CN110305033B - Purification method of cilastatin sodium intermediate - Google Patents
Purification method of cilastatin sodium intermediate Download PDFInfo
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- CN110305033B CN110305033B CN201810227932.8A CN201810227932A CN110305033B CN 110305033 B CN110305033 B CN 110305033B CN 201810227932 A CN201810227932 A CN 201810227932A CN 110305033 B CN110305033 B CN 110305033B
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- C07—ORGANIC CHEMISTRY
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- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
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- C07B2200/07—Optical isomers
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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
- C07B2200/09—Geometrical isomers
Abstract
The invention belongs to the field of drug synthesis, and particularly discloses a method for purifying a cilastatin sodium intermediate, which comprises the steps of adding (E-Z) -7-halo-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester into acetone, stirring, adding a certain amount of organic alcohol, then dropwise adding purified water, adjusting the pH to 4-6 with acid after dropwise adding, cooling to 0-10 ℃, keeping the temperature and stirring for 3-4h, and performing suction filtration to obtain a solid, namely Z-7-halo-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester. The technical scheme of the invention ensures that the HPLC purity of the product Z-7-halogenated-2 ((S) -2, 2-dimethylcyclopropane formamido) -2-heptenoic acid ethyl ester reaches more than 99.0 percent, and the E-configuration impurity is reduced to less than 0.1 percent.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a purification method of a cilastatin sodium intermediate.
Background
Cilastatin sodium (Z) -7- [ (2R) - (2-amino-2-carboxyethyl) thio ] - [ (1s) -2, 2-dimethylcyclopropanecarboxamido ] -2-heptenoic acid sodium salt, which, in combination with imipenem, is a broad-spectrum beta-lactam antibiotic, kills a large proportion of gram-positive and gram-negative aerobic and anaerobic pathogenic bacteria and strains resistant to most beta-lactam antibiotics. Plays an important role in controlling drug-resistant bacteria, enzyme-producing bacteria infection and treatment of immunodeficiency patient infection, and is one of the anti-severe infection medicines with high clinical evaluation. The structure is as follows:
currently, most of the reports on the synthesis of cilastatin sodium are that 7-chloro-2-oxoheptanoate is synthesized, and then the target compound cilastatin sodium is synthesized by taking the synthesized ethyl 7-chloro-2-oxoheptanoate as a raw material, such as patents EP48301, CN101851186A, CN102702051A, CN102875433, and the like, and in all the synthesis steps, the following reactions are involved:
in the reaction process, an isomer impurity E-7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester is inevitably introduced due to the generation of double bonds, the content of the isomer impurity reaches more than 10 percent, the isomer impurity of cilastatin sodium is finally generated along with the reaction, other unknown impurities are generated in the middle, and the impurity content of the product is possibly out of limits.
On the aspect of literature reports, patents US5147868, CN02821284.3, etc. disclose isomerization of the E isomer to cilastatin by heating under acidic conditions, but cilastatin is sensitive to heat and the isomerization process also produces a certain amount of impurities.
The patent CN101307015A application discloses a method for removing isomer impurities by a recrystallization method of dichloromethane and toluene, wherein the steps firstly need to hydrolyze 7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester to obtain 7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid acetic acid, and then use related solvents for recrystallization, in the operation engineering, the hydrolysis reaction time is 10 hours, the standing time in the recrystallization process is 12 hours, the required time is longer, and in the hydrolysis process, the production of other impurities can be possibly caused, the cost is increased in industrial production, and the production requirements of energy conservation, emission reduction and cost reduction are not met.
Patent CN101792410A application discloses a method, which also requires hydrolysis of ethyl 7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoate to obtain 7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoate, then adding alkali solution, and then adjusting the acid to be in the form of metal salt, the operation process is complicated, the overall yield is reduced, the hydrolysis process is 8 hours, the process time is prolonged, and the method is not beneficial to industrial production.
