有していてもよいカルバモイル基であり、
    　Ｗは、へテロアリール基、あるいは下記式（Ａ）、（Ｂ）または（Ｃ）
    Figure JPOXMLDOC01-appb-C000002
     ［式中、
    　Ｑは、Ｃ１－６アルキル基、置換基を有していてもよいアミノ基または窒素原子に結合手を有する含窒素複素環基を表し、
    　Ｒは、Ｃ１－６アルキル基を表し、
    　ｍは、１～３の整数を表し、
    　環Ｃは、含窒素複素環基を表し、
    　Ｙは、窒素原子、酸素原子、硫黄原子またはメチレン基のいずれかを表し、
    　Ｚは、水素原子、Ｃ１－６アルキルで置換されていてもよいアミジノ基、あるいは１位にイミノを有してもよいＣ１－６アルキル基を表す］
    で表される基であり、そして
    　Ｘは、ハロゲン原子である）
    で表される酸ハロゲン化物またはその塩と、式（３）
    Figure JPOXMLDOC01-appb-C000003
     （式中、
    　環Ｂは、Ｃ６－１４アリール基、ヘテロアリール基、含窒素非芳香族複素環基またはＣ３－１０シクロアルキル基であり、
    　Ｔは、水素原子、ハロゲン原子、ヒドロキシ基、置換基を有していてもよいＣ１－１０アルコキシ基、置換基を有していてもよいアシルオキシ基、置換基を有していてもよいカルバモイルオキシ基、置換基を有していてもよいチオカルバモイルオキシ基、アミノ基、シアノ基、ニトロ基、置換基を有していてもよいＣ１－１０アルキル基、置換基を有していてもよいＣ１－１０アルキルアミノ基、置換基を有していてもよいＣ１－１０アルキルチオ基、置換基を有していてもよいアシルアミノ基、カルボキシル基、置換基を有していてもよいＣ１－１０アルコキシ－カルボニル基、置換基を有していてもよいカルバモイル基、または置換基を有していてもよいチオカルバモイル基であり、
    　Ｕは、水素原子、置換基を有していてもよいＣ１－１０アルキル基、カルボキシル基、置換基を有していてもよいＣ１－１０アルコキシ－カルボニル基、または置換基を有していてもよいカルバモイル基であり、
    　Ｌは、窒素原子、酸素原子、硫黄原子またはメチレン基であり、そして
    　ｎは、１～３の整数である）
    で表される化合物またはその塩とを縮合させることを特徴とする、式（４）
    Figure JPOXMLDOC01-appb-C000004
     （式中、各記号は、前記と同じである）
    で表されるアミジン誘導体またはその塩の製造方法。     Formula (1)
    Figure JPOXMLDOC01-appb-C000001
     (Where
    Ring A is a C 6-14 aryl group, a heteroaryl group, a nitrogen-containing non-aromatic heterocyclic group or a C 3-10 cycloalkyl group,
    V represents a hydrogen atom, a halogen atom, a C 1-10 alkyl group which may have a substituent, a C 1-10 alkoxy group which may have a substituent, or a substituent. A C 1-10 alkylamino group, an optionally substituted C 1-10 alkylthio group, a cyano group, a nitro group, or an optionally substituted carbamoyl group,
    W is a heteroaryl group, or the following formula (A), (B) or (C)
    Figure JPOXMLDOC01-appb-C000002
     [Where:
    Q represents a C 1-6 alkyl group, an optionally substituted amino group or a nitrogen-containing heterocyclic group having a bond to the nitrogen atom,
    R represents a C 1-6 alkyl group,
    m represents an integer of 1 to 3,
    Ring C represents a nitrogen-containing heterocyclic group,
    Y represents any of a nitrogen atom, an oxygen atom, a sulfur atom or a methylene group,
    Z represents a hydrogen atom, an amidino group which may be substituted with C 1-6 alkyl, or a C 1-6 alkyl group which may have imino at the 1-position]
    And X is a halogen atom)
    An acid halide represented by the formula:
    Figure JPOXMLDOC01-appb-C000003
     (Where
    Ring B is a C 6-14 aryl group, a heteroaryl group, a nitrogen-containing non-aromatic heterocyclic group or a C 3-10 cycloalkyl group,
