CN109503403B - Pregabalin splitting method - Google Patents
Pregabalin splitting method Download PDFInfo
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- CN109503403B CN109503403B CN201811571061.8A CN201811571061A CN109503403B CN 109503403 B CN109503403 B CN 109503403B CN 201811571061 A CN201811571061 A CN 201811571061A CN 109503403 B CN109503403 B CN 109503403B
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- pregabalin
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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
- C07C227/22—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from lactams, cyclic ketones or cyclic oximes, e.g. by reactions involving Beckmann rearrangement
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- 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
- C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
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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
- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/005—Amino acids other than alpha- or beta amino acids, e.g. gamma amino acids
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- 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
Abstract
The invention provides a method for splitting pregabalin, which takes pregabalin racemate as an initial substance to prepare pregabalin chiral ester under the action of lipase, and the pregabalin chiral ester is subjected to hydrolysis reaction to obtain pregabalin. The pregabalin prepared by the method for splitting pregabalin has high purity, and the method for splitting pregabalin is convenient to operate, safer and more environment-friendly.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a method for splitting pregabalin.
Background
Pregabalin is an analog of the neurotransmitter GABA, a subsequent product of gabapentin. The action mechanism of pregabalin is similar to gabapentin, and has shown anticonvulsant and analgesic effects in different animal models, but the detailed action mechanism is not clear. Pregabalin is structurally similar to neurotransmitter GABA, but does not directly act through a GABA mechanism, and meanwhile, the pregabalin is different from a traditional antiepileptic drug, does not act with GABAA or GABAB receptors, is not metabolized into GABA or GABA agonists, does not inhibit the ingestion and degradation of GABA, does not act on sodium and calcium channels, and releases and intakes glutamate. Meanwhile, the pregabalin does not show an affinity effect with active amino acid receptors such as glutamic acid, GABA and the like, but the pregabalin can replace the combination of marked GABA and calcium ion channels alpha 2 and delta sub-receptors, inhibit a subunit alpha 2-delta protein of a voltage-dependent calcium channel of a central nervous system, reduce calcium ion inflow, reduce the release of excitatory neurotransmitters such as glutamate, norepinephrine and P substances and influence GABA energy neurotransmission. In addition, the pregabalin can obviously increase the level of GABA in a body, and the activity of glutamate decarboxylase can be obviously enhanced by increasing the administration dosage of the pregabalin.
Pregabalin has been approved in the united states for the adjunctive treatment of adult onset partial diabetic peripheral neuralgia, postherpetic neuralgia, fibromyalgia, and neuropathic pain resulting from spinal cord injury. In 8 months 2003, the registered application was first filed in the united states by the company pfeiri, and in 12 months 2004, the FDA in the united states approved the use of pregabalin for Diabetic Peripheral Neuralgia (DPN) and postherpetic neuralgia (PHN), which is also the first drug to be jointly approved in the united states and europe (7 months 2004) for the treatment of 2 types of neuralgia; in 6 months in 2005, pregabalin was approved as an adjuvant therapy for the treatment of partial seizures; in 6 months 2007, pregabalin continues to be approved by the FDA in the united states as the first drug to treat fibromyalgia syndrome; in 6 months 2012, the FDA approved pregabalin as the first drug for treating neuralgia caused by spinal cord injury.
The pregabalin preparation mainly comprises two types of asymmetric synthesis and chemical resolution, wherein the chemical resolution is the mainstream method in the current production, but the yield is low, the reaction condition is severe, and the development of a mild resolution method has important application value.
Disclosure of Invention
The invention aims to disclose a method for splitting pregabalin, which improves the water solubility of the method for splitting pregabalin and is convenient for clinical popularization of medicaments.
In order to achieve the above object, the present invention provides a method for resolving pregabalin, wherein the structural formula of pregabalin is as follows:
the method for splitting the pregabalin represented by the structural formula comprises the following steps: pregabalin racemate is used as an initiator, pregabalin lactam is cyclized, and the pregabalin lactam is hydrolyzed by hand under the action of lipase Novozym435 to obtain pregabalin.
