CN101386588B - Method for preparing cilastatin acid - Google Patents
Method for preparing cilastatin acid Download PDFInfo
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- CN101386588B CN101386588B CN2008101982399A CN200810198239A CN101386588B CN 101386588 B CN101386588 B CN 101386588B CN 2008101982399 A CN2008101982399 A CN 2008101982399A CN 200810198239 A CN200810198239 A CN 200810198239A CN 101386588 B CN101386588 B CN 101386588B
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- heptenoic
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Abstract
The present invention discloses a novel method for preparing cilastatin acid. Under a strongly acidic condition, (E)-7-chlorine-((S)-2,2-dimethyl cyclopropane amido)-2-heptenoic ethyl ester in a mixed liquid which contains (Z)-7-chlorine-((S)-2,2-dimethyl cyclopropane amido)-2-heptenoic ethyl ester and (E)-7-chlorine-((S)-2,2-dimethyl cyclopropane amido)-2-heptenoic ethyl ester is directly isomerized to form a reaction liquid that contains pure (Z)-7-chlorine-((S)-2,2- dimethyl cyclopropane amido)-2-heptenoic ethyl ester, and then pure (Z)-7-chlorine-((S)-2,2- dimethyl cyclopropane amido)-2-heptenoic ethyl sodium is obtained to prepare cilastatin acid. The method has the advantages that the product is high in yield and good in purity; the preparation process consumes less energy, and the like.
Description
Technical field
The present invention relates to a kind of preparation method of cilastatin acid.
Background technology
Cilastatin acid is by a kind of kidney dehydrogenation of MERCK company synthetic Dipeptidase inhibitor, by following formula
1Expression.(Z))-7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid or its sodium salt are the key intermediates of preparation cilastatin acid, by following formula
2Expression.
United States Patent(USP) No. 5147868 discloses a kind of method for preparing cilastatin acid, specifically is to adopt to contain by formula
3E-7-chloro-((S)-2,2-dimethylcyclopropane the carboxamido-group)-2-heptenoic acid and the formula of expression
2The mixture of Z-7-chloro-((S)-2,2-dimethylcyclopropane the carboxamido-group)-2-heptenoic acid of expression, (pH=0.5--3.0) is heated to about 90 ℃ under acidic conditions; About 30 minutes of isomerization reaction; Make E-7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid isomerizing, obtain pure Z-7-chloro-((S)-2; 2-dimethylcyclopropane carboxamido-group)-and the 2-heptenoic acid, thus make the cilastatin acid that contains the Z configuration.Yet the disadvantage of this method is that the isomerizing meeting causes the generation of unknown impuritie under the heating condition, and has the mixture of a great deal of to be degraded to (S)-2 that are difficult in practice remove, 2-dimethylcyclopropane acid amides.
The specification sheets of WO2006/022511 publication discloses a kind of method; Through preparing (Z)-7-chloro-((S)-2; 2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid ethyl ester with (E)-mixture of 7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid ethyl ester, add the excessive sodium hydrate hydrolysis; Extract an alkali metal salt (aqueous solution) of (Z)-7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid then.Concentrate the salt extracted, and from organic solvent crystallization purifying.Yet; The selectivity of this method alkaline hydrolysis process is lower; (E)-7-chloro-((S)-2 that therefore a great deal of is arranged when basic hydrolysis; 2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid ethyl ester with (Z)-hydrolysis takes place in 7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid ethyl ester together, and also contains a large amount of (E) isomer in the alkali salt solution that reclaims.Be this alkali salt solution of purifying, need to wash purifying with organic solvent.This method weak point is E-isomer is not dealt with, and the product purity of (Z)-7-chloro-that obtains ((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid an alkali metal salt is low, and the energy consumption that concentrates water in addition is big.
