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WO2011121389A1 - Procédé pour la préparation de dichlorhydrate de céfépime monohydraté - Google Patents

Procédé pour la préparation de dichlorhydrate de céfépime monohydraté Download PDF

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Publication number
WO2011121389A1
WO2011121389A1 PCT/IB2010/002300 IB2010002300W WO2011121389A1 WO 2011121389 A1 WO2011121389 A1 WO 2011121389A1 IB 2010002300 W IB2010002300 W IB 2010002300W WO 2011121389 A1 WO2011121389 A1 WO 2011121389A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
methyl
preparation
dihydrochloride monohydrate
amino
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/IB2010/002300
Other languages
English (en)
Inventor
Prabhat Kumar Sahoo
Sivakumaran Sundaravadivelan
Senthil Kumar Surulichamy
Manoj Upadhyay
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.)
NECTAR LIFESCIENCES Ltd
Original Assignee
NECTAR LIFESCIENCES 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 NECTAR LIFESCIENCES Ltd filed Critical NECTAR LIFESCIENCES Ltd
Publication of WO2011121389A1 publication Critical patent/WO2011121389A1/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
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
    • C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings
    • 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 is in the field of chemistry and more particularly it relates to the preparation of cefepime dihydrochloride monohydrate of formula (I), by reacting 7-amino-3-[( 1 -methyl- 1 -pyrrolidino)methyl]-3-cephem-carboxylate
  • Cefepime is a valuable fourth generation injectable cephalosporin with antibacterial properties, which is used in the form of a dihydrochloride hydrate.
  • Cefepime dihydrochloride monohydrate is chemically known as 7-[(Z)-2-(2-amino-4- thiazolyl)-2-(methoxyimino) acetamido]-3-[(l -methyl-l-pyrrolidinium)methyl]-3- cephem-4-carboxylate dihydrochloride monohydrate.
  • Cefepime dihydrochloride monohydrate is a cephalosporin that is active against a wide range of gram-positive and gram-negative aerobic organisms. Its chemical structure is depicted below:
  • the semi-synthetic antibiotic cefepime is a useful broad- spectrum antibiotic which was first described in U.S. Patent No. 4,406,899 wherein cefepime was synthesized by a multistep process involving protection and deprotection steps thereby making the process lengthy and laborious.
  • US Patent No 5,594,129 and US Patent No 5,594, 130 disclose the synthesis of cefepime which involves acylation of 7-amino-3-[(l-methyl-l- pyrrolidinio)methyl]-3- cephem-4-carboxylate hydrochloride with syn 2-(2-amino-4-thiazolyl)-2- methoxyiminoacetic acid that is activated by converting to chloride by reacting with chlorinating agents such as thionyl chloride or phosphorous pentachloride etc.
  • the main object of the present invention is to provide a process for the preparation of a compound of formula (I), which is very safe, simple, economical, user- friendly and commercially viable with a greater yield and higher chemical purity
  • Another objective of the present invention is to provide a process for the preparation of a compound of formula (I), which would be easy to implement on commercial scale, and to avoid excessive use of reagent(s) and organic solvent(s) and to avoid hazardous and risky solvents, and thereby making the present invention more safe and eco-friendly as well.
  • Still another objective of the present invention is to provide a process for the preparation of a compound of formula (I), wherein the solvent(s) used during the reaction can be recycled and thereby reused, which makes the process industrially more suitable.
  • the present invention provides an improved process for the preparation of cefepime dihydrochloride monohydrate of formula (I); comprising the steps of:
  • the said alcoholic solvent in step (i) is preferably selected from the group consisting of methanol, ethanol or isopropanol, optionally in combination with chlorinated hydrocarbon solvent such as methylene chloride, more preferably methanol alone.
  • the said base in step (i) is an organic base which may be preferably selected from the group consisting of triethylamine, diethylamine, pyridine, N-methylpiperidine, 1,8-diazabicycloundecene, 4,4-dimethylaminopyridine, dicyclohexylamine, diphenylamine, diisopropylamine, N- tert-butylcyclohexylamine and ⁇ , ⁇ -dibenzylethylenediamine and the like or mixture thereof, more preferably triethylamine.
  • the condensation reaction is carried out at a temperature preferably in the range of -20°C to 10°C, more preferably 0°C to 5°C.
  • the condensation reaction is completed within 3 hrs to 4 hrs.
  • reaction mass was adjusted to 0.5 with concentrated hydrochloric acid and stirred for 15 minutes. 5.0g of charcoal was added to the reaction mixture and stirred for 10 minutes. The reaction mass was filtered through carbon pad and 0.45 micron filter. Ethyl acetate was added to the filtrate and stirred for 30 minutes for complete precipitation. The precipitated mass was filtered, washed with ethyl acetate and dried to get 72g of the titled compound with chromatographic purity of 98.94%.
  • the reaction mixture was stirred at 15°C to 20°C and layers were settled, separated and the aqueous layer was charcolized.
  • the pH of the aqueous layer was adjusted to 0.5 to 0.1 with concentrated hydrochloric acid at 0°C to 5°C.
  • Acetone was added slowly to the aqueous layer at 0°C to 5°C and stirred for one hour at same temperature for complete precipitation.
  • the precipitated mass was filtered, washed with acetone and dried in hot air oven for 3 hours at 40°C to get 34.5g of the titled compound with chromatographic purity of 99.43%.
  • reaction mass was adjusted to 0.5 with concentrated hydrochloric acid and stirred for 15minutes. 5 g of charcoal was added to the reaction mixture and stirred for 10 minutes. The reaction mass was filtered through carbon pad and 0.45 micron filter. Isopropyl alcohol was added to the filtrate and stirred for 30 minutes for complete precipitation. The precipitated mass was filtered, washed with Isopropyl alcohol and suck dried to get 72g of the titled compound with chromatographic purity of 99.54%.
  • the process of the present invention is very safe, simple and yields higher purity and greater yield of a compound of formula (I).
  • the process of the present invention avoids excess usages of reagent(s) and organic solvent(s), thereby promoting green chemistry and ensuring a cleaner surrounding by putting lesser load on environment.
  • the process of the present invention uses a solvent which can be recycled and
  • the process of the present invention is a simple process, which avoids more

