WO2008138228A1

WO2008138228A1 - A process for the preparation of cilastatin sodium

Info

Publication number: WO2008138228A1
Application number: PCT/CN2008/000947
Authority: WO
Inventors: Zhaoqiang Lu; Hengli Zhang
Original assignee: Shenzhen Haibin Pharmaceutical Co., Ltd.
Priority date: 2007-05-16
Filing date: 2008-05-15
Publication date: 2008-11-20
Also published as: CN101307015B; CN101307015A

Abstract

The invention provides a process for the preparation of cilastatin sodium which comprises purifying (Z)-7-chloro-2-((S)-2,2-dimethylcyclopropylcarboxamide)-2-heptenoic acid by crystallization to prepare cilastatin and purifying cilastatin using neutral macroporous resin to prepare cilastatin sodium, thereby improving the purity and yield of cilastatin sodium.

Description

Method for preparing cilastatin sodium

The present invention relates to a process for the preparation of a compound, in particular to a process for preparing cilastatin sodium

(Cilastain Sodium Salt) method. Background technique

The chemical name of cilastatin sodium is [R-[R*,S*(Z)]]-7[(2-amino-2-carboxyethyl)sulfide]-2-[[ (2,2- 2 Sodium methylcyclopropyl)carbonyl]amino]-2-heptenoate having the chemical structure of formula (I) having the formula C ₁₂ H ₂₅ N ₂ Na0 ₅ S and a molecular weight of 380.44. The combination of cilastatin sodium and β-carbapene-based antibiotics such as imipenem inhibits the degradation of imipenem by renal dehydrodipeptide enzyme and increases the concentration of subamperes in the urinary tract. , thereby increasing the activity of imipenem and reducing its nephrotoxicity. Imipenem/cilastatin sodium has been widely used as a broad-spectrum antibacterial agent.

There have been many reports on the preparation of cilastatin sodium. EP 48301 B1 discloses the preparation of cilastatin sodium by reaction of 1-bromo-5-chloropentafluorene with Grignard Rx to form ethyl 7-chloro-2-oxoheptanoate; Donald W. Graham Preparation of cilastatin sodium using 1,3-1,3-dithia-2-carboxylic acid ethyl ester as the starting reactant (Donald W. Graham et al, J. Med. Chem, 1987, 30: 1074), reaction step as follows:

The compound (Z)-7-chloro-2 of the formula (IV) is prepared by reacting ethyl 7-chloro-2-oxoheptanoate (III) with (S)-2,2-dimethylcyclopropanecarboxamide ( (S) -2,2-Dimethylcyclopropylcarboxamido)-2-heptenoic acid ethyl ester.

Since (X) -7-chloro-2 ((S) -2,2-dimethylcyclopropyl) is prepared in step 2 In the reaction of ethylformamide)-2-heptenoic acid, a small amount (about 10% to 13%) of the E isomer (E) -7-chloro-2 ((S) -2,2-di Methylcyclopropylformamido)-2-heptene ethyl ester (VII) is formed, and the oxime isomer is further degraded in the reaction of step 3 to form a compound of the formula (Ε) -7-chloro-2 ( (S) -2,2-Dimethylcyclopropylcarboxamido)-2-heptenoic acid.

01) In order to overcome the above problems, an attempt is made to form a compound of the formula (Ε)-7-(L-amino-2-carboxyethyl)sulfide by acid crystallization or by adding a cysteine reaction to the reaction solution obtained in the above step 3. -2- ( (S) -2,2-dimethylcyclopropylformamido)-2-heptenoic acid, then acidified to remove impurities by heating, but found that the compound of formula (V) (Ζ) -7- The crystallization yield of chloro-2((S)-2,2-dimethylcyclopropylcarboxamido)-2-heptenoic acid is still very low, since by-products (Ε) are formed in the reaction of step 3 - 7-Chloro-2 ((S) -2,2-dimethylcyclopropylformamido)-2-heptenoic acid (Shan), the acidification heating of step 4 further causes unknown impurities (XI) and (S) The formation of -2,2-dimethylcyclopropylformamide (ΧΠ) increases the difficulty of purification separation. The reaction process is as follows:

