CN113816872A - Synthesis method of (S) -2-aminobutanamide - Google Patents

Synthesis method of (S) -2-aminobutanamide Download PDF

Info

Publication number
CN113816872A
CN113816872A CN202010565694.9A CN202010565694A CN113816872A CN 113816872 A CN113816872 A CN 113816872A CN 202010565694 A CN202010565694 A CN 202010565694A CN 113816872 A CN113816872 A CN 113816872A
Authority
CN
China
Prior art keywords
reaction
aminobutyrate
iii
methyl
aminobutanamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202010565694.9A
Other languages
Chinese (zh)
Inventor
郑晨光
李敏勇
龚玉龙
朱元勋
颜峰峰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhejiang Huahai Pharmaceutical Co Ltd
Zhejiang Huahai Tiancheng Pharmaceutical Co Ltd
Zhejiang Huahai Zhicheng Pharmaceutical Co Ltd
Original Assignee
Zhejiang Huahai Pharmaceutical Co Ltd
Zhejiang Huahai Tiancheng Pharmaceutical Co Ltd
Zhejiang Huahai Zhicheng Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zhejiang Huahai Pharmaceutical Co Ltd, Zhejiang Huahai Tiancheng Pharmaceutical Co Ltd, Zhejiang Huahai Zhicheng Pharmaceutical Co Ltd filed Critical Zhejiang Huahai Pharmaceutical Co Ltd
Priority to CN202010565694.9A priority Critical patent/CN113816872A/en
Priority to PCT/CN2021/099297 priority patent/WO2021254235A1/en
Priority to CN202180041077.1A priority patent/CN115943137A/en
Publication of CN113816872A publication Critical patent/CN113816872A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/34—Preparation of optical isomers by separation of optical isomers
    • 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
    • C07C237/04—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 saturated
    • C07C237/06—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 saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • 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
    • 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
    • C12P13/001—Amines; Imines
    • 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
    • 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
    • C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
    • C12P41/005—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of carboxylic acid groups in the enantiomers or the inverse reaction
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Zoology (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Analytical Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

The invention provides a method for preparing (S) -2-aminobutyrate by an enzyme method, which comprises the steps of taking (R/S) -2-aminobutyrate as a raw material, splitting under the action of ester hydrolase to obtain (S) -2-aminobutyrate, and further aminolyzing to obtain (S) -2-aminobutyramide. The method provided by the invention is simple to operate, the amount of three wastes is small, and simultaneously, the purity of the (S) -2-aminobutanamide obtained by the reaction is high, thereby completely meeting the requirements of industrial production.

