WO2017043626A1 - Procédé de production d'un dérivé 4-carbamoyl-2,6-diméthylphénylalanine optiquement actif - Google Patents

Procédé de production d'un dérivé 4-carbamoyl-2,6-diméthylphénylalanine optiquement actif Download PDF

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WO2017043626A1
WO2017043626A1 PCT/JP2016/076605 JP2016076605W WO2017043626A1 WO 2017043626 A1 WO2017043626 A1 WO 2017043626A1 JP 2016076605 W JP2016076605 W JP 2016076605W WO 2017043626 A1 WO2017043626 A1 WO 2017043626A1
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carbamoyl
substituent
following formula
optically active
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西山　章
昇平 山本
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Kaneka Corp
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Kaneka Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B51/00—Introduction of protecting groups or activating groups, not provided for in the preceding groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • 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
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a method for producing an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative useful as an intermediate of an opioid receptor agonist.
  • a dimethyltyrosine derivative is used as a starting material, a phenol hydroxyl group is triflated, and then reacted with carbon monoxide gas in the presence of a palladium catalyst to produce a corresponding carboxylic acid. Subsequently, an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative is produced by condensing carboxylic acid with ammonia to convert to a corresponding amide, and further hydrolyzing the ester.
  • dehydrophenylalanine derivative is asymmetrically hydrogenated in the presence of a rhodium catalyst, and then the ester is hydrolyzed to produce an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative.
  • Patent Document 1 or 2 The method of Patent Document 1 or 2 described above is poor in economic efficiency in that an expensive palladium catalyst is used, and is difficult to implement on an industrial scale in terms of using highly toxic carbon monoxide gas.
  • the method of Patent Document 3 is also economical in that it uses an expensive palladium catalyst, has a high environmental impact in that it uses highly toxic cyanide compounds and heavy metals, and is a suitable process from the viewpoint of industrial implementation. It's hard to say.
  • the problem to be solved by the present invention with respect to the above-described conventional techniques is that high-purity and high-optical purity optically active 4-carbamoyl-2,6-dimethylphenylalanine derivatives required for pharmaceutical intermediates can be easily and efficiently produced. There is to manufacture.
  • the present invention is as follows.
  • R 5 represents a hydrogen atom, a C1-C12 alkyl group which may have a substituent, or a C6-C12 which may have a substituent.
  • a method for producing an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative comprising the following formula (2): 4-carbamoyl-2,6-dimethylbenzoic acid represented by the following formula (3); (Wherein R 1 and R 2 are C1-C12 alkyl groups which may have a substituent, C6-C12 aryl groups which may have a substituent, C7- A C12 aralkyl group, a C3 to C12 cycloalkyl group which may have a substituent, and R 1 and R 2 may form a ring together.)
  • the following formula (4) (Wherein R 1 and R 2 are the same as above), and by reducing the mixed acid anhydride, the following formula (5):
  • the optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative represented by the above formula (1) which comprises a step of producing 4-carbamoyl-2,6-dimethylbenzyl alcohol
  • R 6 Is a C1-C12 alkyl group which may have a substituent, a C6-C12 aryl group which may have a substituent, a C7-C20 aralkyl group which may have a substituent, or a substituent.
  • the base is potassium hydroxide
  • the optically active phase transfer catalyst is (11bR)-( ⁇ )-4,4-dibutyl-4,5-dihydro-2,6-bis (3,4, [5] or [6], which is 5-trifluorophenyl) -3H-dinaphtho [2,1-c: 1 ′, 2′-e] azepinium bromide.
  • the present invention includes the following inventions [II] to [V].
  • R 6 Is a C1-C12 alkyl group which may have a substituent, a C6-C12 aryl group which may have a substituent, a C7-C20 aralkyl group which may have a substituent, or a substituent.
  • a glycine Schiff base represented by the following formula (8): (Wherein R 3 , R 4 , R 6 , and * are the same as those described above) are produced, and are further subjected to acid hydrolysis, or the amino group is protected after acid hydrolysis.
  • a method for producing an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative represented by:
  • R 6 Is a C1-C12 alkyl group which may have a substituent, a C6-C12 aryl group which may have a substituent, a C7-C20 aralkyl group which may have a substituent, or a substituent.
  • a glycine Schiff base represented by the following formula (8): (Wherein R 3 , R 4 , R 6 , and * are the same as those described above) are produced, and are further subjected to acid hydrolysis, or the amino group is protected after acid hydrolysis.
  • a method for producing an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative represented by:
  • the present invention also provides the following formula (6): (Wherein X represents a leaving group) and the 4-carbamoyl-2,6-dimethylbenzyl derivative.
  • the present invention relates to a 4-carbamoyl-2,6-dimethylbenzyl derivative according to [VI], wherein X is a chlorine atom or a bromine atom.
  • the present invention also provides the following formula (4): (Wherein R 1 and R 2 are C1-C12 alkyl groups which may have a substituent, C6-C12 aryl groups which may have a substituent, C7- A C12 aralkyl group, a C3-C12 cycloalkyl group which may have a substituent, and R 1 and R 2 may form a ring together.)
  • R 1 and R 2 may form a ring together.
  • the present invention relates to the mixed acid anhydride according to [VII], wherein R 1 is a methyl group or an ethyl group, and R 2 is a methyl group or an ethyl group.
  • an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative having high purity and high optical purity required for a pharmaceutical intermediate can be easily and efficiently produced.
  • the C1-C12 alkyl group includes a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, an n- A pentyl group, n-hexyl group, n-decyl group, n-dodecyl group and the like can be mentioned.
  • Examples of the C6 to C12 aryl group include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
  • Examples of the aralkyl group of C7 to C20 include benzyl group, 1-phenethyl group, trityl group and the like.
  • Examples of the C3-12 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and an adamantyl group.
