WO2004069802A1

WO2004069802A1 - Process for producing 2-amino-3-substituted pyridine

Info

Publication number: WO2004069802A1
Application number: PCT/JP2004/000995
Authority: WO
Inventors: Yukihito Sumino; Shinobu Wakabayashi
Original assignee: Shionogi & Co., Ltd.
Priority date: 2003-02-06
Filing date: 2004-02-02
Publication date: 2004-08-19
Also published as: JPWO2004069802A1

Abstract

A process for producing a compound (II), characterized by reacting a compound (I) with ammonia in the presence of a catalyst. (In the formulae, X is halogeno; and R is an electron-donating substituent having the property of coordinating to the catalyst.)

Description

Specification

Method for producing 2-amino-3-substituted pyridine

The present invention relates to 2-amimino 3-substituted pyridines (eg, 2,3-diaminopyridine) useful as synthetic intermediates such as cefm antibacterial agents and imidazopyridines, or as pharmaceutical raw materials such as organometallic complex ligands. It relates to a method for producing the salt. Background Art,

As a 2-amino-3-substituted pyridine, for example, 2,3-diaminopyridine is described as a raw material of the 3-position side chain of a septum antibacterial agent (eg, Patent Document 1).

As a typical production method of 2,3-diaminopyridine, a method of synthesizing in four steps using 2-aminoviridine as a starting material is described (eg, Non-Patent Document 1). However, this method uses metals such as bromine and iron as reaction reagents, which is not desirable in terms of environment and safety, and the yield is as low as 26%, which is not a satisfactory method as an industrial method. . Further, in a production method using 3-ethoxycarbonylamino-2-nitropyridine as a starting material, nickel metal, which is concerned with carcinogenicity, is used (eg, Non-Patent Document 2). Since 2,3-diaminopyridine is soluble in both water and organic solvents, extraction after the reaction usually requires a large amount of organic solvent. In addition, in the recrystallization method, it is purified using harmful benzene, which is environmentally unfavorable (eg, Non-Patent Documents 1 and 2).

As a method of isolating 2,3-diaminopyridine as an acid addition salt, palladium reduction of 2-amino-5-bromo-3-nitropyridine is performed, and then 2,3-diaminopyridine is converted to dihydrobromide. Methods for isolation and purification are known (eg, Patent Document 2). However, in this purification method, the reaction solution is crystallized by adding an organic solvent to the concentrated slurry solution, and the purification operation is complicated, which is not preferable as a mass production method.

As a method for synthesizing an aminoviridine derivative using a copper catalyst, an amination reaction between bromopyridine and ammonia is known (eg, Non-Patent Document 3). However, Under the reaction conditions, the amination reaction with chloro-open pyridine, which is more inert than bromopyridine, has not been successful. In this reaction, for example, in the case of 2-chloro-1-5-nitropyridine having an electron-withdrawing substituent that enhances the reactivity of the chromatol group, an aminoviridine derivative is produced. No amination reaction with an aminochloropyridine having an electron donating substituent which weakens the reactivity of the group is described. Also, there is no description of a method for removing a water-soluble copper catalyst which has a risk of water pollution used as a reaction catalyst.

(Patent Document 1) International Publication No. 0/3 2 6 06

(Patent Document 2) Japanese Patent Application Laid-Open No. 05-33 39 2 36,

(Non-Patent Document 1) Barham (W.E.Barham), Organic Synthesis (Org. Syn), USA, Vol. 44, P 34-39 (1964)

(Non-Patent Document 2) J. W. Clark—Lewins, et al., J. Cheni. Soc., UK, P442—447 (1957)

(Non-Patent Document 3) Lang et al., Tett. Lett, USA, Vol. 42, P3251-3254 (2001) Disclosure of the invention

(Problems to be solved by the invention)

Therefore, there has been a demand for the development of a new industrially useful method for producing 2,3-diaminopyridine and salts thereof. There was also a demand for the development of new methods for producing other 2-amino-3-substituted pyridines.

