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WO2018011823A1 - Sel de (1s,2r,4s)-1,2-amino-n, n-diméthylcyclohexane-4-carboxamide protégé par des amines - Google Patents

Sel de (1s,2r,4s)-1,2-amino-n, n-diméthylcyclohexane-4-carboxamide protégé par des amines Download PDF

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Publication number
WO2018011823A1
WO2018011823A1 PCT/IN2017/050286 IN2017050286W WO2018011823A1 WO 2018011823 A1 WO2018011823 A1 WO 2018011823A1 IN 2017050286 W IN2017050286 W IN 2017050286W WO 2018011823 A1 WO2018011823 A1 WO 2018011823A1
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formula
group
process according
protecting group
mixtures
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PCT/IN2017/050286
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English (en)
Inventor
Ramesh Dandala
Sureshbabu JAYACHANDRA
Sonny SEBASTAIAN
Jagadeeshwar Rao
Rajareddy ANUPATI
Ataharodin KHAJA
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Mylan Laboratories Limited
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Priority to JP2019501697A priority Critical patent/JP6831447B2/ja
Priority to EP17768248.1A priority patent/EP3484893A1/fr
Publication of WO2018011823A1 publication Critical patent/WO2018011823A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/19—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates generally to the synthesis of active pharmaceutical agents and more specifically to the preparation of an amine -protected (lS,2R,4S)-l,2-amino-N,N- dimethylcyclohexane-4-carboxamide)camphor sulfonate, which may be an intermediate used in the synthesis of Edoxaban and pharmaceutically acceptable salts, solvates, or salt of solvates thereof. Further, the present invention further provides methods for the synthesis of this intermediate with improved purity.
  • Edoxaban exhibits an inhibitory effect on activated blood coagulation factor X (FXa) and as such, is an oral anticoagulant drug used to prevent or treat thrombotic diseases.
  • Edoxaban is marketed in the United States as SAVAYSA® and LIXIANA®by Daiichi Sankyo.
  • Edoxaban is chemically known as N'-(5-chloropyridin-2-yl)-N-[(lS,2R,4S)-4-(dimethylcarbamoyl)-2-[(5- methyl-6,7-dihydro-4H-[l,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide and is represented by the formula below:
  • Edoxaban tosylate monohydrate which is represented below as Formula 1:
  • Edoxaban (and salts/solvates thereof) may be prepared by a variety of methods.
  • One such method involves use of an intermediate as depicted below, wherein PG is an amine protecting group (herein referred to as amine-protected (lS,2R,4S)-l,2-amino-N,N-dimethylcyclohexane-4- carboxamide)
  • U.S. Patent No. 8,686,189 discloses this Boc-protected intermediate as well, along withacid addition salts thereof.
  • U.S. Patent No. 8,357,808 discloses a process for the preparation of Edoxabanusingan oxalate salt ofthe Boc-protected intermediate:
  • the present invention provides methods for the preparationof a substantiallypure camphor sulfonate salt ofamine- protected( 1 S,2R,4S)- 1 ,2-amino-N,N-dimethylcyclohexane-4-carboxamide (represented by formula (X) below).
  • the present invention provides methods for the preparation of camphor sulfonate salt of aBoc-protected [(lR,2S,5S)-l,2-amino-5 [(dimethylamino)carbonyl]cyclohexane]intermediate (( 1 S,2R,4S)- 1 -amino-2-(boc-amino)-N,N dimethylcyclohexane-4-carboxamide), depicted below, with high purity.
  • the present invention provides a compound of formula (X), wherein PG is an amine protecting group:
  • the amine protecting group is a t-butyloxycarbonyl (Boc) group.
  • the present invention provides a process for the preparation of formula (X), which may include the steps of: a) treating formula (Vll)with a base in a solventto obtain formula (VIII)
  • PG is an amine protecting group
  • the amine protecting group is a t-butyloxycarbonyl (Boc) group.
  • the base may be, for example (but not limited to), sodium hydroxide, potassium hydroxide, and lithium hydroxide.