Further, the reaction process of the pregabalin lactam is divided into 2 steps, and the specific steps are as follows:
a: adding pregabalin racemate and a catalyst into a reaction bottle, refluxing, stirring and reacting for 6 hours, naturally cooling to room temperature, recrystallizing in a refrigerator, and performing suction filtration to obtain a white solid;
b: and (b) adding the white solid prepared in the step (a) and a dissolving solvent into a reaction bottle, stirring for dissolving, adding concentrated sulfuric acid, refluxing and stirring for reaction, naturally cooling to room temperature, adjusting the pH value of sodium hydroxide to 5, concentrating, extracting residues with ethanol, adding cyclohexane in a refluxing state until the residues are slightly turbid, dropwise adding ethanol to a solution, stirring in an ice bath for crystallization, and performing suction filtration to obtain the pregabalin lactam.
Further, the catalyst comprises acetic anhydride or sulfuric acid.
Further, the dissolving solvent is one or a mixture of more than two of ethyl acetate, dichloromethane, chloroform or tetrahydrofuran in any proportion.
Further, the reaction process of the pregabalin is as follows: dissolving the pregabalin lactam in an organic solvent, adding lipase Novozym, carrying out a constant temperature shaking table, reacting for 24 hours, carrying out suction filtration and concentration at room temperature, dissolving and recrystallizing to obtain pregabalin.
Further, the temperature of the shaker was 35 ℃.
Further, the rotating speed of the shaking table is 200 r/min.
Further, the organic solvent is toluene.
Compared with the prior art, the invention has the beneficial effects that: improves the purity of the pregabalin, and the splitting method is safe, environment-friendly and convenient to operate.
Detailed Description
The present invention is described in detail below with reference to various embodiments, but it should be understood that these embodiments are not intended to limit the present invention, and those skilled in the art should be able to make modifications and substitutions on the functions, methods, or structures of these embodiments without departing from the scope of the present invention.
The invention provides a method for splitting pregabalin, which has the following structural formula:
the method for splitting the pregabalin represented by the structural formula comprises the following steps: pregabalin racemate is used as an initiator, pregabalin lactam is cyclized, and the pregabalin lactam is hydrolyzed by hand under the action of lipase Novozym435 to obtain pregabalin.
The reaction process of the pregabalin lactam is divided into 2 steps, and the specific steps are as follows:
a: adding pregabalin racemate and a catalyst into a reaction bottle, refluxing, stirring and reacting for 6 hours, naturally cooling to room temperature, recrystallizing in a refrigerator, and performing suction filtration to obtain a white solid;
b: and (b) adding the white solid prepared in the step (a) and a dissolving solvent into a reaction bottle, stirring for dissolving, adding concentrated sulfuric acid, refluxing and stirring for reaction, naturally cooling to room temperature, adjusting the pH value of sodium hydroxide to 5, concentrating, extracting residues with ethanol, adding cyclohexane in a refluxing state until the residues are slightly turbid, dropwise adding ethanol to a solution, stirring in an ice bath for crystallization, and performing suction filtration to obtain the pregabalin lactam. The catalyst comprises acetic anhydride or sulfuric acid. The dissolving solvent is one or a mixture of more than two of ethyl acetate, dichloromethane, chloroform or tetrahydrofuran in any proportion.
The reaction process of pregabalin is as follows: dissolving the pregabalin lactam in an organic solvent, adding lipase Novozym, carrying out a constant temperature shaking table, reacting for 24 hours, carrying out suction filtration and concentration at room temperature, dissolving and recrystallizing to obtain pregabalin. The temperature of the shaker was 35 ℃. The rotating speed of the shaking table is 200 r/min. The organic solvent is toluene.
The first embodiment is as follows:
the embodiment discloses pregabalin prepared by the method, which comprises the following specific reaction steps:
adding 15.9g of pregabalin racemate and 300ml of acetic anhydride into a 1L reaction bottle, refluxing, stirring and reacting for 6 hours, naturally cooling to room temperature, recrystallizing in a refrigerator, and performing suction filtration to obtain 10.7g of white solid. Adding 15.9g of white solid and 200ml of ethyl acetate into a 05L reaction bottle, stirring for dissolving, adding 5ml of concentrated sulfuric acid, refluxing and stirring for reacting for 24 hours, naturally cooling to room temperature, adjusting the pH value to 5 with 2M sodium hydroxide, concentrating, adding cyclohexane to slight turbidity in a refluxing state after ethanol extraction of residues, then dropwise adding ethanol to clear solution, stirring for crystallizing for 2 hours in an ice bath, and performing suction filtration to obtain 11.5g of pregabalin lactam.
