WO2010058577A1 - Procédé de fabrication d'un dérivé d'acide aminocarboxylique insaturé - Google Patents

Procédé de fabrication d'un dérivé d'acide aminocarboxylique insaturé Download PDF

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WO2010058577A1
WO2010058577A1 PCT/JP2009/006219 JP2009006219W WO2010058577A1 WO 2010058577 A1 WO2010058577 A1 WO 2010058577A1 JP 2009006219 W JP2009006219 W JP 2009006219W WO 2010058577 A1 WO2010058577 A1 WO 2010058577A1
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unsaturated
general formula
formula
compound
acid derivative
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大黒一美
坂泰宏
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株式会社カネカ
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/26—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing carboxyl groups by reaction with HCN, or a salt thereof, and amines, or from aminonitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/30—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated 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
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/30—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same unsaturated acyclic carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/04—Alpha- or beta- amino acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures
    • C12P41/007—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures by reactions involving acyl derivatives of racemic amines

Definitions

  • the present invention relates to a method for producing an unsaturated aminocarboxylic acid derivative, particularly 2-amino-8-nonenoic acid.
  • 2-Amino-8-nonenoic acid is a raw material compound useful for the production of pharmaceuticals and the like.
  • An optically active unsaturated aminocarboxylic acid derivative is a compound useful for the production of pharmaceuticals, particularly HCV protease inhibitors (Non-patent Document 1).
  • an optically active 2-amino-8-nonenoic acid derivative can be obtained by enantiomerically and regioselectively reducing the compound of 1) above with a chiral rhodium catalyst (Patent Document 1).
  • an optically active 2-amino-8-nonenoic acid derivative can be obtained by reducing the 5-position oxo group of the compound 2) with tosylhydrazine (Patent Document 2).
  • an optically active 2-amino-8-nonenoic acid derivative can be obtained by enzymatic asymmetric hydrolysis (Patent Document 3).
  • an optically active 2-amino-8-nonenoic acid derivative can be obtained by using acylase (Non-patent Document 2).
  • N-Boc-pyroglutamic acid ethyl ester and 3-butenylmagnesium bromide which are optically active 5-oxo-2-amino-8-nonenoic acid ethyl ester, are available at low cost. It is preferable in that it can be easily synthesized. However, since it is necessary to use an explosive hydrazine compound for induction to the target optically active compound, it is not suitable for industrial use.
  • Patent Document 3 The method described in Patent Document 3 is preferable in that the unsaturated hydantoin of 3) can be easily synthesized from the corresponding unsaturated aldehyde in one step.
  • the hydantoin compound generally has high crystallinity and is hardly soluble in various organic solvents. For this reason, handling is difficult in the isolation and purification after the reaction, and it is not suitable as an industrial production method because the equipment load is large in the operation of filtering and isolating crystals.
  • Non-Patent Document 2 The method described in Non-Patent Document 2 is an excellent method in terms of obtaining an optically active substance.
  • the production of racemic 2-N-acetylamino-8-nonenoic acid as a raw material requires expensive 1-chloro-6-heptene and further requires a multi-step synthesis, which is a problem in the raw material production method. There is.
  • the present invention has the general formula (2):
  • n is the same as above; A represents OH or NH 2 ).
  • the unsaturated aminonitrile represented by the formula (3) produced as described above is represented by the general formula (4):
  • R 1 represents hydrogen, a substituted or unsubstituted alkyl group having 1 to 18 carbon atoms, a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, a substituted or unsubstituted carbon atom, Represents an aralkyl group of formula 7 to 20.
  • R 2 and R 3 are each independently hydrogen, a substituted or unsubstituted alkyl group having 1 to 18 carbon atoms, a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, a substituted or unsubstituted carbon number; And an aralkyl group of 7 to 20.
  • R 2 and R 3 may be combined to form a ring) to react with an acid anhydride, thereby giving a general formula (6):
  • the present invention relates to a method for producing N-acylaminocarboxylic acid derivatives.