  • the solvent may be, for example, a ketone solvent, an ester solvent, acetonitrile, or mixtures thereof.
  • suitable ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone, methyl ethyl ketone, and mixtures thereof.
  • ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, and mixtures thereof.
  • formula (X) may be further converted to Edoxaban, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a combination thereof.
  • the present invention provides a compound of formula (Villa), wherein PG is an amine protecting group
  • the amine protecting group is a t-butyloxycarbonyl (Boc) group.
  • formula (Villa) may be prepared by a process that includes treating formula (VII) with a base followed by (S)-(alpha)-phenylethylamine in the presence of a solvent
  • the base may be, for example (but not limited to), sodium hydroxide, potassium hydroxide, and lithium hydroxide.
  • the solvent may be, for example, a ketone solvent, an ester solvent, acetonitrile, or mixtures thereof.
  • suitable ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone, methyl ethyl ketone, and mixtures thereof.
  • ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, and mixtures thereof.
  • Formula (Villa) may be further converted to formula (IX).
  • this conversion may be carried out in a solvent.
  • suitable solvents include, but are not limited to chlorinated solvents, ketone solvents, ester solvents, toluene, acetonitrile, and mixtures thereof.
  • suitable chlorinated solvents include, but are not limited to, methylene dichloride, chloroform, and mixtures thereof.
  • suitable ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone, methyl ethyl ketone, and mixtures thereof.
  • ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, and mixtures thereof.
  • This conversion may be carried out with a suitable base, for example (though not limited to), triethylamine, diisopropylethylamine, diisopropylamine, or N-methylmorpholine.
  • formula (IX) may be further converted to formula (X) by a process that includes the following steps: a) reducing the azide of formula (IX);and
  • PG amine protecting group
  • Edoxaban pharmaceutically acceptable salts, solvates, and solvated salts thereof, prepared by methods disclosed herein may be incorporated into a pharmaceutical dosage form that optionally includes further excipients.
  • the present invention provides formula (X):
  • PG is an amine -protecting group.
  • suitable amine protecting groups as well as suitable conditions for protecting and deprotecting, can be found in prior art, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999; "The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981 ; in “Methoden der organischenChemie", Houben-Weyl, 4th edition, Vol.
  • R P is a -C(R PI ) 3 , wherein each R PI is hydrogen or optionally substituted aryl, provided that at least one R PI is not hydrogen;
  • Optionally substituted as used herein means the reference group is substituted by one or more groups (e.g., 1 to 5, or 1 to 3, or 1 to 2 groups, or 1 group) that are each independently halo, alkyl, alkoxy, nitro, cyano, tri(Ci_ 3 alkyl)silyl (e.g., trimethylsilyl).
  • groups e.g., 1 to 5, or 1 to 3, or 1 to 2 groups, or 1 group
  • amine protecting groups include, carbonyls (e.g., methyl carbamate, 9- fluorenylmethyoxycarbonyl (Fmoc), trichloroethoxycarbonyl (Troc), t-butoxycarbonyl (BOC), 2-trimethylsilylethyloxycarbonyl (Teoc), allyloxycarbonyl (Alloc), p-methoxybenzyl carbonyl (Moz), and carboxybenzyl (Cbz)), sulfonyls (e.g., p-toluenesufonyl (Ts), trimethylsilylethanesulfoyl (Ses), t-butylsulfonyl (Bus), 4-methoxyphenylsulfonyl, 4- nitrobenzenesulfonyl (nosyl)), trityl (trt), benzyl (Bn), 3,4-dimethyls
  • alkenyl means a straight or branched chain hydrocarbon containing from 2 to 10 carbons, unless otherwise specified, and containing at least one carbon-carbon double bond.
  • alkenyl include, but are not limited to, ethenyl, 2- propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l- heptenyl, 3-decenyl, and 3, 7-dimethylocta-2,6-dienyl.
  • alkoxy as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, t-butoxy, pentyloxy, and hexyloxy.
  • alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, unless otherwise specified.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, isobutyl, t- butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3- dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
  • aryl means a monocyclic (i.e., phenyl), bicyclic, or tricyclic ring fused or bridged system containing at least one phenyl ring.
