CN103374595A - Method for preparing beta-lactam derivative through enzymatic reaction - Google Patents
Method for preparing beta-lactam derivative through enzymatic reaction Download PDFInfo
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- CN103374595A CN103374595A CN201210110381XA CN201210110381A CN103374595A CN 103374595 A CN103374595 A CN 103374595A CN 201210110381X A CN201210110381X A CN 201210110381XA CN 201210110381 A CN201210110381 A CN 201210110381A CN 103374595 A CN103374595 A CN 103374595A
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Abstract
The invention relates to a method for preparing beta-lactam derivative through enzymatic reaction. The method for preparing beat-lactam derivative through enzymatic reaction comprises the step of synthesizing a compound shown in a formula I by virtue of an enzymatic reaction, and the compound can be used for preparing antibacterial cefcapene pivoxil, wherein R is the conventional amino protection groups like a t-butyloxycarboryl group. A biological enzyme catalyst used in the enzymatic reaction is immobilized deacetyl esterase, and the method for synthesizing the compound shown in the formula I has the advantages of mild conditions, low cost and environmental friendliness, and is easy to operate.
Description
Technical field
The present invention relates to the method that a kind of enzymatic reaction prepares beta-lactan derivatives, this derivative can be used for preparing the antimicrobial drug S-1108.
Background technology
S-1108 is oral cephalosporin analog antibiotic of the 4th generation, by the exploitation of the wild adopted company of Japanese salt, and listing in 1997, chemical structural formula is as follows:
It all has very strong anti-microbial effect to various bacteria, and existing cephalosporin kind anti-microbial activity that can be oral is strong, and using dosage is little.
Early stage patent, document etc. are many to the operational path report of S-1108; representative patent WO2008/155615 once disclosed the synthetic method of S-1108; employing D-7ACA is starting raw material; through the acylation reaction of cephalosporin nucleus 7-N atom, the carbamylation reaction of 3-hydroxyl, the esterification of 4-carboxyl prepares S-1108.Syntheti c route is as follows:
Formula one compound 7 β that this patent provides-[(Z)-2-(2-t-butoxycarbonyl amino thiazole-4-yl)-the 2-butylene acyl group] synthetic method of amino-3-methylol-3-cephem-4-carboxylic acid, the starting raw material D-7ACA that it adopts is expensive, and D-7ACA also needs after two protections of 4-carboxyl and 3-hydroxyl and side chain condensation preparation formula one compound again, employed silylation protection reagent toxicity is large in the protection process, expensive, carrying capacity of environment is heavy; Condensation reaction, hydrolysis reaction condition harsh (temperature of reaction of palpus deep cooling), energy consumption is high, complicated operation, yield is low, and cost is high.
Zhejiang chemical industry 2011,42(7): it is starting raw material without the synthetic method of direct preparation formula one compound of protection that 10-13 provides by D-7ACA, and syntheti c route is as follows:
With respect to WO2008/155615, the synthetic method that this periodical provides avoids using silylation protection reagent, but still exists starting material D-7ACA expensive, the defectives such as severe reaction conditions.
J. Antibiot.1994,
47: 466 provide 7-ACA by diphenyl-methyl protection be starting raw material preparation formula two compounds 7 β-[(Z)-2-(2-t-butoxycarbonyl amino thiazole-4-yl)-the 2-butylene acyl group] synthetic method of amino-3-acetyl-o-methyl-3-cephem-4-carboxylic acid:
This preparation method avoids using expensive D-7ACA to be starting raw material; but 7-ACA goes through on the 4-carboxyl two reactions steps of protection and lower protection, and route is not terse, and step is long; preparation cost has no obvious reduction, and the synthetic method by formula two preparation formulas one is not provided.
US4500716 preparation example 24 also provides the preparation method of formula two compounds, and described method is more terse, and cost is lower:
But US4500716 does not provide the method by formula two preparation formulas one yet.
Consult all documents, all do not have Patents and periodical literature report by formula two preparation formulas one, make at last the method for S-1108.Simultaneously, by other operational path investigation, be not difficult all to find that formula one compound is the important intermediate during S-1108 synthesizes, the preparation cost of this intermediate, yield, quality play conclusive impact to cost and the quality of S-1108.