Dissolving 14.1g of pregabalin lactam in 1.5L of toluene, adding 1g of lipase, wherein the lipase is Novozym435 lipase, the reaction temperature is 35 ℃, the reaction temperature is 24h, and the rotating speed of a shaking table is 200 r/min. Vacuum-filtering and concentrating at room temperature, and recrystallizing with isopropanol to obtain white solid 9.6g, i.e. high-purity pregabalin.
The purity of the high-purity pregabalin finally prepared in this example was 99.45% using a chemical analysis method.
Example two:
the embodiment discloses pregabalin prepared by the method, which comprises the following specific reaction steps:
adding 15.9g of white solid and 200ml of ethyl acetate into a 0.5L reaction bottle, stirring for dissolving, adding 5ml of concentrated sulfuric acid, refluxing and stirring for reacting for 24 hours, naturally cooling to room temperature, adjusting the pH value to 5 with 2M sodium hydroxide, concentrating, adding cyclohexane into the residue in a refluxing state after ethanol extraction until the residue is slightly turbid, then dropwise adding ethanol into the solution until the solution is clear, stirring in an ice bath for crystallizing for 2 hours, and performing suction filtration to obtain 11.5g of pregabalin lactam.
Dissolving 14.1g of pregabalin lactam in 1.5L of toluene, adding 1g of lipase, wherein the lipase is Novozym435 lipase, the reaction temperature is 35 ℃, the reaction temperature is 24h, and the rotating speed of a shaking table is 200 r/min. Vacuum-filtering and concentrating at room temperature, and recrystallizing with isopropanol to obtain white solid 9.6g, i.e. high-purity pregabalin.
The purity of pregabalin finally prepared in this example was 99.52% using a chemical analysis method.
The above-listed detailed description is only a specific description of a possible embodiment of the present invention, and they are not intended to limit the scope of the present invention, and equivalent embodiments or modifications made without departing from the technical spirit of the present invention should be included in the scope of the present invention.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.
Claims (8)
1. A method for splitting pregabalin, which is characterized in that the structural formula of the pregabalin is as follows:
the method for splitting the pregabalin represented by the structural formula comprises the following steps: pregabalin racemate is used as an initiator, pregabalin lactam is cyclized, and the pregabalin lactam is hydrolyzed by hand under the action of lipase Novozym435 to obtain pregabalin.
2. The resolution method according to claim 1, wherein the reaction process of the pregabalin lactam is divided into 2 steps, and the specific steps are as follows:
a: adding pregabalin racemate and a catalyst into a reaction bottle, refluxing, stirring and reacting for 6 hours, naturally cooling to room temperature, recrystallizing in a refrigerator, and performing suction filtration to obtain a white solid;
b: and (b) adding the white solid prepared in the step (a) and a dissolving solvent into a reaction bottle, stirring for dissolving, adding concentrated sulfuric acid, refluxing and stirring for reaction, naturally cooling to room temperature, adjusting the pH value of sodium hydroxide to 5, concentrating, extracting residues with ethanol, adding cyclohexane in a refluxing state until the residues are slightly turbid, dropwise adding ethanol to a solution, stirring in an ice bath for crystallization, and performing suction filtration to obtain the pregabalin lactam.
3. The resolution process of claim 2, wherein the catalyst comprises acetic anhydride or sulfuric acid.
4. The resolution method according to claim 3, wherein the dissolving solvent is one or a mixture of two or more of ethyl acetate, dichloromethane, chloroform or tetrahydrofuran in any proportion.
5. The resolution method according to claim 4, wherein the pregabalin is reacted by the following steps: dissolving the pregabalin lactam in an organic solvent, adding lipase Novozym, carrying out a constant temperature shaking table, reacting for 24 hours, carrying out suction filtration and concentration at room temperature, dissolving and recrystallizing to obtain pregabalin.