  • Non-phenyl rings that are part of a bicyclic or tricyclic ring system may be fully or partially saturated, may contain one or more heteroatoms, each selected from N, S, and O, and may be optionally substituted with one or two oxo and/or thio groups.
  • aryl groups include phenyl, napthyl, anthracenyl, and fluorenyl.
  • arylalkyl as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylalkylin include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, fluorenylmethyl and 2-naphth-2-ylethyl.
  • halo or halogen as used herein, means -CI, -Br, -I, or -F.
  • haloalkyl as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, perfluorononyl, and 2-chloro-3-fluoropentyl.
  • heteroaryl means a monocyclic, bicyclic, or tricyclic ring system containing at least one heteroaromatic ring. Any additional rings that are part of a bicyclic or tricyclic ring system may be fully or partially saturated or may be aromatic rings, and each may optionally contain one or more heteroatoms, each selected from N, S, and O.
  • monocyclic and bicyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, triazinyl,benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl, dihydroquinolinyl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl, and tetrahydr
  • heteroarylalkyl as used herein, means a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of heteroarylalkyl include, but are not limited to, furylmethyl, imidazolylmethyl, pyridinylethyl, pyridinylmethyl, pyrimidinylmethyl, and thienylmethyl.
  • t-butyloxycarbonyl(Boc) protecting group is found to be particularly useful as an amine -protecting group.
  • formula (X) may be prepared by a process that includes the steps of: a) treating formula (Vll)with a base to obtain formula VIII)
  • formula (VIII) may formed by treating formula (VII) with a base.
  • suitable bases include sodium hydroxide, potassium hydroxide, and lithium hydroxide.
  • This reaction may be carried out in a suitable solvent, for example, an organic solvent.
  • suitable organic solvents include, but are not limited to, acetonitrile,ketones, esters, or mixtures thereof.
  • suitable ketones include, but are not limited to, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and mixtures thereof.
  • suitable esters include, but are not limited to,ethyl acetate, isopropyl acetate, and mixtures thereof.
  • formula (VIII) may be converted to formula (IX). This may be carried out using a "direct conversion” or a "two-step conversion.”
  • formula (VIII) may be converted directly to formula (IX) bytreating formula (VIII) with a base.
  • suitable bases include, but are not limited to,triethylamine, diisopropylethylamine, diisopropylamine, and N-methylmorpholine.
  • This reaction may be carried out in a suitable solvent.
  • suitable solvents include, but are not limited to, chlorinated solvents, ketone solvents, ester solvents, toluene, acetonitrile, or mixtures thereof.
  • suitable chlorinated solvents include, but are not limited to,methylene dichloride, chloroform, and mixtures thereof.
  • ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and mixtures thereof.
  • suitable estersolvents include, but are not limited to, ethyl acetate, isopropyl acetate, and mixtures thereof.
  • formula (VIII) may be converted to formula (IX) by first converting formula (VIII) to formula (Villa). This may be carried out by treating formula (VIII) with (S)-(alpha)- phenylethylamine. This may be carried out in a suitable solvent, for example (but not limited to), acetonitrile, a ketone solvent, an ester solvent, or mixtures thereof.
  • suitable ketones include but are not limited to, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and mixtures thereof.
  • esters include, but are not limited to,ethyl acetate, isopropyl acetate,and mixtures thereof.
  • formula (Villa) may be converted to formula (IX). This may be performed using a base.
  • suitable bases include, but are not limited to, triethylamine, diisopropylethylamine, diisopropylamine,andN-methylmorpholine. This reaction may be carried out in a solvent.
  • Suitable solvents include, but are not limited to, acetonitrile, toluene, chlorinated solvents (e.g., methylene dichloride, chloroform, and mixtures thereof), ketones (e.g., acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and mixtures thereof), esters (e.g., ethyl acetate, isopropyl acetate, and mixtures thereof), and mixtures thereof.
