WO2006022511A1 - Nouveau procede de preparation d'un sel de sodium de cilastatine - Google Patents

Nouveau procede de preparation d'un sel de sodium de cilastatine Download PDF

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Publication number
WO2006022511A1
WO2006022511A1 PCT/KR2005/002782 KR2005002782W WO2006022511A1 WO 2006022511 A1 WO2006022511 A1 WO 2006022511A1 KR 2005002782 W KR2005002782 W KR 2005002782W WO 2006022511 A1 WO2006022511 A1 WO 2006022511A1
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WO
WIPO (PCT)
Prior art keywords
salt
cilastatin
water
chloro
chemical formula
Prior art date
Application number
PCT/KR2005/002782
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English (en)
Inventor
Man Dong Rho
Dong Yeol Baek
Han Won Lee
Dong Yub Lee
Sang Woo Bang
Kyung Hoi Cha
Hee Sock Park
Original Assignee
Dong Kook Pharm. 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 Dong Kook Pharm. Co., Ltd. filed Critical Dong Kook Pharm. Co., Ltd.
Publication of WO2006022511A1 publication Critical patent/WO2006022511A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/82—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • 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
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to novel process for preparing cilastatin sodium salt used as a dehydropeptidase 1 inhibitor.
  • Cilasatin sodium salt i.e., [R-[R*, S*-(Z)]] -
  • EP 48301 Bl discloses a method for the preparation of a cilastatin sodium salt using by Grignard reaction started from l-bromo-5-chloropentane (2') explained by following Reaction Scheme 1; Donald W.
  • Graham et al discloses a preparation method using ethyl- 1, 3-dithian-2-carboxylate as a starting material (Donald W. Graham et al, J. Med. Chem., 30, pplO74, 1987) etc. [4] [Reaction Scheme 1]
  • PCTAVO 0318544 discloses the isolation method using by neutral HP 20 resin column instead of cationic resin disclosed in EP 48301 Bl
  • PCTAVO 02094742 discloses the method for preparing cilastatin sodium salt (Ia) from cilastatin (6'), the disclosure of which cited documents are incorporated herein by reference.
  • the present inventors have made extensive researches to discover novel method for preparing cilastatin sodium salt with high yield and mass production and finally completed the invention by founding novel preparation for obtaining purposed cilastatin sodium salt; i.e., selectively hydrolyzing (Z)-7-chloro-2-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoate, isolating (Z)-7-chloro-2-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoic acid metal salt from the reaction mixture, adopting the cilastatin amine salt instead of free acid form disclosed in cited references and the use of sodium hydroxide and cationic exchange resin with pH control in order to obtain cilastatin sodium salt with high purity and high yield.
  • the present invention provides novel method for preparing cilastatin sodium salt used as a dehy- dropeptidase 1 inhibitor.
  • the present invention provides novel method for preparing (Z)-7-chloro-2-((S)-2,
  • 2-dimethylcyclopropanecarboxamido)-2-heptenoic acid metal salt represented by general chemical formula (12) comprising the steps consisting of: selectively hy ⁇ drolyzing (Z)-7-chloro-2-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoate represented by chemical formula (4) in reaction solvent under basic condition and removing un-reacted product remained in reaction solvent layer with washing organic solvent with controlling the pH of reaction solution with acid to be neutralization at the 1 st step; concentrating remaining water layer, adding alcohol thereto with heating, stirring to the extent to dissolve the solid, filtering out un-dissolved salt, and con ⁇ centrating the filtrate under reduced pressure at the 2 nd step; adding organic solvent to solidify the concentrate, filtrating the solution to isolate and purify (Z)-7-chloro-2-((S )-2, 2-dimethylcyclopropanecarboxamido)-2-heptenoic acid metal salt represented by chemical formula (12)
  • the reaction solvent may be used water, lower alcohol such as methanol, ethanol and propanol, or the mixture thereof, preferably the mixture of water and methanol, water and ethanol or water and propanol may be preferably used, and the reaction is preferably to be finished where the ratio of (Z) and (E) isomer is 100-10: 1, more preferably 50-15: 1, most preferably 30-20: 1 to provide with selective hydrolysis.
  • Strong base such as lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH) etc may be preferably used and the organic solvent such as diisopropylether, dichloromethane, carbon tetrachloride, chloroform, hexane etc are preferable as a washing organic solvent.
  • the pH of reaction solution ranging from 6 to 8, preferably about 7 may be used to neutralization by controlling with strong acid such as hydrochloric acid, sulfuric acid etc or weak acid such as acetic acid etc at the 1 st step.
  • the stirring with alcohol preferably is performed at the temperature ranging from about 10 to 80°C, preferably about 30 to 60°C, more preferably about 50°C, for the period ranging from 10 minutes to 24 hours, preferably 30 minutes to 1 hour and the lower alcohol such as methanol, ethanol and propanol, or mixture thereof may be preferably used to remove formed inorganic salt.