  • an enzyme that stereoselectively hydrolyzes an N-acyl group is allowed to act on the unsaturated N-acylaminocarboxylic acid derivative represented by the formula (6) produced as described above.
  • the present invention relates to a process for producing an optically active unsaturated amino acid derivative.
  • the unsaturated aminonitrile represented by the above formula (2) is represented by the general formula (7): HB (7) (Wherein B represents an anion) an acid represented by the general formula (8):
  • n and B are the same as defined above, and a method for producing a salt of an unsaturated aminonitrile.
  • n an integer of 4 to 10
  • n an integer of 4 to 10
  • n an integer of 4 to 10
  • B represents an anion
  • an unsaturated aminocarboxylic acid derivative particularly a 2-amino-8-nonenoic acid derivative, which is a compound useful for the production of pharmaceuticals and the like, is produced in an industrially advantageous manner, that is, inexpensive and It can be manufactured in a short process. Furthermore, this unsaturated aminocarboxylic acid derivative can be easily led to an optically active unsaturated aminocarboxylic acid derivative through an unsaturated N-acylaminocarboxylic acid derivative. Thereby, the optically active unsaturated aminocarboxylic acid derivative can be produced inexpensively and easily, and is suitable for industrial production.
  • a process for producing an unsaturated aminonitrile derivative represented by the formula In the following, the compound represented by the general formula (1) may be represented as the compound (1) and the compound represented by the general formula (2) may be represented as the compound (2) (the same applies to other compounds). is there).
  • compound (2) is obtained by reacting compound (1) with a cyanide compound and an ammonia compound.
  • cyan compound either an inorganic cyan compound or an organic cyan compound can be suitably used.
  • Examples of the inorganic cyanide include lithium cyanide, sodium cyanide, potassium cyanide, cesium cyanide, magnesium cyanide, calcium cyanide, nickel cyanide, copper cyanide and zinc cyanide.
  • organic cyanide compounds include silyl cyanides such as trimethylsilyl cyanide and triethylsilyl cyanide, cyanohydrins such as acetone cyanohydrin, quaternary ammonium salts such as tetrabutylammonium cyanide and tetraethylammonium cyanide, and the like. it can.
  • cyanide can be used.
  • inorganic cyanide compounds are preferable, and specific examples include lithium cyanide, sodium cyanide, potassium cyanide, and copper cyanide. Of these, sodium cyanide and potassium cyanide are more preferable.
  • the amount of the cyan compound to be used is not particularly limited, but is usually 0.5 to 50 times molar equivalent, more preferably 0.8 to 25 times mol with respect to the amount of the compound (1) used. Equivalent, particularly preferably 1.0 to 10-fold molar equivalent.
  • the ammonia compound to be used is not particularly limited, and examples thereof include ammonia gas, an aqueous ammonia solution, an ammonia solution in which ammonia is dissolved in an organic solvent, ammonium chloride, ammonium sulfate, ammonium formate, ammonium oxalate, and ammonium acetate. Can be used. These can be used alone or in combination of a plurality of them. Of these, ammonium chloride, aqueous ammonia solution, and ammonia gas are preferred. In addition, when ammonia is used in a solution, its concentration is not particularly limited. When used in the form of ammonia gas, it may be directly blown into a solvent to be used and dissolved before use in the reaction, or ammonia gas may be blown directly into the reaction solution during the reaction.
  • the amount of the ammonia compound to be used is not particularly limited, but it is usually sufficient to use it at least 1 mol per mol of the amount of compound (1), and there is no particular upper limit, but preferably 1 to 100 times
  • the molar equivalent is more preferably in the range of 1 to 50 times molar equivalent.
  • the reaction is usually carried out in the presence of a solvent.