Summary of the invention
In view of the above-mentioned problems; the present invention is intended to avoid in the existing preparation formula one compound process that reagent toxicity is large, severe reaction conditions, complicated operation, cost height and carrying capacity of environment heavily wait defective, and provide by the method for formula two compounds through immobilization deacetylate esterase (CE enzyme) preparation formula one compound:
This synthetic method difference with the prior art is that with enzymatic reaction synthesis method synthesis type one compound concrete grammar is to adopt immobilization deacetylate esterase (CE enzyme) catalytic hydrolysis formula two compounds to prepare formula one compound.
Concrete preparation method is as follows in this enzymatic reaction: formula two compounds are added entry; or add entry and can be total in the mixed solvent of molten organic solvent composition with water; make into 90-1200mM; be preferably 180-600mM; with conventional mineral alkali or organic adjusting PH with base to 6-10; be preferably 7-9; add 1-5KU immobilization deacetylate esterase; be equivalent to its catalytic substrate formula two compound amount 40-66g, be preferably 1-3.5KU, in 0-40 ℃; preferred 15-35 ℃; reaction 0.5h-40h is preferably 2-10h, after reacting completely; filtered and recycled enzyme (reclaiming enzyme can be recycled), the filtrate acid adding is transferred pH to 2-5 crystallization; washing; the dry compound formula one that gets.
The organic solvent that the present invention is used and water is miscible is acetone, dioxane, N, N, and-dimethyl formamide, N, N ,-N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), acetonitrile are preferably acetone, acetonitrile, dioxane; Used mineral alkali is the carbonate of ammoniacal liquor, sodium hydroxide, potassium hydroxide, ammonium carbonate salts, basic metal or alkaline-earth metal, is preferably yellow soda ash, sodium bicarbonate, saleratus in volatile salt, basic metal or the alkaline earth metal carbonate in ammoniacal liquor, the ammonium carbonate salts; Used organic bases is trimethylamine, is preferably triethylamine; After reacting completely, the used acid of acidifying is hydrochloric acid, phosphoric acid, acetic acid.
Present method reaction conditions is gentle, simple to operate, with low cost, environmental friendliness.
Below continue by reference example and embodiment that the present invention will be described, various replacements or combination according to ordinary skill knowledge and customary means are made all should comprise within the scope of the invention.
Embodiment
Reference example 1:7 β-[(Z)-2-(2-t-butoxycarbonyl amino thiazole-4-yl)-the 2-butylene acyl group] synthetic (with reference to the US4500716) of amino-3-acetyl-o-methyl-3-cephem-4-carboxylic acid (formula two)
(Z)-2-(2-t-butoxycarbonyl amino thiazole-4-yl)-2-butylene acid 142g(0.5mol), triethylamine 76mL(0.55mol) adds in the methylene dichloride (400mL), be cooled to-50 ℃, drip methylsulfonyl chloride 40mL(0.52mol), between temperature control-50 ℃~-40 ℃, drip and finish ,-50 ℃~-40 ℃ are stirred 5h.Drip 7-ACA 163g(0.6mol in backward this reaction solution) and triethylamine 180mL(1.3mol) methylene dichloride (400mL) solution, between temperature control-50 ℃~-40 ℃, drip and finish ,-50 ℃~-40 ℃ are reacted 3h.With using ethyl acetate extraction after the dilute hydrochloric acid acidifying.Extraction liquid salt solution and rare sodium bicarbonate water washing; concentrate after the drying, solidify 7 β-[(Z)-2-(2-t-butoxycarbonyl amino thiazole-4-yl)-the 2-butylene acyl group] amino-3-acetyl-o-methyl-3-cephem-4-carboxylic acid (formula two); HPLC method detection level 〉=95% is directly for the lower step.
Embodiment 1:7 β-[(Z)-2-(2-t-butoxycarbonyl amino thiazole-4-yl)-the 2-butylene acyl group] amino-3-methylol-3-cephem-4-carboxylic acid (formula one) synthetic
Compound formula two 40g(72.4mmol) add among the purified water 240mL, making formula two concentration is 300mM, transfers pH to 7.8 to make formula two compounds entirely molten with 25% ammoniacal liquor, adds immobilization deacetylate esterase 2KU, 25 ℃ of reaction 6h.Suction filtration, filtrate is transferred pH to 2-5 with dilute hydrochloric acid, separates out white solid, suction filtration, dry compound formula one 34.6g, the yield 94% of getting.
