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WO2006035300A2 - Procede de preparation de meropenem - Google Patents

Procede de preparation de meropenem Download PDF

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Publication number
WO2006035300A2
WO2006035300A2 PCT/IB2005/002889 IB2005002889W WO2006035300A2 WO 2006035300 A2 WO2006035300 A2 WO 2006035300A2 IB 2005002889 W IB2005002889 W IB 2005002889W WO 2006035300 A2 WO2006035300 A2 WO 2006035300A2
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WO
WIPO (PCT)
Prior art keywords
formula
meropenem
compound
aqueous layer
reaction mass
Prior art date
Application number
PCT/IB2005/002889
Other languages
English (en)
Other versions
WO2006035300A3 (fr
Inventor
Neera Tewari
Hashim Nizar Poovanathil Nagoor Meeran
Bishwa Prakash Rai
Avinash Sheshrao Mane
Yatendra Kumar
Original Assignee
Ranbaxy Laboratories Limited
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 Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2006035300A2 publication Critical patent/WO2006035300A2/fr
Publication of WO2006035300A3 publication Critical patent/WO2006035300A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20—Sulfur atoms

Definitions

  • the present invention provides a one-pot process for the preparation of meropenem.
  • the present invention further provides a process for the preparation of meropenem trihydrate.
  • meropenem is indicated as single-agent therapy for the treatment of the following infections when caused by the following susceptible strains: complicated appendicitis and peritonitis caused by viridians group Streptococci, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, B. thetaiotaomicron, and Peptostreptococcus species; bacterial meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae (b-lactamase and non-b-lactamase- producing strains), and Neisseria meningitidis.
  • Meropenem has been found to be effective in eliminating concurrent bacteremia in association with bacterial meningitis.
  • Meropenem is commercially available as a crystalline trihydrate form having Formula II.
  • U.S. Patent No. 4,888,344 provides a process for the preparation of the crystalline trihydrate of meropenem.
  • U.S. Patent Nos. 4,943,569 and 5,122,604 provide similar processes for the preparation of meropenem trihydrate.
  • Sunagawa et al., J. Antibiotics, XLIIL 1176 (1990) discusses several methods for preparation of carbapenem derivatives, specifically meropenem.
  • the processes reported in the prior art provide meropenem trihydrate which involves lyophilization of an aqueous layer containing meropenem.
  • the amorphous material so obtained is crystallized to get meropenem trihydrate.
  • the process involves column chromatographic purification of reaction product followed by concentration of the aqueous layer by reverse osmosis. To the concentrated aqueous layer, acetone or tetrahydrofuran or isopropanol is added for the precipitation of meropenem trihydrate.
  • the yield of meropenem trihydrate thus obtained is generally low, and the purity is variable.
  • meropenem can be prepared by condensation reaction of the enol-phosphate of Formula III with thiopyrrolidine of Formula IV to produce the compound of Formula V, and deprotection the compound of Formula V without isolation to obtain meropenem.
  • meropenem trihydrate can be isolated from the aqueous reaction layer without any chromatographic purification or reverse osmosis technique, rather by adding water miscible co-solvents such as acetone, tetrahydrofuran or isopropanol.
  • the processes of the present invention are high- yielding, cost-effective and easily scalable at commercial scale.
  • Meropenem trihydrate obtained according to processes described herein has a purity in excess of 98% w/w when measured by HPLC.
  • a one-pot process for preparation of meropenem which comprises: a) condensing an enol-phosphate of Formula III with the thiopyrrolidine of Formula IV to produce the protected product of Formula V,
  • processes for preparation of meropenem which comprises: a) condensing an enol-phosphate of Formula III with the thiopyrrolidine of Formula IV to produce the compound of Formula V,
  • processes for preparation of meropenem which comp ⁇ ses: a) condensing enol-phosphate of Formula III with thiopyrrolidine of Formula IV to produce the compound of Formula V,
  • processes for the preparation of meropenem trihydrate which comprises: a) deprotecting the compound of Formula V by hydrogenolysis, FORMULA V b) separating the aqueous layer containing meropenem from the reaction mass, c) adding a water miscible organic solvent to the aqueous layer to precipitate meropenem trihydrate from the aqueous solution, and d) isolating pure meropenem trihydrate from the reaction mass thereof.
  • meropenem trihydrate having purity greater than 98% is provided, prepared by a process comprising a) deprotecting the compound of Formula V by hydrogenolysis,
