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WO2011141847A1 - Procédé amélioré pour la préparation de méropénem - Google Patents

Procédé amélioré pour la préparation de méropénem Download PDF

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Publication number
WO2011141847A1
WO2011141847A1 PCT/IB2011/051869 IB2011051869W WO2011141847A1 WO 2011141847 A1 WO2011141847 A1 WO 2011141847A1 IB 2011051869 W IB2011051869 W IB 2011051869W WO 2011141847 A1 WO2011141847 A1 WO 2011141847A1
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WO
WIPO (PCT)
Prior art keywords
meropenem
preparation
methanol
water
added
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2011/051869
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English (en)
Inventor
Sanjay Nivrutti Karale
Arvind Atamaram Jangale
Ram Dattatraya Kaldate
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Orchid Pharma Ltd
Original Assignee
Orchid Chemicals and Pharmaceuticals 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 Orchid Chemicals and Pharmaceuticals Ltd filed Critical Orchid Chemicals and Pharmaceuticals Ltd
Publication of WO2011141847A1 publication Critical patent/WO2011141847A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention provides an improved process for the preparation of methylcarbapenem derivative of formula (I) or its pharmaceutically acceptable salts or hydrates thereof in a pure form.
  • the compound of the formula (I) is generically known as meropenem and is used as antibiotic agent in the treatment of pneumonia, urinary tract infections, intra-abdominal, gynecological, skin, and soft tissue infections, meningitis, septicemia and febrile neutropenia.
  • EP 126587 discloses an amorphous powder of Meropenem which is obtained by lyophilization.
  • the product obtained according to this patent has insufficient stability in storage, so that long-term storage under typical storage conditions disadvantageously leads to decrease of its antibiotic potency.
  • biphasic solvent system such as Water- THF-Ethyl acetate was utilized for deprotection (where R' is allyloxycarbonyl). After deprotection of the protecting groups, the aqueous layer was subjected to lyophilization to afford the crude product which was crystallized by the addition of THF to yield Meropenem trihydrate.
  • U.S. Pat. No. 4,888,344 discloses the compound of formula (I) in crystalline form and its use as an antibiotic agent.
  • the crystalline Meropenem prepared according to this patent was in trihydrate form.
  • Meropenem is dissolved in water, where upon small amount of Meropenem crystals formed and further addition of acetone yielded Meropenem trihydrate. Since the sterile preparation requires complete dissolution, this technique is not suitable for sterile preparation.
  • Non-sterile Meropenem trihydrate dissolved in water optionally in the presence of organic solvent using ammonia.
  • the solution obtained was subjected to sterile filtration and then pH of the filtrate was adjusted to using aqueous formic acid. Addition of organic solvent yields the title compound in pure form.
  • the main objective of the present invention is to provide a simple and commercially viable process for the preparation of compound of the formula (I) or it's pharmaceutically acceptable salts or hydrates thereof as sterile product in pure form.
  • Another objective of the present invention is to provide a simple and commercially viable process for the preparation of compound of the formula (I), in higher yield on larger scale.
  • Another objective of the present invention is to provide a simple and commercially viable process for the preparation of compound of the formula (I), with desired characteristic of rapid reconstitution time.
  • the present invention provides an improved process for the compound of formula (I) its pharmaceutically acceptable salts or hydrates thereof,
  • the alcohol used in the step (a) is selected from methanol, ethanol, isopropanol, 1-propanol and the like or mixtures thereof; preferably methanol.
  • the solution of Meropenem in methanol is cooled to lower temperature preferably 10° C, more preferably below 5° C, to yield methanol solvate of Meropenem.
  • the clear solution of Meropenem trihydrate in methanol was treated with EDTA and sodium hydro sulphite to remove the impurities.
  • isolation of Meropenem trihydrate is carried out either by adding anti-solvent or by cooling.