  • Substituents for C1-C12 alkyl groups, C6-C12 aryl groups, C7-C12 aralkyl groups and C3-12 cycloalkyl groups include, for example, halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom Atom; hydroxyl group; alkoxy group such as methoxy group and ethoxy group; methylthio group; trifluoromethyl group; acetyl group; benzoyl group; cyano group; nitro group; carboxyl group; alkoxycarbonyl group such as methoxycarbonyl group and ethoxycarbonyl group Is mentioned.
  • the number of substitution groups and the substitution position are not particularly limited.
  • optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative which is the target product of the present invention, has the following formula (1);
  • P represents a hydrogen atom or an amino-protecting group.
  • P represents a hydrogen atom or an amino-protecting group.
  • carbamate-type protecting group such as methoxycarbonyl group, ethoxycarbonyl group, isopropoxycarbonyl group, allyloxycarbonyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group, fluoren-9-ylmethoxycarbonyl group; formyl Acyl-type protecting groups such as acetyl, acetyl, trifluoroacetyl, pivaloyl, benzoyl and p-nitrobenzoyl groups; sulfonyl-type protecting groups such as mesyl, p-toluenesulfonyl and p-nitrobenzenesulfonyl More preferably a hydrogen atom, a tert-butoxycarbonyl group, or a benzyloxycarbonyl group, and
  • R 5 is a hydrogen atom, an optionally substituted C1 to C12 alkyl group, an optionally substituted C6 to C12 aryl group, or an optionally substituted C7 to C20.
  • a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a 1-adamantyl group, a cyclohexyl group, a phenyl group, a p-chlorophenyl group, a p-nitrophenyl group, a benzyl group, or a trityl group A hydrogen atom, a methyl group, an ethyl group, or a tert-butyl group is more preferable, a hydrogen atom or a methyl group is still more preferable, and a hydrogen atom is particularly preferable.
  • the absolute configuration of compound (1) may be either R or S, and the preferred absolute configuration is S.
  • the optical purity of the R-form or S-form compound (1) obtained by the production method according to the present invention is preferably 70% ee or more, more preferably 80% ee or more, and further preferably 90% ee or more.
  • the compound (1) is preferably a compound of the following formulas (1-1) to (1-12), more preferably (S) -3- (4-carbamoyl-2,6-dimethylphenyl) -2- It is methyl (tert-butoxycarbonylamino) propanoic acid or (S) -3- (4-carbamoyl-2,6-dimethylphenyl) -2- (tert-butoxycarbonylamino) propanoic acid.
  • This compound can be easily produced from 2,4,6-trimethylbenzoic acid, which is easily available at low cost, according to the method described in JP-A-63-253061.
  • 2,4,6-trimethylbenzoic acid is oxidized with potassium permanganate to produce 2,6-dimethylbenzene-1,4-dicarboxylic acid, and treated with methanol in the presence of a sulfuric acid catalyst.
  • 4-methoxycarbonyl-2,6-dimethylbenzoic acid can be obtained, followed by treatment with ammonia gas, whereby the 4-carbamoyl-2,6-dimethylbenzoic acid can be produced.
  • the carbamoyl chloride used in the present invention has the following formula (3):
  • R 1 and R 2 each independently have a C1-C12 alkyl group which may have a substituent, a C6-C12 aryl group which may have a substituent, or a substituent. Or a C7 to C12 aralkyl group or a C3 to C12 cycloalkyl group which may have a substituent.
  • R 1 and R 2 may be different but are preferably the same.
  • R 1 and R 2 are methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, cyclobutyl.
  • R 1 and R 2 may form a ring together.
  • R 1 and R 2 examples include a butylene group, a pentylene group, a diethyl ether-2,2′-diyl group, and the like.
  • R 1 and R 2 are preferably a methyl group or an ethyl group, and more preferably an ethyl group.
  • Compound (3) is preferably a compound of the following formulas (3-1) to (3-9), more preferably dimethylcarbamoyl chloride or diethylcarbamoyl chloride, and still more preferably diethylcarbamoyl chloride.
  • the mixed acid anhydride which is an intermediate product of the present invention has the following formula (4):
  • R 1 and R 2 are the same as described above.
  • This compound is a novel compound not described in any literature.
  • the compound (4) is preferably a compound of the following formulas (4-1) to (4-9), more preferably 4-carbamoyl-2,6-dimethylbenzoic acid, N, N-dimethylcarbamic anhydride or 4-carbamoyl-2,6-dimethylbenzoic acid is N, N-diethylcarbamic anhydride, more preferably 4-carbamoyl-2,6-dimethylbenzoic acid is N, N-diethylcarbamic anhydride.
  • 4-carbamoyl-2,6-dimethylbenzyl alcohol which is an intermediate product of the present invention, has the following formula (5):
  • the intermediate product of the present invention 4-carbamoyl-2,6-dimethylbenzyl derivative, has the following formula (6):
  • X represents a leaving group. Specifically, halogen atoms such as chlorine atom, bromine atom and iodine atom; methanesulfonyloxy group, ethanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group, p-nitrobenzenesulfonyloxy group, trifluoromethanesulfonyl Examples include sulfonyloxy groups such as oxy groups.
  • halogen atoms such as a chlorine atom, a bromine atom, and an iodine atom, More preferably, they are a chlorine atom or a bromine atom.
  • This compound is a novel compound not described in any literature.
  • the glycine Schiff base used in the present invention has the following formula (7):
  • R 3 represents a hydrogen atom or a C6 to C12 aryl group which may have a substituent.
  • a hydrogen atom, a phenyl group, a p-chlorophenyl group, a p-nitrophenyl group, and a p-methoxyphenyl group are preferable, and a phenyl group is more preferable.
  • R 4 represents a C6 to C12 aryl group which may have a substituent.
  • R 3 and R 4 are each independently preferably a phenyl group, a p-methylphenyl group, a p-chlorophenyl group, a p-nitrophenyl group, or a p-methoxyphenyl group, and more preferably a phenyl group.