Embodiment 2:7 β-[(Z)-2-(2-t-butoxycarbonyl amino thiazole-4-yl)-the 2-butylene acyl group] amino-3-methylol-3-cephem-4-carboxylic acid (formula one) synthetic
Compound formula two 40g(72.4mmol) add among purified water 60mL and the acetone 60mL, making formula two concentration is 600mM, transfers pH to 7 to make formula two compounds entirely molten with 25% ammoniacal liquor, adds immobilization deacetylate esterase 1KU, 15 ℃ of reaction 10h.Suction filtration, filtrate is transferred pH to 3-4 with dilute hydrochloric acid, separates out white solid, suction filtration, dry compound formula one 33.2g, the yield 90% of getting.
Embodiment 3:7 β-[(Z)-2-(2-t-butoxycarbonyl amino thiazole-4-yl)-the 2-butylene acyl group] amino-3-methylol-3-cephem-4-carboxylic acid (formula one) synthetic
Compound formula two 40g(72.4mmol) add among purified water 262mL and the acetonitrile 100mL, making formula two concentration is 200mM, transfers pH to 7.8 to make formula two compounds entirely molten with 25% ammoniacal liquor, adds immobilization deacetylate esterase 3KU, 40 ℃ of reaction 2h.Suction filtration, filtrate is transferred pH to 3-4 with dilute hydrochloric acid, separates out white solid, suction filtration, dry compound formula one 34.0g, the yield 92% of getting.
Embodiment 4:7 β-[(Z)-2-(2-t-butoxycarbonyl amino thiazole-4-yl)-the 2-butylene acyl group] amino-3-methylol-3-cephem-4-carboxylic acid (formula one) synthetic
Compound formula two 40g(72.4mmol) add purified water 20mL and N, N is in the mixed solvent of-dimethyl formamide 40mL; making formula two concentration is 1200mM; transfer pH to 7.5 to make formula two compounds entirely molten with 25% aqueous sodium hydroxide solution, add immobilization deacetylate esterase 1KU, 0 ℃ of reaction 40h.Suction filtration, filtrate is transferred pH to 2-5 with dilute hydrochloric acid, separates out white solid, suction filtration, dry compound formula one 29.6g, the yield 80% of getting.
Embodiment 5:7 β-[(Z)-2-(2-t-butoxycarbonyl amino thiazole-4-yl)-the 2-butylene acyl group] amino-3-methylol-3-cephem-4-carboxylic acid (formula one) synthetic
Compound formula two 40g(72.4mmol) add purified water 20mL and N, N is in the mixed solvent of-dimethyl formamide 40mL; making formula two concentration is 1200mM; transfer pH to 7.1 to make formula two compounds entirely molten with 25% ammonium carbonate solution, add immobilization deacetylate esterase 1KU, 0 ℃ of reaction 6h.Suction filtration, filtrate is transferred pH to 2-5 with dilute hydrochloric acid, separates out white solid, suction filtration, dry compound formula one 29.6g, the yield 80% of getting.
Embodiment 6:7 β-[(Z)-2-(2-t-butoxycarbonyl amino thiazole-4-yl)-the 2-butylene acyl group] amino-3-methylol-3-cephem-4-carboxylic acid (formula one) synthetic
Compound formula two 40g(72.4mmol) add in the mixed solvent of purified water 700mL and dioxane 100mL; making formula two concentration is 90mM; transfer pH to 7.2 to make formula two compounds entirely molten with 25% sodium bicarbonate water, add immobilization deacetylate esterase 5KU, 35 ℃ of reaction 5h.Suction filtration, filtrate is transferred pH to 2-5 with dilute hydrochloric acid, separates out white solid, suction filtration, dry compound formula one 30.3g, the yield 82% of getting.
Embodiment 7:7 β-[(Z)-2-(2-t-butoxycarbonyl amino thiazole-4-yl)-the 2-butylene acyl group] amino-3-methylol-3-cephem-4-carboxylic acid (formula one) synthetic
Compound formula two 40g(72.4mmol) add purified water 260mL and N, N is in the mixed solvent of-dimethyl formamide 100mL; making formula two concentration is 200mM; transfer pH to 6 to make formula two compounds entirely molten with 25% saleratus water, add immobilization deacetylate esterase 2KU, 15 ℃ of reaction 10h.Suction filtration, filtrate is transferred pH to 2-5 with dilute hydrochloric acid, separates out white solid, suction filtration, dry compound formula one 29.9g, the yield 75% of getting.