    T represents a hydrogen atom, a halogen atom, a hydroxy group, a C 1-10 alkoxy group which may have a substituent, an acyloxy group which may have a substituent, or a carbamoyl which may have a substituent. An oxy group, an optionally substituted thiocarbamoyloxy group, an amino group, a cyano group, a nitro group, an optionally substituted C 1-10 alkyl group, and an optionally substituted group A good C 1-10 alkylamino group, an optionally substituted C 1-10 alkylthio group, an optionally substituted acylamino group, a carboxyl group, an optionally substituted C 1-10 alkoxy-carbonyl group, an optionally substituted carbamoyl group, or an optionally substituted thiocarbamoyl group,
    U has a hydrogen atom, an optionally substituted C 1-10 alkyl group, a carboxyl group, an optionally substituted C 1-10 alkoxy-carbonyl group, or a substituent. A carbamoyl group that may be
    L is a nitrogen atom, oxygen atom, sulfur atom or methylene group, and n is an integer of 1 to 3)
    Wherein the compound represented by the formula (1) or a salt thereof is condensed.
    Figure JPOXMLDOC01-appb-C000004
     (Wherein each symbol is the same as above)
    The manufacturing method of the amidine derivative represented by these, or its salt.
  2. 式（２）
    Figure JPOXMLDOC01-appb-C000005
     （式中、各記号は、請求項１と同じである）
    で表されるカルボン酸化合物またはその塩と、式（３）
    Figure JPOXMLDOC01-appb-C000006
     （式中、各記号は、請求項１と同じである）
    で表される化合物またはその塩とを、縮合剤を用いて縮合させることを特徴とする、式（４）
    Figure JPOXMLDOC01-appb-C000007
     （式中、各記号は、前記と同じである）
    で表されるアミジン誘導体またはその塩の製造方法。     Formula (2)
    Figure JPOXMLDOC01-appb-C000005
     (Wherein each symbol is the same as in claim 1)
    And a carboxylic acid compound represented by formula (3):
    Figure JPOXMLDOC01-appb-C000006
     (Wherein each symbol is the same as in claim 1)
    Wherein the compound represented by formula (1) or a salt thereof is condensed using a condensing agent.
    Figure JPOXMLDOC01-appb-C000007
     (Wherein each symbol is the same as above)
    The manufacturing method of the amidine derivative represented by these, or its salt.
  3. 縮合剤が、Ｎ，Ｎ’－ジシクロヘキシルカルボジイミドである、請求項２に記載の方法。 The process according to claim 2, wherein the condensing agent is N, N'-dicyclohexylcarbodiimide.
  4. 式（２）
    Figure JPOXMLDOC01-appb-C000008
     （式中、各記号は、請求項１と同じである）
    で表されるカルボン酸化合物またはその塩に、酸ハロゲン化剤を反応させて得られた式（１）
    Figure JPOXMLDOC01-appb-C000009
     （式中、各記号は、請求項１と同じである）
    で表される酸ハロゲン化物またはその塩を、単離することなく式（３）
    Figure JPOXMLDOC01-appb-C000010
     （式中、各記号は、請求項１と同じである）
    で表される化合物またはその塩と縮合させることを特徴とする、式（４）
    Figure JPOXMLDOC01-appb-C000011
     （式中、各記号は、前記と同じである）
    で表されるアミジン誘導体またはその塩の製造方法。     Formula (2)
    Figure JPOXMLDOC01-appb-C000008
     (Wherein each symbol is the same as in claim 1)
    Formula (1) obtained by reacting an acid halogenating agent with a carboxylic acid compound represented by the formula:
    Figure JPOXMLDOC01-appb-C000009
     (Wherein each symbol is the same as in claim 1)
    An acid halide represented by the formula (3) is isolated without isolation.
