CN116837047A - Method for preparing (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid - Google Patents
Method for preparing (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid Download PDFInfo
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- CN116837047A CN116837047A CN202210286347.1A CN202210286347A CN116837047A CN 116837047 A CN116837047 A CN 116837047A CN 202210286347 A CN202210286347 A CN 202210286347A CN 116837047 A CN116837047 A CN 116837047A
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- ethyl
- oxo
- alpha
- pyrrolidine
- acetic acid
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- 238000000034 method Methods 0.000 title claims abstract description 34
- IODGAONBTQRGGG-LURJTMIESA-N Levetiracetam acid Chemical compound CC[C@@H](C(O)=O)N1CCCC1=O IODGAONBTQRGGG-LURJTMIESA-N 0.000 title claims abstract description 22
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 239000002068 microbial inoculum Substances 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 230000020477 pH reduction Effects 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- 241000894006 Bacteria Species 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 4
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000000758 substrate Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 230000000813 microbial effect Effects 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims description 2
- 239000012670 alkaline solution Substances 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 238000007444 cell Immobilization Methods 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 15
- -1 1-dimethylethyl Chemical group 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 9
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 description 7
- 229960004002 levetiracetam Drugs 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000001961 anticonvulsive agent Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- HDBMIDJFXOYCGK-DFWYDOINSA-N (2s)-2-aminobutanamide;hydrochloride Chemical compound Cl.CC[C@H](N)C(N)=O HDBMIDJFXOYCGK-DFWYDOINSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229960003965 antiepileptics Drugs 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 230000001037 epileptic effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 1
- IODGAONBTQRGGG-ZCFIWIBFSA-N (2r)-2-(2-oxopyrrolidin-1-yl)butanoic acid Chemical compound CC[C@H](C(O)=O)N1CCCC1=O IODGAONBTQRGGG-ZCFIWIBFSA-N 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- HNNJFUDLLWOVKZ-UHFFFAOYSA-N 2-aminobutanamide Chemical compound CCC(N)C(N)=O HNNJFUDLLWOVKZ-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical compound ClCCCC(Cl)=O CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241001377010 Pila Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 239000000064 cholinergic agonist Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002664 nootropic agent Substances 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
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- 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
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
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- C12N11/00—Carrier-bound or immobilised enzymes; Carrier-bound or immobilised microbial cells; Preparation thereof
- C12N11/14—Enzymes or microbial cells immobilised on or in an inorganic carrier
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- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/001—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by metabolizing one of the enantiomers
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Abstract
The invention provides a method for preparing (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid, which comprises the steps of separating (R/S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid ester under alkaline conditions by ester hydrolase, and separating to obtain (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid ester; and hydrolyzing (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid ester (II) under alkaline condition, and acidifying to obtain the target intermediate. The method provided by the invention avoids the use of chiral resolution reagent, simplifies the production process, saves the cost and protects the environment.
Description
Field of the art
The invention relates to a method for preparing (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid, belonging to the technical field of drug synthesis.
(II) background art
Epilepsy is the second most common disease of neurology next to cerebrovascular disease and is widely distributed worldwide. Antiepileptic drugs are typically amide nootropic agents or choline agonists. Levetiracetam is a novel antiepileptic drug developed by belgium UCB company, belongs to a second generation acetylcholine agonist, and is mainly used for treating localized and secondary whole body epilepsy. Levetiracetam has the characteristics of high therapeutic index, slight adverse reaction, good tolerance, no interaction with other antiepileptic drugs and the like, is a novel antiepileptic drug which is most applied in the current epileptic treatment, and has wide application prospect in the field of epileptic treatment.