For solving the problems of the technologies described above; China publication CN101200434A discloses a kind of method, through the selectivity acid hydrolysis in E-7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid ethyl ester and Z-7-chloro-((S)-2; 2-dimethylcyclopropane carboxamido-group)-E-7-chloro-((S)-2 in the mixture of 2-heptenoic acid ethyl ester; 2-dimethylcyclopropane carboxamido-group)-and 2-heptenoic acid ethyl ester, make pure Z-7-chloro-((S)-2 through basic hydrolysis Z-7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid ethyl ester again; 2-dimethylcyclopropane carboxamido-group)-the 2-heptenoic acid, and then make the sodium-salt aqueous solution of highly purified cilastatin acid.Yet; The disadvantage of this method is that E-7-chloro-((S)-2,2-dimethylcyclopropane the carboxamido-group)-2-heptenoic acid ethyl ester in the mixed solution taken off Z-7-chloro-((S)-2 by sour water in the acid hydrolysis process; 2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid ethyl ester yield is lower; And because of multistep manipulation require concentration technology, energy consumption is big, is unfavorable for industriallization.
Summary of the invention
The technical problem that the present invention will solve is to the above-mentioned defective that exists in the prior art; A kind of new method for preparing cilastatin acid is provided; With in the product yield and quality that improve pure Z configuration cilastatin acid, the step that simplifies the operation cuts down the consumption of energy; And avoid the use of macroporous resin, be easy to industriallization.
For solving the problems of the technologies described above, technical scheme provided by the invention is the preparation method of cilastatin acid, it is characterized in that may further comprise the steps:
A. get contain (Z)-7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid ethyl ester with (E)-mixed solution of 7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid ethyl ester; Direct isomerizing (E)-7-chloro-((S)-2 wherein under strong acidic condition; 2-dimethylcyclopropane carboxamido-group)-and 2-heptenoic acid ethyl ester, obtain containing the reaction solution of pure (Z)-7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid ethyl ester; Wherein, isomerization reaction temperature is-5 ℃～-1 ℃;
B. under strong alkaline condition, the reaction solution of direct hydrolysis A generating step obtains pure (Z)-7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid sodium;
C. with the aqueous phase as acidified in the B step to pH=2.0-3.5; Through SX (Z)-7-chloro-((S)-2; 2-dimethylcyclopropane carboxamido-group)-and the 2-heptenoic acid, the alkali that adds equivalent is again separated out pure (Z)-7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid sodium;
Pure (Z)-7-chloro-of D. separating out with the C step ((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid sodium prepares cilastatin acid.
Contain (Z)-7-chloro-((S)-2 in the A step of the present invention; 2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid ethyl ester with (E)-mixed solution of 7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid ethyl ester can make by disclosed technology among the European patent No.48301.Wherein, directly the used strong acid of isomerization reaction can be selected from hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetate, methylsulfonic acid, Phenylsulfonic acid or tosic acid, and equivalent is preferably 0.5--1.5.The reaction solvent of isomerization reaction can be selected from benzene,toluene,xylene or its any several kinds mixture, even more preferably toluene.Directly isomerization reaction all can be carried out between-10 ℃～100 ℃, is preferably between-5 ℃～35 ℃, is more preferably-5 ℃～-1 ℃.The isomerization reaction time needs 3-24 hour usually.
Alkali in the B step of the present invention can sodium hydroxide, Pottasium Hydroxide, sodium methylate, preferred sodium hydroxide, and wherein alkali is greater than 2 equivalents with respect to ester, temperature of reaction can be room temperature, preferred 3--10 of reaction times hour.
The extraction solvent for use can be selected from propyl ether, butyl ether, methylene dichloride, trichloromethane, ETHYLE ACETATE, butylacetate or wherein any several kinds mixture in the C step of the present invention.Used alkali can be selected from sodium hydroxide, sodium ethylate, sodium methylate, yellow soda ash.
Steps A of the present invention to the reaction process of step C can be expressed with expression:
In D step of the present invention, can prepare cilastatin acid according to traditional method with (the Z)-7-chloro-that obtains from step c) ((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid sodium as starting raw material.As can earlier (Z)-7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid sodium and cysteine hydrochloride, sodium hydroxide be reacted, be acidified to pH=3.0 then; Add solvent again and separate out cilastatin acid; Filter, drying is made with extra care and is obtained pure cilastatin acid.Wherein, separate out the cilastatin acid solvent for use and be selected from acetone, butanone, ETHYLE ACETATE, butylacetate, Virahol, butanols, acetonitrile or wherein any several kinds mixture.(Z)-and the temperature of 7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid sodium and cysteine hydrochloride, sodium hydroxide reaction can be controlled at about 40 ℃, and the stirring reaction time is controlled usually about 10 hours.