Patent CN102030674A mentions a purification method of the intermediate, which is to hydrolyze 7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester to obtain the corresponding acid, then adjust it to the corresponding salt with alkali solution, improve the purity of the compound by repeated recrystallization, and finally adjust it to the corresponding acid with acid. Although the method can obtain the intermediate compound with better purity, the yield of the compound is reduced by hydrolysis and repeated recrystallization, the process operation is complicated, and the cost reduction and the workshop operation are not facilitated.
Patent CN102875433A describes a purification method, also by first hydrolyzing the relevant ester and then using concentrated hydrochloric acid at 25-30 ℃. Stirring for 3-6 hours under the condition, then washing with toluene and water, slowly cooling to 0-5 ℃ with a mixed reagent (the volume ratio of n-hexane to diisopropyl ether is 1/3) at low temperature, filtering and washing with n-heptane, wherein the process has large solvent consumption, long operation time and complicated steps, and is not beneficial to industrial production.
In summary, most of the methods hydrolyze esters into acids, and the purification is achieved by refining the acids or refining the corresponding salts, but the hydrolysis process is too long, new impurities are likely to be produced, and the operation is complicated. Therefore, it is necessary to explore a new purification method and provide a new path for the removal of cilastatin sodium impurity and the industrial production.
Disclosure of Invention
In order to make up the defects and shortcomings of the prior art, the invention provides a purification method of a cilastatin sodium intermediate, which has the following technical scheme:
adding (E-Z) -7-halo-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester into acetone, stirring, adding a certain amount of organic alcohol, then dropwise adding purified water, adjusting the pH to 4-6 with acid after dropwise adding, cooling to 0-10 ℃, keeping the temperature and stirring for 3-4h, and performing suction filtration to obtain a solid, namely Z-7-halo-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester.
Preferably, the mass-to-volume ratio of the (E-Z) -7-halo-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester to acetone is 1: 1-2, wherein the mass is g and the volume is ml.
Preferably, the organic alcohol is selected from one or more of methanol, ethanol, isopropanol and tert-butanol; the mass-volume ratio of the (E-Z) -7-halogenated-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester to the organic alcohol is 1: 1-2, wherein the mass is g, and the volume is ml.
Preferably, the mass-to-volume ratio of the (E-Z) -7-halo-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester to the purified water is 1: 5-10, wherein the mass is g and the volume is ml.
Preferably, the acid used to adjust the pH is one of acetic acid, sulfuric acid or hydrochloric acid; the mass fraction of the acid used for adjusting the pH is 1-5%.
Preferably, the halo in (E-Z) -7-halo-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester is chloro, bromo or fluoro.
The technical scheme of the invention ensures that the HPLC purity of the product Z-7-halogenated-2 ((S) -2, 2-dimethylcyclopropane formamido) -2-heptenoic acid ethyl ester reaches more than 99.0 percent, and the E-configuration impurity is reduced to less than 0.1 percent.
The technical scheme of the invention has simple steps, the impurity removal process is not carried out under the heating condition, the possibility of producing new impurities is reduced, the (E-Z) -7-halogeno-2 ((S) -2, 2-dimethylcyclopropane carboxamido) -2-heptenoic acid ethyl ester can be refined without hydrolyzing into the corresponding acid or salt, the possibility of converting E-configuration impurities into other impurities in the hydrolysis process is reduced, the operation process is simplified, the used reagent is cheap and easy to obtain, the related operation is simple and convenient, and an effective thought is provided for impurity removal and industrial production.
Detailed Description
The advantageous effects of the present invention will now be further described by the following examples, which should be understood as being for illustrative purposes only and not limiting the scope of the present invention, and that changes and modifications apparent to those of ordinary skill in the art in light of the present invention are also included within the scope of the present invention.
The crude source of (E-Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester is not limited in the present invention and can be prepared by the methods of EP48301, CN101851186A, CN102702051A, CN102875433 and the like.
(E-Z) -7-bromo-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester can be prepared by the following method:
the preparation method of the (E-Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropane formamido) -2-heptenoic acid ethyl ester is the same as that of the (E-Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropane formamido) -2-heptenoic acid ethyl ester.