(Means for solving the problem)

As a result of intensive studies, the present inventors have found that ammonia is added to a 2-halogeno 3-substituted pyridine, preferably 3-amine chloro-2-pyridine, which is easily available as a known substance, in the presence of a catalyst (eg, CuCl). It has been found that 2-amino-1-substituted pyridine, preferably 2,3-diaminopyridine, can be efficiently produced in a short step and under mild conditions by the reaction. Copper, which was difficult to recover from the reaction mixture, could be easily removed by treating it with a sulfide compound (eg, sodium thiosulfate). In addition, by isolating 2,3-diaminopyridine as a benzoate, it was possible to produce it in good yield. The present invention is described below.

( 1 set

(I)

, N eight X

(Wherein, X is a halogen; R is a substituent that is electron-donating and has a coordination property to a catalyst), wherein the compound (I) is reacted with ammonia in the presence of a catalyst. formula:

(Wherein R is as defined above), a method for producing the compound (II), a salt thereof, or a solvate thereof.

(2) The production method according to the above (1), wherein R is an electron-donating substituent and the atom in R bonded to the pyridine ring is a heteroatom showing coordination to the catalyst.

2. The production method according to the above 1, wherein (3) is an optionally substituted amino, an optionally substituted hydroxy or an optionally substituted thiol.

(4) R is ^{^{_{NHR 1 N (R 1) 2}}} , OH, 0 R J s NH CO CH 3, SR 1 ( wherein, R ¹ is alkyl), a manufacturing method of claim 1, wherein the.

(5) The production method according to the above 1, wherein R is NH ₂ .

(6) The production method according to the above (1), wherein X is C1.

(7) The production method according to the above (1), wherein the catalyst is a metal-containing catalyst.

(8) The production method according to the above (1), wherein the metal-containing catalyst contains copper.

(9) The production method according to (1) above, wherein the metal-containing catalyst is a copper salt, a copper oxide or copper metal.

(10) The production method according to the above 1, wherein the metal-containing catalyst is a copper salt. (11) The production method according to the above item 10, wherein the copper salt is a copper halide.

β Λ

(12) The production method according to the above (11), wherein the copper halide is CuC1.

(13) The production method according to (1) above, wherein R is NH ₂ ; and the metal-containing catalyst is a copper-containing catalyst.

(14) The production method according to the above (1), wherein the ammonia is reacted as an aqueous ammonia solution.

(15) The production method according to the above (14), wherein the concentration of the aqueous ammonia solution is 20 to 30%.

(16) The production method according to the above (1), wherein the reaction temperature is 110 to 160 ° C.

(17) The production method according to any one of the above items 8 to 13, comprising a step of removing copper by treating the reaction mixture with a sulfide compound.

(18) The method according to any one of (1) to (17) above, wherein R is NH ₂ , and the method comprises a step of isolating the produced 2,3-diaminopyridine as a benzoate after the reaction. .

(19) Benzoic acid salt of 2,3-diaminopyridine.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described in more detail.

The production method of the present invention is constituted or selected from the following three steps.

Step 1 Catalyst

ammonia

(I) (ID

2nd step

1) acid

Copper sulfide

2) Sulfur compound 3rd step

(R is as defined above, preferably NH _2. ) The first step is to react the 3-substituted 1-2-halogenobilizine (I) with ammonia in the presence of a catalyst, preferably a copper catalyst, to form 2- This is a method for producing an amino-3-substituted pyridine (11), preferably 2,3-diaminopyridine.

The second step is a method of removing copper from the reaction mixture of the first step by treating it with a sulfide compound.

In the third step, a method of isolating 2-amino-3-substituted pyridine (II), preferably 2,3-diaminopyridine as a poorly water-soluble salt from the reaction solution from which copper has been removed, and treating the isolated salt with a base. High-quality 2-amino-3-substituted pyridines (II), preferably 2,3-diaminopyridines. Description of reaction conditions

(First step)

The first step is a method of reacting compound (I) with ammonia in the presence of a catalyst to produce 2-amino-1-substituted pyridine (II), preferably 2,3-diaminopyridine.

In the present specification, the halogen is preferably _c including fluorine, chlorine, bromine and iodine, and particularly preferably chlorine.