  • the anti-solvent used for the isolation of meropenem trihydrate is selected from acetone, THF, methyl ethyl ketone, methanol, isopropanol, 1-propanol, ethanol, water and the like or mixtures thereof.
  • the improved process disclosed found to be attractive from commercial and technological perspective. It has been observed that, Sterile product obtained by the present invention has high purity as well as desired reconstitution time (RCT). Reconstitution has direct implications on patient safety, making it a critical parameter to evaluate powder for injection formulations. A short and reproducible reconstitution time will save the precious time. An incompletely dissolved product can be hazardous to the patient, thereby making reconstitution a critical performance parameter for these products. For some drugs a prolonged reconstitution time might be detrimental to drug stability. Therefore, special inputs from scientists are required to optimize the reconstitution time during the development of these dosage forms.
  • Trans-4-hydroxy-L-proline (II) was added to a solution of sodium hydroxide in water at 0-5 °C, and stirred to get a clear solution, followed by p- nitrobenzyloxycarbonyl chloride in dichloromethane (MDC) was added and stirred till completion of reaction. at 0-5 °C.
  • MDC dichloromethane
  • To this reaction mass sodium hydroxide solution was added and the layers were separated.
  • methanol was added and pH was adjusted to acidic using sulphuric acid at 0-5 °C. The solid obtained was filtered, washed with water and dried in vacuum at 50°C to afford the title compound (III) as colorless crystals.
  • the ethyl acetate layer containing the desilylated intermediate (X) was reacted with dodecylbenzene sulfonylazide (70% solution in toluene) using triethylamine as base.
  • the reaction mass was quenched with water and the organic layer was separated and evaporated to get a residue of compound (XI), which was dissolved in acetone and cyclised using rhodium octanoate dimer under reflux to get compound (XII).
  • the reaction mass containing compound (XII) was cooled to - 30°C and ⁇ , ⁇ -Diisopropyl ethyl amine, zinc iodide followed by diphenylchloro phosphate were added.
  • reaction mass was quenched by adding phosphoric acid followed by phosphate buffer and isopropyl ether.
  • the solid obtained was filtered and purified using methanol to get (4R,5S i 6S)-3 ⁇ (diphenyloxy)phosphoryloxy ⁇ 6- [(lR)-l "hydroxyethyl]-4-methyl-7-oxo- ].-azabicyc]o[3.2.0]hept-2-ene-2- carboxylate (XIII),
  • the mass was quenched in phosphate buffer and ethyl acetate and the pH was adjusted to 4 with phosphoric acid.
  • the ethyl acetate layer containing compound (XIV) was treated with carbon and filtered.
  • the ethyl acetate layer containing compound (XIV) was hydrogenated with Palladium on carbon using aqueous solution of 3-(N-morpholino)propanesulfonic acid buffer.
  • the ethyl acetate layer was separated and the aqueous phase containing Meropenem (XV) was treated with carbon and filtered.
  • the filtrate was cooled to 5°C and pH was adjusted using dilute hydrochloric acid (or other organic acids like formic acid, acetic acid etc.) to 3-4 and crystallized the product by adding acetone (or solvents like methanol, ethanol, isopropyl alcohol, 1-propanol or mixtures therof).
  • acetone or solvents like methanol, ethanol, isopropyl alcohol, 1-propanol or mixtures therof.
  • the solid was filtered and dried under vacuum to get Meropenem.
  • the ethyl acetate layer containing diprotected compound (XVI) was treated with Sodium -2- ethylhexanoate (or other alkali metal salts like sodium acetate, sodium carbonate and sodium bicarbonate) followed by 3-(N-mo ⁇ holino)propanesulfonic acid buffer and the mass was hydrogenated using palladium on carbon till completion of the reaction.
  • the filtrate was washed with ethyl acetate (by adjusting the pH of the aqueous phase to 6 to 7.5 with alkali hydroxide or carbonate solution). The pH was of aqueous phase was readjusted to 5 to 6 with acid followed by adding the solvents as mentioned above to crystallize the Ertapenem sodium.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne un procédé amélioré pour la préparation de dérivé de méthyle carbapénem de formule (I) ou ses sels ou hydrates pharmaceutiquement acceptables sous une forme pure.
PCT/IB2011/051869 2010-05-10 2011-04-28 Procédé amélioré pour la préparation de méropénem Ceased WO2011141847A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1300/CHE/2010 2010-05-10
IN1300CH2010 2010-05-10