At present, a plurality of reports on preparation methods of levetiracetam at home and abroad are provided, and chemical resolution method is mainly adopted for synthesis. The synthetic routes commonly used in industry are of the following two types: in the first route, (R/S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid is used as a raw material, and (R) -alpha-methylbenzylamine is used as a resolving agent, resolved in benzene, treated by alkali and acidified to obtain (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid. (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid reacts with ethyl chloroformate, and then ammonia gas is introduced to obtain levetiracetam, and the synthetic route is shown as follows:
in the second route, 2-aminobutanamide is taken as a raw material, and (S) -2-aminobutanamide hydrochloride is obtained through resolution by L-tartaric acid, ammonia dissociation and salification by hydrogen chloride. The (S) -2-aminobutanamide hydrochloride reacts with 4-chlorobutyryl chloride, levetiracetam is obtained through cyclization reaction under the action of a phase transfer catalyst and an alkaline reagent, and the synthetic route is shown as follows:
the synthetic routes all adopt the traditional chemical resolution method to construct chiral centers, and have long process routes and low atom utilization rate. Meanwhile, the solvents and reagents used in the chemical separation method have great environmental hazard, and the three wastes (waste water, waste gas and waste residue) are large in quantity, so that the method is applied industrially to a certain extent.
Bioenzyme processes convert chemically synthesized racemic derivatives, precursors or prochiral compounds to single optically active products using enzymatic reactions or microbial transformations with high regioselectivity and enantioselectivity. Therefore, a brand new thought and method can be provided for the industrial preparation of levetiracetam by selecting a proper biological enzyme to realize chiral resolution of (R/S) -alpha-ethyl-2-oxo-1-pyrrolidine acetate to obtain (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid.
(III) summary of the invention
The invention aims to provide a novel method for preparing levetiracetam intermediate by a biological enzyme method, which has simple process and little environmental pollution. The invention has the advantages that the (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid shown in the formula III is synthesized by adopting an enzyme resolution method, so that the use of a large amount of resolution reagents is avoided, and the synthesis steps are simplified.
The aim of the invention is realized by the following technical scheme:
a process for preparing (S) - α -ethyl-2-oxo-1-pyrrolidineacetic acid (III), comprising the steps of:
(1) Splitting (R/S) -alpha-ethyl-2-oxo-1-pyrrolidine acetate (I) under alkaline conditions by ester hydrolase, and separating to obtain (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetate (II);
(2) Hydrolyzing the (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid ester (II) obtained in the step (1) under alkaline conditions, and acidifying to obtain a target intermediate (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid (III):
r in the formulas (I) and (II) is C 1 ～C 6 Alkyl, preferably R is methyl and ethyl. C (C) 1 ～C 6 Alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, 2-methylpropyl, 1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-dimethylpropyl, 1, 2-dimethylpropyl 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 2-trimethylpropyl,1, 2-trimethylpropyl, 1-methyl-1-ethylpropyl and 1-ethyl-2-methylpropyl.
As a preferred method of the present invention, the ester hydrolase in the step (1) is an immobilized microbial inoculum obtained by treating a methyl-encapsulated microbial inoculum, which is classified as a cxzy-L013 strain of methyl-encapsulated microbial inoculum (methyl pila sp.), deposited in China center for type culture collection, with the accession number: cctccc NO: m2016494. The immobilized microbial inoculum is specifically referred to Chinese patent publication CN106591179A, which is incorporated herein by reference in its entirety.
The immobilized microbial inoculum can specifically hydrolyze (R) -alpha-ethyl-2-oxo-1-pyrrolidine acetate in racemic (R/S) -alpha-ethyl-2-oxo-1-pyrrolidine acetate (I) into corresponding acid, and the corresponding acid is dissolved in an aqueous phase through salification, and the (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetate (II) is obtained through organic solvent extraction.
The amount of the immobilized microbial inoculum is 1 to 40% by mass of the raw material (R/S) -alpha-ethyl-2-oxo-1-pyrrolidine acetate (I), and more preferably 2 to 20% by mass of the raw material (R/S) -alpha-ethyl-2-oxo-1-pyrrolidine acetate (I).
The enzymolysis reaction of the step (1) is carried out in a solvent, wherein the solvent is water. The water is used as the solvent, so that the use of an organic solvent is avoided, and the method is more economical and environment-friendly.
The substrate (R/S) -alpha-ethyl-2-oxo-1-pyrrolidine acetate (I) in the enzymolysis reaction in the step (1) has a mass percentage concentration of 20-70%, and more preferably 30-50%.
