KR100957725B1 - Method for preparing intermediate of cilastatin - Google Patents

Method for preparing intermediate of cilastatin Download PDF

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KR100957725B1
KR100957725B1 KR1020090062543A KR20090062543A KR100957725B1 KR 100957725 B1 KR100957725 B1 KR 100957725B1 KR 1020090062543 A KR1020090062543 A KR 1020090062543A KR 20090062543 A KR20090062543 A KR 20090062543A KR 100957725 B1 KR100957725 B1 KR 100957725B1
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dimethylcyclopropanecarboxamido
acid
organic solvent
halo
method
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KR1020090062543A
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Korean (ko)
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오석
이현국
조명정
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디에이치씨 (주)
오석
이현국
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00Preparation of carboxylic acid amides
    • C07C231/12Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00Preparation of carboxylic acid amides
    • C07C231/22Separation; Purification; Stabilisation; Use of additives
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/40Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton

Abstract

The present invention is hydrolyzed by adding an aqueous alkali solution to ethyl (E, Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenoate ( Obtaining an aqueous solution of E, Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid alkaline salt; Extracting a first organic solvent layer by adding a first organic solvent and an acid to the reactant and then separating the layers; An amine-based material was added to the extracted first organic solvent layer to form (E, Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid. Obtaining a mixed crystal of the amine salt; And recrystallizing the mixed crystal in a second organic solvent to obtain (Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid amine salt. It provides a method for producing a silastatin intermediate comprising.

Description

Method for preparing the cilastatin intermediate {METHOD FOR PREPARING INTERMEDIATE OF CILASTATIN}

The present invention relates to a method for preparing (Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid or an amine salt thereof, which is an intermediate of cilastatin. will be.

Imipenem is a circular carbapenem antibacterial agent and has a very broad spectrum of antibacterial activity. However, in such clinical use of imipenem, it is common to administer with sodium salt of cilastatin to prevent its renal metabolism. These imipenem / cilastatin combinations are potentially broad spectrum antibacterial agents administered intramuscularly, such as sepsis or neutropenia fever, in the abdomen, low respiratory pathways, comparative genitals, gynecology, skin, soft tissues, bones or joints. It can be effectively used in monotherapy for the treatment of infection. The imipenem / cilastatin combination can generally exhibit similar efficacy against a broad spectrum of cephalosporins or other carbapenems.

On the other hand, the cilastatin is a cysteine hydrochloride and (Z) -7-halo-((S) -2,2-dimethylcyclopropanecarboxamido) -2-heptenic acid represented by the following [Formula 1] or salts thereof It is prepared by a multi-step preparation method comprising the step of reacting, which method was first disclosed in US Pat. No. 5,147,868.

Figure 112009041841821-pat00001

X is a halogen element here.

A conventional manufacturing method for preparing the above [Formula 1] is known from EP 48301. Condensation reaction of ethyl 7-chloro-2-oxo-peptanoate with (s) -2,2'-dimethylcyclopropanecarboxamide, as described in EP 48301, yields ethyl (E) -7. Ethyl (Z) -7-chloro-2-((s containing about 10 to 13% of -chloro-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenoate ) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenoate is produced. Hydrolysis of these leads to (Z) -7-chloro-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid as the target compound. As an impurity, isomer (E) -7-chloro- 2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid is contained. Therefore, in the end, it becomes a cause of a yield fall and a new impurity production in silastatin manufacture.

Thus, the present invention is an impurity of (Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid, and isomer (E) -7-halo- 2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid or salts thereof are efficiently removed to obtain high yield and high purity (Z) -7-halo-2-(( s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid and its salt are aimed at.

The present invention is hydrolyzed by adding an aqueous alkali solution to ethyl (E, Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenoate, Obtaining an aqueous solution of (E, Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid alkaline salt; Extracting a first organic solvent layer by adding a first organic solvent and an acid to the reactant and then separating the layers; An amine-based material was added to the extracted first organic solvent layer to form (E, Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid. Obtaining a mixed crystal of the amine salt; And recrystallizing the mixed crystal in a second organic solvent to obtain (Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid amine salt. It provides a method for producing a silastatin intermediate comprising.

The present invention may further comprise adding an acid to the (Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid amine salt.

In the present invention, the mixed crystal is recrystallized in the second organic solvent to give (Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid amine The step of obtaining the salt may be performed one or more times.

