WO2008010042A2 - Procédé amélioré pour la préparation d'un intermédiaire de la céfépime - Google Patents

Procédé amélioré pour la préparation d'un intermédiaire de la céfépime Download PDF

Info

Publication number
WO2008010042A2
WO2008010042A2 PCT/IB2007/001897 IB2007001897W WO2008010042A2 WO 2008010042 A2 WO2008010042 A2 WO 2008010042A2 IB 2007001897 W IB2007001897 W IB 2007001897W WO 2008010042 A2 WO2008010042 A2 WO 2008010042A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
solvent
heptane
preparation
Prior art date
Application number
PCT/IB2007/001897
Other languages
English (en)
Other versions
WO2008010042A3 (fr
Inventor
Sureshkumar Kanagaraj
Mohan Singaravel
Narayanan Arunkumar Lakshmi
Palanisamy Senthilkumar Udayampalayam
Original Assignee
Orchid Chemicals & Pharmaceuticals 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 Orchid Chemicals & Pharmaceuticals Limited filed Critical Orchid Chemicals & Pharmaceuticals Limited
Publication of WO2008010042A2 publication Critical patent/WO2008010042A2/fr
Publication of WO2008010042A3 publication Critical patent/WO2008010042A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D501/02—Preparation
    • C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • 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
    • C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
    • 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