  • chlorinated solvents e.g., methylene dichloride, chloroform, and mixtures thereof
  • ketones e.g., acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and mixtures thereof
  • esters e.g., ethyl acetate, isopropyl acetate, and mixtures thereof
  • Formula (IX) may then be reduced.
  • Reduction may be carried out by methods well known in the art.
  • this reduction may be achieved by hydrogenationaccording to methods and reaction conditions well known to one of skill in the art.
  • hydrogenation may be carried out by bubbling hydrogen into the reaction mixture containing palladium on carbon (Pd/C) in an alcoholic solvent such as methanol, ethanol, isopropanol, or mixtures thereof.
  • Suitable organic solvents include, but are not limited to,acetonitrile, ketones, esters, and mixtures thereof.
  • suitable ketones include, but are not limited to, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and mixtures thereof.
  • suitable esters include, but are not limited to, ethyl acetate, isopropyl acetate, and mixtures thereof.
  • formula (X) may be converted to Edoxaban, salts, solvates, or solvated salts thereof.
  • formula (X) may becondensed with ethyl2-[5- chloropyridin-2-ylamino]-2-oxoacetate to get formula XI.
  • formula Xl Upon condensation with 5-methyl- 4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxylic acid hydrochloride, formula Xlmay be converted toEdoxaban free base.
  • Edoxaban tosylate monohydrate may then be formed by treatingEdoxaban free base with p-toluenesulfonic acid. This set of reactions is depicted as Scheme I below:
  • mesylate is used as a hydroxy protecting group.
  • Edoxaban may be converted to a number of other pharmaceutically acceptable salts, which are well-known in the art. Methods for converting compounds into their acid salt forms are also well known in the art, and may be carried out, for example, by reacting a free base moiety on Edoxabanwith a suitable reagent.
  • suitable acids include, for example, inorganic acids or organic acids.
  • suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid.
  • Suitable organic acids include, for example, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid.
  • a pharmaceutically acceptable salt may alternatively be prepared by other methods well known in the art, for example, ion exchange.
  • Suitable salts include, for example, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, (R,S)-malate, (S)-malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate,
  • Edoxaban or salts, solvates, or solvated salts thereof may be prepared using formula VIII by way of Scheme 3 below, where the amine -protecting group, introduced in formula V, is a t-butyloxycarbonyl (Boc) and the hydroxy protecting group, introduced in formula VI, is a mesylate (Ms) group: (SM-)-cycloriexene carboxylic acid
  • formula (X) When prepared by methods disclosed herein, formula (X) may be prepared with high purity. In some embodiments, when prepared by the methods disclosed herein, formula (X) may display a purity of more than 99% and enantiomeric excess (ee)of greater than 99.5%. Preparation of the formula (X) intermediate with high purity and yield may, in some embodiments, result in increased purity and yield of subsequent intermediate (e.g., formula (XI)) and increased purity and yield of the final Edoxaban and pharmaceutically acceptable salts, solvates, or solvated salts thereof.
  • Mobile phase-B Transfer about 800 mL of Acetonitrile by using a 1000 mL measuring cylinder and 200 mL of Methanol by using a 250 mL (or) 500 mL measuring cylinder into a mobile phase bottle, mix thoroughly to form a uniform mixture of Acetonitrile : Methanol (80:20) v/v and degassed.
  • the Edoxabanand pharmaceutical salts, solvates, or solvated salts thereof disclosed herein and prepared by the disclosed methods may be used to formulate an oral dosage form, such as a tablet or a capsule.
  • an oral dosage form such as a tablet or a capsule.
  • the Edoxaban or pharmaceutical salts thereof of the present invention may be useful to reduce the risk of stroke and systemic embolism in patients withnon-valvular atrial fibrillation, in the treatment of deep vein thrombosis, pulmonary embolism, or any combination thereof.
  • the Edoxaban and pharmaceutical salts, solvates, or solvated salts thereof may be formulated into a tablet which may contain inactive ingredients such as mannitol, pregelatinized starch, crospovidone, hydroxypropyl cellulose, magnesium stearate, talc, carnauba wax, or mixtures thereof.
  • the tablet may, in some embodiments, be coated with a film that includes additional excipients, artificial colors, and flavors.