Embodiment 8:7 β-[(Z)-2-(2-t-butoxycarbonyl amino thiazole-4-yl)-the 2-butylene acyl group] amino-3-methylol-3-cephem-4-carboxylic acid (formula one) synthetic
Compound formula two 40g(72.4mmol) add in the mixed solvent of purified water 100mL and dimethyl sulfoxide (DMSO) 20mL, making formula two concentration is 600mM, transfers pH to 10 to make formula two compounds entirely molten with triethylamine, adds immobilization deacetylate esterase 2KU, 20 ℃ of reaction 4h.Suction filtration, filtrate is transferred pH to 2-5 with dilute hydrochloric acid, separates out white solid, suction filtration, dry compound formula one 27.1g, the yield 68% of getting.
Claims (8)
1. the method for enzymatic reaction synthesis type one compound:
Wherein, the amido protecting group of the routines such as R representative as tertbutyloxycarbonyl, being characterized as of the method: with formula two compounds
R as defined above, add entry or water and the mixed solvent that can form with the miscible organic solvent of water in, to formula two compound dissolutions, make formula one compound through the esterase catalyzed hydrolysis reaction of immobilization deacetylate with conventional mineral alkali or organic bases accent solvent pH.
2. synthetic method as claimed in claim 1 is characterized in that the miscible organic solvent of described and water is acetone, dioxane, N, N,-dimethyl formamide, N, N ,-N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), acetonitrile are preferably acetone, acetonitrile, dioxane.
3. synthetic method as claimed in claim 1, it is characterized in that described mineral alkali is the carbonate of ammoniacal liquor, sodium hydroxide, potassium hydroxide, ammonium carbonate salts, basic metal or alkaline-earth metal, described organic bases is trimethylamine, is preferably yellow soda ash, sodium bicarbonate, saleratus, triethylamine in volatile salt, basic metal or the alkaline earth metal carbonate in ammoniacal liquor, the ammonium carbonate salts.
4. synthetic method as claimed in claim 1 is characterized in that described accent solvent pH between 6-10, is preferably 7-9.
5. synthetic method as claimed in claim 1 is characterized in that the concentration of formula two compounds is 90-1200mM, is preferably 180-600mM.
6. synthetic method as claimed in claim 1 is characterized in that the consumption of described immobilization deacetylate esterase is 1-5KU, is equivalent to its catalytic substrate formula two compound 40-66g, is preferably 1-3.5KU.
7. synthetic method as claimed in claim 1 is characterized in that the temperature of hydrolysis reaction is 0-40 ℃, is preferably 15-35 ℃.
8. synthetic method as claimed in claim 1 is characterized in that the time of hydrolysis reaction is 0.5h-40h, is preferably 2-10h.
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN114540454A (en) * | 2022-03-09 | 2022-05-27 | 浙江东邦药业有限公司 | Method for synthesizing cefcapene pivoxil hydrochloride by enzyme method and synthetic intermediate thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4500716A (en) * | 1981-11-19 | 1985-02-19 | Bayer Aktiengesellschaft | Intermediate products for the preparation of Z-cephalosporins |
WO2008155615A2 (en) * | 2007-06-18 | 2008-12-24 | Orchid Chemicals & Pharmaceuticals Limited | An improved process for the preparation of cephalosporin antibiotic |
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2012
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4500716A (en) * | 1981-11-19 | 1985-02-19 | Bayer Aktiengesellschaft | Intermediate products for the preparation of Z-cephalosporins |
WO2008155615A2 (en) * | 2007-06-18 | 2008-12-24 | Orchid Chemicals & Pharmaceuticals Limited | An improved process for the preparation of cephalosporin antibiotic |
Non-Patent Citations (2)
Title |
---|
李永龙 等: "7-[1-(2-叔丁氧基酰胺唑-4-基)-1(Z)-戊烯酰胺]-3-羟甲基-3-头孢烯-4-羧酸的合成", 《浙江化工》, 31 December 2011 (2011-12-31) * |
柳杏辉: "酶法制备新型医药中间体D-7-ACA工艺研究", 《中国优秀硕士学位论文全文数据库 基础科学辑》, 15 September 2009 (2009-09-15) * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN114540454A (en) * | 2022-03-09 | 2022-05-27 | 浙江东邦药业有限公司 | Method for synthesizing cefcapene pivoxil hydrochloride by enzyme method and synthetic intermediate thereof |
CN114540454B (en) * | 2022-03-09 | 2023-10-17 | 浙江东邦药业有限公司 | Method for synthesizing cefcapene pivoxil hydrochloride by enzyme method and synthesis intermediate thereof |
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