Description

Synthesis method of (S) -2-aminobutanamide
(I) technical field
The invention relates to a synthetic method of an antiepileptic drug levetiracetam intermediate, belonging to the technical field of drug synthesis.
(II) background of the invention
Levetiracetam is a broad-spectrum antiepileptic drug developed by UCB company of Belgium with high efficiency and small toxic and side effects, is mainly used for treating local and secondary generalized epilepsy and has the chemical name of (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetamide.
At present, the preparation method of levetiracetam at home and abroad has many reports, and the levetiracetam is mainly synthesized by a chemical resolution method. Two types of synthesis methods are commonly used in industry:
(1) racemic (R/S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid which is developed by UCB company of Belgium is taken as a raw material, and (R) -alpha-methylbenzylamine is taken as a resolving agent, is resolved in benzene and is treated by alkali to obtain the (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid. (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid reacts with ethyl chloroformate, and levetiracetam is obtained by aminolysis, wherein the synthetic route is as follows:
Figure BDA0002547749080000011
(2) taking 2-aminobutanamide as a raw material, and obtaining (S) -2-aminobutanamide hydrochloride by L-tartaric acid resolution, ammonia dissociation and hydrogen chloride salification. (S) -2-aminobutanamide hydrochloride reacts with 4-chlorobutyryl chloride, and levetiracetam is obtained through cyclization, wherein the synthetic route is as follows:
Figure BDA0002547749080000021
the synthesis routes adopt the traditional chemical resolution method to construct the chiral center, and have long process routes and low atom utilization rate. Meanwhile, solvents and reagents used in the chemical resolution method are harmful to the environment, the amount of three wastes is large, and the industrial application is restricted to a certain extent.
Disclosure of the invention
The invention aims to provide a novel method for synthesizing a levetiracetam intermediate (S) -2-aminobutanamide (IV) by a biological enzyme method, which has simple process and small environmental pollution. The (S) -2-aminobutanamide (IV) can be further prepared into levetiracetam by referring to the prior art.
The present invention provides a method for preparing (S) -2-aminobutanamide (IV), comprising the steps of:
(1) and (3) carrying out enzymolysis reaction: taking (R/S) -2-aminobutyrate (II) as a raw material, and obtaining (S) -2-aminobutyrate (III) through resolution under the action of ester hydrolase;
Figure BDA0002547749080000022
r in the formulae II and III is C1～C6An alkyl group, more preferably a methyl group or an ethyl group;
(2) ammonolysis reaction: adding an ammoniation reagent into the (S) -2-aminobutyrate (III) obtained in the step (1) to carry out ammonolysis reaction to obtain (S) -2-aminobutyramide (IV),
Figure BDA0002547749080000023
in the above method for synthesizing (S) -2-aminobutanamide, the ester hydrolase in step (1) is a methyl-enveloped bacterium treated by a cell immobilization method, the methyl-enveloped bacterium is classified and named as cxzy-L013 strain of methyl-enveloped bacterium (methylpila sp), and the strain is stored in the chinese type culture collection at 2016, 9, 18 th, with the collection number of CCTCC NO: m2016494. The preparation method of the immobilized microbial inoculum can be referred to Chinese patent publication CN 106591179A. The ester hydrolase can specifically hydrolyze (R) -2-aminobutyrate in racemic (R/S) -2-aminobutyrate (II) into corresponding acid, dissolve in water phase by salification, and extract (S) -2-aminobutyrate (III) by organic solvent.
The immobilized microbial inoculum in the step (1) is calculated by wet weight, and the feeding amount in the reaction is 1-50% (mass ratio), preferably 2-20% (mass ratio) of the raw material (R/S) -2-aminobutyrate (II).
In the above method for synthesizing (S) -2-aminobutanamide, the enzymatic hydrolysis reaction in step (1) is performed in a solvent, and the solvent is water. And water is adopted as a solvent, so that an organic solvent is avoided, and the requirement of green chemistry is met.
The mass percentage concentration of the enzymolysis reaction substrate (R/S) -2-aminobutyrate (II) in the step (1) is 20-70%, and preferably 30-50%.
In the method for synthesizing (S) -2-aminobutanamide, the enzymolysis reaction temperature in the step (1) is 10-50 ℃, and the pH value is 6.0-9.0. Preferably, the enzymolysis reaction temperature is 25-40 ℃, and the pH is 6.5-8.0. Stopping the reaction until the isomer (R) -2-aminobutyrate is less than 1%, wherein the reaction time is 6-48 hours.