  • a coating may containhypromellose, titanium dioxide, talc, polyethylene glycol 8000, iron oxide yellow, iron oxide red, and mixtures thereof.
  • the tablets may contain Edoxaban, pharmaceutical salts, solvates, or solvated salts thereof at an effective amount of between 15 mg and 60 mg.
  • the tablets have 15 mg, 30 mg, or 60 mg of effective Edoxaban.
  • an effective amount refers to the amount of active Edoxabanincluded within the dosage form.
  • the salt when a salt of Edoxabanis used, the salt may be included in the dosage form at a higher weight to achieve the nominal effective concentration. For example, 20.2 mg of Edoxaban tosylate monohydrate may be included in a dosage form, resulting in a dosage form with an effective amount of 15 mg Edoxaban.
  • Formula (II) (lOg) was dissolved in ethanol (50 ml). Potassium carbonate (6.59 g) was added to this solution at 75 °C. The mixture was heated to maintain the temperature at 75 °C for 2 hours and then allowed to cool to room temperature. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. A mixture of ethyl acetate (80 ml) and water (20 ml) was added to the obtained residue and the aqueous and organic layers were separated. The organic layer was then dried over anhydrous sodium sulfate (5g) and the solvent was distilled off under reduced pressure to obtainformula(III) as a pale yellow oil (5.5 g).
  • Boc-anhydride was added to a mixture of formula (IV) (5g) in water (40ml) cooled with ice. The reaction mass was stirred at room temperature for 2hours. After completion of the reaction, ethyl acetate was added. The organic layer was separated from the aqueous layer then distilled under reduced pressure to remove the solvent and obtain an oily mass. The obtained oily mass was crystalized with hexanes to obtain formula (V) as a solid (4g).
  • Triethylamine (74.83 g,0.738moles) was added to a solution of formula (VIII) (70g, 0.246 moles) in methylene dichloride (350 ml) and the solution was cooled to -5 to -10 °C.
  • Pivaloyl chloride (29.66 g, 0.246moles) was then slowly added dropwise and the reaction was maintained at the same temperature for 90minutes.
  • Dimethylamine hydrochloride (24.07g, 0.295moles) was then added lot wise and the reaction mixture was maintainedfor 4hours. After completion of the reaction, water (350ml) was added and the layers were separated. The organic layer was subjected to distillation under reduced pressure to remove organic solvent to obtain an oily mass.
  • Triethylamine (52.34 g, 0.518 moles) was added to a solution of formula (Villa) (70 g,0.172moles)in methylene dichloride(350ml) and the solution was cooled to -5to-10°C.
  • Pivaloyl chloride (24.87g,0.206moles) was slowly added dropwise and the reaction mass was maintained at the same temperature for 90minutes.
  • Dimethylamine hydrochloride (16.90g, 0.206moles) was then added lotwise and the reaction mass was maintained at the same temperature for 4hours. After completion of the reaction, water (350ml) was added and the organic and aqueous layers were separated. The organic layer was distilled under reduced pressure to remove the solvent and obtain an oily mass.
  • Triethylamine 16.86 ml, 0.049 moles was added to a solution offormula (X) ( 10.0g,0.019moles) in acetonitrile (55ml) at 60 °C.

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Abstract

L'invention concerne des composés et des procédés pour la préparation d'Edoxaban. En particulier, un sel de sulfonate de camphre d'un [(1R,2S,5S)-1,2-amino-5-[(diméthylamino)-5-[(diméthylamino))carbonyl] cyclohexane, un intermédiaire qui peut être formé dans la synthèse d'Edoxaban, ainsi que des procédés pour sa préparation.
PCT/IN2017/050286 2016-07-13 2017-07-10 Sel de (1s,2r,4s)-1,2-amino-n, n-diméthylcyclohexane-4-carboxamide protégé par des amines WO2018011823A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2019501697A JP6831447B2 (ja) 2016-07-13 2017-07-10 アミン保護（１ｓ，２ｒ，４ｓ）−１，２ーアミノ−ｎ，ｎ−ジメチルシクロヘキサン−４−カルボキサミドの塩
EP17768248.1A EP3484893A1 (fr) 2016-07-13 2017-07-10 Sel de (1s,2r,4s)-1,2-amino-n, n-diméthylcyclohexane-4-carboxamide protégé par des amines

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IN201641023903 2016-07-13

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CN108659004A (zh) * 2018-07-12 2018-10-16 福安药业集团重庆博圣制药有限公司 奥拉西坦异构体的制备方法
CN109942600A (zh) * 2019-04-15 2019-06-28 内蒙古京东药业有限公司 一种依度沙班的制备方法
WO2019158550A1 (fr) * 2018-02-14 2019-08-22 Moehs Iberica, S.L. Procédé de préparation de n-((1r,2s,5s)-2-((2-((5-chloropyridin-2-yl)amino)-2-oxoacétyl)amino)-5-(diméthylcarbamoyl)cyclohexyl)carbamate tert-butyle
CN111393456A (zh) * 2020-03-31 2020-07-10 内蒙古京东药业有限公司 一种由三氯乙酮鎓盐衍生物制备依度沙班的方法
CN111763222A (zh) * 2020-08-03 2020-10-13 珠海市海瑞德新材料科技有限公司 用于制备依度沙班游离碱的中间体及其制备方法和应用
CN111763157A (zh) * 2020-04-26 2020-10-13 中山大学 一种手性氨基化合物及其制备方法和应用、及由其制备依度沙班中间体的制备方法
CN112321613A (zh) * 2020-11-06 2021-02-05 江苏华阳制药有限公司 甲苯磺酸艾多沙班及其异构体的制备方法

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JP7327736B2 (ja) 2018-02-14 2023-08-16 モエス、イベリカ、ソシエダッド、リミターダ ｔｅｒｔ－ブチルＮ－（（１Ｒ，２Ｓ，５Ｓ）－２－（（２－（（５－クロロピリジン－２－イル）アミノ）－２－オキソアセチル）アミノ）－５－（ジメチルカルバモイル）シクロヘキシル）カルバメートを調製するための方法
WO2019158550A1 (fr) * 2018-02-14 2019-08-22 Moehs Iberica, S.L. Procédé de préparation de n-((1r,2s,5s)-2-((2-((5-chloropyridin-2-yl)amino)-2-oxoacétyl)amino)-5-(diméthylcarbamoyl)cyclohexyl)carbamate tert-butyle
EP3752488B1 (fr) 2018-02-14 2023-03-08 Moehs Ibérica, S.L. Procédé de préparation de n-((1r,2s,5s)-2-((2-((5-chloropyridin-2-yl)amino)-2-oxoacétyl)amino)-5-(diméthylcarbamoyl)cyclohexyl)carbamate tert-butyle
CN108659004B (zh) * 2018-07-12 2020-11-10 福安药业集团重庆博圣制药有限公司 奥拉西坦异构体的制备方法
CN108659004A (zh) * 2018-07-12 2018-10-16 福安药业集团重庆博圣制药有限公司 奥拉西坦异构体的制备方法
CN109942600B (zh) * 2019-04-15 2021-08-20 内蒙古京东药业有限公司 一种依度沙班的制备方法
CN109942600A (zh) * 2019-04-15 2019-06-28 内蒙古京东药业有限公司 一种依度沙班的制备方法
CN111393456B (zh) * 2020-03-31 2022-07-12 内蒙古京东药业有限公司 一种由三氯乙酮鎓盐衍生物制备依度沙班的方法
CN111393456A (zh) * 2020-03-31 2020-07-10 内蒙古京东药业有限公司 一种由三氯乙酮鎓盐衍生物制备依度沙班的方法
CN111763157A (zh) * 2020-04-26 2020-10-13 中山大学 一种手性氨基化合物及其制备方法和应用、及由其制备依度沙班中间体的制备方法
CN111763222B (zh) * 2020-08-03 2021-05-25 珠海市海瑞德新材料科技有限公司 用于制备依度沙班游离碱的中间体及其制备方法和应用
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