  • the solvent to be used is not particularly limited, and alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 2-methyl-2-propanol, n-butanol and 2-butanol; acetonitrile, propionitrile and the like Nitriles; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Ethers such as diethyl ether, tert-butyl methyl ether and tetrahydrofuran (THF); n-hexane, n-pentane, cyclohexane and methyl Examples include aliphatic hydrocarbons such as cyclohexane; aromatic hydrocarbons such as toluene, ethylbenzene, o-dichlorobenzene, and water.
  • water, alcohols, amides and ethers are preferable from the viewpoint of reactivity, and water, alcohols and amides are more preferable.
  • these solvents may be used alone, or two or more kinds of solvents may be mixed and used in an arbitrary ratio.
  • the reaction temperature is usually ⁇ 30 to 100 ° C., preferably ⁇ 20 to 60 ° C., more preferably ⁇ 10 to 50 ° C.
  • the reaction time is usually 30 minutes to 96 hours, preferably 1 to 72 hours, although it varies depending on the type and amount of cyanide and ammonia used.
  • the unsaturated aminonitrile derivative represented by the above formula (2) produced in this reaction can be obtained by extraction with an organic solvent such as ethyl acetate, ether, hexane, toluene. If necessary, it may be purified and isolated by operations such as chromatography, crystallization, distillation and the like. In addition, you may use for the following process, without refine
  • the unsaturated amino nitrile derivative obtained is a liquid, it is desirable from an industrial viewpoint in that not only can it be obtained as crystals by treatment with an acid to form a salt, but also purification by recrystallization can be performed. A description of the salt formation will be given later.
  • A represents OH or NH 2 .
  • n is the same as described above.
  • the compound (2) used in this step may be produced by the above step or may be produced by other methods.
  • This step is performed under acidic conditions or alkaline conditions.
  • Examples of the acid used include hydrochloric acid, sulfuric acid, nitric acid, acetic acid, trifluoroacetic acid, chloroacetic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, and the like.
  • the types of bases used include metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and cesium hydroxide; carbonates such as lithium carbonate, sodium carbonate and potassium carbonate, lithium acetate, Examples thereof include acetates such as sodium acetate and potassium acetate; bicarbonates such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate.
  • a side reaction caused by an unsaturated bond in compound (2) may occur (a side reaction involving an unsaturated bond occurs or a side reaction occurs in an unsaturated bond). It is preferably carried out under alkaline conditions.
  • the amount of the acid or base used is not particularly limited, but is usually 0.01 to 100 times molar equivalent, preferably 0.1 to 50 times molar equivalent, relative to the amount of compound (2) used.
  • the organic solvent to coexist is not particularly limited, but alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 2-methyl-2-propanol, n-butanol and 2-butanol; N, N— Amides such as dimethylformamide and N, N-dimethylacetamide; ethers such as diethyl ether, tert-butyl methyl ether and tetrahydrofuran (THF); ketones such as acetone and 2-butanone; n-hexane, n-pentane, Examples thereof include aliphatic hydrocarbons such as cyclohexane and methylcyclohexane; aromatic hydrocarbons such as toluene, ethylbenzene and o-dichlorobenzene.
  • alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 2-methyl-2-propanol, n-butanol and 2-butano
  • an organic solvent that is compatible with water is preferable, specifically, alcohols, amides, and ketones are preferable, and methanol, ethanol, isopropyl alcohol, and acetone are more preferable.
  • these organic solvents may be used independently, or 2 or more types of solvents may be mixed in arbitrary ratios.
  • the reaction temperature is usually ⁇ 5 to 150 ° C., preferably 0 to 120 ° C.
  • the reaction time is usually 30 minutes to 72 hours, preferably 1 to 48 hours.
  • the unsaturated aminocarboxylic acid derivative represented by the above formula (3) generated in this step can be obtained by extraction with an organic solvent such as ethyl acetate, ether, hexane, or toluene. If necessary, it can be purified and isolated by operations such as chromatography, crystallization and distillation. Moreover, you may use for the following process, without refine
  • an organic solvent such as ethyl acetate, ether, hexane, or toluene. If necessary, it can be purified and isolated by operations such as chromatography, crystallization and distillation. Moreover, you may use for the following process, without refine
  • R 1 represents hydrogen, an alkyl group, an aralkyl group, or an aryl group.