According to the present invention, high purity (Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid or salts thereof can be obtained in high yield, The manufacturing process can be simplified and the manufacturing time can be reduced.

As the invention allows for various changes and numerous embodiments, particular embodiments will be illustrated in the drawings and described in detail in the written description. However, this is not intended to limit the present invention to specific embodiments, it should be understood to include all modifications, equivalents, and substitutes included in the spirit and scope of the present invention.

The terminology used herein is for the purpose of describing particular example embodiments only and is not intended to be limiting of the present invention. Singular expressions include plural expressions unless the context clearly indicates otherwise. In this application, the terms "comprise" or "have" are intended to indicate that there is a feature, number, step, operation, component, part, or combination thereof described in the specification, and one or more other features. It is to be understood that the present invention does not exclude the possibility of the presence or the addition of numbers, steps, operations, components, components, or a combination thereof.

Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art. Terms such as those defined in the commonly used dictionaries should be construed as having meanings consistent with the meanings in the context of the related art, and are not construed in ideal or excessively formal meanings unless expressly defined in this application. Do not.

Hereinafter, embodiments of the present invention will be described in detail.

The method for preparing cilastatin of the present invention can be summarized by the following Scheme 1.

Figure 112009041841821-pat00002

Here, X means halogen elements, such as fluorine and chlorine.

Referring to step 1 of [Scheme 1], ethyl (E, Z) -7-halo-2-((s) -2,2'- represented by (A) and (B) of [Scheme 1]. An aqueous alkali solution is added to dimethylcyclopropanecarboxamido) -2-heptenoate.

Wherein ethyl (E, Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenoate is prepared according to the method described in EP 48301. Although not obtained, it is also possible by other methods.

Here, as alkali used, sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, lithium hydroxide, etc. can be used. By addition of alkali, (A) and (B) in [Scheme 1] were hydrolyzed and (E, Z) -7-halo-2-((s) -2,2'-dimethylcyclopropane An aqueous solution of carboxamido) -2-heptenic acid alkaline salt is produced.

Next, a first organic solvent and an acid are added to the reactant to keep the pH of the reactant acidic. At this time, a water-insoluble organic solvent may be used as the organic solvent, for example, aromatic hydrocarbons such as benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1, Halogenated carbons such as 1-trichloroethane, methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanate, ethyl propane, propyl Ester, such as a propanate and a butyl propanoate, etc. can be used, or these solvent can be mixed and used.

Here, as the acid, inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid may be used, and organic acids such as acetic acid may be used.

Next, when the reactants are separated, the first organic solvent layer is (E, Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid. And unknown impurities are extracted.

Then, an amine-based substance (NRR 1 R 2 ) is added to the separated first organic solvent layer to obtain an amine salt represented by (C) and (D) in [Scheme 1].

Here, the amine-based material is a case where R, R 1 , R 2 are each a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or a cyclic aliphatic amine or an aromatic amine, and one of R, R 1 , R 2 is 3 Preference is given to using alkyl amines having up to 8 alkyl groups.

At this time, the amount of the amine-based material is ethyl (E, Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenoate or (E, Z) At least 1 mole should be added to 1 mole of -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid. Preferably, the dose of amine-based material is ethyl (E, Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenoate or (E, Z ) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid may be 1 to 2 times the number of moles, and the reaction temperature is high. There is no limit unless it is decomposed.

In this step, (Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid amine salt represented by (C) in [Scheme 1] and A mixed crystal of (E) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid amine salt represented by (D) in [Scheme 1] is produced. . The reaction can be filtered or distilled to obtain crystals.

Next, referring to step 2 of Scheme 1, this step is a step of recrystallization of the mixed crystal represented by (C) and (D) of [Scheme 1] with an organic solvent.

First, the mixed crystal represented by (C) and (D) of [Scheme 1] is dispersed in a second organic solvent. Here, the second organic solvent can be used a water-insoluble or water-soluble organic solvent or a mixture thereof. For example, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated carbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1-trichloroethane, methyl formate, Esters such as ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanate, ethyl propanate, propyl propane, butyl propanoate, methanol, Alcohols, such as ethanol, n-propanol, isopropanol, ketones, such as acetone and methyl ethyl ketone, tetrahydrofuran, acetonitrile, etc., or these solvents can be mixed and used.