In the above-mentioned method for synthesizing (S) -2-aminobutanamide, the pH of the enzymatic reaction in step (1) is controlled by adding an aqueous solution of a base selected from an alkali metal carbonate, an alkali metal bicarbonate or an alkali metal hydroxide. Preferably, the alkali metal carbonate is selected from sodium carbonate and potassium carbonate, the alkali metal bicarbonate is selected from sodium bicarbonate and potassium bicarbonate, and the alkali metal hydroxide is selected from sodium hydroxide and potassium hydroxide. (R) -2-aminobutyric acid obtained by ester hydrolase hydrolysis reacts with alkali to generate (R) -2-aminobutyric acid salt dissolved in water. Further preferably, an aqueous solution of sodium carbonate, sodium bicarbonate or sodium hydroxide is selected to control the pH of the enzymatic reaction.
In the above method for synthesizing (S) -2-aminobutanamide, the step (1) further comprises the following post-treatments: filtering, recovering immobilized bacteria, adding organic solvent into the filtrate, extracting, layering, collecting organic phase, drying with desiccant, filtering, and distilling the filtrate to obtain (S) -2-aminobutyrate (III). The recovered immobilized microbial inoculum can be recycled. The organic solvent used in the post-treatment of step (1) is not particularly limited as long as it is immiscible with water and is capable of dissolving the (S) -2-aminobutyrate (iii), and is preferably selected from toluene, dichloromethane or ethyl acetate. The drying agent used in the post-treatment of step (1) is preferably anhydrous magnesium sulfate or anhydrous sodium sulfate. The distillation in the post-treatment of the step (1) is preferably reduced pressure distillation, the temperature of the reduced pressure distillation is 20-100 ℃, the preferred temperature is 40-70 ℃, and the pressure of the reduced pressure distillation is-0.05-0.1 MPa. In the context of the present application, a pressure value is a pressure value relative to a standard atmospheric pressure, i.e. a difference between an absolute pressure and a standard atmospheric pressure.
In the above method for synthesizing (S) -2-aminobutanamide, the ammoniating agent used in step (2) is ammonia gas, ammonia water, ammonium formate or ammonium acetate. Preferably, the ammoniation reagent is selected from ammonia gas and ammonia water, and the inorganic ammonia raw materials are easy to obtain, low in cost and small in environmental pollution. Further preferably, the ammoniating agent is ammonia gas.
In the above-mentioned method for synthesizing (S) -2-aminobutanamide, the aminolysis reaction described in the step (2) is carried out in a protic solvent. Preferably the protic solvent used in step (2) is C1～C6Alcohol or water. C1～C6The alcohol is selected from methanol, ethanol, n-propanol, isopropanol, and butanol, pentanol and hexanol.
In the method for synthesizing (S) -2-aminobutanamide, when the ammoniating reagent in the step (2) is ammonia gas, the temperature of the ammonolysis reaction is 0-50 ℃. Preferably, the temperature of the ammonolysis reaction is 20-35 ℃. The ammonolysis reaction is detected by TLC until no raw material is left, the reaction is complete, and the ammonolysis reaction time is 12-18 hours.
In the method for synthesizing (S) -2-aminobutanamide, when the ammoniating reagent in the step (2) is ammonia gas, the pressure of the ammonolysis reaction is 0.1-0.9 MPa. Preferably, the pressure of the ammonolysis reaction is 0.3-0.6 MPa.
In a second aspect of the present invention, there is provided a process for preparing an (S) -2-aminobutyrate ester, comprising the steps of: taking (R/S) -2-aminobutyrate (II) as a raw material, and obtaining (S) -2-aminobutyrate (III) through resolution under the action of ester hydrolase;
Figure BDA0002547749080000041
r in the formulae II and III is C1～C6The alkyl group is more preferably a methyl group or an ethyl group.
Compared with the prior art, the invention has the following advantages:
the invention adopts a brand new biological enzyme method to synthesize (S) -2-aminobutanamide, has easily obtained raw materials, simple operation and small amount of three wastes, and simultaneously, the (S) -2-aminobutanamide obtained by the reaction has high HPLC purity and optical purity and completely meets the requirement of industrial production.
(IV) detailed description of the preferred embodiments
The following examples are given to further illustrate the embodiments of the present invention. The following examples are intended to illustrate the invention only, but not to limit the scope of the invention.
Example 1