(E-Z) -7-fluoro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester can be prepared by the following method:
the preparation method of the (E-Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropane formamido) -2-heptenoic acid ethyl ester is the same as that of the (E-Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropane formamido) -2-heptenoic acid ethyl ester.
Example 1
Weighing 10.0g of (E-Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester crude product (HPLC purity 85% and E configuration impurity 12%), adding 10ml of acetone, stirring, then adding 10ml of ethanol, dropwise adding 50ml of purified water, adjusting pH to 4 by using hydrochloric acid with mass fraction of 1% after dropwise adding, then cooling to 5 ℃, preserving heat, stirring for 3h, and performing suction filtration to obtain 8.4g of solid, namely Z-7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester, wherein the HPLC purity is 99.5% and the E configuration impurity is 0.06%.
Example 2
Weighing 10.0g of (E-Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester crude product (HPLC purity 85% and E-configuration impurity 12%), adding 20ml of acetone, stirring, then adding 10ml of isopropanol, dropwise adding 50ml of purified water, adjusting pH to 6 by using acetic acid with mass fraction of 5% after dropwise adding, then cooling to 10 ℃, preserving heat, stirring for 3h, and performing suction filtration to obtain 8.2g of solid, namely Z-7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester, wherein the HPLC purity is 99.1% and the E-configuration impurity is 0.09%.
Example 3
Weighing 10.0g of (E-Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester crude product (HPLC purity 85% and E-configuration impurity 12%), adding 15ml of acetone, stirring, then adding 20ml of tert-butyl alcohol, dropwise adding 80ml of purified water, adjusting pH to 5 by using 1% sulfuric acid after dropwise adding, then cooling to 0 ℃, preserving heat and stirring for 3h, and performing suction filtration to obtain 8.5g of solid, namely Z-7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester, wherein the HPLC purity is 99.0% and the E-configuration impurity is 0.10%.
Example 4
Weighing 10.0g of (E-Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester crude product (HPLC purity 85% and E configuration impurity 12%), adding 10ml of acetone, stirring, then adding 10ml of ethanol, dropwise adding 100ml of purified water, adjusting pH to 6 by using 2% acetic acid after dropwise adding, then cooling to 5 ℃, preserving heat and stirring for 3h, and performing suction filtration to obtain 8.3g of solid, namely Z-7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester, purity 99.1% and E configuration impurity 0.10%.
Example 5
Weighing 10.0g of (E-Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester crude product (HPLC purity 85% and E-configuration impurity 12%), adding 20ml of acetone, stirring, then adding 20ml of ethanol, dropwise adding 50ml of purified water, adjusting pH to 4 by using hydrochloric acid with mass fraction of 5% after dropwise adding, then cooling to 5 ℃, preserving heat, stirring for 3h, and performing suction filtration to obtain 8.0g of solid, namely Z-7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester, wherein HPLC purity is 99.3% and E-configuration impurity is 0.07%.
Example 6
Weighing 10.0g of (E-Z) -7-bromo-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester crude product (HPLC purity 85% and E-configuration impurity 12%), adding 10ml of acetone, stirring, then adding 10ml of ethanol, dropwise adding 50ml of purified water, adjusting pH to 4 by using hydrochloric acid with mass fraction of 1% after dropwise adding, then cooling to 5 ℃, preserving heat, stirring for 3h, and performing suction filtration to obtain 8.4g of solid, namely Z-7-bromo-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester, wherein HPLC purity is 99.4% and E-configuration impurity is 0.06%.
Example 7
Weighing 10.0g of (E-Z) -7-fluoro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester crude product (HPLC purity 85% and E-configuration impurity 12%), adding 10ml of acetone, stirring, then adding 10ml of ethanol, dropwise adding 50ml of purified water, adjusting pH to 4 by using hydrochloric acid with mass fraction of 1% after dropwise adding, then cooling to 5 ℃, preserving heat, stirring for 3h, and performing suction filtration to obtain 8.5g of solid, namely Z-7-fluoro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester, wherein HPLC purity is 99.3% and E-configuration impurity is 0.06%.