  • the alkyl group is a substituted or unsubstituted alkyl group having 1 to 18 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert group, -Butyl group, n-pentyl group, isopentyl group, n-hexyl group and the like can be mentioned.
  • the aryl group is a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, such as a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a 4-methylphenyl group, a 3-methylphenyl group, 2- Methylphenyl group, 4-ethylphenyl group, 3-ethylphenyl group, 4-methoxyphenyl group, 3-methoxyphenyl group, 2-methoxyphenyl group, 4-nitrophenyl group, 4-phenylphenyl group, 4-chlorophenyl group , 4-bromophenyl group and the like.
  • the aralkyl group is a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, such as benzyl group, 4-methylbenzyl group, 3-methylbenzyl group, 2-methylbenzyl group, 4-methoxybenzyl group, 3-methoxybenzyl group, 2-methoxybenzyl group, 1-phenylethyl group, 2-phenylethyl group, 1- (4-methylphenyl) ethyl group, 1- (4-methoxyphenyl) ethyl group, 3-phenylpropyl And 2-phenylpropyl group.
  • substituents examples include halogen such as fluorine, chlorine, bromine and iodine, nitro group, amino group, ester group, carboxyl group, oxo group and nitrile group.
  • X represents a halogen such as chlorine, bromine or iodine.
  • Compound (4) is preferably acetyl chloride, acetyl bromide, propionate chloride, or propionate bromide, and more preferably acetyl chloride from the viewpoint of economy and reactivity.
  • R 2 and R 3 are each independently a hydrogen, an alkyl group, an aralkyl group, or an aryl group.
  • alkyl group, aralkyl group, and aryl group include those exemplified for R 1 .
  • Compound (5) is preferably acetic anhydride or propionic anhydride, and more preferably acetic anhydride from the viewpoints of economy and reactivity.
  • R 2 and R 3 may form a ring together.
  • Specific examples when the ring is formed include succinic anhydride, glutaric anhydride, phthalic anhydride, maleic anhydride and the like.
  • R represents R 1 , R 2 , or R 3 , and R 1 , R 2 , R 3 are the same as described above.
  • A represents OH or NH 2 .
  • n is the same as described above.
  • the amount of compound (4) or compound (5) used is not particularly limited, but is preferably 0.5 to 30-fold molar equivalent, more preferably 1.0 to 20-fold molar equivalent based on compound (3). It is.
  • the base either an inorganic base or an organic base may be used.
  • Examples of the inorganic base include carbonates such as potassium carbonate, sodium carbonate, and lithium carbonate; acetates such as potassium acetate, sodium acetate, and lithium acetate; bicarbonates such as potassium bicarbonate, sodium bicarbonate, and lithium bicarbonate; sulfuric acid Sulfates such as potassium, sodium sulfate and lithium sulfate; Hydrogen sulfates such as potassium hydrogen sulfate, sodium hydrogen sulfate and lithium hydrogen sulfate; Alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide It is done.
  • carbonates such as potassium carbonate, sodium carbonate, and lithium carbonate
  • acetates such as potassium acetate, sodium acetate, and lithium acetate
  • bicarbonates such as potassium bicarbonate, sodium bicarbonate, and lithium bicarbonate
  • sulfuric acid Sulfates such as potassium, sodium sulfate and lithium sulfate
  • Hydrogen sulfates such as potassium
  • a tertiary amine is usually used as the organic base.
  • examples thereof include triethylamine, tributylamine, trihexylamine, triisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, tricyclohexylamine, and pyridine.
  • preferred bases are inorganic bases, and more preferred are metal hydroxides from the viewpoint of economy.