And (3) carrying out enzymolysis reaction: the reaction flask was charged with (R/S) -methyl 2-aminobutyrate (117g, 1mol) and H2O (180g), heating to 30 ℃ under stirring, adding immobilized bacteria (i.e. immobilized methyl ascomycete, preservation number CCTCC NO: M2016494) (10g), controlling temperature within 25-35 ℃, and dropwise adding 20% Na2CO3Solution, keeping the pH of a reaction system at 6.5-8.0, stopping the reaction until the isomer (R) -2-aminobutyric acid methyl ester is less than 1%, filtering, recovering the immobilized bacteria agent, adding an extracting agent toluene (200g) into the filtrate, stirring for 30 minutes, standing for 30 minutes, layering, collecting an organic phase, repeating the extraction operation for 3 times, combining the organic phases, adding anhydrous magnesium sulfate (20g) into the organic phase, stirring and drying for 30 minutes, filtering, collecting the filtrate, carrying out reduced pressure distillation on the filtrate, controlling the reduced pressure distillation temperature to be 50-60 ℃, and carrying out reduced pressure distillation until no liquid flows out to obtain (S) -2-aminobutyric acid methyl ester, wherein the yield is 50.3g, the yield is 43%, the HPLC purity is 99.3%, and the isomer: 0.32 percent.
Ammonolysis reaction: adding (S) -methyl 2-aminobutyric acid (40g, 0.34mol) and methanol (120g) into a high-pressure reaction kettle, cooling to-10 ℃ under stirring, and charging NH3And (2) when the reaction product is saturated, closing a valve, heating to 25 ℃, controlling the temperature to be 20-30 ℃, keeping the pressure of a reaction kettle at 0.3-0.5 MPa for reaction, tracking by TLC (thin layer chromatography) until the reaction is complete, collecting filtrate after the ammonolysis reaction is finished, evaporating the solvent under reduced pressure to obtain a solid, and drying to obtain (S) -2-aminobutanamide, wherein the yield is 33.5g, the yield is 96.0%, the HPLC purity is 99.2%, and the isomer: 0.52 percent.
Example 2
And (3) carrying out enzymolysis reaction: the reaction flask was charged with (R/S) -methyl 2-aminobutyrate (117g, 1mol) and H2O (120g), heating to 30 ℃ under stirring, adding an immobilized microbial agent (namely immobilized methyl ascomycete, with the preservation number of CCTCC NO: M2016494) (6g), controlling the temperature within the range of 25-35 ℃, and dropwise adding 20% K2CO3The pH of a reaction system is kept at 6.5-7.5, the reaction is stopped until the isomer (R) -2-aminobutyric acid methyl ester is less than 1%, the reaction is stopped, the solution is filtered, the immobilized microbial agent is recovered, an extractant toluene (150g) is added into the filtrate, the mixture is stirred for 30 minutes, the mixture is kept stand for 30 minutes, layering is carried out, an organic phase is collected, the extraction operation is repeated for 3 times, the organic phase is combined, anhydrous sodium sulfate (20g) is added into the organic phase, the mixture is stirred and dried for 30 minutes, the filtrate is collected, the filtrate is subjected to reduced pressure distillation, the reduced pressure distillation temperature is controlled to be 50-60 ℃, the reduced pressure distillation is carried out until no liquid flows out, the (S) -2-aminobutyric acid methyl ester is obtained, the yield is 52.3g, the yield is 44.7%, the HPLC purity is 99.4%, and the isomer: 0.12 percent.
Ammonolysis reaction: adding (S) -methyl 2-aminobutyric acid (40g, 0.34mol) and methanol (160g) into a high-pressure reaction kettle, cooling to-20 ℃ under stirring, and charging NH3And (2) when the reaction product is saturated, closing a valve, heating to 25 ℃, controlling the temperature to be 25-35 ℃, keeping the temperature of the reaction kettle at the pressure of 0.4-0.6 MPa for reaction, tracking by TLC (thin layer chromatography) until the reaction is complete, collecting filtrate after the ammonolysis reaction is finished, evaporating the solvent under reduced pressure to obtain a solid, and drying to obtain (S) -2-aminobutanamide, wherein the yield is 33.8g, the yield is 96.8%, the HPLC purity is 99.3%, and the isomer: 0.33 percent.
Example 3
And (3) carrying out enzymolysis reaction: the reaction flask was charged with (R/S) -methyl 2-aminobutyrate (117g, 1mol) and H2O (150g), heating to 30 deg.C under stirring, adding immobilized bacteria agent (i.e. immobilized Methylocystis sp. with preservation number of CCTCC NO: M2016494) (12g), controlling temperature within 25-35 deg.C, and dropwise adding 10% Na2CO3Keeping the pH value of a reaction system at 7.0-8.0, stopping the reaction until the isomer (R) -2-aminobutyric acid methyl ester is less than 1%, filtering, recovering the immobilized microbial agent, adding an extractant toluene (200g) into the filtrate, stirring for 30 minutes, standing for 30 minutes, layering, collecting an organic phase, and extractingRepeating the operation for 3 times, combining organic phases, adding anhydrous sodium sulfate (20g) into the organic phases, stirring and drying for 30 minutes, filtering, collecting filtrate, carrying out reduced pressure distillation on the filtrate, controlling the reduced pressure distillation temperature to be 50-60 ℃, and carrying out reduced pressure distillation until no liquid flows out to obtain (S) -methyl 2-aminobutyric acid, wherein the yield is 48.8g, the yield is 41.7%, the HPLC purity is 99.6%, and the isomer: 0.19 percent.