The catalyst is preferably a catalyst containing a metal such as cobalt, tin, zinc, iron, aluminum, boron, copper, titanium, arsenic, thallium, nickel, chromium, rhodium, iridium, platinum, palladium, etc. A metal-containing catalyst). The metal is preferably a metal exhibiting a coordination property to the N atom and R of pyridine of the compound (I). The catalyst is preferably a catalyst containing copper (hereinafter, referred to as a copper catalyst). The copper catalyst includes, for example, copper salts, copper oxides, metallic copper and mixtures thereof, and further includes complex salts composed of copper salts, copper oxides, metallic copper or mixtures thereof and organic bases. Copper salts include cuprous chloride, cuprous bromide, cupric chloride, cupric bromide, anhydrous cupric nitrate, cupric nitrate heptahydrate, anhydrous copper sulfate and copper sulfate pentahydrate Japanese products. Examples of copper oxide include cuprous oxide and cupric oxide. Preference is given to copper salts, particularly preferably copper halides, such as cuprous chloride (CuCl). These copper catalysts can be used alone or in combination of two or more. The amount of the copper catalyst to be used is generally in the range of 0.01 to 5 equivalents, preferably 0.01 to 0.5 equivalents, particularly preferably 0.1 to 0.4 equivalents, relative to compound (I). Is equivalent.

This reaction is preferably performed in an aqueous ammonia solution, but may be performed in a polar solvent or an organic base may be added to the reaction solution.

Ammonia used in the amination reaction includes ammonium acetate, ammonium picocarbonate, ammonium benzoate, ammonium carbonate, ammonium formate, ammonia oxalate, aqueous ammonia, and the like. And liquid ammonia. The ammonia is preferably ammonia water having a concentration of 1 to 50%, particularly preferably an aqueous ammonia solution having a concentration of 20 to 30%.

The amount of ammonia to be used is generally 1 to 100 equivalents, preferably 2 to 50 equivalents, particularly preferably 3 to 30 equivalents, relative to compound (I).

Examples of the polar solvent include cyclic amides such as 1-methyl-1-pyrrolidinone, cyclic ureas such as 1,3-dimethyl-12-imidazolidinone, sulfoxides such as dimethyl sulfoxide, and dimethyl sulfone and sulfolane. Sulfones, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, ethylene glycol dialkyl ethers such as triethylene glycol dimethyl ether and polyethylene glycol dimethyl ether, ethers such as 1,4-dioxane, N, N —Dialkyl anilines such as dimethyl aniline and N, N-Jetyl aniline; heterocyclic compounds such as pyridine and quinoline; methanol, ethanol, propanol, 2-propanol, ethylene glycol, propylene glycol, Alcohols such as glycerin and water, and the like. These polarities The solvents can be used alone or as a mixture of two or more. The amount of the solvent is usually about 1 ml to 100 ml with respect to the compound (I) lg.

Examples of the organic base include pyridines such as pyridine, methylpyridine, ethylpyridine, dimethylpyridine, methylethylpyridine, getylviridine, pyridines such as trimethylpyridine, dimethylaminopyridine and 2,2-bipyridyl, triethylamine, tripropylamine and the like. Examples include trialkylamines such as tributylamine, N, N-dialkylanilines such as N, N-dimethylaniline and N, N-getylaniline, and liquid ammonia.

This reaction is carried out under cooling to room temperature, but is preferably carried out under heating. The preferred reaction temperature is usually 30 to 250. More preferably, the temperature is from 80 to 200 ° C, and preferably from 110 to: L60 ° C.

The reaction time is usually several hours to several tens of hours.

This reaction may be carried out under atmospheric pressure, but is preferably carried out in a closed pressurized apparatus, and the internal pressure is usually 0.1 to 10 MPa, preferably 0.1 to 2 MPa, particularly It is preferably 0;; to 0.3 MPa.

R is various substituents as long as it is an electron-donating substituent which exhibits coordination to the above-mentioned catalyst, preferably a metal in the catalyst. In a preferred embodiment of R, the atom bonded to the pyridine ring is a hetero atom that exhibits coordination to the metal in the catalyst. The heteroatom is selected from atoms other than hydrogen or carbon, but is preferably N, 0, S, etc., more preferably N or 0, and particularly preferably N. Examples of the residue bonded to the hetero atom include hydrogen, alkyl, preferably C1 to C6 alkyl (eg, methyl, ethyl, n-propyl, t-butyl, etc.), lower alkylcarbonyl (eg, acetyl, Carbonyl) and the like.