  • the lower alcohol such as methanol, ethanol and propanol, acetone, acetonitrile or the mixture thereof, preferably the mixture of water and alcohol, alcohol and acetonitrile, alcohol and acetone etc may be preferably used to isolate final product.
  • 2-dimethylcyclopropanecarboxamido)-2-heptenoic acid salt represented by following chemical formula (12) can be synthesized with high purity (more than 90%) and the method could provide the next step with reproducibility with quantitative supply in the synthesis of cilastatin amine salt (13).
  • the M group of general chemical formula (12) includes all the alkali metal salt such as lithium salt, sodium salt, potassium salt and the like however the present invention does not intent to limit or define the kind of salt herein.
  • the present invention provides novel method for preparing cilastatin sodium salt represented by chemical formula (1) comprising the steps consisting of: reacting (Z)-7-chloro-2-((S)-2, 2-dimethylcyclopropanecarboxamido)-2-heptanoic acid or the salt thereof represented by chemical formula (12) with cysteine in base solution at the 1 st step; controlling the pH of the reaction solution obtain in step 1, concentrating, adsorbing the concentrate with cationic exchange resin, washing with water, eluting with amine solution to concentrate the elutes at the 2 n step; dissolving the concentrates in recrystallization solvent and subjecting to recrystallization process by adding alcohol in a dropwise manner to afford pure cilastatin amine salt (13) at the 3 r step; reacting cilastatin amine salt (13) with sodium hydroxide and controlling the pH with cationic exchange resin at the 4 step.
  • R is a hydrogen atom or lower alkyl group.
  • the R group of general chemical formula (13) includes a hydrogen atom or C1-C4 alkyl group such as methyl, ethyl, propyl group etc preferably.
  • the product obtained from 1 st step is adjusted to the pH of the solution ranging from 3.0 to 7.0, preferably 5.0 to 5.5, con ⁇ centrated and the alcohol such as methanol, ethanol or propanol is added thereto.
  • the solution is stirred at the temperature ranging from about 10 to 80°C, preferably about 30 to 60°C, more preferably about 50°C, for the period ranging from 10 minutes to 3 hours, preferably 30 minutes to 1.5 hours, more preferably about 1 hour, subjected to filtration to remove resulting inorganic salt and the filtrate is concentrated to the extent that total volume of solution is reduced to about 1/2.
  • the concentrate is adsorbed with cationic exchange resin such as styrene strong acidic resin and the column is washed with water to the extent that the conductivity becomes less than 20 ⁇ s, preferably lO ⁇ s and eluted with amine solution in the concentration ranging from 1 to 5 N, preferably 2N amine solution to concentrate the eluate.
  • cationic exchange resin such as styrene strong acidic resin
  • amine solution in the concentration ranging from 1 to 5 N, preferably 2N amine solution to concentrate the eluate.
  • ammonia water is used as an eluate
  • cilastatin ammonium salt (13) is formed.
  • the cilastatin amine salt (13) of which salt form is varied according to the kind of amine salt may be formed if amine solution is used as an eluate.
  • the water and ammonia water, or the mixture thereof may be used as a recrystallization solvent, preferably the solvent in the amount ranging from 1:3 to 2:1 (w/v) of the weight of cilastatin amine salt is added to the concentrate obtained in step 2 and alcohol such as ethanol, n-propanol, 2-propanol etc, preferably the solvent in the amount ranging from 1 : 10 to 1 :40 (w/v) of the weight of cilastatin amine salt is added.
  • the recrystallization process is preferably performed at less than 100°C, preferably 5 to 97°C.
  • the above-described solvent is added to cilastatin concentrate, subjected to salting out method performed by refluxing for the period ranging from 2 to 3 hours, cooling, and filtrating the solution to obtain purposed cilastatin amine salt (13).
  • the present invention provides novel intermediate represented by chemical formula (13).
  • the novel method of the present invention could prevent the production of (E)-isomer from the preparation of dehydropeptidase 1 inhibitor, i.e., (Z)-7-[chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid metal salt and isolate the dehydropeptidase 1 inhibitor in situ providing simpler process with high yield and high purity. Best Mode for Carrying Out the Invention
  • the novel method of the present invention could prevent the formation of (E )-isomer from the preparation of novel intermediate for preparing cilastatin sodium, i.e., (Z)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid metal salt and isolate the intermediate in situ providing simpler process with high yield and purity. Furthermore, it can provide with highly purified cilastatin sodium salt by isolating novel cilastatin amine salt and using sodium hydroxide and cationic exchange resin. Accordingly, the method can be very useful in preparing cilastatin sodium salt with high yield and high purity.