    Figure JPOXMLDOC01-appb-C000010
     (Wherein each symbol is the same as in claim 1)
    Wherein the compound is condensed with a compound represented by the formula or a salt thereof:
    Figure JPOXMLDOC01-appb-C000011
     (Wherein each symbol is the same as above)
    The manufacturing method of the amidine derivative represented by these, or its salt.
  5. 酸ハロゲン化剤が、塩化チオニルである、請求項４に記載の方法。 The method according to claim 4, wherein the acid halogenating agent is thionyl chloride.
  6. 式（５）
    Figure JPOXMLDOC01-appb-C000012
     （式中、Ｒ’’は、置換基を有していてもよいＣ１－１０アルキル基であり、その他の各記号は、請求項１と同じである）
    で表されるエステル化合物またはその塩と、式（３）
    Figure JPOXMLDOC01-appb-C000013
     （式中、各記号は、請求項１と同じである）
    で表される化合物またはその塩と縮合させることを特徴とする、式（４）
    Figure JPOXMLDOC01-appb-C000014
     （式中、各記号は、前記と同じである）
    で表されるアミジン誘導体またはその塩の製造方法。     Formula (5)
    Figure JPOXMLDOC01-appb-C000012
     (Wherein R ″ is an optionally substituted C 1-10 alkyl group, and other symbols are the same as in claim 1).
    An ester compound represented by the formula:
    Figure JPOXMLDOC01-appb-C000013
     (Wherein each symbol is the same as in claim 1)
    Wherein the compound is condensed with a compound represented by the formula or a salt thereof:
    Figure JPOXMLDOC01-appb-C000014
     (Wherein each symbol is the same as above)
    The manufacturing method of the amidine derivative represented by these, or its salt.
  7. 　環Ａおよび環Ｂが、Ｃ６－１４アリール基であり、
    　ＶおよびＵが、水素原子であり、
    　Ｗが、式（Ａ）
    Figure JPOXMLDOC01-appb-C000015
     （式中、Ｑは、窒素原子に結合手を有する含窒素非芳香族複素環基である）で表される基であり、
    　Ｔが、水素原子、ヒドロキシ基、Ｃ１－１０アルコキシまたはシアノで置換されていてもよいＣ１－１０アルコキシ基であり、
    　Ｌが、酸素原子であり、そして
    　ｎが、１である、請求項１～６のいずれか一項に記載の方法。     Ring A and Ring B are a C 6-14 aryl group,
    V and U are hydrogen atoms,
    W is the formula (A)
    Figure JPOXMLDOC01-appb-C000015
     (Wherein Q is a nitrogen-containing non-aromatic heterocyclic group having a bond to the nitrogen atom),
    T is hydrogen atom, hydroxy group, C 1-10 alkoxy or optionally C 1-10 alkoxy group optionally substituted by cyano,
    The method according to any one of claims 1 to 6, wherein L is an oxygen atom, and n is 1.
  8. 式（３’）
    Figure JPOXMLDOC01-appb-C000016
     （式中、Ｔ’は、ヒドロキシ基、Ｃ１－１０アルコキシ基またはシアノで置換されていてもよいＣ１－１０アルコキシ基である）
    で表される化合物またはその塩。     Formula (3 ')
    Figure JPOXMLDOC01-appb-C000016
     (Wherein, T 'is a hydroxy group, a C 1-10 alkoxy group or C 1-10 alkoxy group optionally substituted by cyano)
    Or a salt thereof.