R is preferably an optionally substituted amino (eg, amino, NHR ¹ N (R 2 (R ¹ is alkyl)) (eg, methylamino, ethylamino, dimethylamino, getylamino), lower alkylcarbonylamino (example: NHC OCH ₃ )), optionally substituted hydroxy (eg, 0 H, OR ¹ (eg, methoxy, ethoxy)) or optionally substituted thiol (eg, thiol, SR ¹ (eg, Methylthio)) It is. R is more preferably an optionally substituted amino, particularly preferably NH ₂ . Since R is an electron donating group, naturally, for example, halogen, nitro, methyl halide and the like are excluded.

The compound (I) as a raw material is a known compound (eg, 3-amino-2-chloropyridin, 3-hydroxy-2-chloropyridine, 3-methoxy-2-chloropyridine) or a known compound containing these. It can be easily synthesized from compounds.

In addition, when an electron donating group such as amino is present at a site adjacent to a halogen atom, etc., generally, compared to the case where an electron withdrawing group such as nitro exists, the conversion from halogen to amination can be performed. Reactivity is greatly reduced. However, in the present invention, it has been found that the use of a catalyst, preferably a metal-containing catalyst, allows the reaction to proceed at a relatively high yield under mild reaction conditions. Although the details of this reaction mechanism are unknown, one hypothesis is that, as illustrated below, a metal (eg, copper) in the catalyst is bonded to the N atom and the 3-position of the pyridine ring. It is thought that the coordination to a heteroatom (eg, N) improves the reactivity of the 2-position halogen (eg, C 1).

Therefore, even if the 3-position substituent on the pyridine ring is an electron-donating group other than amino, it is presumed that the reaction proceeds similarly when the catalyst exhibits coordination as described above. According to the experiments of the present inventors, the amination reaction did not sufficiently proceed with o-chloroaniline and the like. This suggests the possibility of the above reaction mechanism.

After the first step, the compound (II) can be obtained by treating the reaction solution by a conventional method (concentration, extraction, separation, etc.). To obtain a higher quality compound (II), the second and third steps are preferably performed. (2nd step)

The second step is optionally performed when a copper catalyst is used in the reaction of the first step, and is a method of removing copper from the reaction mixture as copper sulfide.

(1) In this step, either acid is added until the reaction mixture becomes acidic, or ammonia is distilled off from the reaction mixture, and then acid is added to the residue to form an acidic mixture.

The acid may be either an organic acid or an inorganic acid, but is preferably an inorganic acid, particularly preferably sulfuric acid. The concentration of sulfuric acid is about 10-80%, preferably 50-70%. The amount of the acid used is, for example, about 1 ml to 10 ml for compound (I) 1 in the case of 64% sulfuric acid.

The temperature at which the acid is added is usually 0 to 50 ° C, preferably 0 to 25 ° C.

② Then, sulfide compounds such as sodium thiosulfate, sodium hydrosulfide, sodium sulfide, ammonium sulfide, potassium sulfide, lithium sulfide and hydrogen sulfide are added to the acidic mixture prepared above, and stirred for several hours to precipitate copper as copper sulfide. After that, the insoluble matter is filtered.

As the sulfurized compound, sodium thiosulfate, sodium hydrosulfide and hydrogen sulfide are particularly preferred, and sodium thiosulfate is particularly preferred. The amount of the sulfide compound used is, for example, about 1 ml to 15 ml for 1 g of the compound (1) in the case of a saturated aqueous solution of sodium thiosulfate.

The temperature at which the sulfide compound is added is usually 0 to 40 ° C, preferably 10 to 30 ° C. The stirring time is usually 1 to 20 hours, depending on the state of copper sulfide precipitation. Copper sulfide usually refers to monovalent and divalent copper sulfides, but may include metallic copper and sulfur.

(3rd step)

The third step is a step of producing a salt of the compound (II) such as 2,3-diaminopyridine and a step of purifying the compound (II) using the salt. Hereinafter, 2,3-diaminopyridine is described as an example.

