CN111285781B

CN111285781B - Preparation method of cilastatin sodium key intermediate

Info

Publication number: CN111285781B
Application number: CN201811485582.1A
Authority: CN
Inventors: 王海波; 提文利
Original assignee: Lunan Pharmaceutical Group Corp
Current assignee: Lunan Pharmaceutical Group Corp
Priority date: 2018-12-06
Filing date: 2018-12-06
Publication date: 2022-08-05
Anticipated expiration: 2038-12-06
Also published as: CN111285781A

Abstract

The invention belongs to the field of organic chemical synthesis, and provides a method for preparing a cilastatin sodium key intermediate, which comprises the following steps: the method comprises the steps of taking 7-halogen-2-oxo ethyl heptanoate and (S) -2, 2-dimethyl cyclopropane formamide as raw materials, carrying out condensation reaction to obtain a reaction solution of Z/E type 7-halogen-2 ((S) -2, 2-dimethyl cyclopropane formamide) -2-ethyl heptenoate, and placing the reaction solution under an ultraviolet lamp for irradiation to obtain the high-purity Z type cilastatin sodium key intermediate. The invention reduces the generation of impurities, improves the efficiency of the isomerization process, simplifies the preparation process and effectively improves the yield and purity of the key intermediate of cilastatin sodium.

Description

Preparation method of cilastatin sodium key intermediate

Technical Field

The invention belongs to the field of organic chemical synthesis, and particularly relates to a preparation method of a cilastatin sodium key intermediate.

Background

Chemical name of cilastatin sodium is (Z) -7- [ (2R) - (2-amino-2-carboxyethyl) sulfur]-2- [ (1S) -2, 2-dimethylcyclopropanecarboxamido]-sodium 2-heptenate, molecular formula: c ₁₆ H ₂₅ N ₂ O ₅ SNa, the chemical structure of which is shown in formula (I):

cilastatin is a high-efficiency specific inhibitor of renal dehydrodipeptidase developed by merck company in America, has no bactericidal effect, but is combined with carbapenem antibiotic imipenem to enhance the concentration of imipenem by inhibiting the decomposition of the renal dehydrodipeptidase on the imipenem, thereby enhancing the curative effect. The compound preparation of cilastatin sodium and imipenem in a ratio of 1:1 can kill most gram-positive and gram-negative aerobic and anaerobic pathogenic bacteria and bacterial strains resistant to most beta-lactam antibiotics, can be effectively used for treating septicemia, neutropenia, fever, respiratory system and other infections, and is widely applied clinically as a broad-spectrum antibacterial medicament.

At present, a plurality of reports are available about the synthesis method of cilastatin sodium, and most of the documents adopt 7-halogeno-2-oxoheptanoic acid ethyl ester or 7-halogeno-2-oxoheptanoic acid as starting materials to synthesize cilastatin sodium; the synthetic route using 7-halo-2-oxoheptanoate as a raw material is as follows:

EP0028778, US5147868 and EP0048301 disclose cilastatin sodium prepared from ethyl 7-chloro-2-oxoheptanoate (4) as a raw material by sequentially reacting with S- (+) -2, 2-dimethylcyclopropanecarboxamide (5) and L-cysteine (6), wherein Dowex cation exchange resin purification and lyophilization are employed in the process, and the total yield is only 50%. In particular, since a certain proportion of the E isomer is formed in each reaction step, it is important how to remove these impurities. In order to remove the E-isomer of cilastatin, the process adopts a mode of adjusting pH to 3.0 and heating to convert the E-isomer into cilastatin, although the E-isomer can be effectively controlled, high temperature causes generation of degradation impurities and other impurities, and the impurities are difficult to purify in the subsequent process, so that the quality of a final product is influenced. In addition, the freeze-drying process of the process is not beneficial to industrial production.

Wherein the 7-halogenated-2-oxoheptanoic acid ethyl ester reacts with (S) -2, 2-dimethylcyclopropanecarboxamide to generate a target product, and an E-type isomer with the concentration of about 10-13% can be obtained at the same time, and the synthetic route is as follows:

the E isomer can participate in subsequent reactions and produce various impurities, which makes purification of the final product cilastatin sodium very difficult. Although patent US5147868 reports a method of converting E-isomer into cistatin by heating under acidic conditions, since cilastatin is extremely unstable at high temperature and easily generates various impurities, 5-8% of impurities are formed during the heating isomerization process, which affects the purity of the final product. Therefore, it is very important to eliminate or convert the E isomer into the Z isomer in time.

In order to eliminate the effect of the E isomer, a purification process of cilastatin is disclosed in CN 1592737A: firstly, adjusting the pH value of the crude cilastatin solution to 0.5-1.5, heating to 85-95 ℃ to convert the E-isomer into cilastatin, and then purifying and concentrating by macroporous adsorption resin to obtain cilastatin with the total yield of 37.6%. The process has similar problems to those of US5147868, and has the problems of difficult purification by a resin column and low yield because degradation impurities and the like are generated in the process of heating isomerization reaction.