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (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)
  • Cephalosporin Compounds (AREA)

Abstract

La présente invention concerne un procédé pour la préparation de dichlorhydrate de céfépime monohydraté. Le procédé comprend la condensation de monochlorhydrate de 7-amino-3-[(1-méthyl-1-pyrrolidino)méthyl]-3-céphém-4-carboxylate dihydraté et de 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-méthoxyiminoacétate en présence d'une base dans un solvant alcoolique.
PCT/IB2010/002300 2010-03-29 2010-09-15 Procédé pour la préparation de dichlorhydrate de céfépime monohydraté Ceased WO2011121389A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN736DE2010 2010-03-29
IN736/DEL/2010 2010-03-29

Publications (1)

Publication Number Publication Date
WO2011121389A1 true WO2011121389A1 (fr) 2011-10-06

Family

ID=44711399

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2010/002300 Ceased WO2011121389A1 (fr) 2010-03-29 2010-09-15 Procédé pour la préparation de dichlorhydrate de céfépime monohydraté

Country Status (1)

Country Link
WO (1) WO2011121389A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103665003A (zh) * 2013-11-28 2014-03-26 山东鑫泉医药有限公司 高纯度头孢吡肟二盐酸盐一水合物的精制方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HAO JUNXIANG: "Studies on the synthesis of Cefepime Dihydrochloride", CHINESE DOCTORAL DISSERTATIONS & MASTER'S THESES FULL-TEXT DATABASE (MASTER) ENGINEERING SCIENCE AND TECHNOLOGY I, 15 December 2004 (2004-12-15) *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103665003A (zh) * 2013-11-28 2014-03-26 山东鑫泉医药有限公司 高纯度头孢吡肟二盐酸盐一水合物的精制方法

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