(1) The production of the salt of 2,3-diaminopyridine is preferably performed in the first step, More preferably, a base is added to the filtrate prepared in the second step to prepare a solution having a pH of preferably 8-9.

The base may be any of an organic base and an inorganic base, but is preferably an inorganic base, particularly preferably a 30 to 50% sodium hydroxide aqueous solution.

The base is used in an appropriate amount. For example, if the base is a 48% aqueous sodium hydroxide solution, add an appropriate amount until the solution has a pH of 8-9.

The temperature at which the base is added is usually 0 to 40 ° C.

(2) An acid capable of forming a salt with 2,3-diaminopyridine, preferably an organic acid (eg, benzoic acid) is added to the solution prepared in (1) above, and the mixture is stirred at room temperature for several hours, and then precipitated 2,3-diaminopyridine To give an acid addition salt of

This acid addition salt may be subjected to desalting treatment as described later to convert it to 2,3-diaminopyridine, and then to another salt.

The amount of the acid used is preferably 0.6 to 10 equivalents to 1 equivalent of the raw material 3-amino 2-chloropyridine. Particularly preferred is 0.8 to 1.4 equivalents. In a preferred method for producing the above salt, crystals are precipitated in about 10 minutes to several tens of hours, preferably several hours, at room temperature with stirring. When no precipitation occurs, the crystals may be precipitated by, for example, applying a stimulus such as ultrasonic treatment and stirring under cooling or adding a seed crystal. Salt binding has the advantage of good operability in the manufacturing process because of good filterability and easy separation from solvents (eg, water). Further, in a salt state at normal temperature and normal pressure, it is easy to obtain a stable and high quality product.

(3) 2,3-Diaminopyridine can be obtained by treating the isolated and purified acid addition salt, preferably benzoate, with a base.

The base may be any of an inorganic base and an organic base, but is preferably an inorganic base. Examples of the inorganic base include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium hydrogen carbonate, and lithium carbonate. Particularly preferred is sodium hydroxide.

2,3-Diaminopyridine can be obtained, for example, by suspending a salt of benzoic acid in water or an organic solvent, or in an organic solvent (eg, methanol, ethanol, chloroform, dichloromethan). After dissolving in ethyl acetate and ethyl acetate (preferably ethyl acetate), a base such as sodium hydroxide is added under cooling, and the mixture is stirred for several hours to produce.

The amount of the solvent is usually about 1 ml to 100 ml per 1 g of the salt.

The amount of the base is preferably 1 to 10 equivalents to 1 equivalent of the salt.

The reaction temperature is generally 0 to 40 ° C, preferably 0 to 30 ° C.

The stirring time is usually 1 to several tens hours, preferably 1 to 2 hours.

2,3-Diaminopyridine is obtained by treating a base-treated solution or a concentrated solution thereof with ethers (eg, dimethyl ether, diisopropyl ether, methyl tert-butyl ether), ethyl acetate, toluene, acetonitrile, and acetone. Alternatively, by diluting with methyl isobutyl ketone or the like, in any case, it can be preferably isolated as crystals.

Organic or inorganic salts may precipitate, but can be removed by washing with a small amount of cold water. When the seed crystal prepared separately is added to the recrystallization, the target crystal can be obtained more efficiently.

Compound (II) may be a solvate coordinated with any number of suitable organic solvents or water.

The compound (で Ι) produced in ④③ can be further converted to various salts by standard methods. For example, it can be crystallized as a benzoate by treating with a hydrated solvent containing benzoic acid.

Examples of the salts of 2,3-diaminopyridine include salts with various bases and acid addition salts. Preferred are acid addition salts, for example, salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, perchloric acid and carbonic acid, formic acid, acetic acid, propionic acid, and trichloroacetic acid. Mouth acetic acid, trifluoro acetic acid, tartaric acid, lactic acid, hydroxyacetic acid, cunic acid, fumaric acid, maleic acid, succinic acid, oxalic acid, mandelic acid, butyric acid, malic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid And salts of organic acids such as p-toluenesulfonic acid, and salts of acidic amino acids such as ordinine, aspartic acid and glutamic acid. Hereinafter, the present invention will be described in more detail with reference to Examples, but these are not intended to limit the present invention. Example 1

Synthesis of 2,3-diaminopyridine benzoate

1) Synthesis of 2,3-diaminobilizine (II) from 3-aminopurine 2-pyridine (I)

In a pressure-resistant reaction tube (closed pressurized device), put 3-amino-2-cyclomouth pyridine (I) 512 mg (4 mmol) and a 25% aqueous ammonia solution (5 ml), and add 120 mg (1.2 nmol) of salted copper (CuCl) Add. After heating and stirring at an oil bath temperature of 120 ° C for 8 hours, cool to room temperature, and leave it at room temperature.