  • the compound (3) is produced by alkaline hydrolysis of the compound (2), since the reaction solution is already alkaline, the compound (4) or the compound (5) can be added to the reaction solution as it is.
  • the solvent used in the reaction is not particularly limited, but alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 2-methyl-2-propanol, n-butanol and 2-butanol; acetonitrile, Nitriles such as propionitrile; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Ethers such as diethyl ether, tert-butyl methyl ether and tetrahydrofuran (THF): n-hexane, n- Examples thereof include aliphatic hydrocarbons such as pentane, cyclohexane and methylcyclohexane; aromatic hydrocarbons such as toluene, ethylbenzene and o-dichlorobenzene, and water. Of these, water, amides and ethers are preferred.
  • these solvents may be used alone or two or more kinds of solvents may be mixed and used at an arbitrary ratio.
  • the reaction temperature is usually ⁇ 20 to 100 ° C., preferably ⁇ 10 to 60 ° C., more preferably ⁇ 10 to 50 ° C.
  • the reaction time is usually 30 minutes to 48 hours, preferably 1 to 30 hours.
  • the compound (6) produced in this step can be obtained by extraction with an organic solvent such as ethyl acetate, ether, hexane, toluene, etc., and if necessary, purified by simple operations such as chromatography, crystallization, distillation, etc. Can be separated.
  • organic solvent such as ethyl acetate, ether, hexane, toluene, etc.
  • optically active unsaturated aminocarboxylic acid derivative represented by:
  • the stereoselective hydrolysis (de-N-acylation) of the compound (6) can be performed using, for example, an enzyme.
  • the enzyme that stereoselectively hydrolyzes compound (6) is one of the enantiomers of an unsaturated N-acylaminocarboxylic acid derivative, that is, either L-form or D-form specifically hydrolyzed (deacylated).
  • an enzyme having an action of producing an L-unsaturated aminocarboxylic acid derivative or a D-unsaturated aminocarboxylic acid derivative and examples thereof include acylase.
  • Many of these enzymes are commercially available and can be easily obtained. Examples of such enzymes include an acylase derived from Streptomyces ⁇ toyocaensis, an acylase I derived from Aspergillus Imelleus, and an acylase I derived from pig liver.
  • the solvent used in the reaction is not particularly limited, and examples thereof include aprotic polar solvents such as N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone, hexamethylphosphoric triamide; Hydrocarbon solvents such as hexamethylbenzene, toluene, n-hexane, cyclohexane; ether solvents such as diethyl ether, tetrahydrofuran (THF), diisopropyl ether, methyl tert-butyl ether, dimethoxyethane; methylene chloride, chloroform, 1,1 Halogen solvents such as 1,1-trichloroethane; ester solvents such as ethyl acetate and butyl acetate; nitrile solvents such as acetonitrile and butyronitrile; methanol, ethanol, isopropanol, butanol, oct
  • the reaction is carried out at a temperature of 10 to 70 ° C, preferably 30 to 55 ° C.
  • the pH of the reaction solution is maintained at 4 to 10, preferably 6 to 9.
  • the optically active unsaturated aminocarboxylic acid derivative produced in this step can be obtained by extraction with an organic solvent such as ethyl acetate, ether, hexane, toluene, etc., and if necessary, chromatography, crystallization, distillation, etc.
  • the product can be purified and isolated by the above procedure.
  • B represents a counter anion of proton
  • specific BH includes mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid; chloroacetic acid, trichloroacetic acid, trifluoroacetic acid, mandel Examples thereof include carboxylic acids such as acid, malic acid and tartaric acid; and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.
  • the amount of compound (7) to be used is not particularly limited as long as it is an equimolar amount or more with respect to compound (2), but it is preferably 1.0 to 3.0 molar equivalents, preferably 1.0 to 2. 0 molar equivalent.
  • the reaction temperature is usually in the range of ⁇ 50 to 80 ° C., preferably ⁇ 30 to 50 ° C.