Definitions

  • the present invention provides an improved process for the preparation of the compound of formula (I).
  • the compound of formula (I) is an important intermediate in the preparation of Cefepime or its salts.
  • Cefepime is chemically known as [6R-[6alpha,7beta(Z)]]-l-[7-[(2-amino-4- thiazolyl)(methoxyimino)acetylamino]-2-carboxy-8-oxo-5-thia-l-azabicyclo [4.2.0]oct- 2-en-3-ylmethyl]-l-methylpyrrolidinium hydroxide inner salt or (6R,7R)-7-[2-(2- aminothiazol-4-yl)-2(Z)-(methoxyimino)acetamido]-3-(l-methylpyrrolidiniomethyl)-3- cephem-4-carboxylate.
  • Cefepime is a fourth-generation cephalosporin that is active against a wide range of gram-positive and gram-negative aerobic organisms and is disclosed in US Patent No. 4,406,899. According to this patent Cefepime is prepared by the following process:
  • the ratio of ⁇ 3 Vs ⁇ 2 is 33/31 with CHCl 3 as solvent, 42/35 with CH 2 Cl 2 as solvent and 37/42 with CCl 4 as solvent.
  • the main objective of the present invention is to provide an improved process for the preparation of compound of formula (I) in good purity, which is substantially free from ⁇ 2 isomer and other impurities.
  • Another objective of the present invention is to provide a process for the preparation of intermediate of formula (I), which is feasible on commercial scale, and avoids cyclohexane that has a potential to form peroxide hazard upon distillation and solvents like Freon, which is classified as ozone depleting chemicals.
  • the present invention provides a process for the preparation of compound of formula (I) or its salt
  • silylating agent used in step (ii) is selected from hexamethyldisilazane (HMDS), trimethylchlorosilane (TMCS), trimethylsilyl iodide (TMSI), N,O-bis-(trimethylsilyl)-acetamide (BSA), methyltrimethylsilyltrifluoroacetamide (MSTFA), bis-silylmethly urea (BSU) N,O-bis-
  • HMDS hexamethyldisilazane
  • TMCS trimethylchlorosilane
  • TMSI trimethylsilyl iodide
  • BSA N,O-bis-(trimethylsilyl)-acetamide
  • MSTFA methyltrimethylsilyltrifluoroacetamide
  • BSU bis-silylmethly urea
  • (I) vary within the class of linear or branched Cs-Ci 2 hydrocarbons, for example, in the case of pentane, applicant has found evaporation of solvent during the course of reaction, which affects the recovery of the solvent or in certain cases the incompletion of reaction; in the case of n-decane, there is no clear solution formation during the course of silylation, wherein the quality as well as quantity of the final product were inferior; in the case of heptanes (fraction containing mixture), the reaction was very slow leading to low yield and selectivity.
  • n-heptane or n-octane Surprisingly in the case of n-heptane or n- octane, the applicant has found good selectivity, yield and optimum reaction time; hence n-heptane or n-octane has been identified as the preferred solvent.
  • iodotrimethylsilane is prepared by reacting hexamethyldisilane (HMD) with iodine at a temperature in the range of 10 0 C to 100 0 C in the presence a solvent selected from group consisting of n- heptane, n-octane or mixtures thereof. To this solution NMP was added to yield solution B.
  • HMD hexamethyldisilane
  • NMP was added to yield solution B.
  • isolation of compound of formula (I) is carried out by reacting the compound of formula (VI) obtained in step (iii) with water or lower alkanol or aqueous lower alkanol such as methanol, isopropyl alcohol, butanol and the like.
  • the compound of formula (I) can be prepared by reacting silylated 7-ACA of formula (II) with N-methylpyrrolidine of formula (IV) using a solvent selected from group consisting of n-heptane, n-octane or mixture thereof, to produce compound of formula (VI), followed by removing the silyl protecting group of formula (VI).
  • the compound of formula (I) is isolated as its hydrogen halide salt preferably hydroiodide salt by the teaching provided in the prior art.
  • the compound of formula (I) is further converted to Cefepime or its pharmaceutically acceptable salts like Cefepime dihydrochloride monohydrate by the conventional method or by the method disclosed in our co-pending application No. 673/CHE/2003, 780/MAS/2002, 1020/CHENP/03, or 848/MAS/2002.
  • the compound of formula (I) prepared according to this invention is acylated to yield Cefepime dihydrochloride monohydrate.
  • the compound of formula (I) is prepared by utilizing the following scheme.
  • the compound of formula (VII) is prepared by reacting silylated 7-ACA of formula (III) with iodotrimethylsilane in the presence of solvent selected from group consisting of n-heptane, n-octane or mixtures thereof.
  • solvent selected from group consisting of n-heptane, n-octane or mixtures thereof.
  • hexamethyldisilane HMD, 70.0 g, 430.4 mmol
  • the resulting suspension was heated to 60-70 0 C under nitrogen atmosphere and maintained for 5 h.
  • the above solution was cooled to O 0 C and added N-methylpyrrolidine (26g, 305.5 mmol) in anhydrous n-octane (25 mL).
  • the resultant slurry was stirred at 0-15 0 C for 30 min.
  • the product was crystallized by adding triethylamine and adjusting the pH to 3.0 - 3.2 at 15-2O 0 C.
  • the slurry was cooled to -5 to O 0 C and the solid obtained was filtered, washed with cold 10% aqueous methanol followed by cold methanol and dried under vacuum at 35 - 4O 0 C afforded pure title compound (43.0 g) ⁇ purity: by HPLC 98.80 % ⁇ .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation du composé de formule (I) dans laquelle X représente un iodo ou un chloro. Le composé de formule (I) est un intermédiaire important dans la préparation de la céfépime ou de ses sels pharmaceutiquement acceptables.
PCT/IB2007/001897 2006-07-18 2007-07-09 Procédé amélioré pour la préparation d'un intermédiaire de la céfépime WO2008010042A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1246/CHE/2006 2006-07-18
IN1246CH2006 2006-07-18

Publications (2)

Publication Number Publication Date
WO2008010042A2 true WO2008010042A2 (fr) 2008-01-24
WO2008010042A3 WO2008010042A3 (fr) 2008-06-12

Family

ID=38957140

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2007/001897 WO2008010042A2 (fr) 2006-07-18 2007-07-09 Procédé amélioré pour la préparation d'un intermédiaire de la céfépime

Country Status (1)

Country Link
WO (1) WO2008010042A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014151255A1 (fr) 2013-03-15 2014-09-25 Monsanto Technology Llc Méthodes et compositions pour lutter contre les mauvaises herbes