CN101200434A discloses a purification method of (Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropylcarboxamido) -2-heptenoic acid: the E-type isomer in the 7-chloro-2 ((S) -2, 2-dimethylcyclopropylcarboxamido) -2-heptenoic acid ethyl ester is selectively hydrolyzed under the acidic condition, then the Z-type isomer is hydrolyzed under the alkaline condition and crystallized by ethyl acetate/n-hexane to obtain pure (Z) -7-chloro-2 ((S) -2, 2-dimethylcyclopropylcarboxamido) -2-heptenoic acid, and the yield is 56%.

CN101307015A discloses the preparation of a 7-halo-2-oxoheptanoic acid ethyl ester with (S) -2, 2-dimethylcyclopropanecarboxamide as an oil of 7-halo-2 ((S) -2, 2-dimethylcyclopropylcarboxamido) -2-heptenoic acid crystallized from dichloromethane/toluene or dioxane/cyclohexane to remove the E isomer.

CN101386588A discloses isomerization of a double bond Z/E isomer mixture of ethyl 7-chloro-2 ((S) -2, 2-dimethylcyclopropylcarboxamido) -2-heptenoate under strongly acidic conditions to give the pure Z isomer. Selecting hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid, and isomerizing for 3-24 hours under controlled temperature. The strong acid working solution produces a large amount of impurities and has poor isomerization effect.

CN101792410A discloses that the influence of the E-type configuration is solved by crystallization on the obtained metal salt of 7-chloro-2 ((S) -2, 2-dimethylcyclopropylcarboxamido) -2-heptene, but 1-2% of the E-type isomer is still contained to influence the subsequent reaction, and the yield is low.

CN102030674A discloses adding alkaline solution into (E, Z) -7-halo-2- ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester for hydrolysis to obtain (E, Z) -7-halo- ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid alkali metal salt; adding a 1 st organic solvent and acid into the reactant for layering, and extracting a 1 st organic phase; adding amine substances into the extracted 1 st organic phase to obtain mixed crystals of (E, Z) -7-halogen-2- ((S) -2, 2-dimethylcyclopropane amido) -2-heptenoic acid amine salt; recrystallizing the mixed crystal in a 2 nd solvent to obtain the (Z) -7-halogen-2- ((S) -2, 2-dimethyl cyclopropane amido) -2-heptenoic acid amine salt. Then hydrolyzing to obtain (Z) -7-halogen- ((S) -2, 2-dimethyl cyclopropane amido) -2-heptenoic acid.

CN102702051A (E, Z) 7-halogen- (2s) -2, 2-dimethyl cyclopropane formamide-2-heptenoic acid and cysteine hydrochloride are subjected to thioetherification reaction under alkaline conditions; adjusting the pH value of the thioetherification reaction solution to be acidic, washing the thioetherification reaction solution by a non-polar solvent, and heating a water phase to perform an isomerization reaction; the isomerization reaction liquid is directly purified by neutral macroporous adsorption resin, and the eluent is subjected to post-treatment to form salt so as to obtain cilastatin sodium solid; the purity and the yield are not high.

CN102875433A the concentrated hydrochloric acid containing 7-chloro-2 [ [ (1s) formamide-2, 2-dimethylcyclopropane ] ] -2-heptenoic acid obtained was stirred at 25-30 ℃ for 3-6 hours until the E isomer disappeared. However, side reactions also occur during acidification.

The process disclosed in WO2011061609A is characterized by: 1) preparing (E, Z) 7-halogen- (2S) -2, 2-dimethylcyclopropane formamide-2-ethyl heptenoate from 7-halogen-2-oxoheptanoic acid ethyl ester and (S) -2, 2-dimethylcyclopropane formamide, carrying out acidolysis to obtain sodium salt, carrying out acidolysis to further obtain sodium salt, and refining to obtain (Z) 7-halogen- (2S) -2, 2-dimethylcyclopropane formamide-2-sodium heptenoate, wherein the yield is 57.4%, the purity is 96.56%, and the E-isomer is 1.37%; 2) the resulting sodium 7-halo- (2S) -2, 2-dimethylcyclopropanecarboxamide-2-heptenoate was hydrolyzed with acid and purified by crystallization from isopropyl ether/n-hexane to give 7-halo-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoate in 79% yield and 99.2% purity (0.05% for E-isomer). The operation process is complicated and the total yield is low.

Shi Xiao Hua et al in Xi Stastin synthesis new technology, ([ J ] (Hebei chemical engineering) 2007.30(12):44-46) on the obtained 7-halogen- (2s) -2, 2-dimethyl cyclopropane formamide-2-heptenoic acid with hydrochloric acid acidification and nitro methane recrystallization yield is only 30%.