The invention provides that feasible, new method prepares cilastatin acid in a kind of industry; Through with (E)-7-chloro-((S)-2 in the mixed solution; 2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid ethyl ester tautomerizes to (Z)-7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid ethyl ester, obtains pure (Z)-7-chloro-((S)-2 under strong acidic condition; 2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid ethyl ester; Not only product yield and purity are high thereby make the cilastatin acid that makes, and operation steps is simple, and energy consumption is low.
Embodiment
To specify the present invention through preferred embodiment below.What need particularly point out is that the content of the detailed description among each embodiment is specific detail file, be used to help those skilled in the art to make much of the present invention, and content of the present invention is not limited to each specific embodiment.
Embodiment 1
The preparation method of cilastatin acid comprises the steps:
A. with 200g 7-chloro-2-oxoheptanoate, 115g (S)-2,2-dimethyl-cyclopropane carboxamide, 2g tosic acid and 1L refluxing toluene reacted 10 hours.After back flow reaction finishes, be cooled to-2 ℃, add concentrated hydrochloric acid 50mL, isomerization reaction 15 hours, tell the toluene layer after the isomerizing after, obtain containing the reaction solution of pure (Z)-7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid ethyl ester.
B. pure to containing (Z)-7-chloro-((S)-2; 2-dimethylcyclopropane carboxamido-group)-and add 300mL sodium hydroxide solution (30%) in the reaction solution of 2-heptenoic acid ethyl ester, room temperature hydrolysis reaction 5 hours, hydrolysis is finished; Obtain pure (Z)-7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid sodium.
C. the water in the B step adds hydrochloric acid adjusting pH to 2.5, and with 2L propyl ether extraction (Z)-7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid; Added the 100g anhydrous sodium sulfate drying 1 hour in the extracting solution; Filter, add the 42g sodium methylate in the filtrating, separate out solid 130g; Be (Z)-7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid sodium.
D. with 100g (Z)-7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid sodium, 70g L-cysteine hydrochloride, 400mL water, 200g sodium hydroxide, 40 ℃ of temperature controls, stirring reaction 10 hours.Reaction is finished, and is cooled to 20 ℃, transfers pH to 3.0 with concentrated hydrochloric acid, is added dropwise to 3L acetone, separates out the cilastatin acid crude, filtration drying.With the above-mentioned bullion of 300g dissolve with methanol, remove by filter insolubles, filtrating drips the 2L acetonitrile.Separate out a large amount of solids, filter, drying gets cilastatin acid product 90g.
Embodiment 2
Present embodiment and embodiment 1 are basic identical, and difference is that the temperature of reaction of direct isomerization reaction in the A step is 30 ℃, and the reaction times is 5 hours.
This specification sheets provides a kind of novel method for preparing cilastatin acid, and is feasible in industry.The foregoing description has been described the preferred embodiments of the invention, but the modification that those skilled in the art is carried out in the claim scope, alternative also within protection domain.
Claims (9)
1. the preparation method of a cilastatin acid is characterized in that may further comprise the steps:
A. get contain (Z)-7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid ethyl ester with (E)-mixed solution of 7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid ethyl ester; Direct isomerizing (E)-7-chloro-((S)-2 wherein under strong acidic condition; 2-dimethylcyclopropane carboxamido-group)-and 2-heptenoic acid ethyl ester, obtain containing the reaction solution of pure (Z)-7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid ethyl ester; Wherein, isomerization reaction temperature is-5 ℃～-1 ℃;
B. under strong alkaline condition, the reaction solution of direct hydrolysis A generating step obtains pure (Z)-7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid sodium;
C. with the aqueous phase as acidified in the B step to pH=2.0-3.5; Through SX (Z)-7-chloro-((S)-2; 2-dimethylcyclopropane carboxamido-group)-and the 2-heptenoic acid, the alkali that adds equivalent is again separated out pure (Z)-7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid sodium;
Pure (Z)-7-chloro-of D. separating out with the C step ((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid sodium prepares cilastatin acid.