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5594131A (en) * 1992-07-24 1997-01-14 Bristol-Myers Squibb Company Process for preparing cephalosporin intermediates
WO2006008749A1 (fr) * 2004-07-16 2006-01-26 Hetero Drugs Limited Procede de preparation d'intermediaires de cephalosporine pures
WO2006075244A2 (fr) * 2005-01-17 2006-07-20 Orchid Chemicals & Pharmaceuticals Ltd Procede ameliore de fabrication d'un intermediaire antibiotique de cephalosporine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5594131A (en) * 1992-07-24 1997-01-14 Bristol-Myers Squibb Company Process for preparing cephalosporin intermediates
WO2006008749A1 (fr) * 2004-07-16 2006-01-26 Hetero Drugs Limited Procede de preparation d'intermediaires de cephalosporine pures
WO2006075244A2 (fr) * 2005-01-17 2006-07-20 Orchid Chemicals & Pharmaceuticals Ltd Procede ameliore de fabrication d'un intermediaire antibiotique de cephalosporine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WALKER D.G. ET AL.: 'Use of bistrimethylsilylated intermediates in the preparation of semisynthetic 7-amino-3-substituted cephems. Expedient syntheses of a new 3-[(1-methyl-1-pyrrolidinio)methyl]cephalos porin' J. ORG. CHEM. vol. 53, no. 5, 1988, pages 983 - 991 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014151255A1 (fr) 2013-03-15 2014-09-25 Monsanto Technology Llc Méthodes et compositions pour lutter contre les mauvaises herbes

Also Published As

Publication number Publication date
WO2008010042A3 (fr) 2008-06-12

Similar Documents

Publication Publication Date Title
AU731413B2 (en) Crystalline amine salt of cefdinir
WO2008155615A2 (fr) Procédé perfectionné pour la préparation d'un antibiotique de la famille des céphalosporines
US20040087787A1 (en) Novel thioester derivatives of thiazolyl acetic acid and their use in the preparation of cephalosporin compounds
JP3675863B2 (ja) セファロスポリン異性体の分離
US20040087786A1 (en) Process for the preparation of 3-propenyl cephalosporin DMF solvate
WO2011042776A1 (fr) Procédé de préparation de l'acide du céfotaxime et de l'un de ses sels pharmaceutiquement acceptables
EP1068211B1 (fr) Procede de purification d'un derive de cephalosporine
US5389627A (en) Cephem compounds
US20100261897A1 (en) Improved Process For the Preparation of Cephalosporin Antibiotic Intermediate
CA2099692C (fr) Procede de preparation d'intermediaires de la cephalosporine
WO2006008749A1 (fr) Procede de preparation d'intermediaires de cephalosporine pures
WO2009004463A1 (fr) Méthode perfectionnée de préparation d'intermédiaire de céfépime.
EP1556388B1 (fr) Procede de fabrication de ceftiofur
WO2008010042A2 (fr) Procédé amélioré pour la préparation d'un intermédiaire de la céfépime
CN108033971B (zh) 一种盐酸头孢卡品酯的合成方法
US20030199712A1 (en) Process for the preparation of cephalosporin intermediate and its use for the manufacture of cephalosporin compounds
CZ282160B6 (cs) Způsob přípravy cefalosporinového antibiotika
US20060149055A1 (en) Process for the manufacture of cefpodoxime proxetil
WO2011042775A1 (fr) Procédé de préparation de l'acide du céfotaxime
US20060009639A1 (en) Process for the preparation of cefpodoxime proxetil
US20100010230A1 (en) Method for the purification of lansoprazole
DE69702463T2 (de) Verfahren zur Herstellung von Cephalosporinderivaten und Zwischenverbindungen
US5831085A (en) Process for manufacture of cephalosporin such as ceftazidime and intermediate thereof
KR980009268A (ko) 세펨유도체의 제조방법
EP1699804A1 (fr) Procede de production de produits intermediaires utilisables dans la synthese de cephalosporine

Legal Events

Date Code Title Description
NENP Non-entry into the national phase in:

Ref country code: DE

NENP Non-entry into the national phase in:

Ref country code: RU

122 Ep: pct application non-entry in european phase

Ref document number: 07804576

Country of ref document: EP

Kind code of ref document: A2