In the same manner, 7-chloro-2 [ (1s) formamide-2, 2-dimethylcyclopropane ] -2-heptenoic acid is acidified by concentrated hydrochloric acid and subjected to column chromatography in the paper "synthesis of cilastatin sodium" (university of chessmen, 2011.) by euonymus, the yield is 67%.

In summary, in order to eliminate the influence of the E-isomer on the product, in the prior art, methods such as acid isomerization, recrystallization separation, column chromatography, and cilastatin non-ionic adsorption resin separation and purification are respectively applied to intermediate products or final products at each stage of the reaction route. However, the yield and purity of cilastatin sodium obtained by these methods are difficult to achieve with expected results.

In order to improve the yield and purity of the obtained cilastatin sodium and ensure simple process, further research on a better method is urgently needed to solve the problem.

Disclosure of Invention

The invention provides a preparation method of a cilastatin sodium key intermediate, which solves the technical problems of low conversion rate, easy generation of impurities and difficult removal of impurities in the heating isomerization process in the prior art, and obviously improves the yield and purity of the final product cilastatin sodium.

The preparation method of the cilastatin sodium key intermediate comprises the following steps:

(1) taking 7-halogenated-2-oxo-heptanoic acid ethyl ester and (S) -2, 2-dimethyl cyclopropane formamide as raw materials, and carrying out catalytic condensation reaction on the raw materials in an organic solvent by using a catalyst to obtain a reaction solution of Z/E type 7-halogenated-2- ((S) -2, 2-dimethyl cyclopropane formamido) -2-heptenoic acid ethyl ester;

(2) and (2) irradiating the reaction liquid obtained in the step (1) for a period of time under an ultraviolet lamp, and then evaporating to remove the organic solvent to obtain Z-type 7-halogeno-2 ((S) -2, 2-dimethylcyclopropane formamido) -2-heptenoic acid ethyl ester.

Specifically, in the condensation reaction in the step (1), the raw material, namely the 7-halogenated-2-oxoheptanoic acid ethyl ester, can be selected from the following groups: ethyl 7-chloro-2-oxoheptanoate or ethyl 7-bromo-2-oxoheptanoate;

the reaction solvent is one or a combination of toluene, benzene and xylene, and toluene is preferred; the catalyst is preferably p-toluenesulfonic acid; carrying out reflux condensation reaction in a reactor provided with a water diversion device;

the molar charge ratio of the ethyl 7-halo-2-oxoheptanoate to the(s) -2, 2-dimethylcyclopropanecarboxamide is preferably 1: 1-1.5; the dosage of the catalyst p-toluenesulfonic acid is 1-2% of the mass of the 7-halo-2-oxoheptanoic acid ethyl ester, and the reaction time is 30-180 min;

carrying out light-induced isomerization reaction at the reaction temperature of 20-40 ℃, wherein an ultraviolet lamp is used for the reaction: the optimal power is 20W, the emission wavelength is 250-300 nm, and the light intensity is 400-500 muW cm ^-2 ；

In a preferred embodiment, after the irradiation in step (2) is completed, the reaction solution is washed with water or diluted hydrochloric acid, and the solvent of the organic layer is evaporated to obtain high-purity Z-form 7-halo-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester.

Wherein in the isomerization reaction, organic solvents used in irradiation are selected, alcohols such as methanol, ethanol, isopropanol and the like; ketones such as acetone; and other solvents such as DMF, dichloromethane and the like, and the solvent selected by the invention has better effect, probably, the solvent selected by the reaction and illumination achieve synergistic effect, the reaction efficiency of isomerization is improved, in addition, the method converts intermediate impurities into a target intermediate, and realizes changing waste into valuable, thereby further improving the purity of cilastatin sodium and simultaneously improving the yield of cilastatin sodium.

The invention has the technical effects that:

the invention provides a method for isomerizing a key intermediate impurity E-type isomer (E) -7-halo-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester of cilastatin sodium into Z-type isomer (Z) -7-halo-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester under the induction of ultraviolet light, which is simple and convenient to operate, converts the key intermediate E-type isomer of cilastatin sodium into Z-type by the induction of light, reduces the generation of a large amount of impurities caused by the existence of the E-type isomer in subsequent reaction, has the molar yield of more than 90 percent, the purity of more than 95 percent and the E-configuration impurity of less than 0.15 percent, and is suitable for industrial production.

Detailed Description

The invention will be further described by the following examples, which are included to make the invention clearer and more readily understood. It is to be understood that these examples are for illustrative purposes only and do not limit the scope of the present invention, and that various changes and modifications obvious to one of ordinary skill in the art in light of the present disclosure are intended to be included therein.