  • R 3 and R 4 may be the same as or different from each other, but are preferably the same.
  • R 6 is an optionally substituted C1-C12 alkyl group, an optionally substituted C6-C12 aryl group, an optionally substituted C7-C20 aralkyl group, or a substituted group. Represents a C3-12 cycloalkyl group which may have a group.
  • it is a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a 1-adamantyl group, a cyclohexyl group, a phenyl group, a p-chlorophenyl group, a p-nitrophenyl group, a benzyl group, or a trityl group, more preferably A methyl group, an ethyl group, or a tert-butyl group, more preferably a methyl group or a tert-butyl group, and particularly preferably a tert-butyl group.
  • R 6 may be the same as or different from R 5 depending on the synthesis route.
  • Compound (7) is preferably a compound of the following formulas (7-1) to (7-15), more preferably 2- (diphenylmethylidene) glycine tert-butyl ester.
  • optically active amino acid derivative that is an intermediate product of the present invention has the following formula (8):
  • R 3 , R 4 , R 6 and * are the same as described above.
  • the compound (8) is preferably a compound of the following formulas (8-1) to (8-15), more preferably (S) -3- (4-carbamoyl-2,6-dimethylphenyl) -2- (Diphenylmethylideneamino) tert-butyl propanoate.
  • the dehydroamino acid derivative which is an intermediate product of the present invention has the following formula (10):
  • the compound (10) is preferably a compound of the following formulas (10-1) to (10-4), more preferably 3- (4-carbamoyl-2,6-dimethylphenyl) -2- (tert-butoxy Carbonylamino) methyl acrylate.
  • the present invention is illustrated as follows, and each step will be described step by step.
  • the amount of the carbamoyl chloride to be used is preferably 1 to 10 equivalents (times mol), more preferably 1 to 3 equivalents (times mol) based on the compound (2).
  • Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like; trimethylamine And amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] undec-7-ene, pyridine, quinoline, and imidazole. These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited.
  • amines such as trimethylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] undec-7-ene, pyridine, quinoline, imidazole, etc. More preferably triethylamine or pyridine.
  • the amount of the base used is preferably 1 to 10 equivalents (fold moles), more preferably 1 to 3 equivalents (fold moles) relative to the compound (2).
  • the solvent in this step is not particularly limited as long as it does not affect the reaction. Specifically, for example, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether, etc.
  • Ether solvents such as acetonitrile and nitrile solvents such as propionitrile; ester solvents such as ethyl acetate, n-propyl acetate and isopropyl acetate; aliphatic hydrocarbon solvents such as pentane, hexane, heptane and methylcyclohexane; benzene Aromatic hydrocarbon solvents such as toluene, xylene, ethylbenzene and mesitylene; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; halogen solvents such as methylene chloride and 1,2-dichloroethane; Sulfoxide solvents such as til sulfoxide; N, N-dimethylformamide, N, N-dimethylacetamide, N, N-diethylacetamide, N-methyl-2-pyrrolidone, N-ethy
  • the mixing ratio is not particularly limited.
  • Preferred are ether solvents, nitrile solvents, ketone solvents, or amide solvents, more preferred are tetrahydrofuran, acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, and particularly preferred is N. , N-dimethylformamide, or N, N-dimethylacetamide.
  • the upper limit is preferably 100 times weight, more preferably 50 times weight with respect to the compound (2). Particularly preferred is 20 times the weight.
  • the lower limit is preferably 0.1 times the weight of the compound (2), more preferably 0.5 times the weight, and particularly preferably 1 times the weight.
  • the reaction temperature in this reaction is not particularly limited and may be set as appropriate.
  • the upper limit is preferably 150 ° C., more preferably 100 ° C., and particularly preferably 50 ° C.
  • the lower limit is preferably ⁇ 80 ° C., more preferably ⁇ 30 ° C., and particularly preferably 0 ° C.
  • the reaction time in this reaction is not particularly limited and may be appropriately set.
  • the upper limit is preferably 100 hours, more preferably 50 hours, and particularly preferably 25 hours.
  • the lower limit is preferably 0.1 hour, more preferably 1 hour, and particularly preferably 3 hours.
  • a general process for obtaining a product from the reaction solution may be performed.
  • the reaction solution after completion of the reaction is subjected to an extraction operation using water, a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane and the like.
  • a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane and the like.
  • the desired product is obtained.
  • water is added to the reaction solution
  • the target product precipitates as a solid, which may be filtered off.
  • the target product thus obtained has a sufficient purity that can be used in the subsequent steps.
  • crystallization, fractional distillation, solution washing, column chromatography, etc. are generally used.
  • the purity may be further increased by a simple purification method.
  • the reduction may be performed using a reducing agent.
  • Reducing agents include lithium aluminum hydride, diisobutylaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, triacetoxyaluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride, hydrogenated Calcium boron, sodium cyanoborohydride, lithium triethylborohydride, lithium tri (sec-butyl) borohydride, potassium tri (sec-butyl) borohydride, borane, tributyltin hydride, silane, trichlorosilane, trimethoxy Examples thereof include silane and triethoxysilane.
  • the amount of the reducing agent to be used is preferably 1 to 20 equivalents (times mole), more preferably 1 to 5 equivalents (times mole) based on the compound (4).
  • the solvent in this step is not particularly limited as long as it does not affect the reaction.
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, and ethylene glycol are used.
  • Solvents ether solvents such as tetrahydrofuran, methyltetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether; nitrile solvents such as acetonitrile and propionitrile; ethyl acetate, n-propyl acetate, Ester solvents such as isopropyl acetate; Aliphatic hydrocarbon solvents such as pentane, hexane, heptane, and methylcyclohexane; Aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene, and mesitylene Solvents: N, N-dimethylformamide, N, N-dimethylacetamide, N, N-diethylacetamide, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone,
  • the upper limit is preferably 100 times weight, more preferably 50 times weight, relative to the compound (4). Particularly preferred is 20 times the weight.