2) Copper removal operation

The aqueous ammonia in the above reaction mixture was distilled off under reduced pressure, and the residue was dissolved in a 64% aqueous sulfuric acid solution (4 ml). A saturated aqueous sodium thiosulfate solution (3 ml) is added to the solution, and the mixture is stirred at room temperature for 2 hours. A brown solid containing copper sulfide and sulfur precipitates, and this is filtered off to obtain a reddish brown transparent solution.

3) 2,3-diaminopyridine benzoate

Add a 48% aqueous sodium hydroxide solution to the above reddish brown transparent solution to adjust the pH to 8-9. To this solution, benzoic acid (488 mg, 4 mmol) dissolved in methanol (0.9 ml) is added, and the mixture is stirred at room temperature for 2 hours to precipitate a black-brown solid. The solid collected by filtration is washed with cold water and dried to give 576 mg (64% yield) of 2,3-diaminopyridine benzoate. . IHDNMR (3 0 0MH z, CD 3 0 D, ppm) δ: 6. 58 (dd, J = 6, 7. 5 H z, 1 H), 6. 9 7 (dd, J = 1. 2, 7.5 Hz, 2H), 7.17 (dd, J = 1.2, 6Hz, 2H), 7.28-- 7.40 (m, 3H), 7.87 — 7.90 (m, 2 H) Industrial applicability

The present invention relates to 2-amino-3-substituted pyridines such as 2,3-diaminopyridine and the like. An industrially advantageous process for preparing the salts or solvates thereof is provided. By using this production method, pharmaceuticals (eg, CFM antibacterial agents) or their raw materials can be industrially and efficiently produced.

Claims

Claim formula:

(Wherein, X is a halogen; R is a substituent that is electron-donating and has a coordination property to the catalyst), wherein the compound (I) is reacted with ammonia in the presence of a catalyst. formula:

2. The production method according to claim 1, wherein R is an electron-donating substituent and the atom in R bonded to the pyridine ring is a heteroatom that exhibits coordination to the catalyst.

3. The production method according to claim 1, wherein R is an optionally substituted amino, an optionally substituted hydroxy, or an optionally substituted thiol.

4. R is NHR ¹ N (R ¹ ) ₂ , OH, OR NH COCH ₃ , SR ¹ (where

The production method according to claim 1, wherein R ¹ is alkyl).

5. R is NH _2, A process according to claim 1, wherein.

6. The method according to claim 1, wherein X is C1.

7. The production method according to claim 1, wherein the catalyst is a metal-containing catalyst.

8. The production method according to claim 1, wherein the metal-containing catalyst contains copper.

9. The method according to claim 1, wherein the metal-containing catalyst is a copper salt, a copper oxide, or copper metal.

10. The production method according to claim 1, wherein the metal-containing catalyst is a copper salt.

11. The production method according to claim 10, wherein the copper salt is a copper halide.

2. The method according to claim 11, wherein the copper halide is CuC1.

3. The production method according to claim 1, wherein R is NH ₂ ; and the metal-containing catalyst is a copper-containing catalyst.

4. The method according to claim 1, wherein the ammonia is reacted as an aqueous ammonia solution.

5. The method according to claim 14, wherein the concentration of the aqueous ammonia solution is 20 to 30%.

1 6. The production method according to claim 1, wherein the reaction temperature is 110 to 160 ° C.

17. The method according to any one of claims 8 to 13, further comprising a step of removing copper by treating the reaction mixture with a sulfide compound.

18. The production method according to any one of claims 1 to 17, wherein R is NH ₂ , and the method comprises a step of isolating the generated 2,3-diaminopyridine as a benzoate after the reaction.

19.2 The benzoate of 2,3-diaminopyridine.