CN101386588A - Method for preparing cilastatin acid - Google Patents
Method for preparing cilastatin acid Download PDFInfo
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- CN101386588A CN101386588A CNA2008101982399A CN200810198239A CN101386588A CN 101386588 A CN101386588 A CN 101386588A CN A2008101982399 A CNA2008101982399 A CN A2008101982399A CN 200810198239 A CN200810198239 A CN 200810198239A CN 101386588 A CN101386588 A CN 101386588A
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- dimethylcyclopropane
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- cilastatin
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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 1 expression.(Z))-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid or its sodium salt are the key intermediates of preparation cilastatin acid, by following formula 2 expressions.
U.S. Patent 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 amide group)-2-heptenoic acid and the formula of expression
2Z-7-chloro-((S)-2 of expression, 2-dimethylcyclopropane amide group)-mixture of 2-heptenoic acid, (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 amide group)-2-heptenoic acid isomerization, obtain pure Z-7-chloro-((S)-2,2-dimethylcyclopropane amide 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 isomerization 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, by preparing (Z)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid ethyl ester and (E)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-mixture of 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 amide 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 amide group)-2-heptenoic acid ethyl ester with (Z)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-hydrolysis takes place in 2-heptenoic acid ethyl ester together, and also contain 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 amide 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, by the selectivity acid hydrolysis in E-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid ethyl ester and Z-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-E-7-chloro-((S)-2 in the mixture of 2-heptenoic acid ethyl ester, 2-dimethylcyclopropane amide group)-2-heptenoic acid ethyl ester, again by basic hydrolysis Z-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid ethyl ester makes pure Z-7-chloro-((S)-2,2-dimethylcyclopropane amide 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 E-7-chloro-((S)-2 in the mixed solution, 2-dimethylcyclopropane amide group)-2-heptenoic acid ethyl ester taken off by sour water in the acid hydrolysis process, Z-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid ethyl ester yield is lower, and because of multistep manipulation require concentration technology, energy consumption is big, is unfavorable for industrialization.
Summary of the invention
The technical problem to be solved in the present invention is at 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, step simplifies the operation, cut down the consumption of energy, and avoid using macroporous resin, be easy to industrialization.
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 and contain (Z)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid ethyl ester and (E)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-mixed solution of 2-heptenoic acid ethyl ester, direct isomerization (E)-7-chloro-((S)-2 wherein under strong acidic condition, 2-dimethylcyclopropane amide group)-2-heptenoic acid ethyl ester, obtain containing the reaction solution of pure (Z)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid ethyl ester;
B. under strong alkaline condition, the reaction solution that direct hydrolysis A step produces obtains pure (Z)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid sodium;
C. with the aqueous phase as acidified in the B step to PH=2.0-3.5, by solvent extraction (Z)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-and the 2-heptenoic acid, the alkali that adds equivalent is again separated out pure (Z)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid sodium;
D. pure (Z)-7-chloro-of separating out with the C step ((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid sodium prepares cilastatin acid.
Contain (Z)-7-chloro-((S)-2 in the A step of the present invention, 2-dimethylcyclopropane amide group)-mixed solution of 2-heptenoic acid ethyl ester and (E)-7-chloro-((S)-2,2-dimethylcyclopropane amide 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 mixtures, 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, potassium 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 hours of reaction times.
The extraction solvent for use can be selected from propyl ether, butyl ether, methylene dichloride, trichloromethane, ethyl acetate, butylacetate or wherein any several 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 following expression formula:
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 amide group)-2-heptenoic acid sodium as starting raw material.As can earlier (Z)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid sodium and aminothiopropionic acid hydrochloride, sodium hydroxide being 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, ethyl acetate, butylacetate, Virahol, butanols, acetonitrile or wherein any several mixture.(Z)-and the temperature of 7-chloro-((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid sodium and aminothiopropionic acid hydrochloride, sodium hydroxide reaction can be controlled at about 40 ℃, and the stirring reaction time is controlled usually about 10 hours.
The invention provides a kind of industrial feasible, new method and prepare cilastatin acid, by with (E)-7-chloro-((S)-2 in the mixed solution, 2-dimethylcyclopropane amide group)-2-heptenoic acid ethyl ester tautomerizes to (Z)-7-chloro-((S)-2 under strong acidic condition, 2-dimethylcyclopropane amide group)-2-heptenoic acid ethyl ester, obtain pure (Z)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid ethyl ester, thereby make the cilastatin acid that makes not only product yield and purity height, and operation steps is simple, and energy consumption is low.
Embodiment
To be described in detail the present invention by preferred embodiment below.It needs to be noted that the content of the detailed description among each embodiment is specific detail file, be used to help those skilled in the art to fully understand 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 isomerization after, obtain containing the reaction solution of pure (Z)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid ethyl ester.
B. pure to containing (Z)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-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 amide 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 amide group)-the 2-heptenoic acid, added the 100g anhydrous sodium sulfate drying 1 hour in the extracting solution, filter, add the 42g sodium methylate in the filtrate, separate out solid 130g, be (Z)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid sodium.