  • the solvent used in this step is not particularly limited, and examples thereof include aprotic polar solvents such as N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone, hexamethylphosphoric triamide; hexamethyl Hydrocarbon solvents such as benzene, toluene, n-hexane, cyclohexane; ether solvents such as diethyl ether, tetrahydrofuran (THF), diisopropyl ether, methyl tert-butyl ether, dimethoxyethane; methylene chloride, chloroform, 1,1,1 -Halogen solvents such as trichloroethane; ester solvents such as ethyl acetate and butyl acetate; nitrile solvents such as acetonitrile and butyronitrile; methanol, ethanol, isopropanol, butanol,
  • Compound (8) is usually easily obtained by precipitating from a solvent as a crystalline salt and filtering it. Moreover, it is possible to improve the purity of a compound by refine
  • the compound (8) thus obtained can be converted to the compound (2) by salting and further subjected to the step of obtaining the above compound (3) and the like.
  • Example 1 100 ml of 2-amino-8-nonenenitrile methanol was cooled to 0 ° C., and ammonia gas was blown therein to prepare a saturated ammonia solution. While maintaining 0 ° C., 4.6 g of sodium cyanide, 10.6 g of ammonium chloride, and 10 g of 7-octenal were sequentially added. The reaction mixture was naturally warmed to room temperature and stirred at room temperature for a further 48 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to distill off methanol, and 500 ml of diethyl ether and 300 ml of water were added to extract the product.
  • Example 2 2-Amino-8-nonenenitrile trifluoroacetate To an ethyl acetate solution (50 ml) of 5.0 g of the crude 2-amino-8-nonenenitrile obtained in Example 1 was added triethyl at room temperature under a nitrogen atmosphere. 3.7 g of fluoroacetic acid was added. Next, 200 ml of hexane was added dropwise, and the mixture was stirred at room temperature for 30 minutes and then at 0 ° C. for 1 hour.
  • Example 3 2-Amino-8-nonenenitrile / toluenesulfonate To 0.15 g of the crude 2-amino-8-nonenenitrile nitrile obtained in Example 1 in acetonitrile (1 ml) was added p-toluene under a nitrogen atmosphere. A toluene solution (1 ml) of sulfonic acid monohydrate 0.19 g was added at room temperature. After stirring at room temperature for 30 minutes, 3 ml of acetonitrile was added, and after further stirring for 30 minutes, the precipitated crystals were filtered to obtain 0.18 g of the title compound (yield: 56%).
  • Example 4 2-Amino-8-nonenenitrile methanesulfonate Toluene sulfone sulfone was added to 0.15 g of the crude 2-amino-8-nonenenitrile nitrile obtained in Example 1 in acetonitrile (1 ml) under a nitrogen atmosphere. Toluene solution (1 ml) of acid monohydrate 0.19 g was added at room temperature. After stirring at room temperature for 30 minutes, 3 ml of acetonitrile was added, and after further stirring for 30 minutes, the precipitated crystals were collected by filtration to obtain 0.22 g of the title compound (yield: 86%).
  • Example 5 2 -Amino-8-nonenoic acid A mixture comprising 10.3 g of the crude 2-amino-8-nonenenitrile obtained in Example 1 and 16.8 ml of a 10N aqueous sodium hydroxide solution and 51 ml of ethanol at 80 ° C. The reaction was performed for 68 hours. When the reaction was completed, concentrated hydrochloric acid was added to adjust the pH to 9, and a white solid was precipitated. 25 ml of water was added thereto, and the pH was adjusted to 6 with concentrated hydrochloric acid, followed by stirring for 1 hour. The precipitated white solid was filtered to obtain 9.1 g of the title compound (yield: 79%).
  • Example 6 2 -Amino-8-nonenoamide A solution composed of 0.53 g of 2-amino-8-nonenenitrile trifluoroacetate obtained in Example 2, 10 ml of water and 0.5 ml of acetone was added to 0 After cooling to 0 ° C., 0.5 ml of a 20 wt% aqueous sodium hydroxide solution was added and stirred at 0 ° C. for 5 hours to obtain a solution of the title compound.