Η

ΝΗ ₂

(Κ)

+

H

NH

Mixture with (E) (X)

In order to solve this problem, the WO 2006/022511 A1 application discloses the following method: Hydrolysis of a compound of the formula (IV) (Z) -7-chloro-2 ((S) -2,2-dimethylcyclopropane under basic conditions Ethyl carboxamide) -2-heptenoic acid ethyl ester, the pH of the reaction solution is adjusted to neutral, and then it is crystallized with an organic solvent to prepare a compound of the formula (XIII) (Z) -7-chloro-2 (( S) -2,2-Dimethylcyclopropylcarboxamido)-2-heptenoic acid metal salt, thereby removing the compound of formula (V) 7-chloro-2 ((S)-2,2-dimethyl The E-isomer of cyclopropylcarbamido)-2-heptenoic acid prevents the next reaction from forming the E-isomer impurity of cilastatin (VI); then the compound of formula (ΧΠΙ) Z) -7-Chloro-2 ((S) -2,2-dimethylcyclopropylformamido) -2-heptenoic acid metal salt reacts with cysteine, adsorbed by cation exchange resin, washed with ammonia Extracting, concentrating and adding alcohol to obtain cilastatin ammonium compound of formula (XIV); preparing sodium cilostatin (XIV) solution by sodium exchange of cation exchange resin to obtain cilastatin sodium (1 ), the reaction steps are as follows:

(X IV)

(I)

However, in the above method of WO 2006/022511 Al, the heat released by the acid-base reaction causes a small decomposition of cilastatin (VI) to reduce the yield and purity of the product during the alkali exchange operation of the cation exchange resin; In addition, the process of preparing cilastatin sodium (I) by cilastatin ammonium (XIV) is cumbersome and does not meet economic requirements, so it is still not a good industrial production of cilastatin sodium (I). method. Summary of the invention

Therefore, in order to make up for the deficiencies of the prior art, the preparation of sodium cilastatin is suitable for industrial production, and the present invention provides a novel method for preparing cilastatin sodium.

The invention is achieved by the following technical solutions:

A preparation chemical formula is (1), and the chemical name is [R-[R*,S*(Z)]]-7[(2-amino-2-carboxyl) A method of sodium thio]-2-[[(2,2-dimethylcyclopropyl)carbonyl]amino]-2-heptenoate comprising the steps of:

1) preparing a crystal of the compound (Z) -7-X-2 ((S) -2,2-dimethylcyclopropylformyl)-2-heptenoic acid of the formula (XV);

2) Crystals of formula (XV) compound (Z) -7-X-2 ((S) -2,2-dimethylcyclopropylformyl)-2-heptenoic acid and cysteine or Preparation of the compound of formula (VI) cilastatin by cysteine hydrochloride reaction;

3) Purifying the cilastatin of the compound of the formula (VI) prepared in the step 2) by a neutral macroporous adsorption resin;

4) reacting the purified compound of formula (VI) cilastatin with an alkaline sodium salt solution to prepare a sodium cilastatin (I) solid;

(I) Wherein X is a halogen atom.

Preparation of the crystal of the compound (Z) -7-X-2 ((S) -2,2-dimethylcyclopropylformyl)-2-heptenoic acid of the formula (XV) described in the step 1) Methods include:

a) reacting ethyl 7-X-2-oxoheptanoate with (+)-(S)-2,2-dimethylcyclopropanecarboxamide to prepare compound (Z) -7-X- of formula (XV) 2 ((S) -2,2-dimethylcyclopropylformamido)-2-heptenoic acid; b) The compound (Z) -7-X-2 of the formula (XV) can be obtained by the step a) ((S) -2,2-Dimethylcyclopropylformyl)-2-heptenoic acid is crystallized from dichloromethane and toluene to give a crystal of the compound of formula (XV);