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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

Nouveau procédé de préparation d'un sel de sodium de cilastatine utilisé comme inhibiteur de déhydropeptidase 1. Le nouveau procédé permet d'éviter la formation de (E)-isomère à partir de la préparation d'un intermédiaire pour la préparation du sodium de cilastatine, notamment un sel métallique d'acide (Z)-7-chloro-2-((S)-2,2-diméthylcyclopropanecarboxarnido)-2-hepténoïque et d'isoler l'intermédiaire sur place assurant ainsi un procédé plus simple à haut rendement et forte parité. On obtient par ailleurs un sel de sodium de cilastatine très pur par isolement d'un nouveau sel d'amine de cilastatine et au moyen d'un hydroxyde de sodium d'une résine d'échange cationique. Le procédé s'avère très utile dans la préparation du sel de sodium de cilastatine à haut rendement et pureté élevée.
PCT/KR2005/002782 2004-08-25 2005-08-24 Nouveau procede de preparation d'un sel de sodium de cilastatine WO2006022511A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2004-0067119 2004-08-25
KR1020040067119A KR100638471B1 (ko) 2004-08-25 2004-08-25 실라스타틴 나트륨염의 신규한 제조 방법

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7371897B1 (en) * 2006-12-11 2008-05-13 Wischem Co., Ltd. Preparation method for (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid
WO2008138228A1 (fr) * 2007-05-16 2008-11-20 Shenzhen Haibin Pharmaceutical Co., Ltd. Procédé de préparation de sodium de cilastatine
WO2010005175A2 (fr) * 2008-07-09 2010-01-14 (주)하이텍팜 Nouvelles cilastatines sous forme de sels d'ammonium cristallins et procédé de préparation
CN102030674A (zh) * 2009-07-09 2011-04-27 Dhc有限公司 西司他丁中间体的制备方法
WO2011080648A1 (fr) * 2010-01-01 2011-07-07 Orchid Chemicals And Pharmaceuticals Limited Procédé amélioré pour la préparation de cilastatine sodique
EP2402312A1 (fr) 2005-11-09 2012-01-04 Orchid Chemicals&Pharmaceuticals Limited Procédé amélioré pour la préparation de l'acide de cilastatine
CN102702051A (zh) * 2011-03-26 2012-10-03 山东省新时代药业有限公司 一种西司他丁钠的制备方法
CN104649948A (zh) * 2013-11-19 2015-05-27 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
CN110305033A (zh) * 2018-03-20 2019-10-08 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
CN111285781A (zh) * 2018-12-06 2020-06-16 鲁南制药集团股份有限公司 一种西司他丁钠关键中间体的制备方法