Example 1

Step (1), in a reaction device with a water separator, 50g (0.24mol) of ethyl 7-chloro-2-oxoheptanoate, 27.16g (0.24mol) of (S) -2, 2-dimethylcyclopropanecarboxamide and 0.9g of p-toluenesulfonic acid are added into 240mL of toluene, the mixture is subjected to heat preservation and reflux for 10h, and after the reaction is finished, the reaction solution is cooled to room temperature, the HPLC purity is 89.5%, and the E-configuration impurity is 10%.

Step (2), placing the reaction liquid obtained in the previous step in a 30 ℃ thermostat, and carrying out ultraviolet irradiation under a 20W ultraviolet lamp (the emission wavelength is 280nm, and the light intensity is controlled to be 450 muW cm) ^-2 ) After 60min of irradiation, the reaction solution was washed twice with water, the organic layer was dried over anhydrous sodium sulfate, filtered, and toluene was evaporated to obtain (Z) ethyl 7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoate in a molar yield of 99.5%, a HPLC purity of 99.8%, and an E-configuration impurity of 0.03%.

Example 2

Step (1), in a reaction device with a water separator, 50g (0.24mol) of ethyl 7-chloro-2-oxoheptanoate, 27.16g (0.24mol) of (S) -2, 2-dimethylcyclopropanecarboxamide and 0.9g of p-toluenesulfonic acid are added into 240mL of benzene, reflux is carried out for 13h under heat preservation, and after the reaction is finished, the reaction liquid is cooled to room temperature, the HPLC purity is 87.3%, and the E configuration impurity is 12%.

Step (2), placing the reaction liquid obtained in the previous step in a 30 ℃ thermostat, and carrying out ultraviolet irradiation under a 20W ultraviolet lamp (the emission wavelength is 300nm, and the light intensity is controlled to be 450 muW cm) ^-2 ) After 60min of irradiation, the reaction solution was washed twice with water, and the organic layer was dried over anhydrous sodium sulfate, filtered, and benzene was evaporated to give (Z) ethyl 7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoate in a molar yield of 98.5%, a HPLC purity of 99.6%, and an E-configuration impurity of 0.05%.

Example 3

Step (1), in a reaction device with a water separator, 50g (0.24mol) of ethyl 7-chloro-2-oxoheptanoate, 41.74g (0.36mol) of (S) -2, 2-dimethylcyclopropanecarboxamide and 0.9g of p-toluenesulfonic acid are added into 240mL of xylene, the mixture is subjected to heat preservation and reflux for 10h, and after the reaction is finished, the reaction liquid is cooled to room temperature, the HPLC purity is 88.0%, and the E-configuration impurity is 9%.

Step (2), placing the reaction liquid obtained in the previous step in a constant temperature box at 40 ℃, and carrying out ultraviolet irradiation under a 20W ultraviolet lamp (the emission wavelength is 250nm, and the light intensity is controlled to be 450 muW cm) ^-2 ) After 60min of irradiation, the reaction solution was washed twice with water, the organic layer was dried over anhydrous sodium sulfate, filtered, and xylene was evaporated to obtain (Z) 7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester with a molar yield of 98.2%, a HPLC purity of 99.5%, and an E-configuration impurity of 0.03%.

Example 4

Step (1), adding 60.5g (0.24mol) of ethyl 7-bromo-2-oxoheptanoate, 27.16g (0.24mol) of (S) -2, 2-dimethylcyclopropanecarboxamide and 1.1g of p-toluenesulfonic acid into 240mL of toluene, carrying out heat preservation and reflux for 10h, cooling the reaction solution to room temperature after the reaction is finished, wherein the HPLC purity is 89.4% and the E-configuration impurity is 10%.

Step (2), placing the reaction liquid obtained in the previous step in a 30 ℃ thermostat, and carrying out ultraviolet irradiation under a 20W ultraviolet lamp (the emission wavelength is 280nm, and the light intensity is controlled to be 450 muW cm) ^-2 ) After 70min of irradiation, the reaction solution was washed twice with water, the organic layer was dried over anhydrous sodium sulfate, filtered, and toluene was evaporated to obtain (Z) ethyl 7-bromo-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoate with a molar yield of 98.4%, a HPLC purity of 99.7%, and an E-configuration impurity of 0.03%.

Example 5

Step (1), in a reaction device with a water separator, 50g (0.24mol) of ethyl 7-chloro-2-oxoheptanoate, 27.16g (0.24mol) of (S) -2, 2-dimethylcyclopropanecarboxamide and 0.9g of p-toluenesulfonic acid are added into 240mL of toluene, the mixture is subjected to heat preservation and reflux for 10h, and after the reaction is finished, the reaction solution is cooled to room temperature, the HPLC purity is 89.4%, and the E-configuration impurity is 10%.