Comparative example 1
Weighing 10.0g (HPLC purity 85%, E configuration impurity 12%) of (E-Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester crude product, adding 10ml butanone, stirring, then adding 10ml ethanol, dropwise adding 50ml purified water, adjusting pH4 with 1% diluted hydrochloric acid after dropwise adding, then cooling to 5 ℃, keeping the temperature and stirring for 3h, and finally obtaining oily liquid which can not be filtered and purified.
Comparative example 2
Weighing 10.0g of (E-Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester crude product (HPLC purity 85% and E configuration impurity 12%), adding 10ml of acetone, stirring, then adding 10ml of ethylene glycol, dropwise adding 50ml of purified water, adjusting pH4 with 1% diluted hydrochloric acid after dropwise adding, then cooling to 5 ℃, preserving heat and stirring for 3h, and performing suction filtration to obtain 7.2g of solid, namely Z-7-halo-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester, wherein HPLC purity is 92.2% and E configuration impurity is 1.6%.
Comparative example 3
Weighing 10.0g of (E-Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester crude product (HPLC purity 85% and E configuration impurity 12%), adding 10ml of acetone, stirring, then adding 10ml of ethanol, dropwise adding 50ml of purified water, adjusting pH1 with 1% diluted hydrochloric acid after dropwise adding, then cooling to 5 ℃, preserving heat and stirring for 3h, and performing suction filtration to obtain 7.8g of solid, namely Z-7-halo-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester, wherein HPLC purity is 94.2% and E configuration impurity is 0.7%.
Comparative example 4
Weighing 10.0g of (E-Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester crude product (HPLC purity 85% and E configuration impurity 12%), adding 10ml of acetone, stirring, then adding 40ml of ethanol, dropwise adding 50ml of purified water, adjusting pH4 with 1% diluted hydrochloric acid after dropwise adding, then cooling to 20 ℃, preserving heat, stirring for 3h, and performing suction filtration to obtain 4.8g of solid, namely Z-7-halo-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester, wherein HPLC purity is 96.7% and E configuration impurity is 1.7%.
Comparative example 5
Weighing 10.0g of (E-Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester crude product (HPLC purity 85% and E configuration impurity 12%), adding 40ml of acetone, stirring, then adding 10ml of ethanol, dropwise adding 50ml of purified water, adjusting pH4 with 1% diluted hydrochloric acid after dropwise adding, then cooling to 5 ℃, preserving heat and stirring for 3h, and performing suction filtration to obtain 5.8g of solid, namely Z-7-halo-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester, wherein HPLC purity is 98.0% and E configuration impurity is 0.16%.
Comparative example 6
Weighing 10.0g of (E-Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester crude product (HPLC purity 85% and E configuration impurity 12%), adding 10ml of acetone, stirring, then adding 10ml of ethanol, dropwise adding 20ml of purified water, adjusting pH4 with 1% diluted hydrochloric acid after dropwise adding, then cooling to 5 ℃, preserving heat and stirring for 3h, and performing suction filtration to obtain 6.8g of solid, namely Z-7-halo-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester, wherein the HPLC purity is 97.6% and the E configuration impurity is 0.22%.
Comparative example 7
15.0g of crude (E-Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester (HPLC purity 85%, E configuration impurity 12%) is weighed, 30ml of 10% sodium hydroxide solution is added, the reaction process is monitored by HPLC, and the reaction is carried out at 30-45 ℃ for 8 hours. 10ml of toluene was added to the reaction solution obtained by hydrolysis each time, and the reaction solution was repeatedly washed three times. The organic phase was discarded and acidified by addition of concentrated hydrochloric acid and the pH of the aqueous phase was adjusted to 3.5. The feed layer was extracted three times with 25ml toluene, the aqueous phase was discarded, and the organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. Adding 45ml anhydrous ethanol into the concentrate, stirring thoroughly to dissolve, and filtering to remove insoluble impurities. And slowly adding a 30% sodium hydroxide solution into the filtrate, adjusting the pH value to 7.0, stopping dropwise adding the sodium hydroxide solution, continuously stirring for 1.0 hour, and concentrating the reaction solution under reduced pressure after the pH value is stable. The concentrated solution is kept stand at low temperature for crystallization, a large amount of solid precipitated in the solution is collected by filtration and dried in vacuum to obtain 7.7g of (Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropane formamido) -2-heptenoic acid sodium solid, the HPLC purity is 97.2 percent, and the E configuration impurity is 0.8 percent.