  9. ４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジンまたはその塩；
    ４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンズアミジンまたはその塩；
    ３－（２－ヒドロキシエトキシ）－４－メトキシベンズアミジンまたはその塩；
    ４－エトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジンまたはその塩；ならびに
    ３－（２－ヒドロキシエトキシ）－４－（２－メチルプロポキシ）ベンズアミジンまたはその塩
    から選択される化合物。     4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof;
    4-hydroxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof;
    3- (2-hydroxyethoxy) -4-methoxybenzamidine or a salt thereof;
    A compound selected from 4-ethoxy-3- (2-hydroxyethoxy) benzamidine or a salt thereof; and 3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzamidine or a salt thereof.
  10. ４－シアノメトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン、またはその塩酸塩；
    ４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン　酢酸塩および塩酸塩；
    ３－（２－ヒドロキシエトキシ）－４－メトキシベンズアミジン　酢酸塩および塩酸塩；
    ４－エトキシ－３－（２－ヒドロキシエトキシ）ベンズアミジン、またはその酢酸塩および塩酸塩；ならびに
    ３－（２－ヒドロキシエトキシ）－４－（２－メチルプロポキシ）ベンズアミジン　酢酸塩および塩酸塩
    から選択される化合物。     4-cyanomethoxy-3- (2-hydroxyethoxy) benzamidine, or hydrochloride thereof;
    4-hydroxy-3- (2-hydroxyethoxy) benzamidine acetate and hydrochloride;
    3- (2-hydroxyethoxy) -4-methoxybenzamidine acetate and hydrochloride;
    Selected from 4-ethoxy-3- (2-hydroxyethoxy) benzamidine, or acetates and hydrochlorides thereof; and 3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzamidine acetates and hydrochlorides Compound.
  11. 式（３’）
    Figure JPOXMLDOC01-appb-C000017
     （式中、Ｔ’は、ヒドロキシ基、Ｃ１－１０アルコキシ基またはシアノで置換されていてもよいＣ１－１０アルコキシ基である）
    で表される化合物またはその塩を合成するための合成中間体である、式（３’’）
    Figure JPOXMLDOC01-appb-C000018
     （式中、Ｔ’’は、ナトリウム原子、水素原子、またはＣ１－１０アルコキシで置換されていてもよいＣ１－１０アルキル基であり、Ｇは、シアノ基、またはヒドロキシで置換されていてもよいアミジノ基である）
    で表される化合物またはその塩。     Formula (3 ')
    Figure JPOXMLDOC01-appb-C000017
     (Wherein, T 'is a hydroxy group, a C 1-10 alkoxy group or C 1-10 alkoxy group optionally substituted by cyano)
    Which is a synthetic intermediate for synthesizing a compound represented by the formula or a salt thereof:
    Figure JPOXMLDOC01-appb-C000018
     (Wherein T ″ is a sodium atom, a hydrogen atom, or a C 1-10 alkyl group which may be substituted with C 1-10 alkoxy; G is a cyano group or substituted with hydroxy; A good amidino group)
    Or a salt thereof.
  12. 式（３’）
    Figure JPOXMLDOC01-appb-C000019
     （式中、Ｔ’は、ヒドロキシ基、Ｃ１－１０アルコキシ基またはシアノで置換されていてもよいＣ１－１０アルコキシ基である）
    で表される化合物またはその塩を合成するための合成中間体である、式（３’’’）
    Figure JPOXMLDOC01-appb-C000020
     （式中、Ｔ’’’は、Ｃ１－１０アルコキシで置換されるＣ１－１０アルキル基であり、Ｒ’’’は、水素原子またはＣ１－１０アルキル基である）
    で表される化合物またはその塩。     Formula (3 ')
    Figure JPOXMLDOC01-appb-C000019
     (Wherein, T 'is a hydroxy group, a C 1-10 alkoxy group or C 1-10 alkoxy group optionally substituted by cyano)
    Is a synthetic intermediate for synthesizing a compound represented by the formula or a salt thereof: Formula (3 ′ ″)
    Figure JPOXMLDOC01-appb-C000020
     Wherein T ′ ″ is a C 1-10 alkyl group substituted with C 1-10 alkoxy, and R ′ ″ is a hydrogen atom or a C 1-10 alkyl group.