Step (2), placing the reaction liquid obtained in the previous step in a 30 ℃ thermostat, and carrying out ultraviolet irradiation under a 20W ultraviolet lamp (the emission wavelength is 360nm, and the light intensity is controlled to be 450 muW cm) ^-2 ) After 60min of irradiation, the reaction solution was washed twice with water, the organic layer was dried over anhydrous sodium sulfate, filtered, and toluene was evaporated to give (Z) 7-chloro-2((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester, molar yield 94.5%, HPLC purity 99.1%, E-configuration impurity 0.07%.

Example 6

Step (2), placing the reaction liquid obtained in the previous step in a 30 ℃ thermostat, and carrying out ultraviolet irradiation under a 20W ultraviolet lamp (the emission wavelength is 220nm, and the light intensity is controlled to be 450 mu W cm) ^-2 ) After 70min of irradiation, the reaction solution was washed twice with water, the organic layer was dried over anhydrous sodium sulfate, filtered, and toluene was evaporated to obtain (Z) 7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester, the molar yield was 95.6%, the HPLC purity was 99.6%, and the E-configuration impurity was 0.08%.

Example 7

Step (1), in a reaction device with a water separator, 50g (0.24mol) of ethyl 7-chloro-2-oxoheptanoate, 27.16g (0.24mol) of (S) -2, 2-dimethylcyclopropanecarboxamide and 1.0g of p-toluenesulfonic acid are added into 240mL of toluene, the mixture is subjected to heat preservation and reflux for 10h, and after the reaction is finished, the reaction solution is cooled to room temperature, the HPLC purity is 87.8%, and the E-configuration impurity is 12%.

Step (2), placing the reaction liquid obtained in the previous step in a constant temperature box at 40 ℃, and carrying out ultraviolet irradiation under a 20W ultraviolet lamp (the emission wavelength is 280nm, and the light intensity is controlled to be 450 muW cm) ^-2 ) After 50min of irradiation, the reaction solution was washed twice with diluted hydrochloric acid, the organic layer was dried over anhydrous sodium sulfate, filtered, and toluene was evaporated to obtain (Z) 7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester, the molar yield was 95.7%, the HPLC purity was 99.7%, and the E-configuration impurity was 0.08%.

Example 8

Step (1), in a reaction device with a water separator, 50g (0.24mol) of ethyl 7-chloro-2-oxoheptanoate, 27.16g (0.24mol) of (S) -2, 2-dimethylcyclopropanecarboxamide and 0.9g of p-toluenesulfonic acid are added into 240mL of toluene, the mixture is subjected to heat preservation and reflux for 10h, and after the reaction is finished, the reaction liquid is cooled to room temperature, the HPLC purity is 89.6%, and the E-configuration impurity is 10.1%.

Step (2), placing the reaction liquid obtained in the previous step in a constant temperature box at 20 ℃, and carrying out ultraviolet irradiation under a 20W ultraviolet lamp (the emission wavelength is 280nm, and the light intensity is controlled to be 450 muW cm) ^-2 ) After 90min of irradiation, the reaction solution was washed twice with dilute hydrochloric acid, the organic layer was dried over anhydrous sodium sulfate, filtered, and toluene was evaporated to obtain (Z) ethyl 7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoate in a molar yield of 94.7%, a HPLC purity of 99.5%, and an E-configuration impurity of 0.07%.

Example 9

Step (1), in a reaction device with a water separator, 50g (0.24mol) of ethyl 7-chloro-2-oxoheptanoate, 27.16g (0.24mol) of (S) -2, 2-dimethylcyclopropanecarboxamide and 0.9g of p-toluenesulfonic acid are added into 240mL of toluene, the mixture is subjected to heat preservation and reflux for 10h, and after the reaction is finished, the reaction liquid is cooled to room temperature, the HPLC purity is 89.1%, and the E-configuration impurity is 10.5%.

Step (2), placing the reaction liquid obtained in the previous step in a 10 ℃ constant temperature box, and carrying out ultraviolet irradiation under a 20W ultraviolet lamp (the emission wavelength is 280nm, and the light intensity is controlled to be 450 muW cm) ^-2 ) After irradiation for 220min, the reaction solution was washed twice with water, the organic layer was dried over anhydrous sodium sulfate, filtered, and toluene was evaporated to give (Z) ethyl 7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoate in a molar yield of 92.4%, a HPLC purity of 99.3%, and an E-configuration impurity of 0.09%.

Example 10

Step (1), in a reaction device with a water separator, 50g (0.24mol) of ethyl 7-chloro-2-oxoheptanoate, 27.16g (0.24mol) of (S) -2, 2-dimethylcyclopropanecarboxamide and 0.9g of p-toluenesulfonic acid are added into 240mL of toluene, the mixture is subjected to heat preservation and reflux for 10h, and after the reaction is finished, the reaction liquid is cooled to room temperature, the HPLC purity is 89.2%, and the E-configuration impurity is 10.4%.