2. according to the preparation method of the said a kind of cilastatin acid of claim 1, it is characterized in that:
Directly the reaction times of isomerization reaction is 3-24 hour in the said A step.
3. according to the preparation method of the said a kind of cilastatin acid of claim 1, it is characterized in that:
Said strong acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetate, methylsulfonic acid, Phenylsulfonic acid or tosic acid.
4. according to the preparation method of the said a kind of cilastatin acid of claim 2, it is characterized in that:
The reaction solvent of the isomerization reaction in the said A step is selected from benzene,toluene,xylene or its any several kinds mixture.
5. according to the preparation method of the said a kind of cilastatin acid of claim 1, it is characterized in that:
Said C step extraction solvent for use is selected from propyl ether, butyl ether, methylene dichloride, trichloromethane, ETHYLE ACETATE, butylacetate or wherein any several kinds mixture.
6. according to the preparation method of the said a kind of cilastatin acid of claim 1, it is characterized in that:
The used alkali of said C step is selected from sodium hydroxide, sodium ethylate, sodium methylate, yellow soda ash.
7. according to the preparation method of the said a kind of cilastatin acid of claim 1, it is characterized in that:
In said D step, earlier (Z)-7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid sodium and cysteine hydrochloride, sodium hydroxide are reacted; After be acidified to pH=3.0, add solvent again and separate out cilastatin acid, filter; Drying is made with extra care and is obtained pure cilastatin acid.
8. according to the preparation method of the said a kind of cilastatin acid of claim 7, it is characterized in that:
Separate out the cilastatin acid solvent for use and be selected from acetone, butanone, ETHYLE ACETATE, butylacetate, Virahol, butanols, acetonitrile or wherein any several kinds mixture.
9. according to the preparation method of the said a kind of cilastatin acid of claim 7, it is characterized in that:
The temperature of said (Z)-7-chloro-((S)-2,2-dimethylcyclopropane carboxamido-group)-2-heptenoic acid sodium and cysteine hydrochloride, sodium hydroxide reaction is controlled at about 40 ℃, and the stirring reaction time was controlled at about 10 hours.
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| CN2008101982399A CN101386588B (en) | 2008-08-28 | 2008-08-28 | Method for preparing cilastatin acid |
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| CN2008101982399A CN101386588B (en) | 2008-08-28 | 2008-08-28 | Method for preparing cilastatin acid |
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| CN101386588B true CN101386588B (en) | 2012-05-09 |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| KR100957725B1 (en) * | 2009-07-09 | 2010-05-12 | 디에이치씨 (주) | Method for preparing intermediate of cilastatin |
| CN102675175B (en) * | 2011-03-08 | 2014-02-19 | 深圳市海滨制药有限公司 | Method for separating and purifying cilastatin |
| CN102702051B (en) * | 2011-03-26 | 2016-04-13 | 山东新时代药业有限公司 | A kind of preparation method of cilastatin sodium |
| CN102875433A (en) * | 2012-10-29 | 2013-01-16 | 江西金顿香料有限公司 | Preparation method of cilastatin acid |
| CN110305033B (en) * | 2018-03-20 | 2020-08-28 | 鲁南制药集团股份有限公司 | Purification method of cilastatin sodium intermediate |
| CN109111381A (en) * | 2018-10-30 | 2019-01-01 | 雅本化学股份有限公司 | A kind of preparation method of cilastatin |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5147868A (en) * | 1978-07-24 | 1992-09-15 | Merck & Co., Inc. | Thienamycin renal peptidase inhibitors |
| CN101200434A (en) * | 2006-12-11 | 2008-06-18 | 维思凯有限公司 | Preparation method for (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid |
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2008
- 2008-08-28 CN CN2008101982399A patent/CN101386588B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5147868A (en) * | 1978-07-24 | 1992-09-15 | Merck & Co., Inc. | Thienamycin renal peptidase inhibitors |
| CN101200434A (en) * | 2006-12-11 | 2008-06-18 | 维思凯有限公司 | Preparation method for (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid |
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