D. with 100g (Z)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid sodium, 70g L-aminothiopropionic acid 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 crude product of 300g dissolve with methanol, remove by filter insolubles, filtrate drips the 2L acetonitrile.Separate out a large amount of solids, filter, drying gets cilastatin acid product 90g.
Embodiment 2
Present embodiment is substantially the same manner as Example 1, 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 industrial be feasible.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 (10)
1, a kind of preparation method of cilastatin acid is characterized in that may further comprise the steps:
A. get and contain (Z)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid ethyl ester and (E)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-mixed solution of 2-heptenoic acid ethyl ester, direct isomerization (E)-7-chloro-((S)-2 wherein under strong acidic condition, 2-dimethylcyclopropane amide group)-2-heptenoic acid ethyl ester, obtain containing the reaction solution of pure (Z)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid ethyl ester;
B. under strong alkaline condition, the reaction solution that direct hydrolysis A step produces obtains pure (Z)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid sodium;
C. with the aqueous phase as acidified in the B step to PH=2.0-3.5, by solvent extraction (Z)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-and the 2-heptenoic acid, the alkali that adds equivalent is again separated out pure (Z)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid sodium;
D. pure (Z)-7-chloro-of separating out with the C step ((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid sodium prepares cilastatin acid.
2, according to the preparation method of the described a kind of cilastatin acid of claim 1, it is characterized in that:
The temperature of reaction of direct isomerization reaction is carried out under-5 ℃ of-35 ℃ of conditions in the described A step.
3, according to the preparation method of the described 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 described A step.
4, according to the preparation method of the described a kind of cilastatin acid of claim 1, it is characterized in that:
Described strong acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetate, methylsulfonic acid, Phenylsulfonic acid or tosic acid.
5, according to the preparation method of the described a kind of cilastatin acid of claim 3, it is characterized in that:
The reaction solvent of the isomerization reaction in the described A step is selected from benzene,toluene,xylene or its any several mixture.
6, according to the preparation method of the described a kind of cilastatin acid of claim 1, it is characterized in that:
Described C step extraction solvent for use is selected from propyl ether, butyl ether, methylene dichloride, trichloromethane, ethyl acetate, butylacetate or wherein any several mixture.
7, according to the preparation method of the described a kind of cilastatin acid of claim 1, it is characterized in that:
The used alkali of described C step is selected from sodium hydroxide, sodium ethylate, sodium methylate, yellow soda ash.
8, according to the preparation method of the described a kind of cilastatin acid of claim 1, it is characterized in that:
In the step D, earlier (Z)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid sodium and aminothiopropionic acid 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.
9, the preparation method of described a kind of cilastatin acid according to Claim 8 is characterized in that:
Separate out the cilastatin acid solvent for use and be selected from acetone, butanone, ethyl acetate, butylacetate, Virahol, butanols, acetonitrile or wherein any several mixture.
10, the preparation method of described a kind of cilastatin acid according to Claim 8 is characterized in that:
The temperature of described (Z)-7-chloro-((S)-2,2-dimethylcyclopropane amide group)-2-heptenoic acid sodium and aminothiopropionic acid hydrochloride, sodium hydroxide reaction is controlled at about 40 ℃, and the stirring reaction time was controlled at about 10 hours.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102030674A (en) * | 2009-07-09 | 2011-04-27 | Dhc有限公司 | Method for preparing intermediate of cilastatin |
| CN102675175A (en) * | 2011-03-08 | 2012-09-19 | 深圳市海滨制药有限公司 | Method for separating and purifying cilastatin |
| CN102702051A (en) * | 2011-03-26 | 2012-10-03 | 山东省新时代药业有限公司 | 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 |
| 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 |
| CN110305033A (en) * | 2018-03-20 | 2019-10-08 | 鲁南制药集团股份有限公司 | A kind of purification process of cilastatin sodium intermediate |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5147868A (en) * | 1978-07-24 | 1992-09-15 | Merck & Co., Inc. | Thienamycin renal peptidase inhibitors |
| KR100833202B1 (en) * | 2006-12-11 | 2008-05-28 | (주)위즈켐 | A preparation method for 7-chloro-(2,2-dimethylcyclopropanecarbox amido)-2-heptenoic acid |
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2008
- 2008-08-28 CN CN2008101982399A patent/CN101386588B/en active Active
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102030674A (en) * | 2009-07-09 | 2011-04-27 | Dhc有限公司 | Method for preparing intermediate of cilastatin |
| CN102675175A (en) * | 2011-03-08 | 2012-09-19 | 深圳市海滨制药有限公司 | Method for separating and purifying cilastatin |
| CN102702051A (en) * | 2011-03-26 | 2012-10-03 | 山东省新时代药业有限公司 | Preparation method of cilastatin sodium |
| 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 |
| CN110305033A (en) * | 2018-03-20 | 2019-10-08 | 鲁南制药集团股份有限公司 | A kind of purification process 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 |
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