The enzymolysis reaction temperature in the step (1) is 20-50 ℃ and the pH value is 6.0-9.0. The enzymatic hydrolysis requires proper temperature and pH, and the reaction activity of the enzyme is reduced when the temperature and pH are out of the corresponding ranges. Preferably, the enzymolysis reaction temperature is 25-40 ℃ and the pH is 7.0-8.0.
The pH of the enzymatic reaction is controlled by adding an aqueous solution of a base selected from the group consisting of alkali metal carbonates, alkali metal bicarbonates and alkali metal hydroxides. 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. The (R) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid obtained after ester hydrolase hydrolysis reacts with the above base to generate corresponding salt, and the corresponding salt can be dissolved in an aqueous phase. Further preferably, sodium carbonate or sodium hydroxide aqueous solution is selected to control the pH of the enzymatic hydrolysis reaction.
As a preferred method of the invention, step (1) further comprises the following post-treatments: filtering, recovering immobilized bacteria, adding organic solvent into the filtrate, extracting to obtain (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetate (II). The recovered immobilized microbial inoculum can be recycled. The organic solvent used in the post-treatment of step (1) is preferably toluene, methylene chloride or ethyl acetate.
As a preferred method of the present invention, the alkali solution in the step (2) is an aqueous solution of an inorganic alkali. The inorganic base is selected from alkali metal hydroxides and alkali metal carbonates. Preferred inorganic bases are sodium hydroxide or potassium hydroxide. The amount of the base to be used is not less than 0.5 times, preferably 0.6 to 2.0 times, the molar amount of the substrate (R/S) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid ester (I).
The hydrolysis reaction in the step (2) is carried out at the temperature of-20 to 50 ℃ and the pH value is controlled to be more than or equal to 10.0. Too high hydrolysis can isomerize the target product (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid (III), resulting in increased isomers; too low a hydrolysis temperature slows down the hydrolysis reaction rate. The hydrolysis reaction temperature is preferably 0 to 30 ℃.
As a preferred method of the invention, step (2) further comprises the following post-treatments: layering, acidifying the water phase, filtering and drying to obtain (S) -2-ethyl-2-oxo-1-pyrrolidine acetic acid (III). The acid used for the acidification in step (2) is selected from mineral acids, preferably hydrochloric acid or sulfuric acid. In the acidification process, the control of pH is particularly important, and if the acidity is insufficient, the acidification is incomplete and the yield is low. In the step (2), the pH value is controlled to be less than or equal to 6.0. Preferably, the pH of the acidification is between 0 and 2.0.
The invention provides a method for preparing (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid (III) by adopting ester hydrolase resolution. The enzymolysis process adopts green solvent water as a resolution solvent, avoids the problems existing in the use of organic solvents such as benzene and the like as the resolution solvent, and meets the production requirements of bulk drugs better. Meanwhile, enzymolysis resolution is adopted, so that the use of chiral resolution reagents is avoided, the production process is simplified, the cost is saved, and the environment is protected.
(IV) detailed description of the invention
The following describes the embodiments of the present invention in further detail with reference to examples. The following examples are only illustrative of the present invention and are not intended to limit the scope of the invention.
Example 1
(R/S) -2-ethyl-2-oxo-1-pyrrolidineacetic acid methyl ester (90 g,0.49 mol) and H were added to the reaction flask 2 O (210 g) is heated to 30 ℃ under stirring, immobilized microbial inoculum (15 g) is added, the temperature is controlled within the range of 25-35 ℃, and 20% Na is added dropwise 2 CO 3 And (3) stopping the reaction when the pH value of the reaction system is kept at 7.0-8.0 and the isomer (R) -alpha-ethyl-2-oxo-1-pyrrolidine methyl acetate is less than 1%, filtering, recovering the immobilized microbial inoculum, adding extracting agent toluene (100 g) into the filtrate, stirring for 30 minutes, standing for 30 minutes, layering, collecting an organic phase, repeating the extraction operation for 3 times, and combining the organic phases to obtain the toluene solution of the (S) -alpha-ethyl-2-oxo-1-pyrrolidine methyl acetate.