Where X is chlorine or bromine;

(XV) Crystalline Compound (Z) -7-X-2 ((S) -2,2-dimethylcyclopropylformyl)-2-heptenoic acid of formula (XV) as described in step 1) The preparation method of the crystal includes:

Al) Preparation of a compound of formula (XV) (Z) -7-chloro by reacting ethyl 7-X-2-oxoheptanoate with (+)-(S)-2,2-dimethylcyclopropanecarboxamide 2 ((S) -2,2-dimethylcyclopropylformamido)-2-heptenoic acid; Bl) The compound (Z) -7-X-2 ((S) -2,2-dimethylcyclopropylformyl)-2-heptenoic acid of the formula (XV) can be obtained in the step a) in dioxane Crystallization from a six ring and cyclohexane to give a crystal of the compound of formula (XV);

Where X is chlorine or bromine;

(X V ) Crystallized The neutral macroporous adsorption resin described above is a HP-10 resin column, and the eluent is a mixed solution of water, methanol and water.

The weight ratio of methanol to water in the methanol and water mixed solution is 1:9.

The alkaline sodium salt described in the step 4) is sodium hydroxide.

The above method is prepared by crystallization to obtain a high purity compound (Z) -7-X-2 ((S) -2,2-dimethylcyclopropylformamido)-2-heptenoic acid of the formula (XV), capable of Effectively prevents the formation of the E-isomer of formula (VI) cilastatin; purification of cilastatin solution by neutral macroporous resin reduces thermal decomposition to form other impurities, thereby increasing cilastatin sodium (I Purity and yield. detailed description

The invention is further described by the following examples in which the invention is more clearly understood and understood.

Step 1 (Z) Preparation of -7-chloro-2 ((S)-2,2-dimethylcyclopropylcarboxamido)-2-heptenoic acid (V)

(Z)-7-Chloro-2((S)-2,2-dimethylcyclopropylcarboxamido)-2-heptenoic acid (V) according to the method reported in EP 48301 B1 with 247.8 g of 7-chloro Ethyl 2-(oxoheptanoate (III), 135.6 g (+)-S-2,2-dimethylcyclopropanecarboxamide and 1.6 g of p-toluenesulfonic acid were synthesized in 1200 mL of toluene, and concentrated to recover toluene. 359.3g brown viscous liquid, the product is not used for the next reaction,

359.3 g of the brown viscous liquid obtained in the previous step was added to 600 mL of ethanol and 720 g of 10% sodium hydroxide solution, heated to 45~50 ° C, stirred and reacted for reaction, and the reaction was monitored by HPLC, and the reaction was completed in about 10 hours; Then, the reaction solution was washed three times with t-butyl ether. Each time, 100 mL of t-butyl ether was added, the organic layer was discarded, and the aqueous layer was acidified with concentrated hydrochloric acid to adjust the pH to 3 to 3.5. The ethyl acetate was added in an amount of 1000 mL each time, the aqueous layer was discarded, and the ethyl acetate layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure and ethyl acetate was evaporated to give a brown solid.

Step 2 (Z) -7-Chloro-2 ((S) -2,2-dimethylcyclopropylcarboxamido)-2-heptenoic acid (V) The preparation of the solid can be carried out in two ways:

Method 1 Dissolve 200 g of (Z) -7-chloro-2((S) -2,2-dimethylcyclopropylformamido)-2-heptenoic acid (V) in a brown viscous liquid at room temperature. In 500 mL of dichloromethane, then 1350 mL of toluene was added, and after stirring, the resulting solution was allowed to stand at 0 ° C for 12 hours, and a large amount of solid precipitated in the solution was collected, and dried under vacuum to obtain white (Z) -7-chloro-2 ( S) -2,2-Dimethylcyclopropylcarboxamido)-2-heptenoic acid (V) 98.5 g. At the same time, the mother liquor after crystallization was concentrated under reduced pressure to a constant weight to obtain 85 g of a brown viscous solution. According to the above method, 85 g of a brown viscous solution was added to 200 mL of dichloromethane and 500 mL of toluene at room temperature, and frozen at 0 ° C for 12 hours. The solid which precipitated from the solution was collected and dried in vacuo to give white (Z) -7-chloro-2 ((S) -2,2-dimethylcyclopropylcarboxamido)-2-heptenoic acid (V) solid. 19.2go was obtained twice before and after (Z)-7-chloro-2((S)-2,2-dimethylcyclopropylcarboxamido)-2-heptenoic acid (V) solid 117.7g, determined by HPLC Its purity was 98.7% and the yield was 56%.