Step (2), placing the reaction liquid obtained in the previous step in a constant temperature box at 60 ℃, and carrying out ultraviolet irradiation under a 20W ultraviolet lamp (the emission wavelength is 280nm, and the light intensity is controlled to be 450 muW cm) ^-2 ) Irradiation ofAfter 50min, the reaction solution was washed twice with water, the organic layer was dried over anhydrous sodium sulfate, filtered, and toluene was evaporated to give (Z) ethyl 7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoate in a molar yield of 92.7%, an HPLC purity of 99.1%, and an E-configuration impurity of 0.15%.

Example 11

Step (1), in a reaction device with a water separator, 50g (0.24mol) of ethyl 7-chloro-2-oxoheptanoate, 27.16g (0.24mol) of (S) -2, 2-dimethylcyclopropanecarboxamide and 0.9g of p-toluenesulfonic acid are added into 240mL of toluene, the mixture is subjected to heat preservation and reflux for 10h, and after the reaction is finished, the reaction liquid is cooled to room temperature, the HPLC purity is 89.3%, and the E-configuration impurity is 10.2%.

Step (2), placing the reaction liquid obtained in the previous step in a 30 ℃ thermostat, and carrying out ultraviolet irradiation under a 20W ultraviolet lamp (the emission wavelength is 280nm, and the light intensity is controlled to be 500 muW cm) ^-2 ) After 30min of irradiation, the reaction solution was washed twice with water, the organic layer was dried over anhydrous sodium sulfate, filtered, and toluene was evaporated to obtain (Z) ethyl 7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoate with a molar yield of 98.5%, a HPLC purity of 99.5%, and an E-configuration impurity of 0.08%.

Example 12

Step (1), adding 60.5g (0.24mol) of ethyl 7-bromo-2-oxoheptanoate, 27.16g (0.24mol) of (S) -2, 2-dimethylcyclopropanecarboxamide and 0.48g of p-toluenesulfonic acid into 240mL of toluene, carrying out heat preservation and reflux for 10h, cooling the reaction solution to room temperature after the reaction is finished, wherein the HPLC purity is 86% and the E-configuration impurity is 13%.

Step (2), placing the reaction liquid obtained in the previous step in a 30 ℃ thermostat, and irradiating ultraviolet light (emission wavelength is 280nm, and light intensity is controlled to be 400 muW cm) under a 20W ultraviolet lamp ^-2 ) After 80min of irradiation, the reaction solution was washed twice with water, the organic layer was dried over anhydrous sodium sulfate, filtered, and toluene was evaporated to obtain (Z) ethyl 7-bromo-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoate in a molar yield of 94.4%, a HPLC purity of 97.3%, and an E-configured impurity of 0.08%.

Example 13

Step (1), in a reaction device with a water separator, 50g (0.24mol) of ethyl 7-chloro-2-oxoheptanoate, 27.16g (0.24mol) of (S) -2, 2-dimethylcyclopropanecarboxamide and 0.9g of p-toluenesulfonic acid are added into 240mL of toluene, the mixture is subjected to heat preservation and reflux for 10h, and after the reaction is finished, the reaction liquid is cooled to room temperature, the HPLC purity is 89.3%, and the E-configuration impurity is 10.4%.

Step (2), placing the reaction liquid obtained in the previous step in a 30 ℃ thermostat, and carrying out ultraviolet irradiation under a 20W ultraviolet lamp (the emission wavelength is 280nm, and the light intensity is controlled to be 600 muW cm) ^-2 ) After 50min of irradiation, the reaction solution was washed twice with water, and the organic layer was dried over anhydrous sodium sulfate, filtered, and toluene was evaporated to obtain (Z) ethyl 7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoate in a molar yield of 94.7%, a HPLC purity of 95.6%, and an E-configuration impurity of 0.09%.

Example 14

Step (1), in a reaction device with a water separator, 50g (0.24mol) of ethyl 7-chloro-2-oxoheptanoate, 27.16g (0.24mol) of (S) -2, 2-dimethylcyclopropanecarboxamide and 0.9g of p-toluenesulfonic acid are added into 240mL of toluene, the mixture is refluxed for 10h under the condition of heat preservation, and after the reaction is finished, the reaction solution is concentrated to be dry, the HPLC purity is 89.3%, and the E-configuration impurity is 10.4%.

Adding methanol into the concentrate obtained in the previous step, placing in a 30 deg.C thermostat, and irradiating with ultraviolet light (emission wavelength is 280nm, and light intensity is controlled to be 450 μ W cm) under a 20W ultraviolet lamp ^-2 ) After 50min of irradiation, methanol was distilled off to obtain (Z) ethyl 7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoate in a molar yield of 95.7%, an HPLC purity of 96.6% and an E-configuration impurity of 0.22%. In the same operation, the methanol is replaced by ethanol, acetone, DMF and dichloromethane to obtain the product with E-configuration impurity content of 0.3-0.5%.