Adding toluene solution of (S) -alpha-ethyl-2-oxo-1-pyrrolidine methyl acetate into a reaction bottle, controlling the temperature within the range of 0-10 ℃, adding 75g of 10% NaOH solution, controlling the pH of the solution to be more than 10.0, keeping the temperature and stirring for 30min, layering, dropwise adding hydrochloric acid into a water phase to adjust the pH to 1.0-2.0, stirring for 10min, retesting the pH to 1.0-2.0, filtering, and drying to obtain (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid, wherein the yield is 36.8g, the yield is 44.2%, the HPLC purity is 99.1%, and the isomer is 0.53%.
Example 2
(R/S) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid methyl ester (90 g,0.49 mol) and H were added to the reaction flask 2 O (210 g) is heated to 30 ℃ under stirring, immobilized microbial inoculum (15 g) is added, the temperature is controlled within the range of 25-35 ℃, and 20% Na is added dropwise 2 CO 3 The solution is reacted until the isomer (R) -alpha-ethyl-2-oxo-1-pyrrolidine methyl acetate is less than 1 percent, and the reaction is stopped, filtered, recovered and fixed when the pH value of the reaction system is kept between 7.0 and 8.0And (3) dissolving the microbial inoculum, adding an extracting agent toluene (100 g) into the filtrate, stirring for 30 minutes, standing for 30 minutes, layering, collecting an organic phase, repeating the extraction operation for 3 times, and combining the organic phases to obtain a toluene solution of (S) -alpha-ethyl-2-oxo-1-pyrrolidine methyl acetate.
Adding toluene solution of (S) -alpha-ethyl-2-oxo-1-pyrrolidine methyl acetate into a reaction bottle, controlling the temperature within the range of 10-20 ℃, adding 75g of 10% NaOH solution, controlling the pH of the solution to be more than 10.0, keeping the temperature and stirring for 30min, layering, dropwise adding hydrochloric acid into a water phase to adjust the pH to 1.0-2.0, stirring for 10min, retesting the pH to 1.0-2.0, filtering, and drying to obtain (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid, wherein the yield is 34.3g, the yield is 41.2%, the HPLC purity is 99.4%, and the isomer is 0.60%.
Example 3
(R/S) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid methyl ester (90 g,0.49 mol) and H were added to the reaction flask 2 O (90 g) is heated to 30 ℃ under stirring, immobilized microbial inoculum (15 g) is added, the temperature is controlled within the range of 25-35 ℃, and saturated NaHCO is added dropwise 3 And (3) stopping the reaction when the pH value of the reaction system is kept at 7.0-8.0 and the isomer (R) -alpha-ethyl-2-oxo-1-pyrrolidine methyl acetate is less than 1%, filtering, recovering the immobilized microbial inoculum, adding extracting agent toluene (100 g) into the filtrate, stirring for 30 minutes, standing for 30 minutes, layering, collecting an organic phase, repeating the extraction operation for 3 times, and combining the organic phases to obtain the toluene solution of the (S) -alpha-ethyl-2-oxo-1-pyrrolidine methyl acetate.
Adding toluene solution of (S) -alpha-ethyl-2-oxo-1-pyrrolidine methyl acetate into a reaction bottle, controlling the temperature within the range of 10-20 ℃, adding 100g of 10% KOH solution, controlling the pH of the solution to be more than 10.0, keeping the temperature and stirring for 30min, layering, dropwise adding hydrochloric acid into a water phase to adjust the pH to 1.0-2.0, stirring for 10min, retesting the pH to 1.0-2.0, filtering, and drying to obtain (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid, wherein the yield is 33.8g, the yield is 40.6%, the HPLC purity is 99.0%, and the isomer is 0.68%.