  • Enol-phosphate of Formula III and thiopyrrolidine of Formula IV can be prepared by processes reported in the prior art. These two compounds can be dissolved in an organic solvent and the resultant reaction mass under stirring may be cooled to about - 60° to -1O 0 C. The organic solvent may be inert and may keep the reactants substantially in solution when cooled. To this reaction mass is added diisopropylamine dropwise to control the temperature. After stirring from about 30 minutes to about 6 hours, the reaction mixture can be poured in a mixture of ethyl acetate and water.
  • the organic layer is directly subjected to hydrogeno lysis for deprotection of the protecting groups.
  • Water is added to the organic layer containing the product and the resultant biphasic mass is hydrogenated using a noble metal catalyst.
  • hydrogen gas or a compound capable of generating hydrogen gas can be used as source of hydrogen.
  • a buffering agent comprising N-methylmorpholine and an acid may be added.
  • the acid to be used could be an organic or an inorganic acid.
  • Hydrogenation carried out in a biphasic system offers several advantages. Firstly, side products such as p-toluidine and coloring impurities remain in the organic layer whereas deprotected meropenem is present in aqueous layer. Secondly, isolation of meropenem from aqueous layer is easy, as removal of impurities present in organic layer is facilitated by layer separation.
  • Use of N-methylmorpholine and an acid as a buffer offers advantage in terms of cost and availability.
  • the buffer system also serves as a tool for carrying out the reaction at a pH of about 7.
  • the aqueous layer containing the product is washed with an organic solvent and to the combined aqueous layers is added a miscible organic solvent so as to precipitate meropenem trihydrate from the solution thereof.
  • the precipitation can be carried out at lower temperature of about -20 to 25°C.
  • the separated meropenem trihydrate is then isolated by means of filtration or centrifuge and dried suitably to get pure meropenem trihydrate having purity in excess of 98%.
  • Step a) Preparation of 4-Nitrobenzyl (4R,5S,6S)-3-( ⁇ (3S,5S)-5- [(dimethylamino)carbonyl]-l-[(4-nitrophenoxy)carbonxyl] pyrroIidin-3-yl ⁇ thio)-6- [(l ⁇ -l-hydorxyethyl ⁇ -methyl-T-oxo-l-azabicclo ⁇ J.Olhept-Z-ene-Z-carboxylate 4-nitrobenzyl (4 ⁇ ,5i?,65)-3-[(diphenoxyphosphoryl)oxy]-6-[(li?)-l -hydroxyethyl]-
  • Step b) Preparation of (4R,5S,6S)-3-( ⁇ (3S,5S)-5- [(Dimethylamino)carbonyl]pyrrolidin-3-yl ⁇ thio)-6-[(lR)-l-hydroxyethyl]-4-methyl-7- oxo-l-azabicyc!o[3.2.0]hept-2-ene-2-carboxylic acid
  • the above biphasic reaction mass was hydrogenated for 3 hours under pressure at 20-25 0 C. After completion of the reaction, the mixture was filtered and aqueous layer was separated. The aqueous layer was concentrated by reverse osmosis and to the condensate was added tetrahydrofuran at a temperature of about 5-1O 0 C. The resultant mixture was stirred for about 5 hours to get crystalline meropenem trihydrate in a yield of 50 gm.
  • the above biphasic reaction mass was hydrogenated for 3 hours under pressure at 20-25 0 C. After completion of the reaction, the mixture was filtered and aqueous layer was separated. The aqueous layer was extracted with ethyl acetate (300 ml). To the aqueous layer was added acetone (1.5 Lit) slowly at a temperature of about 0-5 0 C and the resultant mass was stirred for 3 hours at 0-5 0 C. The separated solids were filtered, washed with chilled acetone and dried at ambient temperature under vacuum to get meropenem trihydrate in a yield of 24.5 gm.
  • Example 4 Synthesis of Meropenem trihvdrate To 4-nitrobenzyl (4R,5S,6 1 S)-3-( ⁇ (3S,5S)-5-[(dimethylamino)carbonyl]-l-[(4- nitrobenzyloxy)carbonyl]pyrrolidin-3-yl ⁇ thio)-6-[( 1 r)- 1 -hydroxyethyl]-4-methyl-7-oxo- 1 - azabicyclo[3.2.0]hept-2-ene-2-carboxylate (100 gm) in ethyl acetate (1.0 L) was added a mixture of 5% palladium on carbon (100 gm) in aqueous buffer (1.0 L) containing N- methylmorpholine and acetic acid (pH about 7.0).
  • the above biphasic reaction mass was hydrogenated for 3 hours under pressure at 20-25 0 C. After completion of the reaction, the mixture was filtered and aqueous layer was separated. The aqueous layer was extracted with ethyl acetate (300 ml). To the aqueous layer was added isopropyl alcohol (1.5 L) slowly at a temperature of about 0-5 0 C and the resultant mass was stirred for 3 hours at 0-5 0 C. The separated solids were filtered, washed with chilled acetone and dried at ambient temperature under vacuum to get meropenem trihydrate in a yield of 22.0 gm.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé monotope de préparation de meropenem. L'invention concerne également un procédé de préparation de trihydrate de meropenem trihydrate.
PCT/IB2005/002889 2004-09-30 2005-09-28 Procede de preparation de meropenem WO2006035300A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN1896/DEL/2004 2004-09-30
IN1896DE2004 2004-09-30
IN1895DE2004 2004-09-30
IN1895/DEL/2004 2004-09-30