Comparative example 1

25g of ethyl-7-chloro-2-oxo-heptanoate, (S) -2, 2-dimethylcyclopropanecarboxamide, 13.68g and 0.125g of p-toluenesulfonic acid were refluxed in toluene with a water trap to azeotropically remove water from the reaction mixture. After completion of the condensation, the reaction mixture was washed with concentrated hydrochloric acid and an aqueous solution of sodium bisulfite to remove unreacted (S) -2, 2-dimethylcyclopropanecarboxamide and ethyl-7-chloro-2-oxo-heptanoate, respectively. The organic solvent was then concentrated to recover toluene under reduced pressure. The obtained oily ethyl 7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoate was hydrolyzed with an aqueous sodium hydroxide solution at room temperature in the presence of denatured alcohol, and the E isomer in the hydrolyzed product was 10%. The reaction mixture was concentrated to half volume under reduced pressure and washed with toluene. To the aqueous layer were added cysteine hydrochloride monohydrate 29.7g and aqueous sodium hydroxide solution. The reaction mixture was stirred at room temperature until complete conversion of 7-chloro-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid to the product. The reaction mixture was heated at 85-90 ℃ after adjusting the pH to 0.5 with concentrated hydrochloric acid to isomerize the reacted E isomer to cilastatin.

The resulting reaction mixture was placed in a column containing a diaion hp-20 resin as adsorbent. The column was washed with water to remove sodium chloride and the product was then eluted with an aqueous solution of methanol. The column fractions containing pure product were collected and concentrated to obtain pure cilastatin in a molar yield of 30.1%, an HPLC purity of 99.2%, and an E isomer of 2.11%.

Comparative example 2

200g of 7-chloro-2-oxoheptanoic acid ethyl ester, 115g of (S) -2, 2-dimethylcyclopropanecarboxamide, 2g of p-toluenesulfonic acid and 1L of toluene were reacted under reflux for 10 hours. After the reflux reaction is finished, the temperature is reduced to minus 2 ℃, 50ml of concentrated hydrochloric acid is added, the isomerization reaction is carried out for 15 hours, and a toluene layer after the isomer is separated out, so as to obtain a reaction solution containing pure (Z) 7-chloro-2 ((S) -2, 2-dimethylcyclopropane carboxamide) -2-heptenoic acid ethyl ester, wherein the molar yield is 70.2%, the HPLC purity is 89.1%, and the E-configuration impurity is 2.51%.

Comparative example 3

100g of 7-chloro-2-oxoheptanoic acid ethyl ester, 53g of (S) -2, 2-dimethylcyclopropanecarboxamide and 1.3g of p-toluenesulfonic acid were reacted in 600ml of toluene under reflux for 10 hours. After the reaction, toluene was concentrated and recovered. Adding 300ml of sodium hydroxide (10%) into the concentrated solution, detecting the reaction process by HPLC, and reacting for 8 hours at 30-45 ℃. 100ml of toluene is added into the reaction solution obtained by hydrolysis each time, and the reaction solution is repeatedly washed for 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 280ml of toluene, the aqueous phase was discarded, and the organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. 450ml of absolute ethyl alcohol is added into the concentrate, the mixture is fully stirred and dissolved, and insoluble impurities are removed by filtration.

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. Standing the concentrated solution at low temperature for crystallization, filtering and collecting a large amount of solid precipitated from the solution, and drying in vacuum to obtain (Z) 7-chloro-2 ((S) -2, 2-dimethylcyclopropane formamido) -2-heptenoic acid solid. Purity by HPLC was 97.8%, molar yield 48.3%, E configuration impurity 1.40%.

Comparative example 4

200g (0.66mo1) (Z) -7-chloro- ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester were dissolved in 600mL of dichloromethane. 126g of p-toluenesulfonic acid were added to the mixture and stirred at 20 ℃. When the molar ratio of ethyl (Z) -7-chloro- ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoate to ethyl (E) -7-chloro- ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoate is stable according to gas chromatographic analysis, the pH of the mixture is adjusted to 8 to 9 by adding 0.5M caustic soda solution and the organic phase is separated. The separated organic phase was concentrated under reduced pressure and added to 1000mL of acetonitrile. Next, 1420mL of 0.65M caustic soda solution was added and stirred at room temperature until the ethyl (Z) -7-chloro- ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ester had completely reacted. Most of the acetonitrile was evaporated under reduced pressure and the aqueous phase was washed with 270mL of dichloromethane. The pH of the aqueous phase was adjusted to 3.5 by adding hydrochloric acid and extracted with 670mL of dichloromethane. At this point the organic phase was added to 70g of anhydrous magnesium sulphate, stirred, left to stand, filtered and concentrated under reduced pressure. The residue was crystallized from a mixed solvent of ethyl acetate and n-hexane (about 1:4), filtered, and dried in hot air at 40 ℃ for 10 hours to obtain the objective compound, (Z) -7-chloro- ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid in a molar yield of 51.1%, an HPLC purity of 99.1%, and an E-configuration impurity of 2.80%.