Families Citing this family (4)

* Cited by examiner, † Cited by third party
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US7875556B2 (en) 2005-05-16 2011-01-25 Air Products And Chemicals, Inc. Precursors for CVD silicon carbo-nitride and silicon nitride films
US8530361B2 (en) 2006-05-23 2013-09-10 Air Products And Chemicals, Inc. Process for producing silicon and oxide films from organoaminosilane precursors
US7875312B2 (en) 2006-05-23 2011-01-25 Air Products And Chemicals, Inc. Process for producing silicon oxide films for organoaminosilane precursors
KR101649733B1 (ko) * 2014-10-17 2016-08-22 임대식 효소를 이용한 실라스타틴 나트륨염의 신규한 제조 방법

Citations (2)

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US5147868A (en) * 1978-07-24 1992-09-15 Merck & Co., Inc. Thienamycin renal peptidase inhibitors
WO2003018544A1 (fr) * 2001-08-24 2003-03-06 Ranbaxy Laboratories Limited Procede de preparation de cilastatine

Patent Citations (2)

* 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
WO2003018544A1 (fr) * 2001-08-24 2003-03-06 Ranbaxy Laboratories Limited Procede de preparation de cilastatine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GRAHAM D.W. ET AL: "Inhibition of the mammalian beta-lactamase renal dipeptidase (dehydropeptidase-I) by (Z)-2-(acylamino)-3-substituted-propenoic acids", J. MED. CHEM., vol. 30, 1987, pages 1074 - 1090 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8247606B2 (en) 2005-11-09 2012-08-21 Orchid Chemicals & Pharmaceuticals Limited Process for the preparation of cilastatin and sodium salt
EP2402312A1 (fr) 2005-11-09 2012-01-04 Orchid Chemicals&Pharmaceuticals Limited Procédé amélioré pour la préparation de l'acide de cilastatine
US8134026B2 (en) 2005-11-09 2012-03-13 Orchid Chemicals & Pharmaceuticals Limited Process for the preparation of Cilastatin and sodium salt
US20120078009A1 (en) * 2005-11-09 2012-03-29 Orchid Chemicals & Pharmaceuticals Limited Process for the preparation of cilastatin and sodium salt
US7371897B1 (en) * 2006-12-11 2008-05-13 Wischem Co., Ltd. Preparation method for (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid
WO2008138228A1 (fr) * 2007-05-16 2008-11-20 Shenzhen Haibin Pharmaceutical Co., Ltd. Procédé de préparation de sodium de cilastatine
WO2010005175A2 (fr) * 2008-07-09 2010-01-14 (주)하이텍팜 Nouvelles cilastatines sous forme de sels d'ammonium cristallins et procédé de préparation
WO2010005175A3 (fr) * 2008-07-09 2010-03-11 (주)하이텍팜 Nouvelles cilastatines sous forme de sels d'ammonium cristallins et procédé de préparation
CN102030674A (zh) * 2009-07-09 2011-04-27 Dhc有限公司 西司他丁中间体的制备方法
WO2011080648A1 (fr) * 2010-01-01 2011-07-07 Orchid Chemicals And Pharmaceuticals Limited Procédé amélioré pour la préparation de cilastatine sodique
CN102702051A (zh) * 2011-03-26 2012-10-03 山东省新时代药业有限公司 一种西司他丁钠的制备方法
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
CN104649948A (zh) * 2013-11-19 2015-05-27 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
CN110305033A (zh) * 2018-03-20 2019-10-08 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
CN111285781A (zh) * 2018-12-06 2020-06-16 鲁南制药集团股份有限公司 一种西司他丁钠关键中间体的制备方法

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