Method 2 200 g of a brown viscous liquid solution containing (Z) -7-chloro-2((S) -2,2-dimethylcyclopropylcarboxamido)-2-heptenoic acid (V) under reflux In 600 mL of dioxane, 1260 mL of cyclohexane was added thereto, and after stirring uniformly, the resulting solution was allowed to stand at room temperature for 12 hours, and a large amount of precipitated solid was collected. Drying in vacuo gave white (Z) -7-chloro-2 ((S) -2,2-dimethylcyclopropylcarboxamido)-2-heptenoic acid (V) as a solid 123.5 g. It was 98.7% and the yield was 59%.

Step 3 Preparation of cilastatin (VI)

164.3 g of white (Z) -7-chloro-2 ((S) -2,2-dimethylcyclopropylcarboxamido)-2-heptenoic acid (V) solid was added to 1200 g of 10% under ice bath. In a sodium hydroxide solution, the temperature is controlled to be lower than or equal to 10 ° C, stirred and purged with nitrogen, to (Z) -7-chloro-2 ((S) -2,2-dimethylcyclopropyl formamide After all the -2-heptenoic acid (V) solids were dissolved, 105.3 g of cysteine hydrochloride monohydrate was added while controlling the temperature to be lower than or equal to 10 Torr; after the addition, stirring was continued at about 5 °C. After 0.5 hours, the temperature was raised to 55~60 ° C, and the reaction was stirred with stirring. The progress of the reaction was monitored by HPLC, and the reaction was completed in about 8 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and washed with dichloromethane. Adding dichloromethane to 600 mL each time, discarding the organic layer, adding one volume of water to the reaction solution, and then adding concentrated brine to adjust the pH of the solution to 2.5~3.0; after acidification, adding dichloromethane to the solution to wash the reaction solution 4 Then, each time the amount of methylene chloride was 800 mL, the organic layer was discarded, and concentrated under reduced pressure at 55 ° C until the solution volume reached half of the initial volume. The obtained solution was added to a HP-10 resin column, and eluted first with water. After the sodium chloride formed in the reaction was eluted, it was eluted with 10/90 (wt/wt) methanol/water solution to collect the obtained sista. The butyl solution was concentrated to dryness at 55 ° C, and dried under vacuum to a constant weight to give a pale yellow cilastatin solid (VI) 127.8 g, which was determined by HPLC to have a purity of 98.5 % and a yield of 59.5%.

Step 4 Preparation of cilastatin sodium (I)

150 g of cilastatin (VI) solid obtained in the third step was added to 500 mL of water, stirred, and slowly added dropwise 2.08 mol/L (16.6 g of sodium hydroxide in 200 mL of water) of sodium hydroxide to pH in an ice bath. The value is 7.0, stop the dropwise addition of sodium hydroxide solution, continue to stir for 0.5 hours, after the pH value and temperature of the solution are stable, add 3.5 g of activated carbon to the solution, and decolorize and decolorize at 40 ° C for 15 minutes, using 0.45 μπι micropores. The filter was suction filtered, and the filtrate was filtered through a 0.20 μηι filter to a sterile room. The filtrate was collected and the filtrate was placed in a freezer, and lyophilized to obtain white sterile cilastatin sodium (I) lyophilized powder 143.3 g. HPLC The purity was determined to be 98.8%, and the yield was 90%.

(VI)

(I)

The above embodiments are not intended to limit the invention in any way, and the present invention is intended to cover such modifications and variations as it is within the scope of the appended claims.