Ammonolysis reaction: adding (S) -methyl 2-aminobutyric acid (40g, 0.34mol) and ethanol (120g) into a high-pressure reaction kettle, cooling to-20 ℃ under stirring, and filling NH3And (2) when the reaction product is saturated, closing a valve, heating to 25 ℃, controlling the temperature to be 25-35 ℃, keeping the temperature of the reaction kettle at the pressure of 0.3-0.5 MPa for reaction, tracking by TLC (thin layer chromatography) until the reaction is complete, collecting filtrate after the ammonolysis reaction is finished, evaporating the solvent under reduced pressure to obtain a solid, and drying to obtain (S) -2-aminobutanamide, wherein the yield is 33.4g, the yield is 95.8%, the HPLC purity is 99.5%, and the isomer: 0.43 percent.
Example 4
And (3) carrying out enzymolysis reaction: the reaction flask was charged with (R/S) -ethyl 2-aminobutyrate (131g, 1mol) and H2O (200g), heating to 30 ℃ under stirring, adding an immobilized bacteria agent (namely immobilized methyl ascomycete, with the preservation number of CCTCC NO: M2016494) (10g), controlling the temperature within the range of 25-35 ℃, dropwise adding 10% NaOH solution, keeping the pH of a reaction system at 7.0-8.0, stopping the reaction until the content of isomer (R) -2-amino ethyl butyrate is less than 1%, filtering, recovering the immobilized bacteria agent, adding an extracting agent ethyl acetate (200g) into the filtrate, stirring for 30 minutes, standing for 30 minutes, layering, collecting an organic phase, repeating the extraction operation for 3 times, combining the organic phases, adding anhydrous sodium sulfate (20g) into the organic phase, stirring and drying for 30 minutes, filtering, collecting the filtrate, carrying out reduced pressure distillation on the filtrate, controlling the distillation temperature to be 50-60 ℃, carrying out reduced pressure distillation until NO liquid flows out to obtain (S) -2-amino ethyl butyrate, yield 56.7g, yield 43.3%, HPLC purity 99.6%, isomer: 0.27 percent.
Ammonolysis reaction: adding (S) -ethyl 2-aminobutyric acid (50g, 0.38mol) and methanol (150g) into a high-pressure reaction kettle, cooling to-20 ℃ under stirring, and charging NH3When the temperature is saturated, the valve is closed, the temperature is raised to 25 ℃, and the temperature is controlled to be withinPerforming heat preservation reaction at the temperature of 20-30 ℃ and the pressure of a reaction kettle within the range of 0.5-0.6 MPa, tracking by TLC until the reaction is complete, collecting filtrate after the ammonolysis reaction is finished, evaporating the solvent under reduced pressure to obtain a solid, and drying to obtain (S) -2-aminobutanamide, wherein the yield is 37.2g, the yield is 96.1%, the HPLC purity is 99.6%, and the isomer: 0.56 percent.
Example 5
And (3) carrying out enzymolysis reaction: the reaction flask was charged with (R/S) -methyl 2-aminobutyrate (117g, 1mol) and H2O (150g), heating to 30 deg.C under stirring, adding immobilized bacteria agent (i.e. immobilized Methylocystis sp. with preservation number of CCTCC NO: M2016494) (12g), controlling temperature within 25-35 deg.C, and dropwise adding 10% Na2CO3The pH of a reaction system is kept to be 7.0-8.0, the reaction is stopped when the isomer (R) -2-aminobutyric acid methyl ester is less than 1%, the reaction is stopped, the solution is filtered, the immobilized microbial agent is recovered, an extractant dichloromethane (200g) is added into the filtrate, the mixture is stirred for 30 minutes, the mixture is kept stand for 30 minutes, layering is carried out, an organic phase is collected, the extraction operation is repeated for 3 times, the organic phases are combined, anhydrous magnesium sulfate (20g) is added into the organic phase, stirring and drying are carried out for 30 minutes, filtering is carried out, the filtrate is collected, the filtrate is subjected to reduced pressure distillation, the reduced pressure distillation temperature is controlled to be 50-60 ℃, reduced pressure distillation is carried out until no liquid flows out, the (S) -2-aminobutyric acid methyl ester is obtained, the yield is 50.1g, the yield is 42.8%, the HPLC purity is 99.6%, and the isomer: 0.29 percent.
Ammonolysis reaction: adding (S) -methyl 2-aminobutyric acid (50g, 0.43mol) and methanol (200g) into a high-pressure reaction kettle, cooling to-15 ℃ under stirring, and charging NH3And (2) when the reaction product is saturated, closing a valve, heating to 25 ℃, controlling the temperature to be 25-35 ℃, keeping the temperature of the reaction kettle at the pressure of 0.4-0.6 MPa for reaction, tracking by TLC (thin layer chromatography) until the reaction is complete, collecting filtrate after the ammonolysis reaction is finished, evaporating the solvent under reduced pressure to obtain a solid, and drying to obtain (S) -2-aminobutanamide, wherein the yield is 41.4g, the yield is 95.1%, the HPLC purity is 99.5%, and the isomer: 0.57 percent.