Comparative example 8
Weighing 37.0g (HPLC purity 85%, E configuration impurity 12%) of crude (E-Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester, cooling to 5-10 deg.C, adding 15g sodium hydroxide and 50ml water, continuing stirring at 25-30 deg.C for 8 hours until the ester layer disappears, separating toluene, washing the water layer with toluene, adjusting pH of the water layer to 4.0-4.5 with 6N hydrochloric acid, extracting with 100ml toluene, washing the toluene layer containing 7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid with 100ml water, layering, wherein in the reaction solution, the isomer ratio Z: E is 90: 10%, stirring the toluene layer obtained in the above step with 100ml concentrated hydrochloric acid at 25-30 deg.C for 3-6 hours until the E isomer disappears, the toluene layer was washed with 100ml of water and 100ml of brine, dried over 20g of sodium sulfate, and then concentrated to 50% by volume under reduced pressure, 100ml of a mixed reagent (n-hexane/diisopropyl ether in a volume ratio of 1/3) was added at 50 ℃, slowly cooled to 0 to 5 ℃, filtered, washed with 20ml of n-hexane, and dried under vacuum to obtain 16.8g of Z-7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid as a white solid with an HPLC purity of 97.7% and an E-configuration impurity of 0.6%.
Comparative example 9
Weighing 36.0g (HPLC purity 85%, E configuration impurity 12%) of crude (E-Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester, adding 60mL of ethanol and 72g of 10% sodium hydroxide solution, heating to 45-50 ℃, keeping the temperature and stirring for reaction, and monitoring the reaction process by TLC (thin layer chromatography) for about 10 hours after the reaction is finished; then, tert-butyl ether was added to wash the reaction solution three times, 100ml of tert-butyl ether was added each time, the organic layer was discarded, concentrated hydrochloric acid was added to the aqueous layer to acidify, the pH was adjusted to 3 to 3.5, ethyl acetate was added to extract the acidified solution three times, the amount of ethyl acetate added each time was 100ml, the aqueous layer was discarded, anhydrous sodium sulfate was added to the ethyl acetate layer to dry, then filtration was performed, the filtrate was concentrated under reduced pressure and ethyl acetate was recovered to obtain 31.2g of brown viscous liquid.
20g of a brown viscous liquid of (Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropylcarboxamido) -2-heptenoic acid (W) was dissolved in 50ml of dichloromethane at room temperature, 140ml of toluene was then added thereto, and after stirring the mixture uniformly, the resulting solution was left to stand at 0 ℃ for 12 hours, and a large amount of solid precipitated from the solution was collected and dried under vacuum to obtain 9.8g of a white (Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropylcarboxamido) -2-heptenoic acid (W) solid. Meanwhile, mother liquor obtained after crystallization is decompressed and concentrated to constant weight, 8.5g brown viscous solution is obtained, according to the method, 8.5g brown viscous solution is added with 20ml dichloromethane and 50ml toluene at room temperature, the mixture is frozen for 12 hours at 0 ℃, solid separated out from the solution is collected and dried in vacuum, and 1.9g white (Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropylcarboxamide) -2-heptenoic acid (W) solid is obtained. The solid (Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropylcarboxamido) -2-heptenoic acid (W) was obtained in a total amount of 10.7g, HPLC purity 98.7% and E-form impurity 0.82%.