Publications (2)

Publication Number Publication Date
WO2006035300A2 true WO2006035300A2 (fr) 2006-04-06
WO2006035300A3 WO2006035300A3 (fr) 2006-08-31

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007031858A3 (fr) * 2005-09-15 2007-07-12 Orchid Chemicals & Pharm Ltd Procede ameliore de preparation d'un antibiotique beta-lactame
KR100869165B1 (ko) 2007-09-13 2008-11-19 조동옥 메로페넴의 개선된 제조방법
EP2098525A1 (fr) * 2008-02-26 2009-09-09 Savior Lifetec Corporation Composé de carbapenem cristallin et son procédé de production
WO2010022590A1 (fr) * 2008-08-29 2010-03-04 深圳市海滨制药有限公司 Procédé de préparation du méropénèm
CN101891742A (zh) * 2010-07-20 2010-11-24 深圳市海滨制药有限公司 美罗培南三水合物结晶的制备方法
CN101914098A (zh) * 2010-07-20 2010-12-15 深圳市海滨制药有限公司 美罗培南三水合物结晶的制备方法
WO2010104336A3 (fr) * 2009-03-13 2010-12-23 주식회사 대웅제약 Procédé amélioré pour la préparation de meropenem à l'aide de poudre de zinc
EP2006290A4 (fr) * 2006-03-28 2011-01-05 Kaneka Corp Procédé amélioré de production d'un composé de carbapenem
CN102153554A (zh) * 2010-09-21 2011-08-17 重庆天地药业有限责任公司 一种制备美罗培南的方法
CN102250096A (zh) * 2011-09-05 2011-11-23 江西华邦药业有限公司 一种美罗培南的制备方法
US8097719B2 (en) 2008-07-15 2012-01-17 Genesen Labs Meropenem intermediate in novel crystalline form and a method of manufacture of meropenem
CN102372715A (zh) * 2011-12-07 2012-03-14 凯莱英医药集团（天津）股份有限公司 一种制备美罗培南的方法
WO2012052978A1 (fr) 2010-10-22 2012-04-26 Ranbaxy Laboratories Limited Procédé de préparation de méropénème trihydraté pur
KR101142757B1 (ko) * 2009-12-03 2012-05-08 (주)하이텍팜 메로페넴 삼수화물의 제조방법
CN102532140A (zh) * 2010-12-21 2012-07-04 北大方正集团有限公司 一种美罗培南三水合物的制备方法
US8318716B2 (en) 2009-12-31 2012-11-27 Kbp Biosciences Co., Ltd. Carbapenem derivatives
KR20140147262A (ko) 2013-06-19 2014-12-30 제이더블유중외제약 주식회사 결정형 메로페넴 삼수화물의 제조방법
CN105194436A (zh) * 2015-10-26 2015-12-30 张刚 一种用于消除阑尾脓肿的外敷药物
RU2575979C2 (ru) * 2009-04-30 2016-02-27 СиЭсПиСи ЧЖУНЦИ ФАРМАСЬЮТИКАЛ ТЕКНОЛОДЖИ (ШИЦЗЯЧЖУАН)КО., ЛТД. Способ получения промежуточного соединения эртапенема
CN111992205A (zh) * 2020-09-07 2020-11-27 西安凯立新材料股份有限公司 一种一锅法制备美罗培南用催化剂的方法