    Or a salt thereof.
  13. ３－（２－ヒドロキシエトキシ）－４－メトキシベンゾニトリル；
    ナトリウム　４－シアノ－２－（２－ヒドロキシエトキシ）フェノキシド；
    ４－ヒドロキシ－３－（２－ヒドロキシエトキシ）ベンゾニトリル；
    ４－（２，２－ジメトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンゾニトリル；
    ４－（２，２－ジメトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミド＝オキシム；
    ４－（２，２－ジメトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミジン　塩酸塩；
    ４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンゾニトリル；
    ４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミド＝オキシム；
    ４－（２，２－ジエトキシエトキシ）－３－（２－ヒドロキシエトキシ）ベンズアミジン　酢酸塩；
    ４－（２，２－ジエトキシエトキシ）－３－メトキシベンゾニトリル；
    ４－エトキシ－３－（２－ヒドロキシエトキシ）ベンゾニトリル；および
    ３－（２－ヒドロキシエトキシ）－４－（２－メチルプロポキシ）ベンゾニトリル
    から選択される化合物。     3- (2-hydroxyethoxy) -4-methoxybenzonitrile;
    Sodium 4-cyano-2- (2-hydroxyethoxy) phenoxide;
    4-hydroxy-3- (2-hydroxyethoxy) benzonitrile;
    4- (2,2-dimethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile;
    4- (2,2-dimethoxyethoxy) -3- (2-hydroxyethoxy) benzamide oxime;
    4- (2,2-dimethoxyethoxy) -3- (2-hydroxyethoxy) benzamidine hydrochloride;
    4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzonitrile;
    4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzamide oxime;
    4- (2,2-diethoxyethoxy) -3- (2-hydroxyethoxy) benzamidine acetate;
    4- (2,2-diethoxyethoxy) -3-methoxybenzonitrile;
    A compound selected from 4-ethoxy-3- (2-hydroxyethoxy) benzonitrile; and 3- (2-hydroxyethoxy) -4- (2-methylpropoxy) benzonitrile.
  14. 式（１’）
    Figure JPOXMLDOC01-appb-C000021
     （式中、
    　Ｒ’は、置換基を有しても良いアルコキシ基またはハロゲン原子であり、そして
    　Ｑ’’は、Ｃ１－１０アルコキシ基、置換基を有していてもよいアミノ基または窒素原子に結合手を有する含窒素複素環基を表す）
    で表される化合物またはその塩。     Formula (1 ')
    Figure JPOXMLDOC01-appb-C000021
     (Where
    R ′ is an alkoxy group which may have a substituent or a halogen atom, and Q ″ is a bond to a C 1-10 alkoxy group, an amino group which may have a substituent or a nitrogen atom. Represents a nitrogen-containing heterocyclic group having
    Or a salt thereof.
  15. ４－［イミノ（ピロリジン－１－イル）メチル］安息香酸ハライドまたはその塩。 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid halide or a salt thereof.
  16. ４－［イミノ（ピロリジン－１－イル）メチル］安息香酸メチルまたはその塩。 4- [Imino (pyrrolidin-1-yl) methyl] methyl benzoate or a salt thereof.
  17. ４－［イミノ（ピロリジン－１－イル）メチル］安息香酸クロリドまたはその塩酸塩。 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid chloride or its hydrochloride.
  18. ４－［イミノ（ピロリジン－１－イル）メチル］安息香酸メチル　塩酸塩。 4- [Imino (pyrrolidin-1-yl) methyl] benzoic acid methyl hydrochloride.
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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2017179065A1 (en) * 2016-04-15 2017-10-19 Davuluri Ramamohan Rao Improved process for the preparation of apremilast
US10774041B2 (en) 2016-04-15 2020-09-15 Davuluri Ramamohan Rao Process for the preparation of apremilast

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