WO2008138228A1 - Procédé de préparation de sodium de cilastatine - Google Patents

Procédé de préparation de sodium de cilastatine Download PDF

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Publication number
WO2008138228A1
WO2008138228A1 PCT/CN2008/000947 CN2008000947W WO2008138228A1 WO 2008138228 A1 WO2008138228 A1 WO 2008138228A1 CN 2008000947 W CN2008000947 W CN 2008000947W WO 2008138228 A1 WO2008138228 A1 WO 2008138228A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
heptenoic acid
cilastatin
preparation
Prior art date
Application number
PCT/CN2008/000947
Other languages
English (en)
Chinese (zh)
Inventor
Zhaoqiang Lu
Hengli Zhang
Original Assignee
Shenzhen Haibin Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenzhen Haibin Pharmaceutical Co., Ltd. filed Critical Shenzhen Haibin Pharmaceutical Co., Ltd.
Publication of WO2008138228A1 publication Critical patent/WO2008138228A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/26—Separation; Purification; Stabilisation; Use of additives
    • C07C319/28—Separation; Purification

Definitions

  • the present invention relates to a process for the preparation of a compound, in particular to a process for preparing cilastatin sodium
  • 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 ⁇ -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.
  • 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.
  • step 2 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 ( ⁇ ) -7-chloro-2 ( (S) -2,2-Dimethylcyclopropylcarboxamido)-2-heptenoic acid.
  • 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 ( ⁇ )
  • the preparation of sodium cilastatin is suitable for industrial production, and the present invention provides a novel method for preparing cilastatin sodium.
  • 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:
  • X is chlorine or bromine
  • X is chlorine or bromine
  • 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.
  • Step 1 Preparation of -7-chloro-2 ((S)-2,2-dimethylcyclopropylcarboxamido)-2-heptenoic acid (V)
  • 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.
  • the mother liquor after crystallization was concentrated under reduced pressure to a constant weight to obtain 85 g of a brown viscous solution.
  • 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.
  • 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
  • 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%.
  • 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.
  • 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 ⁇ micropores.
  • the filter was suction filtered, and the filtrate was filtered through a 0.20 ⁇ filter to a sterile room.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation de sodium de cilastatine qui consiste à purifier de l'acide (Z)-7-chloro-2-((S)-2,2-diméthylcyclopropylcarboxamide)-2-hepténoïque par cristallisation afin d'obtenir de la cilastatine, et à purifier la cilastatine au moyen d'une résine macroporeuse neutre afin d'obtenir du sodium de cilastatine. L'invention permet d'améliorer la pureté et le rendement du sodium de cilastatine.
PCT/CN2008/000947 2007-05-16 2008-05-15 Procédé de préparation de sodium de cilastatine WO2008138228A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200710099332.X 2007-05-16
CN 200710099332 CN101307015B (zh) 2007-05-16 2007-05-16 一种制备西司他丁钠的方法

Publications (1)

Publication Number Publication Date
WO2008138228A1 true WO2008138228A1 (fr) 2008-11-20

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Application Number Title Priority Date Filing Date
PCT/CN2008/000947 WO2008138228A1 (fr) 2007-05-16 2008-05-15 Procédé de préparation de sodium de cilastatine

Country Status (2)

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CN (1) CN101307015B (fr)
WO (1) WO2008138228A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110845354A (zh) * 2018-08-21 2020-02-28 鲁南制药集团股份有限公司 一种西司他丁钠中间体的制备方法
CN115108934A (zh) * 2022-07-08 2022-09-27 珠海联邦制药股份有限公司 一种西司他丁中间体钠的制备方法

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* Cited by examiner, † Cited by third party
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CN102675175B (zh) * 2011-03-08 2014-02-19 深圳市海滨制药有限公司 一种西司他丁的分离纯化方法
CN102702051B (zh) * 2011-03-26 2016-04-13 山东新时代药业有限公司 一种西司他丁钠的制备方法
CN104649948B (zh) * 2013-11-19 2017-05-24 江苏迪赛诺制药有限公司 一种西司他丁钙结晶体及其制备方法和应用
CN106518741B (zh) * 2016-10-21 2018-11-16 深圳市海滨制药有限公司 一种西司他丁钠原料药的制备方法
CN107522642A (zh) * 2017-08-14 2017-12-29 新乡海滨药业有限公司 一种西司他丁的精制方法
CN110305033B (zh) * 2018-03-20 2020-08-28 鲁南制药集团股份有限公司 一种西司他汀钠中间体的纯化方法
CN109111381A (zh) * 2018-10-30 2019-01-01 雅本化学股份有限公司 一种西司他丁的制备方法
CN115260067A (zh) * 2022-08-26 2022-11-01 同舟纵横（厦门）流体技术有限公司 一种西司他丁母液纯化的方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0048301A1 (fr) * 1980-09-24 1982-03-31 Merck & Co. Inc. 2-(Cyclopropancarboxamido)-2-alcèneacides, leurs esters et sels, et compositions bactériostatiques à base de ces composés avec un composé du type thiénamycine
CN1592737A (zh) * 2001-08-24 2005-03-09 兰贝克赛实验室有限公司 制造西司他汀的方法
WO2006022511A1 (fr) * 2004-08-25 2006-03-02 Dong Kook Pharm. Co., Ltd. Nouveau procede de preparation d'un sel de sodium de cilastatine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0048301A1 (fr) * 1980-09-24 1982-03-31 Merck & Co. Inc. 2-(Cyclopropancarboxamido)-2-alcèneacides, leurs esters et sels, et compositions bactériostatiques à base de ces composés avec un composé du type thiénamycine
CN1592737A (zh) * 2001-08-24 2005-03-09 兰贝克赛实验室有限公司 制造西司他汀的方法
WO2006022511A1 (fr) * 2004-08-25 2006-03-02 Dong Kook Pharm. Co., Ltd. Nouveau procede de preparation d'un sel de sodium de cilastatine

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110845354A (zh) * 2018-08-21 2020-02-28 鲁南制药集团股份有限公司 一种西司他丁钠中间体的制备方法
CN110845354B (zh) * 2018-08-21 2020-08-25 鲁南制药集团股份有限公司 一种西司他丁钠中间体的制备方法
CN115108934A (zh) * 2022-07-08 2022-09-27 珠海联邦制药股份有限公司 一种西司他丁中间体钠的制备方法
CN115108934B (zh) * 2022-07-08 2024-02-06 珠海联邦制药股份有限公司 一种西司他丁中间体钠的制备方法

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CN101307015B (zh) 2012-06-13
CN101307015A (zh) 2008-11-19

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