Claims

Claim

1. A preparation chemical formula of (1), the chemical name is [R-[R*,S*(Z)]]-7[(2-amino-2-carboxyethyl)sulfan]-2-[[ A method for sodium (2,2-dimethylcyclopropyl)carbonyl]amino]-2-heptenoate, comprising the steps of:

1) preparing a crystal of the compound (Z) -7-X-2 ((S) -2,2-dimethylcyclopropylformamido)-2-heptenoic acid of the formula (XV);

2) Crystalline compound and cysteine of compound (Z) -7-X-2 ((S) -2,2-dimethylcyclopropylformamido)-2-heptenoic acid of formula (XV) Or cysteine hydrochloride reaction to prepare the compound (VI) cilastatin;

4) reacting the purified compound of formula (VI) cilastatin with a basic sodium salt solution to prepare a sodium cilastatin solid of the compound of formula (I);

Where X is a halogen atom,

(I)

The method according to claim 1, wherein the compound (Z) -7-X-2 ((S) -2,2-dimethylcyclopropylformamide group of the formula (XV) according to the step 1) The preparation method of the crystal of -2-heptenoic acid comprises: a) ethyl 7-X-2-oxoheptanoate and (+)-(S)-2,2-dimethylcyclopropene Preparation of compound (Z) -7-X-2 ((S) -2,2-dimethylcyclopropylformamido)-2-heptenoic acid of formula (XV) by amide reaction; b) Preparation of step a) The compound of the formula (XV) (Z) -7-X-2 ((S) -2,2-dimethylcyclopropylcarboxamide)-2-heptenoic acid is obtained by crystallization from dichloromethane and toluene. a crystal of (XV) compound;

Wherein X is chlorine or bromine;

(X V ) crystall

The method according to claim 1, wherein the compound (Z) -7-X-2 ((S) -2,2-dimethylcyclopropylformamide group of the formula (XV) according to the step 1) The preparation method of the crystal of -2-heptenoic acid includes: a) ethyl 7-X-2-oxoheptanoate and (+)-(S)-2,2-dimethylcyclopropene Preparation of compound (Z) -7-X-2 ((S)-2,2-dimethylcyclopropylcarboxamide)-2-heptenoic acid by amide reaction; The obtained compound of the formula (XV) (Z) -7-X-2 ((S)-2,2-dimethylcyclopropylformamide)-2-heptenoic acid in dioxane and cyclohexane Crystallization to give a crystal of the compound of formula (XV);

Wherein X is chlorine or bromine;

Dioxane and cyclohexane

(X V ) crystal

4. The method according to claim 1, wherein said neutral macroporous adsorption resin is an HP-10 resin column, and the eluent is a mixed solution of water, methanol and water.

The method according to claim 4, wherein the methanol to water mixed solution has a weight ratio of methanol to water of 1:9.

6. The method of claim 1 wherein the alkaline sodium salt of step 4) is sodium hydroxide.

7. The method of claim 1 comprising the steps of:

1) Preparation of compound (Z)-7-chloro-2 by reacting ethyl 7-chloro-2-oxoheptanoate (III) with (+)-(S)-2,2-dimethylcyclopropanecarboxamide ((S) -2,2-dimethylcyclopropylformamido)-2-heptenoic acid (V);

2) The compound (Z) -7-chloro-X-2 ((S) -2,2-dimethylcyclopropylformamido)-2-heptenoic acid (V) prepared in the step 1) Crystallization of the solvent methylene chloride and toluene or dioxane and cyclohexane to give a crystal of the compound of formula (V);

3) Crystalline compound and cysteine of compound (Z)-7-chloro-2((S)-2,2-dimethylcyclopropylcarboxamido)-2-heptenoic acid of formula (V) Or cysteine hydrochloride reaction to prepare the compound cilastatin (VI);

4) reacting cilastatin (VI) with a sodium hydroxide solution to prepare a sodium cilastatin (I) solid;

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