At this time, the amine salt of Z form (C) of [Scheme 1] and the amine salt of E form of (D) of [Scheme 1] have different solubility with respect to the said 2nd organic solvent. That is, the amine salt of the E form is dissolved in the second organic solvent, and the amine salt of the Z form is precipitated and recrystallized.

The temperature of the recrystallization varies depending on the type of the second organic solvent, but a range of -30 degrees to 50 degrees is appropriate. The number of recrystallizations can be repeated once to several times because the removal efficiency of impurities varies depending on the solvent.

Through the recrystallization step as described above, (D) in [Scheme 1] is removed, and high purity (Z) -7-halo-2-((s) -2, represented by (C) in [Scheme 1], 2'-dimethylcyclopropanecarboxamido) -2-heptenic acid amine salt crystals can be obtained.

Step 3 of Scheme 1 acidifies high-purity (Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid amine salt crystals with an acid. (acidify) step.

Water crystals of high purity (Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid amine salt represented by (C) in [Scheme 1] Is dissolved in, and the pH is adjusted to 3 or less with acid. In this case, inorganic acids or organic acids such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, formic acid, methyl sulfonic acid and toluene sulfonic acid may be used.

Next, the produced crystal | crystallization was filtered and (E, Z) -7-halo-2-((s) -2,2'- dimethylcyclopropanecarboxamido)-which is represented by (E) of [Scheme 1]- 2-heptenic acid can be obtained.

The invention can be better understood by the following examples, which are intended to illustrate the invention and are not intended to limit the scope of protection thereof.

Reference Example

Ethyl (E, Z) -7- Chloro -2-((s) -2,2'- Dimethylcyclopropanecarboxamido )-2- Heptenoate  Produce

25.0 g (0.1209 mole) of ethyl 7-chloro-2-oxo-heptanoate, 13.68 g of (s) -2,2'-dimethylcyclopropanecarboxamide with reference to the method described in EP-48301 0.1209 mole), 125 ml of toluene and 0.25 g of toluene sulfonic acid are placed in a 500 ml flask and refluxed for 23 hours. Toluene is then distilled off to yield ethyl (E, Z) -7-chloro-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenoate.

Experimental Example  One

Step 1: ethyl (E, Z) -7- Chloro -2-((s) -2,2'- Dimethylcyclopropanecarboxamido )-2- Heptenoate  Hydrolysis and (E, Z) -7- Chloro -2-((s) -2,2'- Dimethylcyclopropanecarboxamido )-2- Heptenoic acid  n-propyl Amine salt  Produce

To ethyl (E, Z) -7-chloro-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenoate obtained in Reference Example 1, 50 ml of water and 40% aqueous sodium hydroxide solution 15.1 g was added at room temperature, followed by stirring at the same temperature for 24 hours, thereby containing (Z) -7-chloro-2-((s) -2,2 'containing about 10 to 13% of the isomer of (E) form. -Dimethylcyclopropanecarboxamido) -2-heptenic acid sodium salt aqueous solution is obtained.

150 ml of toluene was added to an aqueous solution of (E, Z) -7-chloro-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid sodium salt, and the pH was adjusted to 3 with aqueous hydrochloric acid solution. do. The layers are then separated, anhydrous magnesium sulfate is added to the organic solvent layer and filtered. 8.93 g of mono-n-propylamine was added to the filtered reaction solution, and the mixture was stirred for 1 hour, followed by distillation of toluene under reduced pressure. 40 g of (E, Z) -7-chloro-2-((s) -2,2'-dimethylcyclo Propanecarboxamido) -2-heptenic acid n-propyl amine salt is obtained.

Stage 2: (Z) -7- Chloro -2-((s) -2,2'- Dimethylcyclopropanecarboxamido )-2- Hep Tenic acid n-propyl Amine salt  Recrystallization

200 ml of isopropyl alcohol was added to (E, Z) -7-chloro-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid n-propyl amine salt obtained in step 1. It is dissolved completely by heating, and then crystallized by cooling below -20 degrees. Then, it was filtered and dried in vacuo at 40 degrees to give (Z) -7-chloro-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid n-propyl amine salt 32g (purity 94.1%) is obtained.

32 g of crystals were recrystallized twice with 200 ml of isopropyl alcohol, and 25 g (purity 99.3%) of pure (Z) -7-chloro-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2 -Heptenoic acid n-propyl amine salt is obtained.