Comparative example 5

247.8g of ethyl 7-chloro-2-oxoheptanoate, 135.6g of (+) -S-2, 2-dimethylcyclopropanecarboxamide and 1.68g of p-toluenesulfonic acid were synthesized in 1200mL of toluene, and toluene was recovered by concentration to obtain 359.3g of brown viscous liquid, which was used in the next reaction without isolation. Adding 359.3g of brown viscous liquid obtained in the last step into 600mL of ethanol and 720g of 10% sodium hydroxide solution, heating to 45-50 ℃, keeping the temperature and stirring to enable the mixture to react, and monitoring the reaction process by using HPLC (high performance liquid chromatography), wherein the reaction is finished in about 10 hours; and then adding tert-butyl ether to wash the reaction solution for three times, adding 1000mL of tert-butyl ether each time, discarding the organic layer, adding concentrated hydrochloric acid into the water layer for acidification, adjusting the pH to 3-3.5, adding ethyl acetate to extract the acidified solution for three times, wherein the amount of the ethyl acetate added each time is 1000mL, discarding the water layer, adding anhydrous sodium sulfate into the ethyl acetate layer for drying, then filtering, concentrating the filtrate under reduced pressure, and recovering ethyl acetate to obtain 312.2g of brown viscous liquid.

At room temperature, 200g of brown viscous liquid of (Z) -7-chloro-2- ((S) -2, 2-dimethylcyclopropylcarboxamido) -2-heptenoic acid is dissolved in 500mL of dichloromethane, 1350mL of toluene is added, the obtained solution is placed at 0 ℃ for standing for 12h after being uniformly stirred, a large amount of solid separated out from the solution is collected, and the white (Z) -7-chloro-2- ((S) -2, 2-dimethylcyclopropylcarboxamido) -2-heptenoic acid solid is obtained after vacuum drying. And simultaneously, concentrating the crystallized mother liquor under reduced pressure to constant weight to obtain 85g of brown viscous solution, adding 200mL of dichloromethane and 500mL of toluene into the 85g of brown viscous solution at room temperature according to the method, freezing for 12h at 0 ℃, collecting the solid precipitated from the solution, and drying in vacuum to obtain white (Z) -7-chloro-2- ((S) -2, 2-dimethylcyclopropylcarboxamido) -2-heptenoic acid solid. The (Z) -7-chloro-2- ((S) -2, 2-dimethylcyclopropylcarboxamido) -2-heptenoic acid solid is obtained twice in the front and back, the molar yield is 52.0%, the purity is 98.7% by HPLC determination, and the E-configuration impurity is 2.70%.

Claims

1. A preparation method of a key intermediate of cilastatin sodium is characterized by comprising the following steps:

(1) taking 7-halogen-2-oxo-heptanoic acid ethyl ester and (S) -2, 2-dimethyl cyclopropane formamide as raw materials, and carrying out catalytic condensation reaction in an organic solvent by a catalyst to obtain a reaction solution of Z/E type 7-halogen-2 ((S) -2, 2-dimethyl cyclopropane formamido) -2-heptenoic acid ethyl ester;

(2) irradiating the reaction solution of Z/E type 7-halogen-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester under ultraviolet light to obtain Z type 7-halogen-2 ((S) -2, 2-dimethylcyclopropanecarboxamido) -2-heptenoic acid ethyl ester,

the catalyst is p-toluenesulfonic acid; the organic solvent is one or a combination of toluene, benzene or xylene;

the reaction temperature in the step (2) is 20-40 ℃;

irradiating the reaction solution in the step (2) under ultraviolet light, wherein the ultraviolet light source is a 20W sterilizing lamp, and the emission wavelength of the ultraviolet light source is 250-300 nm;

the light intensity of the ultraviolet light source used in the reaction in the step (2) is 400-500 mu W-cm ^-2 ；

The reaction time in the step (2) is 30-180 min.

2. The process according to claim 1, wherein in the step (1), the ethyl 7-halo-2-oxoheptanoate is ethyl 7-chloro-2-oxoheptanoate or ethyl 7-bromo-2-oxoheptanoate.

3. The process according to claim 1, wherein in the step (1), the p-toluenesulfonic acid is used in an amount of 1.0 to 2.0% by mass based on the ethyl 7-halo-2-oxoheptanoate.

4. The production method according to claim 1 or 3, wherein in the step (1), the p-toluenesulfonic acid is used in an amount of 1.8% by mass of ethyl 7-halo-2-oxoheptanoate.

5. The method according to claim 1, wherein the molar ratio of ethyl 7-halo-2-oxoheptanoate to the charge of (S) -2, 2-dimethylcyclopropanecarboxamide in step (1) is 1:1 to 1.5.