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EP0169410A1 (fr) * 1984-07-02 1986-01-29 Merck & Co. Inc. Carbapénèmes ayant en position 2 un substituant quaternisé pyridine alkylthio ou alkylénethio, compositions les contenant et leurs combinaisons avec des inhibiteurs de DHP
US4888344A (en) * 1986-07-30 1989-12-19 Sumitomo Pharmaceuticals Company, Limited Carbapenem compound in crystalline form, and its production and use
US5122604A (en) * 1983-05-09 1992-06-16 Sumitomo Pharmaceuticals Co., Ltd. β-lactam compounds
US5140030A (en) * 1985-06-10 1992-08-18 Merck 2-aza-substituted 1-carbadethiapen-2-em-3-carboxylic acids
US20020128283A1 (en) * 2000-07-13 2002-09-12 American Home Products Corporation Process improvement in the preparation of (4R, 5S, 6S)-3-[[(2R,3R)-2-[[[(S)-2-amino-3-methyl-1-oxobutyl]amino]methyl]tetrahydro-3-furanyl]thio]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
WO2002094828A1 (fr) * 2001-05-18 2002-11-28 Ranbaxy Laboratories Limited Procede relatif a l'elaboration d'imipenem
WO2005118586A1 (fr) * 2004-06-02 2005-12-15 Sandoz Ag Intermediaire de meropenem sous forme cristalline

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5122604A (en) * 1983-05-09 1992-06-16 Sumitomo Pharmaceuticals Co., Ltd. β-lactam compounds
EP0169410A1 (fr) * 1984-07-02 1986-01-29 Merck & Co. Inc. Carbapénèmes ayant en position 2 un substituant quaternisé pyridine alkylthio ou alkylénethio, compositions les contenant et leurs combinaisons avec des inhibiteurs de DHP
US5140030A (en) * 1985-06-10 1992-08-18 Merck 2-aza-substituted 1-carbadethiapen-2-em-3-carboxylic acids
US4888344A (en) * 1986-07-30 1989-12-19 Sumitomo Pharmaceuticals Company, Limited Carbapenem compound in crystalline form, and its production and use
US20020128283A1 (en) * 2000-07-13 2002-09-12 American Home Products Corporation Process improvement in the preparation of (4R, 5S, 6S)-3-[[(2R,3R)-2-[[[(S)-2-amino-3-methyl-1-oxobutyl]amino]methyl]tetrahydro-3-furanyl]thio]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
WO2002094828A1 (fr) * 2001-05-18 2002-11-28 Ranbaxy Laboratories Limited Procede relatif a l'elaboration d'imipenem
WO2005118586A1 (fr) * 2004-06-02 2005-12-15 Sandoz Ag Intermediaire de meropenem sous forme cristalline