Stage 3: (Z) -7- Chloro -2-((s) -2,2'- Dimethylcyclopropanecarboxamido )-2- Hep  Preparation of Tennic Acid

25 g (purity 99.3%) of pure (Z) -7-chloro-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid n-propyl amine salt obtained in step 2 Dissolve completely in 200 ml of water, and then adjust the pH to 3 or less with hydrochloric acid. The resulting crystals were then filtered and dried in vacuo to give 20.1 g (purity 99.3%) of (Z) -7-chloro-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-hep Get tennic acid.

Experimental Example  2

Step 1: ethyl (E, Z) -7- Chloro -2-((s) -2,2'- Dimethylcyclopropanecarboxamido )-2- Heptenoate  Hydrolysis and (E, Z) -7- Chloro -2-((s) -2,2'- Dimethylcyclo Ropancarboxamido) -2- Heptenoic acid tert -Butyl Amine salt  Produce

In the same manner as described in Experiment 1, (Z) -7-chloro-2-((s) -2,2'-dimethylcyclopropanecar containing about 10 to 13% of the isomer of form (E). Radiation-free) -2-heptenic acid sodium salt aqueous solution is obtained.

Next, 250 ml of ethyl acetate was added to an aqueous solution of (E, Z) -7-chloro-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid sodium salt, followed by PH Is adjusted to 3.0 and the layers are separated. Then, anhydrous magnesium sulfate is added to the organic solvent layer and filtered. Add 10.61 g of tert-butyl amine to the filtrate and warm it to dissolve completely. Next, the mixture was cooled to 0 degrees or less, crystallized, filtered, and dried in vacuo at 40 degrees to give (Z) -7-chloro-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2. 25 g (purity 96.0%) of tert-butyl amine salt is obtained.

Stage 2: (Z) -7- Chloro -2-((s) -2,2'- Dimethylcyclopropanecarboxamido )-2- Hep Tensan tert -Butyl Amine salt  Produce

250 ml of ethyl acetate was added to (E, Z) -7-chloro-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid tert-butyl amine salt obtained in step 1, followed by heating. Completely dissolved, cooled to 0 degrees or less, crystallized, filtered, and dried in vacuo at 40 degrees (Z) -7-chloro-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2. 23.5 g (purity 98.3%) of tert-butyl amine salt is obtained.

23.5 g (purity 98.3%) crystals were recrystallized again with 250 ml of ethyl acetate to give 22.0 g (99.3% pure) pure (Z) -7-chloro-2-((s) -2,2'-dimethylcyclopropanecarboxa. Mido) -2-heptenic acid tert-butyl amine salt is obtained.

Stage 3: (Z) -7- Chloro -2-((s) -2,2'- Dimethylcyclopropanecarboxamido )-2- Hep Preparation of Tennic Acid

The 22.0 g (purity 99.3%) crystals obtained in step 2 were completely dissolved in 200 ml of water, and the pH was adjusted to 3 or less with hydrochloric acid. 7-chloro-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid is obtained.

Experimental Example  3

Step 1: ethyl (E, Z) -7- Chloro -2-((s) -2,2'- Dimethylcyclopropanecarboxamido Hydrolysis of) -2-heptenoate and (E, Z) -7- Chloro -2-((s) -2,2'- Dimethylcyclo Ropancarboxamido) -2- Heptenoic acid tert -Butyl Amine salt  Produce

To (Z) -7-chloro-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid sodium salt aqueous solution obtained by the same method as described in Experimental Example 1, 1, 150 ml of 2-dichloroethane are added, the pH is adjusted to 3.0 with aqueous hydrochloric acid solution, and the layers are separated. Then, anhydrous magnesium sulfate is added to the organic solvent layer and filtered. 10.61 g of tert-butyl amine was added to the filtrate, and after stirring for 1 hour, the solvent was distilled off under reduced pressure. 42 g of (E, Z) -7-chloro-2-((s) -2,2'-dimethylcyclopropanecarboxamido)- 2-heptenic acid tert-butylamine salt is obtained.