Example 4
Into the reaction flask were charged (R/S) -ethyl-2-oxo-1-pyrrolidineacetic acid ethyl ester (150 g,0.75 mol) and H 2 O (150 g) was heated to 30℃with stirringAdding immobilized bacteria (15 g), controlling the temperature within 25-35 ℃, and dripping 20% Na 2 CO 3 And (3) stopping the reaction when the pH value of the reaction system is kept at 7.0-8.0 and the isomer (R) -alpha-ethyl-2-oxo-1-pyrrolidine ethyl acetate is less than 1%, filtering, recovering the immobilized microbial inoculum, adding extracting agent toluene (100 g) into the filtrate, stirring for 30 minutes, standing for 30 minutes, layering, collecting an organic phase, repeating the extraction operation for 3 times, and combining the organic phases to obtain the toluene solution of the (S) -alpha-ethyl-2-oxo-1-pyrrolidine ethyl acetate.
Adding toluene solution of (S) -alpha-ethyl-2-oxo-1-pyrrolidine ethyl acetate into a reaction bottle, controlling the temperature within the range of 0-5 ℃, adding 200g of 10% NaOH solution, controlling the pH of the solution to be more than 10.0, carrying out heat preservation and stirring for 1h, layering, dropwise adding hydrochloric acid into a water phase to adjust the pH to 1.0-2.0, stirring for 10min, retesting the pH to 1.0-2.0, filtering, and drying to obtain (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid, wherein the yield is 53.6g, the yield is 41.6%, the HPLC purity is 99.3%, and the isomer is 0.37%.
The specific embodiments described herein are offered by way of illustration only. Those skilled in the art to which the invention relates may make various modifications or additions to the specific embodiments described or substitutions in a similar manner without departing from the spirit of the invention or exceeding the scope of the invention as defined in the accompanying claims.
Claims (10)
1. A process for preparing (S) - α -ethyl-2-oxo-1-pyrrolidineacetic acid (iii), the process comprising the steps of:
(1) Splitting (R/S) -alpha-ethyl-2-oxo-1-pyrrolidine acetate (I) under alkaline conditions by ester hydrolase, and separating to obtain (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetate (II);
(2) Hydrolyzing (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid ester (II) obtained in the step (1) under alkaline condition, acidifying to obtain a target intermediate (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid (III),
r in the formulas (I) and (II) is C 1 ～C 6 An alkyl group.
2. The process according to claim 1, wherein R in the formulae (I), (II) is preferably methyl or ethyl.
3. The method of claim 1, wherein the ester hydrolase in step (1) is an immobilized microbial inoculum, the immobilized microbial inoculum is a methyl-encapsulated bacteria treated by a cell immobilization method, and the preservation number of the methyl-encapsulated bacteria is CCTCC NO: m2016494.
4. The method according to claim 1, wherein the amount of the immobilized microbial agent in the step (1) is 1 to 40% by mass, more preferably 2 to 20% by mass, based on the wet weight of the starting material (R/S) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid ester (I).
5. The process of claim 1, wherein the reaction of step (1) is carried out in water.
6. The process according to claim 1, wherein the substrate (R/S) - α -ethyl-2-oxo-1-pyrrolidineacetic acid ester in step (1) is present in a mass percentage concentration of 20% to 70%, preferably 30% to 50%.
7. The method according to claim 1, wherein the enzymolysis reaction temperature in the step (1) is 20-50 ℃ and the pH is 6.0-9.0; preferably, the enzymolysis reaction temperature is 25-40 ℃ and the pH is 7.0-8.0.
8. The process according to claim 1, wherein the alkaline solution in step (2) is an aqueous solution of an inorganic base, which is an alkali metal hydroxide and an alkali metal carbonate, preferably sodium hydroxide or potassium hydroxide; the amount of the base to be used is not less than 0.5 times, preferably 0.6 to 2.0 times, the molar amount of the substrate (R/S) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid ester (I).
9. The process according to claim 1, wherein the hydrolysis reaction in step (2) is carried out at a temperature of-20 to 50 ℃ and a pH value of not less than 10.0, preferably at a hydrolysis reaction temperature of 0 to 30 ℃.
10. The process according to claim 1, wherein the acid used for the acidification in the post-treatment of step (2) is selected from mineral acids, preferably hydrochloric acid or sulfuric acid, and the pH is controlled to be less than or equal to 6.0, preferably the acidification pH is between 0 and 2.0.
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