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007031858A3 (fr) * 2005-09-15 2007-07-12 Orchid Chemicals & Pharm Ltd Procede ameliore de preparation d'un antibiotique beta-lactame
US8148520B2 (en) 2005-09-15 2012-04-03 Orchid Chemicals And Pharmaceuticals Limited Process for the preparation of beta-lactam antibiotic meropenem trihydrate
EP1934221A4 (fr) * 2005-09-15 2011-10-26 Orchid Chemicals & Pharm Ltd Procede ameliore de preparation d'un antibiotique beta-lactame
EP2006290A4 (fr) * 2006-03-28 2011-01-05 Kaneka Corp Procédé amélioré de production d'un composé de carbapenem
KR100869165B1 (ko) 2007-09-13 2008-11-19 조동옥 메로페넴의 개선된 제조방법
EP2098525A1 (fr) * 2008-02-26 2009-09-09 Savior Lifetec Corporation Composé de carbapenem cristallin et son procédé de production
US8097719B2 (en) 2008-07-15 2012-01-17 Genesen Labs Meropenem intermediate in novel crystalline form and a method of manufacture of meropenem
WO2010022590A1 (fr) * 2008-08-29 2010-03-04 深圳市海滨制药有限公司 Procédé de préparation du méropénèm
KR101491871B1 (ko) 2009-03-13 2015-02-12 주식회사 대웅제약 아연 분말을 이용한 메로페넴의 개선된 제조방법
WO2010104336A3 (fr) * 2009-03-13 2010-12-23 주식회사 대웅제약 Procédé amélioré pour la préparation de meropenem à l'aide de poudre de zinc
CN102348710B (zh) * 2009-03-13 2014-12-17 株式会社大熊制药 利用锌粉制备美罗培南的改进方法
US9233963B2 (en) 2009-03-13 2016-01-12 Daewoong Pharmaceutical Co., Ltd. Method for preparing meropenem using zinc powder
CN102348710A (zh) * 2009-03-13 2012-02-08 株式会社大熊制药 利用锌粉制备美罗培南的改进方法
JP2012520293A (ja) * 2009-03-13 2012-09-06 ダエウン ファーマシューティカル カンパニー リミテッド 亜鉛粉末を用いるメロペネムの改善された製造方法
RU2575979C2 (ru) * 2009-04-30 2016-02-27 СиЭсПиСи ЧЖУНЦИ ФАРМАСЬЮТИКАЛ ТЕКНОЛОДЖИ (ШИЦЗЯЧЖУАН)КО., ЛТД. Способ получения промежуточного соединения эртапенема
KR101142757B1 (ko) * 2009-12-03 2012-05-08 (주)하이텍팜 메로페넴 삼수화물의 제조방법
US8318716B2 (en) 2009-12-31 2012-11-27 Kbp Biosciences Co., Ltd. Carbapenem derivatives
CN101891742B (zh) * 2010-07-20 2012-06-27 深圳市海滨制药有限公司 美罗培南三水合物结晶的制备方法
CN101891742A (zh) * 2010-07-20 2010-11-24 深圳市海滨制药有限公司 美罗培南三水合物结晶的制备方法
CN101914098B (zh) * 2010-07-20 2012-08-15 深圳市海滨制药有限公司 美罗培南三水合物结晶的制备方法
CN101914098A (zh) * 2010-07-20 2010-12-15 深圳市海滨制药有限公司 美罗培南三水合物结晶的制备方法
CN102153554A (zh) * 2010-09-21 2011-08-17 重庆天地药业有限责任公司 一种制备美罗培南的方法
WO2012052978A1 (fr) 2010-10-22 2012-04-26 Ranbaxy Laboratories Limited Procédé de préparation de méropénème trihydraté pur
US9000150B2 (en) 2010-10-22 2015-04-07 Ranbaxy Laboratories Limited Process for the preparation of pure meropenem trihydrate
CN102532140B (zh) * 2010-12-21 2015-03-11 北大方正集团有限公司 一种美罗培南三水合物的制备方法
CN102532140A (zh) * 2010-12-21 2012-07-04 北大方正集团有限公司 一种美罗培南三水合物的制备方法
CN102250096A (zh) * 2011-09-05 2011-11-23 江西华邦药业有限公司 一种美罗培南的制备方法
CN102250096B (zh) * 2011-09-05 2016-04-06 江西华邦药业有限公司 一种美罗培南的制备方法
CN102372715A (zh) * 2011-12-07 2012-03-14 凯莱英医药集团（天津）股份有限公司 一种制备美罗培南的方法
KR20140147262A (ko) 2013-06-19 2014-12-30 제이더블유중외제약 주식회사 결정형 메로페넴 삼수화물의 제조방법
CN105194436A (zh) * 2015-10-26 2015-12-30 张刚 一种用于消除阑尾脓肿的外敷药物
CN111992205A (zh) * 2020-09-07 2020-11-27 西安凯立新材料股份有限公司 一种一锅法制备美罗培南用催化剂的方法
CN111992205B (zh) * 2020-09-07 2023-06-16 西安凯立新材料股份有限公司 一种一锅法制备美罗培南用催化剂的方法

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