Publications (1)

Publication Number Publication Date
WO2011141847A1 true WO2011141847A1 (fr) 2011-11-17

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110288290A1 (en) * 2010-05-19 2011-11-24 Savior Lifetec Corporation Process for the preparation of carbapenem using cabapenem intermediates and recovery of cabapenem
CN102702203A (zh) * 2012-06-19 2012-10-03 浙江海翔药业股份有限公司 一种美罗培南的精制方法
KR101331762B1 (ko) * 2012-12-28 2013-11-20 주식회사 대웅제약 메로페넴의 삼수화물의 제조방법
CN103772389A (zh) * 2012-10-25 2014-05-07 浙江医药股份有限公司新昌制药厂 一种厄他培南中间体的制备方法
KR20140147262A (ko) 2013-06-19 2014-12-30 제이더블유중외제약 주식회사 결정형 메로페넴 삼수화물의 제조방법
WO2018065778A1 (fr) * 2016-10-05 2018-04-12 Helperby Therapeutics Limited Combinaison
CN113880839A (zh) * 2021-11-01 2022-01-04 石药集团中诺药业（石家庄）有限公司 一种厄他培南钠粗品的合成新方法
CN115521338A (zh) * 2022-11-04 2022-12-27 山东金城医药化工有限公司 美罗培南中间体map的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0256377A1 (fr) * 1986-07-30 1988-02-24 Sumitomo Pharmaceuticals Company, Limited Composé de carbapénème en forme cristalline, sa préparation et son utilisation
EP2098525A1 (fr) * 2008-02-26 2009-09-09 Savior Lifetec Corporation Composé de carbapenem cristallin et son procédé de production
WO2009138847A2 (fr) * 2008-05-14 2009-11-19 Orchid Chemicals And Pharmaceuticals Ltd. Procédé de préparation amélioré de céfozoprane
US20090299057A1 (en) * 2008-07-15 2009-12-03 Khemka Ashwin A Meropenem intermediate in novel crystalline form and a method of manufacture of meropenem

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0256377A1 (fr) * 1986-07-30 1988-02-24 Sumitomo Pharmaceuticals Company, Limited Composé de carbapénème en forme cristalline, sa préparation et son utilisation
EP2098525A1 (fr) * 2008-02-26 2009-09-09 Savior Lifetec Corporation Composé de carbapenem cristallin et son procédé de production
WO2009138847A2 (fr) * 2008-05-14 2009-11-19 Orchid Chemicals And Pharmaceuticals Ltd. Procédé de préparation amélioré de céfozoprane
US20090299057A1 (en) * 2008-07-15 2009-12-03 Khemka Ashwin A Meropenem intermediate in novel crystalline form and a method of manufacture of meropenem

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TAKEUCHI, Y. ET AL.: "Studies on the structures of meropenem (SM-7338) and its primary metabolite", JOURNAL OF ANTIBIOTICS, vol. 46, no. 5, 1993, pages 827 - 832, XP009104241 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8729260B2 (en) * 2010-05-19 2014-05-20 Savior Lifetec Corporation Process for the preparation of carbapenem using cabapenem intermediates and recovery of cabapenem
US20110288290A1 (en) * 2010-05-19 2011-11-24 Savior Lifetec Corporation Process for the preparation of carbapenem using cabapenem intermediates and recovery of cabapenem
CN102702203A (zh) * 2012-06-19 2012-10-03 浙江海翔药业股份有限公司 一种美罗培南的精制方法
CN103772389A (zh) * 2012-10-25 2014-05-07 浙江医药股份有限公司新昌制药厂 一种厄他培南中间体的制备方法
US9328115B2 (en) 2012-12-28 2016-05-03 Daewoong Pharmaceutical Co., Ltd. Process for preparing meropenem trihydrate
WO2014104583A1 (fr) 2012-12-28 2014-07-03 Daewoong Pharmaceutical Co., Ltd. Procédé pour la préparation de trihydrate de méropénème
CN104903324A (zh) * 2012-12-28 2015-09-09 大熊制药株式会社 制备美罗培南三水合物的方法
JP2016504371A (ja) * 2012-12-28 2016-02-12 デウン ファーマシューティカル カンパニー リミテッド メロペネム三水和物の製造方法
KR101331762B1 (ko) * 2012-12-28 2013-11-20 주식회사 대웅제약 메로페넴의 삼수화물의 제조방법
CN104903324B (zh) * 2012-12-28 2017-07-18 大熊制药株式会社 制备美罗培南三水合物的方法
KR20140147262A (ko) 2013-06-19 2014-12-30 제이더블유중외제약 주식회사 결정형 메로페넴 삼수화물의 제조방법
WO2018065778A1 (fr) * 2016-10-05 2018-04-12 Helperby Therapeutics Limited Combinaison
JP2019531303A (ja) * 2016-10-05 2019-10-31 ヘルパービー セラピューティクス リミテッドＨｅｌｐｅｒｂｙ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｌｉｍｉｔｅｄ 組み合わせ
CN113880839A (zh) * 2021-11-01 2022-01-04 石药集团中诺药业（石家庄）有限公司 一种厄他培南钠粗品的合成新方法
CN115521338A (zh) * 2022-11-04 2022-12-27 山东金城医药化工有限公司 美罗培南中间体map的制备方法

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