6. The method for splitting according to claim 5, wherein the temperature of the shaker is 35 ℃.
7. The method for splitting according to claim 5, wherein the shaking table rotates at a speed of 200 r/min.
8. The resolution process according to claim 5, characterized in that the organic solvent is toluene.
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| CN201811571061.8A CN109503403B (en) | 2018-12-21 | 2018-12-21 | Pregabalin splitting method |
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| CN201811571061.8A CN109503403B (en) | 2018-12-21 | 2018-12-21 | Pregabalin splitting method |
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| CN109503403B true CN109503403B (en) | 2021-11-16 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20080220441A1 (en) * | 2001-05-16 | 2008-09-11 | Birnbaum Eva R | Advanced drug development and manufacturing |
| US20040132826A1 (en) * | 2002-10-25 | 2004-07-08 | Collegium Pharmaceutical, Inc. | Modified release compositions of milnacipran |
| EA015418B1 (en) * | 2004-06-21 | 2011-08-30 | УОРНЕР-ЛАМБЕРТ КОМПАНИ ЭлЭлСи | Preparation of pregabalin and related compounds |
| EP1992609A1 (en) * | 2007-05-14 | 2008-11-19 | Dipharma Francis S.r.l. | A process for the preparation of a (S)(+)-3-(aminomethyl)-5-methylhexanoic acid |
| MX2010012698A (en) * | 2008-05-21 | 2011-03-15 | Sandoz Ag | Process for the stereoselective enzymatic hydrolysis of 5-methyl-3-nitromethyl-hexanoic acid ester. |
| CN101597626A (en) * | 2009-07-02 | 2009-12-09 | 浙江工业大学 | Biocatalysis preparation (S)-(+)-2, the method for 2-dinethyl cyclopropane carboxylic acid |
| US8466297B2 (en) * | 2010-11-01 | 2013-06-18 | Milan Soukup | Manufacturing process for (S)-Pregabalin |
| DK2935572T3 (en) * | 2012-12-21 | 2020-11-16 | Codexis Inc | MODIFIED BIOCATALYSTERS AND CHIRALE AMINE SYNTHESIZATION METHODS |
| GB201418068D0 (en) * | 2014-10-13 | 2014-11-26 | Cambridge Entpr Ltd | Polymer |
| CN104829515A (en) * | 2015-06-02 | 2015-08-12 | 浙江华海药业股份有限公司 | Pregabalin impurity preparation method |
| CN105348125A (en) * | 2015-11-26 | 2016-02-24 | 太仓运通生物化工有限公司 | Method for synthesizing Pregabalin by taking isovaleraldehyde as raw material |
| CN106748843B (en) * | 2016-11-28 | 2018-10-19 | 无锡福祈制药有限公司 | A kind of preparation method of levocarnitine |
| CN108239019B (en) * | 2016-12-27 | 2021-05-04 | 浙江医药股份有限公司新昌制药厂 | Synthesis method of (2S,5S or 5R) -N-tert-butyloxycarbonyl-5-hydroxy-2-ethyl piperidinecarboxylate |
| WO2019232706A1 (en) * | 2018-06-06 | 2019-12-12 | 浙江华海药业股份有限公司 | Method for preparing pregabalin intermediate (r)-3-(carbamoylmethyl)-5-methylhexanoic acid |
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Address after: 219 Furong Zhongsi Road, Xishan Economic and Technological Development Zone, Wuxi City, Jiangsu Province, 214000 Applicant after: Zhuohe Pharmaceutical Group Co.,Ltd. Address before: 219 Furong Zhongsi Road, Xishan Economic and Technological Development Zone, Wuxi City, Jiangsu Province, 214000 Applicant before: Zhuohe Pharmaceutical Group Co.,Ltd. Address after: 219 Furong Zhongsi Road, Xishan Economic and Technological Development Zone, Wuxi City, Jiangsu Province, 214000 Applicant after: Zhuohe Pharmaceutical Group Co.,Ltd. Address before: 214000 No.2, Rongyang 1st Road, Xishan Economic and Technological Development Zone, Wuxi City, Jiangsu Province Applicant before: JIANGSU ZHUOHE PHARMACEUTICAL Co.,Ltd. |
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