  • the compound was identified by inducing the title compound into N-Boc form. That is, 0.66 g of Boc 2 O was added to the reaction solution, and the mixture was stirred at room temperature for 15 hours. To this, 15 ml of ethyl acetate and 10 ml of water were added to extract the reaction product. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain 0.78 g of a crude N-Boc product of the title compound. This was quantitatively analyzed by HPLC and contained 0.37 g of the title compound (yield: 71%).
  • Example 7 2- (4-Carboxybutanoylamino) -8-nonenoic acid A mixture comprising 2.0 g of 2-amino-8-nonenoic acid obtained in Example 5 and 3 ml of 30 wt% aqueous sodium hydroxide solution To the solution, 1.8 g of succinic anhydride was added and reacted at room temperature for 5 hours. Further, 1.8 g of succinic anhydride was added and reacted for 18 hours. The pH was adjusted to 2 with concentrated hydrochloric acid, and the precipitated white crystals were filtered off. 300 ml of ethyl acetate was added to the mother liquor, and the product was extracted with ethyl acetate.

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Abstract

L'invention porte sur un procédé de fabrication d'un dérivé d'acide aminocarboxylique insaturé, qui est utile en tant que matière première de produit pharmaceutique, à faible coût. De façon spécifique, un dérivé d'acide aminocarboxylique insaturé est produit par hydrolyse d'un dérivé d'aminonitrile insaturé. Le dérivé d'aminonitrile insaturé peut être obtenu, par exemple, par réaction d'un aldéhyde insaturé avec un composé cyanogène et un composé de l'ammoniac. De plus, un dérivé d'acide aminocarboxylique insaturé optiquement actif peut être facilement obtenu à partir du dérivé d'acide aminocarboxylique insaturé, par l'intermédiaire d'un dérivé d'acide N-acylaminocarboxylique insaturé. En conséquence, un dérivé d'acide aminocarboxylique insaturé optiquement actif peut être facilement produit à faible coût.
PCT/JP2009/006219 2008-11-20 2009-11-19 Procédé de fabrication d'un dérivé d'acide aminocarboxylique insaturé WO2010058577A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62103056A (ja) * 1985-07-01 1987-05-13 Mitsui Toatsu Chem Inc アシルアミノブテニルニトリル誘導体、その製造法およびそれらを含有する除草剤および農園芸用殺菌剤
US5534542A (en) * 1994-01-24 1996-07-09 Northwestern University Methods and materials relating to a bi-metallic cross-linking species
JP2007510002A (ja) * 2003-11-05 2007-04-19 ノバルティス アクチエンゲゼルシャフト 大環状ラクタムおよびその医薬的使用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62103056A (ja) * 1985-07-01 1987-05-13 Mitsui Toatsu Chem Inc アシルアミノブテニルニトリル誘導体、その製造法およびそれらを含有する除草剤および農園芸用殺菌剤
US5534542A (en) * 1994-01-24 1996-07-09 Northwestern University Methods and materials relating to a bi-metallic cross-linking species
JP2007510002A (ja) * 2003-11-05 2007-04-19 ノバルティス アクチエンゲゼルシャフト 大環状ラクタムおよびその医薬的使用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LARISSA B. WOLF ET AL.: "A Biocatalytic Route to Enantiomerically Pure Unsaturated alpha-H-alpha-Amino Acids", ADV. SYNTH. CATAL., vol. 343, no. 6-7, 2001, pages 662 - 674 *
XIAO-JUN WANG ET AL.: "Efficient Synthesis of (S)-2-(Cyclopentyloxycarbonyl)-amino-8-nonenoic Acid: Key Building Block for BILN 2061, an HCV NS3 Protease Inhibitor", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 11, 2007, pages 60 - 63 *

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