Stage 2: High Purity (Z) -7- Chloro -2-((s) -2,2'- Dimethylcyclopropanecarboxami Fig.)-2- Heptenoic acid tert - Butylamine   Produce

250 ml of ethyl acetate was added to (E, Z) -7-chloro-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid n-propylamine salt obtained in step 1, followed by heating. Completely dissolved, cooled to 0 degrees or less, crystallized and filtered. Then, it was vacuum dried at 40 degrees to give 25 g of (Z) -7-chloro-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid tert-butyl amine salt (purity 95.8). %)

25 g of crystals were recrystallized twice from 250 ml of ethyl acetate twice to obtain 21 g (purity 99.4%) of pure (Z) -7-chloro-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2- Heptenoic acid tert-butylamine salt is obtained.

Stage 3: (Z) -7- Chloro -2-((s) -2,2'- Dimethylcyclopropanecarboxamido )-2- Hep Preparation of Tennic Acid

21 g (purity 99.4%) of pure (Z) -7-chloro-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid tert-butyl amine salt obtained in step 2 Dissolve completely in 200 ml of water and adjust the pH to 3 or less with hydrochloric acid. The resulting crystals were filtered and dried in vacuo to give 17.1 g (purity 99.4%) of (Z) -7-chloro-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid. .

As described above, according to an embodiment of the present invention, ethyl (E, Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenoate By non-selectively hydrolyzing with alkali, forming an amine salt and recrystallization, by a simple process, (Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido of high purity It is understood that) -2-heptenic acid or a salt thereof can be obtained.

Claims (7)

  1. Hydrolysis was performed by adding an aqueous alkali solution to ethyl (E, Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenoate to give (E, Z) Obtaining an aqueous solution of) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid alkaline salt;
    Extracting a first organic solvent layer by adding a first organic solvent and an acid to the reactant and then separating the layers;
    The amine-based material represented by the formula NRR 1 R 2 in the extracted first organic solvent layer, wherein R, R 1 and R 2 are each hydrogen, an alkyl group having 1 to 8 carbon atoms, or a cyclic aliphatic amine or aromatic amine. In some instances, one of R, R 1 , R 2 has an alkyl amine having 3 to 8 carbon atoms, and (E, Z) -7-halo-2-((s) -2,2 ' Obtaining a mixed crystal of dimethylcyclopropanecarboxamido) -2-heptenic acid amine salt; And
    Recrystallizing the mixed crystals under a second organic solvent to obtain (Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid amine salt;
    Method for producing a silastatin intermediate comprising a.
  2. The method of claim 1,
    (Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-heptenic acid A method for producing an intermediate, further comprising the step of adding an acid to the amine salt .
  3. The method of claim 1,
    The first organic solvent is a water-insoluble organic solvent, the second organic solvent is any one selected from a non-aqueous organic solvent, a water-soluble organic solvent or a mixed solvent thereof.
  4. The method of claim 1,
    And said alkali is sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate or lithium hydroxide.
  5. The method according to claim 1 or 2,
    The acid is a method for producing a silastatin intermediate, an inorganic acid or an organic acid.
  6. delete
  7. 2. The mixed crystal of claim 1, wherein the mixed crystal is recrystallized in the second organic solvent to give (Z) -7-halo-2-((s) -2,2'-dimethylcyclopropanecarboxamido) -2-hep. Obtaining the tenic acid amine salt is a method for producing a cilastatin intermediate is carried out repeatedly one or more times.
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KR100833202B1 (en) 2006-12-11 2008-05-28 (주)위즈켐 A preparation method for 7-chloro-(2,2-dimethylcyclopropanecarbox amido)-2-heptenoic acid
JP2009514939A (en) 2005-11-09 2009-04-09 オーキッド ケミカルズ アンド ファーマスーティカルズ リミテッド Improved process for the preparation of cilastatin and sodium salt

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5147868A (en) * 1978-07-24 1992-09-15 Merck & Co., Inc. Thienamycin renal peptidase inhibitors
KR100638471B1 (en) * 2004-08-25 2006-10-25 동국제약 주식회사 Novel process for the preparation of cilastatin sodium salt
CN101386588B (en) * 2008-08-28 2012-05-09 珠海联邦制药股份有限公司 Method for preparing cilastatin acid

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009514939A (en) 2005-11-09 2009-04-09 オーキッド ケミカルズ アンド ファーマスーティカルズ リミテッド Improved process for the preparation of cilastatin and sodium salt
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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