  • the lower limit is preferably 0.1 times the weight of the compound (4), more preferably 0.5 times the weight, and particularly preferably 1 times the weight.
  • the reaction temperature in this reaction is not particularly limited and may be set as appropriate.
  • the upper limit is preferably 150 ° C., more preferably 100 ° C., and particularly preferably 50 ° C.
  • the lower limit is preferably ⁇ 80 ° C., more preferably ⁇ 30 ° C., and particularly preferably 0 ° C.
  • the reaction time in this reaction is not particularly limited and may be appropriately set.
  • the upper limit is preferably 100 hours, more preferably 50 hours, and particularly preferably 25 hours.
  • the lower limit is preferably 0.1 hour, more preferably 1 hour, and particularly preferably 3 hours.
  • a general process for obtaining a product from the reaction solution may be performed.
  • the reaction solution after completion of the reaction is subjected to an extraction operation using water, a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane and the like.
  • a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane and the like.
  • the reaction solvent and the extraction solvent are distilled off from the resulting extract by an operation such as heating under reduced pressure
  • the desired product is obtained.
  • the target product precipitated from the reaction solution is filtered off and washed with methanol or ethanol.
  • the target product thus obtained has a sufficient purity that can be used in the subsequent steps.
  • crystallization, fractional distillation, solution washing, column chromatography, etc. are generally used.
  • the purity may be further increased by a simple purification method.
  • the compound (5) is sulfonylated to methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, trifluoromethanesulfonic anhydride, etc.
  • Agents such as trimethylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] undec-7-ene, pyridine, quinoline, imidazole It is good to let them.
  • the amount of the sulfonylating agent to be used is preferably 1 to 10 equivalents (fold moles), more preferably 1 to 3 equivalents (fold moles) relative to the compound (5).
  • the amine is preferably used in an amount of 1 to 10 equivalents (times mole), more preferably 1 to 3 equivalents (times mole) based on the compound (5).
  • the compound (5) includes sulfonyl chloride, phosphorus trichloride, phosphorus pentachloride, sulfonyl bromide, phosphorus tribromide, iodine / triphenylphosphine, boron tribromide, thionyl chloride and the like.
  • a halogenating agent may be allowed to act.
  • Preferred is sulfonyl chloride, phosphorus tribromide, or thionyl chloride, and more preferred is phosphorus tribromide.
  • the amount of the halogenating agent to be used is preferably 1 to 10 equivalents (fold moles), more preferably 1 to 3 equivalents (fold moles) relative to the compound (5).
  • these halogenating agents are allowed to act, if necessary, trimethylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] undec-7- Amines such as ene, pyridine, quinoline and imidazole may be used.
  • the amount of the amine to be used is preferably 0.01 to 1 mol, more preferably 0.05 to 0.5 mol, per 1 mol of the compound (5).
  • sodium chloride, potassium chloride, tetrabutylammonium chloride, sodium bromide, potassium bromide, tetrabutylammonium bromide, sodium iodide, iodine X may be converted to the compound (6) wherein a halogen atom such as a chlorine atom, a bromine atom or an iodine atom is allowed to act on a halide such as potassium iodide or tetrabutylammonium iodide.
  • the solvent in this step is not particularly limited as long as it does not affect the reaction. Specifically, for example, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether, etc.
  • Ether solvents such as acetonitrile and nitrile solvents such as propionitrile; ester solvents such as ethyl acetate, n-propyl acetate and isopropyl acetate; aliphatic hydrocarbon solvents such as pentane, hexane, heptane and methylcyclohexane; benzene Aromatic hydrocarbon solvents such as toluene, xylene, ethylbenzene and mesitylene; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; halogen solvents such as methylene chloride and 1,2-dichloroethane; Sulfoxide solvents such as til sulfoxide; N, N-dimethylformamide, N, N-dimethylacetamide, N, N-diethylacetamide, N-methyl-2-pyrrolidone, N-ethy
  • the mixing ratio is not particularly limited.
  • Preferred are ether solvents, nitrile solvents, ester solvents, halogen solvents, or amide solvents, and more preferred are tetrahydrofuran, acetonitrile, ethyl acetate, methylene chloride, N, N-dimethylformamide, or N, N—.
  • Dimethylacetamide particularly preferably tetrahydrofuran, acetonitrile, ethyl acetate, or methylene chloride.
  • the upper limit is preferably 100 times weight, more preferably 50 times weight, relative to the compound (5). Particularly preferred is 20 times the weight.
  • the lower limit is preferably 0.1 times the weight of the compound (5), more preferably 0.5 times the weight, and particularly preferably 1 times the weight.
  • the reaction temperature in this reaction is not particularly limited and may be set as appropriate.
  • the upper limit is preferably 100 ° C., more preferably 70 ° C., and particularly preferably 40 ° C.
  • the lower limit is preferably ⁇ 80 ° C., more preferably ⁇ 50 ° C., and particularly preferably ⁇ 20 ° C.
  • the reaction time in this reaction is not particularly limited and may be appropriately set.
  • the upper limit is preferably 100 hours, more preferably 50 hours, and particularly preferably 25 hours.
  • the lower limit is preferably 0.1 hour, more preferably 1 hour, and particularly preferably 3 hours.
  • the mixing order of compound (5) in this step, solvent, sulfonylating agent, amine, or compound (5) in this step, solvent, and halogenating agent is not particularly limited.
  • a general process for obtaining a product from the reaction solution may be performed.
  • the reaction solution after completion of the reaction is subjected to an extraction operation using water, a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane and the like.
  • a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane and the like.
  • the reaction solvent and the extraction solvent are distilled off from the resulting extract by an operation such as heating under reduced pressure, the desired product is obtained.