Claims (10)

1. A method for synthesizing (S) -2-aminobutanamide comprises the following steps:
(1) and (3) carrying out enzymolysis reaction: taking (R/S) -2-aminobutyrate (II) as a raw material, and obtaining (S) -2-aminobutyrate (III) through resolution under the action of ester hydrolase;
Figure FDA0002547749070000011
r in the formulae II and III is C1～C6An alkyl group, more preferably a methyl group or an ethyl group;
(2) ammonolysis reaction: adding an ammoniation reagent into the (S) -2-aminobutyrate (III) obtained in the step (1) to carry out ammonolysis reaction to obtain (S) -2-aminobutyramide (IV),
Figure FDA0002547749070000012
2. a method for synthesizing (S) -2-aminobutyrate (III) comprises the following steps:
taking (R/S) -2-aminobutyrate (II) as a raw material, and obtaining (S) -2-aminobutyrate (III) through resolution under the action of ester hydrolase;
Figure FDA0002547749070000013
r in the formulae II and III is C1～C6The alkyl group is more preferably a methyl group or an ethyl group.
3. The method according to claim 1 or 2, wherein the ester hydrolase in step (1) is a methyl-enveloped bacterium treated by a cell immobilization method, wherein the methyl-enveloped bacterium is classified and named as cxzy-L013 strain of methyl-enveloped bacterium (methylpila sp), is stored in the chinese type culture collection on 18/9/2016 under the collection number of CCTCC NO: m2016494.
4. The method according to claim 1 or 2, wherein the immobilized microbial inoculum in step (1) is fed in the reaction in an amount of 1-50%, preferably 2-20% of the mass of the raw material (R/S) -2-aminobutyrate (II) on a wet weight basis.
5. The method according to claim 1 or 2, wherein the solvent for enzymatic hydrolysis in step (1) is water.
6. The method according to claim 1 or 2, wherein the concentration of the substrate (R/S) -2-aminobutyrate (II) in the enzymatic reaction in step (1) is 20-70% by weight, preferably 30-50% by weight.
7. The method according to claim 1 or 2, wherein the temperature of the enzymolysis reaction in the step (1) is 10-50 ℃ and the pH is 6.0-9.0, preferably, the temperature of the enzymolysis reaction is 25-40 ℃ and the pH is 6.5-8.0.
8. The process according to claim 1 or 2, characterized in that the pH of the enzymatic hydrolysis reaction in step (1) is controlled by adding an aqueous solution of a base selected from alkali metal carbonates, alkali metal bicarbonates or alkali metal hydroxides, preferably selected from sodium carbonate, sodium bicarbonate or sodium hydroxide.
9. The method according to claim 1, wherein the ammoniating agent in step (2) is ammonia gas, ammonia water, ammonium formate or ammonium acetate.
10. The process according to claim 1, wherein the ammonolysis reaction in step (2) is carried out in a protic solvent, preferably the protic solvent used in step (2) is C1～C6Alcohols, or water, more preferably methanol, ethanol, n-propanol, isopropanol, and butanol, pentanol, and hexanol.
CN202010565694.9A 2020-06-19 2020-06-19 Synthesis method of (S) -2-aminobutanamide Pending CN113816872A (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN202010565694.9A CN113816872A (en) 2020-06-19 2020-06-19 Synthesis method of (S) -2-aminobutanamide
PCT/CN2021/099297 WO2021254235A1 (en) 2020-06-19 2021-06-10 Synthetic method of (s)-2-aminobutanamide
CN202180041077.1A CN115943137A (en) 2020-06-19 2021-06-10 Synthesis method of (S) -2-aminobutanamide