Comparative example 10
37.0g (HPLC purity 85%, E configuration impurity 12%) of crude (E-Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester is weighed, 50ml of water and 15.1g of sodium hydroxide are added, and the mixture is stirred at 20-25 ℃ for 24 hours to obtain an isomer (Z) -7-chloro-2- ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid sodium salt aqueous solution containing 10-13% of (E) form.
To an aqueous solution of sodium (E, Z) -7-chloro-2- (S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid in water was added 150ml of toluene, and the pH was adjusted to 3 with an aqueous hydrochloric acid solution. After the separation, anhydrous magnesium sulfate was added to the organic solvent layer, followed by filtration. To the remaining solution was added 8.93g of n-propylamine, and after stirring for 1 hour, toluene was subjected to rotary distillation to obtain 40g of (E, Z) -7-chloro-2- ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid n-propylamine sodium salt.
250ml of ethyl acetate was added to n-propylamine (E, Z) -7-chloro-2- ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid, heated to completely melt, cooled to 0 ℃ to form crystals, then filtered, and vacuum-dried at 40 ℃ to obtain 25g of tert-butylamine (Z) -7-chloro-2- ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid salt having an HPLC purity of 95.8%. The above 25g of crystals were recrystallized again from 250ml of ethyl acetate, and repeated twice to obtain 21g of (Z) -7-chloro-2- ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid n-propylamine sodium salt with an HPLC purity of 99.0%. 21g of the crystals having an HPLC purity of 99.1% were completely dissolved in 200ml of water, the pH was adjusted to 3 with chloric acid, and the crystals were filtered off to obtain 17.1g of (Z) -7-chloro-2- ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid having an HPLC purity of 99.2% and an E-form impurity of 0.5% by vacuum drying.
Comparative example 11
Crude (E-Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester 10.0g (HPLC purity 85%, E configuration impurity 12%) was weighed, and after adjusting pH to 0.5 with concentrated hydrochloric acid, the reaction mixture was heated at 85-90 ℃ for 30 minutes to isomerize the corresponding E structure to give the product 94.4% HPLC purity, 0.7% remaining E configuration impurity.
Claims (4)
1. A purification method of a cilastatin sodium intermediate is characterized by comprising the following steps: adding (E-Z) -7-halo-2 ((S) -2, 2-dimethylcyclopropane methyl phthaleinyl) -2-heptenoic acid ethyl ester into acetone, stirring, adding a certain amount of organic alcohol, then dropwise adding purified water, adjusting pH to 4-6 with acid after dropwise adding, cooling to 0-10 ℃, keeping the temperature and stirring for 3-4h, and performing suction filtration to obtain a solid, namely Z-7-halo-2 ((S) -2, 2-dimethylcyclopropane methyl phthaleinyl) -2-heptenoic acid ethyl ester; wherein the organic alcohol is selected from one or more of methanol, ethanol, isopropanol and tert-butanol; the mass volume ratio of the (E-Z) -7-halogenated-2 ((S) -2, 2-dimethylcyclopropane methyl phthalein amido) -2-heptenoic acid ethyl ester to acetone is 1: 1-2, the mass volume ratio of the (E-Z) -7-halogenated-2 ((S) -2, 2-dimethylcyclopropane methyl phthalein amido) -2-heptenoic acid ethyl ester to the organic alcohol is 1: 1-2, and the mass volume ratio of the (E-Z) -7-halogenated-2 ((S) -2, 2-dimethylcyclopropane methyl phthalein amido) -2-heptenoic acid ethyl ester to the purified water is 1: 5-10, wherein the mass is g, and the volume is ml.
2. The purification process according to claim 1, wherein the acid used to adjust the pH is one of acetic acid, sulfuric acid or hydrochloric acid.
3. The purification method according to claim 1, wherein the mass fraction of the acid used for adjusting the pH is 1 to 5%.
4. The purification process according to claim 1, wherein the halogenation in ethyl (E-Z) -7-halo-2 ((S) -2, 2-dimethylcyclopropanemethanesulfonamido) -2-heptenoate is one of chloro, bromo or fluoro.
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