  • the target product precipitated from the reaction solution is filtered off and washed with water, ethyl acetate, methylene chloride, hexane, heptane or the like.
  • the target product thus obtained has a sufficient purity that can be used in the subsequent steps.
  • crystallization, fractional distillation, solution washing, column chromatography, etc. are generally used.
  • the purity may be further increased by a simple purification method.
  • Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and the like.
  • Sodium hydroxide or potassium hydroxide is preferable, and potassium hydroxide is more preferable.
  • the amount of the base used is preferably 0.5 to 50 equivalents (fold moles), more preferably 1 to 10 equivalents (fold moles) relative to the compound (6).
  • optically active phase transfer catalyst examples include an optically active quaternary ammonium salt phase transfer catalyst, an optically active quaternary phosphonium salt phase transfer catalyst having a biphenyl skeleton and / or a binaphthyl skeleton, and a complex with an optically active metal atom.
  • optically active phase transfer catalyst examples include the formed phase transfer catalyst.
  • optically active quaternary ammonium salt having biphenyl skeleton and / or binaphthyl skeleton, optically active tartaric acid type quaternary ammonium salt, or optically active cinchona alkaloid type quaternary ammonium salt, biphenyl skeleton and / or binaphthyl skeleton
  • Optically active quaternary phosphonium salt phase transfer catalyst nickel complexed with N, N′-bis (salicylidene) -1,2-cyclohexanediamine derivative (Jacobsen ligand), or copper catalyst .
  • the upper limit is preferably 1 equivalent (times mol), more preferably 0, relative to the compound (6).
  • the lower limit is preferably 0.0001 equivalent (times mol), more preferably 0.001 equivalent (times mol), and particularly preferably 0.01 equivalent (times mol) relative to the compound (6). It is.
  • the amount of the compound (7) to be used is preferably 1 to 10 equivalents (times mole), more preferably 1 to 3 equivalents (times mole) with respect to the compound (6).
  • the solvent in this step is not particularly limited as long as it does not affect the reaction.
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, and ethylene glycol are used.
  • Solvents ether solvents such as tetrahydrofuran, methyltetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether; nitrile solvents such as acetonitrile and propionitrile; ethyl acetate, n-propyl acetate, Ester solvents such as isopropyl acetate; Aliphatic hydrocarbon solvents such as pentane, hexane, heptane, and methylcyclohexane; Aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene, and mesitylene Solvents; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; halogen solvents such as methylene chloride and 1,2-dichloroethane;
  • ether solvents preferably tetrahydrofuran, methyl tert-butyl ether, hexane, heptane, toluene, xylene, ethylbenzene, mesitylene, methylene chloride, Or 1,2-dichloroethane, particularly preferably methyl tert-butyl ether, toluene, xylene, ethylbenzene, or mesitylene.
  • the upper limit is preferably 100 times weight, more preferably 50 times weight with respect to the compound (6). Particularly preferred is 20 times the weight.
  • the lower limit is preferably 0.1 times the weight of the compound (6), more preferably 0.5 times the weight, and particularly preferably 1 times the weight.
  • water may be added for the purpose of accelerating the reaction rate of this reaction.
  • the amount of water used is preferably 0.1 to 100 equivalents (times mole), more preferably 1 to 30 equivalents (times mole), relative to the compound (6).
  • the reaction temperature in this reaction is not particularly limited and may be set as appropriate.
  • the upper limit is preferably 120 ° C., more preferably 50 ° C., and particularly preferably 30 ° C.
  • the lower limit is preferably ⁇ 80 ° C., more preferably ⁇ 50 ° C., and particularly preferably ⁇ 20 ° C.
  • the reaction time in this reaction is not particularly limited and may be appropriately set.
  • the upper limit is preferably 120 hours, more preferably 100 hours, and particularly preferably 80 hours.
  • the lower limit is preferably 0.1 hour, more preferably 1 hour, and particularly preferably 3 hours.
  • a general process for obtaining a product from the reaction solution may be performed.
  • the reaction solution after completion of the reaction is subjected to an extraction operation using water, a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane and the like.
  • a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane and the like.
  • the optical purity of the R-form or S-form compound (8) obtained by this step is preferably 80% ee (where% ee represents the enantiomeric excess), more preferably 85% ee or more, and still more preferably 88 % Ee or higher.
  • the target product thus obtained has a sufficient purity that can be used in the subsequent steps.
  • crystallization, fractional distillation, solution washing, column chromatography, etc. are generally used.
  • the purity may be further increased by a simple purification method.
  • optically active amino acid derivative represented by the formula (8) is produced and further subjected to acid hydrolysis, or the amino group is protected after acid hydrolysis, whereby the optical activity represented by the formula (1).
  • a process for producing a 4-carbamoyl-2,6-dimethylphenylalanine derivative will be described.
  • the acid used for the acid hydrolysis is preferably hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, citric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, more preferably sulfuric acid or methane. Sulfonic acid.
  • the amount of the acid used is preferably 0.5 to 100 equivalents (fold moles), more preferably 1 to 20 equivalents (fold moles) relative to the compound (8).
  • the amount of water used is preferably 0.1 to 100 times the weight of the compound (8), more preferably 1 to 30 weights.
  • the reaction temperature in this hydrolysis is not particularly limited and may be appropriately set.
  • the upper limit is preferably 120 ° C., and more preferably 100 ° C.
  • it is 0 degreeC as a minimum, More preferably, it is 20 degreeC.
  • Protecting conditions for the amino group may be appropriately set according to the type of protecting group (P). Specifically, for example, when tert-butoxycarbonyl protection or benzyloxycarbonyl protection is performed, an aqueous solution of optically active 4-carbamoyl-2,6-dimethylphenylalanine obtained by the hydrolysis is added with sodium hydroxide, potassium hydroxide. After neutralization with a base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc., di-tert-butyl dicarbonate or benzyloxycarbonyl chloride may be added. For the purpose of accelerating the reaction, the base may be further added to control the pH during the reaction to 7 or more.
  • P type of protecting group
  • the optical purity of the R-form or S-form compound (1) obtained in this step is the same as that of the raw material compound (8) or lower than that of the raw material compound (8), or the compound (8). Higher optical purity.
  • the optical purity of the R-form or S-form compound (1) is preferably 85% ee, more preferably 88% ee or more, and even more preferably 89% ee or more.
  • the compound (1) thus obtained has a sufficient purity that can be used in the subsequent steps.
  • the compound (1) can be further purified by a general purification method such as column chromatography. May be raised.
  • the compound (1) having high chemical purity and high optical purity can be obtained by crystallization from methanol or a mixed solvent of methanol / water.
  • the optical purity of the R-form or S-form compound (1) after purification is preferably 90% ee or more, more preferably 95% ee or more, and further preferably 98% ee or more.
  • oxidation reaction As a method for converting alcohol to aldehyde, a generally well-known oxidation reaction may be used. Specifically, for example, Jones oxidation reaction using chromic acid or pyridinium chlorochromate; oxidation reaction using sulfur trioxide / pyridine complex, etc .; Swan using dimethyl sulfoxide / trifluoroacetic anhydride, dimethyl sulfoxide / oxalyl chloride, etc.
  • Oxidation reaction sodium hypochlorite / 2,2,6,6-tetramethylpiperidine-1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-acetamido-2 , 2,6,6-tetramethylpiperidine-1-oxyl and other oxyl radicals, etc.
  • a tempo oxidation reaction is preferred.
  • the amount of the sodium hypochlorite to be used is preferably 1 to 10 equivalents (times mole), more preferably 1 to 3 equivalents (times mole) based on the compound (5).
  • the amount of the oxyl radical used is preferably 0.001 to 1 equivalent (times mole), more preferably 0.01 to 0.5 equivalent (times mole) with respect to the compound (5). is there.
  • the solvent in this step is not particularly limited as long as it does not affect the reaction. Specifically, for example, water; tetrahydrofuran, methyltetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol Ether solvents such as dimethyl ether; nitrile solvents such as acetonitrile and propionitrile; ester solvents such as ethyl acetate, n-propyl acetate and isopropyl acetate; aliphatic hydrocarbon solvents such as pentane, hexane, heptane and methylcyclohexane Aromatic hydrocarbon solvents such as benzene, toluene, xylene, ethylbenzene and mesitylene; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; halogen solvent
  • the mixing ratio is not particularly limited.
  • water, ether solvent, ester solvent, aromatic hydrocarbon solvent, or halogen solvent more preferably water, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, toluene , Xylene, ethylbenzene, mesitylene, methylene chloride, or 1,2-dichloroethane, particularly preferably water, methyl tert-butyl ether, ethyl acetate, or toluene.
  • the upper limit is preferably 100 times weight, more preferably 50 times weight, relative to the compound (5). Particularly preferred is 20 times the weight.
  • the lower limit is preferably 0.1 times the weight of the compound (5), more preferably 0.5 times the weight, and particularly preferably 1 times the weight.
  • the reaction temperature in this reaction is not particularly limited and may be set as appropriate.
  • the upper limit is preferably 100 ° C., more preferably 50 ° C., and particularly preferably 20 ° C.
  • the lower limit is preferably ⁇ 80 ° C., more preferably ⁇ 50 ° C., and particularly preferably ⁇ 20 ° C.
  • the reaction time in this reaction is not particularly limited and may be appropriately set.
  • the upper limit is preferably 120 hours, more preferably 100 hours, and particularly preferably 80 hours.
  • the lower limit is preferably 0.1 hour, more preferably 1 hour, and particularly preferably 3 hours.
  • a general process for obtaining a product from the reaction solution may be performed.
  • the reaction solution after completion of the reaction is subjected to an extraction operation using water, a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane and the like.
  • a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane and the like.
  • the target product thus obtained has a sufficient purity that can be used in the subsequent steps.
  • crystallization, fractional distillation, solution washing, column chromatography, etc. are generally used.
  • the purity may be further increased by a simple purification method.
  • Examples of the glycine derivative include phosphonoglycine derivatives.
  • the phosphonoglycine derivative is preferably N- (tert-butoxycarbonyl) -phosphonoglycine trimethyl ester, N- (tert-butoxycarbonyl) -phosphonoglycine triethyl ester, N- (benzyloxycarbonyl) -phosphonoglycine. And trimethyl ester, N- (benzyloxycarbonyl) -phosphonoglycine triethyl ester, and the like.
  • the amount of the phosphonoglycine derivative to be used is preferably 1 to 10 equivalents (fold moles), more preferably 1 to 3 equivalents (fold moles) relative to the compound (9).
  • the base when reacting the phosphonoglycine derivative, it is better to use a base.
  • the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate.
  • Inorganic bases such as lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate; lithium methoxide, lithium ethoxide, lithium isopropoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert Alkoxides such as butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide; metal hydrides such as sodium hydride, potassium hydride, calcium hydride; Ethylamine, triethylamine, tributylamine, diisopropylethylamine, N- methylpyrrolidine, N- methylmorpholine, 1,8-diazabicyclo [5,4,0] undec-7-ene, pyridine, quinoline, include amines such as imidazole.
  • the mixing ratio is not particularly limited.
  • the amount of the base to be used is preferably 1 to 10 equivalents (fold moles), more preferably 1 to 3 equivalents (fold moles) relative to the compound (9).
  • the solvent in this step is not particularly limited as long as it does not affect the reaction.
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, and ethylene glycol are used.
  • Solvents ether solvents such as tetrahydrofuran, methyltetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether; nitrile solvents such as acetonitrile and propionitrile; ethyl acetate, n-propyl acetate, Ester solvents such as isopropyl acetate; Aliphatic hydrocarbon solvents such as pentane, hexane, heptane, and methylcyclohexane; Aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene, and mesitylene Solvents; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; halogen solvents such as methylene chloride and 1,2-dichloroethane;
  • the mixing ratio is not particularly limited.
  • Preferred are ether solvents, ester solvents, aromatic hydrocarbon solvents, or halogen solvents, more preferably tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, toluene, xylene, ethylbenzene.
  • the upper limit is preferably 100 times weight, more preferably 50 times weight with respect to the compound (9). Particularly preferred is 20 times the weight.
  • the lower limit is preferably 0.1 times the weight of the compound (9), more preferably 0.5 times the weight, and particularly preferably 1 times the weight.
  • the reaction temperature in this reaction is not particularly limited and may be set as appropriate.
  • the upper limit is preferably 120 ° C., more preferably 80 ° C., and particularly preferably 50 ° C.
  • the lower limit is preferably ⁇ 80 ° C., more preferably ⁇ 30 ° C., and particularly preferably 0 ° C.
  • the reaction time in this reaction is not particularly limited and may be appropriately set.
  • the upper limit is preferably 120 hours, more preferably 100 hours, and particularly preferably 80 hours.
  • the lower limit is preferably 0.1 hour, more preferably 1 hour, and particularly preferably 3 hours.
  • a general process for obtaining a product from the reaction solution may be performed.
  • the reaction solution after completion of the reaction is subjected to an extraction operation using water, a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane and the like.
  • a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane and the like.
  • the target product thus obtained has a sufficient purity that can be used in the subsequent steps.
  • crystallization, fractional distillation, solution washing, column chromatography, etc. are generally used.
  • the purity may be further increased by a simple purification method.
  • a method for producing an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative represented by the formula (1) by asymmetric hydrogenation of the dehydroamino acid derivative represented by the formula (10) As for, there is no particular limitation as long as the desired configuration can be obtained. Examples thereof include a method of reducing by hydrogenation using an optically active transition metal complex as a catalyst, or a method of reducing by a microorganism such as yeast. Among them, a method of reducing by hydrogenation using an optically active transition metal complex as a catalyst is preferable.
  • the optically active transition metal catalyst is preferably an optically active phosphorus-containing ligand, more preferably an optically active bisphosphine, and particularly preferably (R, R) -1,2-ethanediylbis [(2 -Methoxyphenyl) phenylphosphine] ((R, R) -DIPAMP).
  • the transition metal catalyst is preferably palladium, rhodium, platinum, or iridium, preferably rhodium.
  • the usage amount of the catalyst, the reaction temperature, the reaction solvent, the hydrogen pressure, and the like may be in accordance with the conditions described in Patent Document 2.
  • the optical purity of the R-form or S-form compound (1) obtained by this step is preferably 85% ee, more preferably 88% ee or more, and still more preferably 89% ee or more.
  • the precipitated manganese dioxide was filtered off and washed with a 5% aqueous sodium hydroxide solution (1000 mL). Concentrated hydrochloric acid (about 600 mL) was added to the filtrate and acidified to precipitate a solid, which was stirred at 10 ° C. for 5 hours. The solid was filtered off under reduced pressure, washed with water (3000 mL), and the wet crystals were transferred to another container. Methanol (2500 mL) and water (2500 mL) were added thereto, and the mixture was refluxed for 3 hours. The mixture was cooled to 20 to 25 ° C., and the precipitated solid was filtered off under reduced pressure. The solid was washed with water (2000 mL) and dried under reduced pressure to give 2,6-dimethylbenzene-1,4-dicarboxylic acid as a white solid (285 g, yield: 48%).
  • Example 1 4-Carbamoyl-2,6-dimethylbenzoic acid Production of N, N-diethylcarbamic anhydride
  • An N, N-dimethylformamide solution of the compound obtained in Reference Example 1 255 g, 1.32 mol
  • diethylcarbamoyl chloride 270 g, 1.98 mol
  • triethylamine 213 g, 2.11 mol
  • pyridine 104 g, 1.32 mol
  • Example 2 Preparation of 4-carbamoyl-2,6-dimethylbenzyl alcohol
  • the solid (339 g, 1.28 mol) obtained in Example 1 was added to ethanol (6780 mL), water (339 mL), and sodium borohydride ( 154 g, 4.06 mol) was added continuously at 10-20 ° C.
  • the reaction temperature was raised to 30 to 35 ° C. and the mixture was stirred for 8 hours.
  • the precipitated solid was filtered off and washed with ethanol (200 mL).
  • the obtained filtrate was concentrated under reduced pressure to obtain 239 g of the title compound (yield: 100%).
  • 1 H NMR (CDCl 3 ): ⁇ 7.48 (s, 2H), 4.78 (d, J 5.5 Hz, 2H), 2.49 (s, 6H)
  • Example 3 Production of 4-carbamoyl-2,6-dimethylbenzyl bromide
  • methylene chloride 2390 mL
  • phosphorus tribromide 376 g, 1.39 mol
  • water 2400 mL
  • the precipitated solid was collected by filtration, washed with cold water (500 mL), and dried under reduced pressure.
  • Example 5 Production of (S) -3- (4-carbamoyl-2,6-dimethylphenyl) -2- (tert-butoxycarbonylamino) propanoic acid Solution obtained in Example 4 (88 g, 20 mmol) was heated to 60 ° C., methanesulfonic acid (19 g, 200 mmol) was added and stirred for 2 hours. The reaction solution was ice-cooled, water (60 mL) was added, and the mixture was stirred at room temperature for 30 min.
  • Example 8 Preparation of 4-carbamoyl-2,6-dimethylbenzaldehyde To the solid (179 mg, 1 mmol) obtained in Example 2, water (2 mL), sodium hydrogen carbonate (252 mg, 3 mmol), 2, 2, 6,6-Tetramethylpiperidine-1-oxyl (7.8 mg, 0.05 mmol) and ethyl acetate (2 mL) were added and cooled to 5 ° C. A solution consisting of sodium hypochlorite pentahydrate (296 mg, 1.8 mmol) and water (4 mL) was added dropwise over 10 minutes. After stirring at 5 ° C.
  • Example 9 Preparation of methyl 3- (4-carbamoyl-2,6-dimethylphenyl) -2- (tert-butoxycarbonylamino) acrylate
  • the solid (177 mg, 1 mmol) obtained in Example 8 was mixed with N -(Tert-butoxycarbonyl) -phosphonoglycine trimethyl ester (357 mg, 1.2 mmol), methylene chloride (10 mL), 1.8-diazabicyclo [5,4,0] undec-7-ene (198 mg, 1.3 mmol) ) And stirred at 25 ° C. for 4 days.
  • Example 10 Preparation of methyl (S) -3- (4-carbamoyl-2,6-dimethylphenyl) -2- (tert-butoxycarbonylamino) propanoate
  • the solid obtained in Example 9 (174 mg, 0 0.5 mmol), methanol (20 mL), tetrafluoroboric acid (R, R)-( ⁇ )-1,2-bis [(o-methoxyphenyl) (phenyl) phosphino] ethane (1,5-cyclooctadiene)
  • R, R tetrafluoroboric acid
  • R, R tetrafluoroboric acid
  • R, R tetrafluoroboric acid
  • R, R tetrafluoroboric acid
  • R, R tetrafluoroboric acid
  • R, R tetrafluoroboric acid
  • I rhodium

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Abstract

L'invention concerne un procédé de production d'un dérivé 4-carbamoyl-2,6-diméthylphénylalanine optiquement actif, qui est un composé utile en tant qu'intermédiaire d'un médicament, d'une manière simple et à un rendement élevé. De l'acide 4-carbamoyl-2,6-diméthylbenzoïque, un chlorure de carbamoyle et une base sont mis à réagir ensemble pour produire un mélange d'anhydride d'acide correspondant, puis le mélange d'anhydride d'acide est réduit pour produire de l'alcool 4-carbamoyl-2,6-diméthylbenzylique. L'utilisation de ce composé permet de produire un dérivé 4-carbamoyl-2,6-diméthylphénylalanine optiquement actif d'une manière simple et à un rendement élevé.
PCT/JP2016/076605 2015-09-11 2016-09-09 Procédé de production d'un dérivé 4-carbamoyl-2,6-diméthylphénylalanine optiquement actif Ceased WO2017043626A1 (fr)

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CN201680052341.0A CN108026032B (zh) 2015-09-11 2016-09-09 光学活性4-氨基甲酰基-2,6-二甲基苯基丙氨酸衍生物的制造方法

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN121378044A (zh) * 2025-12-25 2026-01-23 成都艾迪医药技术有限公司 一种3-氰甲基-5-甲基苯甲酰胺的制备方法

Families Citing this family (2)

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CN110092735B (zh) * 2018-01-31 2021-05-11 尚科生物医药（上海）有限公司 一种l-丙氨酸衍生物的制备方法
CN111377832A (zh) * 2018-12-27 2020-07-07 江苏联昇化学有限公司 一种伊卢多啉中间体制备的新方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007529527A (ja) * 2004-03-15 2007-10-25 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ オピオイド受容体調節薬としての新規な化合物
JP2008533141A (ja) * 2005-03-14 2008-08-21 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ オピオイド調節物質の製造方法
JP2012506909A (ja) * 2008-10-27 2012-03-22 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ 保護ｌ−アラニン誘導体の調製方法
JP2012250943A (ja) * 2011-06-03 2012-12-20 Kaneka Corp 光学活性２，６−ジメチルフェニルアラニン誘導体の製造法
WO2015076346A1 (fr) * 2013-11-21 2015-05-28 株式会社カネカ Procédé pour produire un dérivé optiquement actif de 2,6-diméthyltyrosine

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1842846A1 (fr) * 2006-04-07 2007-10-10 Santhera Pharmaceuticals (Schweiz) AG Dérivés de phénylpipéridine comme modulateurs du récepteur de la mélanocortine-4
JP2017512762A (ja) * 2014-03-03 2017-05-25 ステルス バイオセラピューティックス コープ 薬学的に妥当な芳香族カチオン性ペプチド及びその生成方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007529527A (ja) * 2004-03-15 2007-10-25 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ オピオイド受容体調節薬としての新規な化合物
JP2008533141A (ja) * 2005-03-14 2008-08-21 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ オピオイド調節物質の製造方法
JP2012506909A (ja) * 2008-10-27 2012-03-22 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ 保護ｌ−アラニン誘導体の調製方法
JP2012250943A (ja) * 2011-06-03 2012-12-20 Kaneka Corp 光学活性２，６−ジメチルフェニルアラニン誘導体の製造法
WO2015076346A1 (fr) * 2013-11-21 2015-05-28 株式会社カネカ Procédé pour produire un dérivé optiquement actif de 2,6-diméthyltyrosine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BENDER, AARON M. ET AL.: "Rapid Synthesis of Boc-2',6'-dimethyl-L-tyrosine and Derivatives and Incorporation into Opioid Peptidomimetics", ACS MED. CHEM. LETT., vol. 6, 19 October 2015 (2015-10-19), pages 1199 - 1203, XP055367676 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN121378044A (zh) * 2025-12-25 2026-01-23 成都艾迪医药技术有限公司 一种3-氰甲基-5-甲基苯甲酰胺的制备方法
CN121378044B (zh) * 2025-12-25 2026-04-17 成都艾迪医药技术有限公司 一种3-氰甲基-5-甲基苯甲酰胺的制备方法

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