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010565694.9A CN113816872A (en) 2020-06-19 2020-06-19 Synthesis method of (S) -2-aminobutanamide

Publications (1)

Publication Number Publication Date
CN113816872A true CN113816872A (en) 2021-12-21

Family

ID=78912004

Family Applications (2)

Application Number Title Priority Date Filing Date
CN202010565694.9A Pending CN113816872A (en) 2020-06-19 2020-06-19 Synthesis method of (S) -2-aminobutanamide
CN202180041077.1A Pending CN115943137A (en) 2020-06-19 2021-06-10 Synthesis method of (S) -2-aminobutanamide

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN202180041077.1A Pending CN115943137A (en) 2020-06-19 2021-06-10 Synthesis method of (S) -2-aminobutanamide

Country Status (2)

Country Link
CN (2) CN113816872A (en)
WO (1) WO2021254235A1 (en)

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2455155C (en) * 2001-08-10 2012-04-10 Ucb, S.A. Oxopyrrolidine compounds, preparation of said compounds and their use in the manufacturing of levetiracetam and analogues
CN101492382A (en) * 2009-02-26 2009-07-29 绍兴新东泽化工有限公司 Novel method for preparing levetiracetam midbody S-(+)-2-aminobutyrate hydrochlorate
CN101575300B (en) * 2009-06-11 2012-10-03 绍兴文理学院 Production method of S-2-aminobutanamide
CN105646265A (en) * 2016-01-25 2016-06-08 江苏中邦制药有限公司 Method for synthesizing (S)-2-aminobutanamide
CN106591179B (en) * 2016-12-05 2018-07-03 长兴制药股份有限公司 Methyl packing bacterium and its prepare the application on (S)-α-ethyl -2- oxygen -1- pyrrolidine acetic acid salt in selective fractionation
WO2019028666A1 (en) * 2017-08-08 2019-02-14 浙江华海药业股份有限公司 Method for synthesizing levetiracetam
CN110831924A (en) * 2017-08-08 2020-02-21 浙江华海药业股份有限公司 Preparation method of levetiracetam

Also Published As

Publication number Publication date
WO2021254235A1 (en) 2021-12-23
CN115943137A (en) 2023-04-07

Similar Documents

Publication Publication Date Title
CN110799495B (en) Synthesis method of levetiracetam
CN105063120B (en) A kind of preparation method of Levetiracetam
CN110831924A (en) Preparation method of levetiracetam
CN109207531A (en) The biological preparation method of Thiamphenicol and Florfenicol key intermediate
CN102260721A (en) Process for preparing (S)-2-aminobutanamide by using enzyme method
CN100510093C (en) Method for preparing 3-heteroarylradical-3-hydroxy-propionic acid derivative
CN110616236A (en) Preparation method of (R) -N1, N1-diethyl-1, 4-pentanediamine
CN112500323B (en) Preparation method of L-penicillamine
CN102382780A (en) Microbacterium oxydans and method for preparing chiral bis(trifluoromethyl) phenyl ethanol by using same
Zheng et al. Industrial production of chiral intermediate of cilastatin by nitrile hydratase and amidase catalyzed one-pot, two-step biotransformation
CN113816872A (en) Synthesis method of (S) -2-aminobutanamide
CN101709323B (en) Method for producing R-mandelic acid with biocatalysis and separating and coupling method
CN104164469A (en) Method for using Candida antarctica lipase B to produce ticagrelor chiral medicine intermediate
CN102603603A (en) Method for preparing (S)-oxiracetam
CN111321177B (en) Method for synthesizing cinacalcet intermediate (R) -1- (1-naphthyl) ethylamine by enzyme method
KR102347459B1 (en) Extraction of glutaric acid
US20230151397A1 (en) Method and Equipment of Phenethylamine Production
CN102851238A (en) Sphingobacterium and method for preparing levetiracetam acid by utilizing same
CN101284797B (en) Decomposing method of N-protected allyl glycinate
CA2016913A1 (en) Preparation of n-acyl alkylamines
CN102603600A (en) Method for preparing (S)-oxiracetam
EP1290209A1 (en) Method for preparing an r- or s-form of alpha-substituted heterocyclic carboxylic acid and a counter enantiomeric form of alpha-substituted heterocyclic carboxylic acid ester thereto using enzyme
CN114908028B (en) One-pot synthesis process of nitrile compound by chemical enzyme method cascading catalysis under two-phase system
CN109206330B (en) Preparation method of nitrogen substituted aspartic acid
CN116836099A (en) Method for recovering (R/S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid from wastewater

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication