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WO2009004463A1 - Improved process for the preparation of cefepime intermediate - Google Patents

Improved process for the preparation of cefepime intermediate Download PDF

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Publication number
WO2009004463A1
WO2009004463A1 PCT/IB2008/001734 IB2008001734W WO2009004463A1 WO 2009004463 A1 WO2009004463 A1 WO 2009004463A1 IB 2008001734 W IB2008001734 W IB 2008001734W WO 2009004463 A1 WO2009004463 A1 WO 2009004463A1
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Prior art keywords
formula
compound
hexamethyldisilane
preparation
cefepime
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Ceased
Application number
PCT/IB2008/001734
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French (fr)
Inventor
Palanisamy Senthilkumar Udayampalayam
Sureshkumar Kanagaraj
Mohan Singaravel
Sekar Jeyaraj Michael
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Orchid Pharma Ltd
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Orchid Chemicals and Pharmaceuticals Ltd
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Publication of WO2009004463A1 publication Critical patent/WO2009004463A1/en
Anticipated expiration legal-status Critical
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    • 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
    • C07D501/20—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
    • C07D501/48—Methylene radicals, substituted by hetero rings
    • C07D501/56—Methylene radicals, substituted by hetero rings with the 7-amino radical acylated by carboxylic acids containing hetero rings

Definitions

  • the present invention provides an improved process for the preparation of the compound of formula (I).
  • HX represents HI, HCl, H 2 SO 4 and the like.
  • the compound of formula (I) is an important intermediate in the preparation of Cefepime or its salts.
  • Cefepime is chemically known as [6R-[6 ⁇ , 7 ⁇ (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- methylpyrrolidiniornethyl)-3-cephem-4-carboxylate.
  • Cefepime is the 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:
  • WO 2006/075244 (Application No: IN 27/CHE/2005) discloses the preparation of compound of formula (I) using decalin, tetralin, hexane, cyclohexane and petroleum ether as solvent systems.
  • the main objective of the present invention is to provide a process for the preparation of compound of formula (I) in good purity, which is substantially free from ⁇ 2 isomer.
  • Another objective of the present invention is to provide a process for the preparation of intermediate of formula (I), which is easy to implement on commercial scale, and avoids solvents like cyclohexane, dichloromethane (MDC), and decalin.
  • MDC dichloromethane
  • silylating agent used in step (ii) is selected from hexamethyldisilazane (HMDS), trimethylchlorosilaneOTMCS), trimethylsilyl iodide (TMSI), N,O-bis-(trimethylsilyl)-acetamide (BSA), methyltrimethylsilyltrifluoroacetamide (MSTFA), N,O-bis-
  • the present invention makes use of hexamethyldisilane as a solvent system for carrying out the reaction, the use of which has been found to have advantages over the conventional solvent system. None of the prior art hitherto suggests or motivates the use of hexamethyldisilane as a solvent system. Accordingly, the use of hexamethyldisilane as a solvent system constitutes the novelty of the present invention. The conventional solvent system requires cumbersome solvent recovery process.
  • hexamethyldisilane obviates such problems and the recovery of hexamethydisilane is found to be good over the cycloalkane as the use of hexamethyldisilane yields good quality as well as quantity of final compound, and hence industrially advantageous.
  • cycloalkanes like cyclohexane methyl cyclopentane becomes a peroxide hazard if concentrated, through distillation or evaporation as mentioned in Jackson, J. Chem. Ed., 1970. Since, industrial process prefers recovery of solvent system, the present invention prefers such advantage. Accordingly, the present invention provides a novel solvent system that avoids the drawbacks associated with the processes reported in the prior art.
  • the present invention identifies the dual role of hexamethyldisilane as a solvent system and reagent.
  • iodotrimethylsilane is prepared by reacting hexamethyldisilane (HMD) with iodine at a temperature in the range of 10 0 C to 100 0 C. To this solution 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) in hexamethyldisilane as a solvent system, to produce compound of formula (VI), followed by removing the silyl protecting group of formula (VI).
  • the compound of formula (I) can be prepared by utilizing the following scheme.
  • the compound of formula (VII) is prepared by reacting silylated 7-ACA of formula (III) with iodotrimethylsilane in hexamethyldisilane.
  • a suspension of iodine [88.5 g] in hexamethyldisilane was heated to 60-70 0 C under nitrogen atmosphere and maintained for 3-6 hours.
  • the above solution was cooled to O 0 C and added N-methylpyrrolidine (26 g) in hexamethyldisilane (25 mL).
  • the resultant slurry was stirred at 0-15 0 C for 30 minutes.
  • the suspension was heated to 30-50 0 C and maintained till completion of reaction.
  • reaction mixture was cooled to 3-5 0 C.
  • Cold aqueous methanol (50%) was added at 5-10 0 C followed by concentrated hydrochloric acid.
  • the aqueous phase was separated and combined with the aqueous methanol extract of the organic phase.
  • methanol and activated carbon were added, stirred and filtered.
  • the filtrate was diluted with aqueous methanol.
  • the product was crystallized by adjusting the pH using triethylamine at 15-2O 0 C.
  • the crystallized product was filtered and washed with cold aqueous methanol (10%) followed by cold methanol. Drying under vacuum at 35 -4O 0 C afforded pure title compound.
  • a suspension of iodine [88.5g] in hexamethyldisilane at 20-30 0 C was heated to 60-70 0 C under nitrogen atmosphere and maintained for 3-6 hours.
  • the above solution was cooled to O 0 C and added N-methylpyrrolidine in hexamethyldisilane.
  • the resultant slurry was stirred at 0-15 0 C for 30 minutes.
  • the suspension was heated to 30-50 0 C and maintained till completion of reaction.
  • reaction mixture was cooled to 3-5 0 C.
  • Cold aqueous methanol (50%) was added into the reaction mixture followed by concentrated hydrochloric acid.
  • the aqueous phase was separated and combined with aqueous methanol extract of the organic phase.
  • methanol and activated carbon were added, stirred and filtered.
  • the filtrate was diluted with aqueous methanol.
  • the product was crystallized by adjusting the pH to 3.0 - 3.5 using triethylamine.
  • the crystallized product was filtered and washed with cold aqueous methanol followed by cold methanol. Drying under vacuum at 35 -4O 0 C afforded pure title compound.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)

Abstract

The present invention provides a process for the preparation of the compound of formula (I) wherein HX represents HI, HCl, H2SO4 and the like. The compound of formula (I) is an important intermediate in the preparation of Cefepime.

Description

IMPROVED PROCESS FOR THE PREPARATION OF CEFEPIME
INTERMEDIATE
Field of the Invention
The present invention provides an improved process for the preparation of the compound of formula (I).
Figure imgf000002_0001
wherein HX represents HI, HCl, H2SO4 and the like. The compound of formula (I) is an important intermediate in the preparation of Cefepime or its salts.
Background of the Invention
Cefepime is chemically known as [6R-[6α, 7β(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- methylpyrrolidiniornethyl)-3-cephem-4-carboxylate. Cefepime is the 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:
Figure imgf000002_0002
US patent No. 4,868,294 claims a process for the preparation of stable, crystalline 7-amino-3-[(l -methyl- l-pyrrolidinio)methyl] ceph-3-em-4-carboxylate salts substantially free of the Δ2 isomer starting from 7-aminocephalosporanic acid (7- ACA) in 1,1,2-trichlorotrifluoroethane (Freon TF) or 1,1,1-trichlorotrifluoroethane as the solvent as shown below :
Figure imgf000003_0001
Figure imgf000003_0002
US patent No. 5,594,131 claims almost a similar process for the preparation of stable, crystalline 7-amino-3-[(l -methyl- l-pyrrolidinio)methyl]ceph-3-em-4- carboxylate salts substantially free of the Δ2 isomer by utilizing Cs-8 cycloalkanes as solvent.
WO 2006/075244 (Application No: IN 27/CHE/2005) discloses the preparation of compound of formula (I) using decalin, tetralin, hexane, cyclohexane and petroleum ether as solvent systems.
In WO 2008/010042 (Application Number IN 1246/CHE/2006), the applicant has disclosed a process for the preparation of compound of formula (I) using n- heptane, n-octane or mixtures thereof. During our continued search we have identified a process, which yield the compound of formula (I) in good purity, which is substantially free from Δ2 isomer and useful in the preparation of Cefepime. The present invention identifies the dual role of hexamethyldisilane as a solvent and reagent. Objective of the Invention
The main objective of the present invention is to provide a process for the preparation of compound of formula (I) in good purity, which is substantially free from Δ2 isomer.
Another objective of the present invention is to provide a process for the preparation of intermediate of formula (I), which is easy to implement on commercial scale, and avoids solvents like cyclohexane, dichloromethane (MDC), and decalin.
Summary of the Invention
Accordingly, the present invention provide a process for the preparation of compound of formula (I)
Figure imgf000004_0001
(I) which comprises the steps of: i) preparing "solution A" by reacting N-methylpyrrolidine of formula (IV)
(NMP) with iodine in hexamethyldisilane (HMD), ii) preparing "solution B" by reacting 7-ACA of formula (II) with silylating agent in hexamethyldisilane (HMD), iii) condensing "solution A" with "solution B" to produce compound of formula
(VI), and iv) treating the compound of formula (VI) with aqueous alcoholic solvent or alcoholic solvent or water and isolating the compound of formula (I). The process is shown in Scheme-2
Figure imgf000005_0001
(I)
Scheme-2
Detailed description of the invention
In an embodiment of the present invention silylating agent used in step (ii) is selected from hexamethyldisilazane (HMDS), trimethylchlorosilaneOTMCS), trimethylsilyl iodide (TMSI), N,O-bis-(trimethylsilyl)-acetamide (BSA), methyltrimethylsilyltrifluoroacetamide (MSTFA), N,O-bis-
(trimethylsilyl)trifluoroacetamide (BSTFA) or mixtures there of.
In another embodiment, the present invention makes use of hexamethyldisilane as a solvent system for carrying out the reaction, the use of which has been found to have advantages over the conventional solvent system. None of the prior art hitherto suggests or motivates the use of hexamethyldisilane as a solvent system. Accordingly, the use of hexamethyldisilane as a solvent system constitutes the novelty of the present invention. The conventional solvent system requires cumbersome solvent recovery process. The use of hexamethyldisilane obviates such problems and the recovery of hexamethydisilane is found to be good over the cycloalkane as the use of hexamethyldisilane yields good quality as well as quantity of final compound, and hence industrially advantageous. Apart from these advantages, cycloalkanes like cyclohexane, methyl cyclopentane becomes a peroxide hazard if concentrated, through distillation or evaporation as mentioned in Jackson, J. Chem. Ed., 1970. Since, industrial process prefers recovery of solvent system, the present invention prefers such advantage. Accordingly, the present invention provides a novel solvent system that avoids the drawbacks associated with the processes reported in the prior art. Thus, the present invention identifies the dual role of hexamethyldisilane as a solvent system and reagent.
In still another embodiment of the present invention iodotrimethylsilane is prepared by reacting hexamethyldisilane (HMD) with iodine at a temperature in the range of 10 0C to 100 0C. To this solution NMP was added to yield "solution B."
In yet another embodiment of the present invention 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.
In one more embodiment of the present invention the compound of formula (I) can be prepared by reacting silylated 7-ACA of formula (II) with N-methylpyrrolidine of formula (IV) in hexamethyldisilane as a solvent system, to produce compound of formula (VI), followed by removing the silyl protecting group of formula (VI).
In still another embodiment of the present invention the compound of formula (I) can be prepared by utilizing the following scheme.
Figure imgf000006_0001
(VII)
Figure imgf000006_0002
In yet another embodiment of the present invention, the compound of formula (VII) is prepared by reacting silylated 7-ACA of formula (III) with iodotrimethylsilane in hexamethyldisilane.
In yet another embodiment of the present invention the compound of formula
(I) further converted to 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 present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention.
Example 1 (όRJRW-Amino-S-IQ-methyl-l-pyrrolidino^methyllceph-S-eπM-earboxylate hydroiodide salt.
Solution A:
A suspension of iodine [88.5 g] in hexamethyldisilane was heated to 60-700C under nitrogen atmosphere and maintained for 3-6 hours. The above solution was cooled to O0C and added N-methylpyrrolidine (26 g) in hexamethyldisilane (25 mL).
The resultant slurry was stirred at 0-150C for 30 minutes.
Solution B:
To a suspension of 7-ACA (50 g) in hexamethyldisilane (150 mL) was added
BSA (78 g) at 10-300C. The resulting mixture was stirred for 1-3 hours under nitrogen atmosphere.
Condensation:
The silylated 7-ACA solution [Solution B] was added to the Solution A at O0C.
The suspension was heated to 30-500C and maintained till completion of reaction.
After the completion of the reaction, reaction mixture was cooled to 3-50C. Cold aqueous methanol (50%) was added at 5-100C followed by concentrated hydrochloric acid. The aqueous phase was separated and combined with the aqueous methanol extract of the organic phase. To the aqueous phase, methanol and activated carbon were added, stirred and filtered. The filtrate was diluted with aqueous methanol. The product was crystallized by adjusting the pH using triethylamine at 15-2O0C. The crystallized product was filtered and washed with cold aqueous methanol (10%) followed by cold methanol. Drying under vacuum at 35 -4O0C afforded pure title compound.
Example 2 f6R,7R)-7-Amino-3-[(l-methyl-l-pyrroIidino)methyllceph-3-em-4-carboxylate hydroiodide salt- Solution A:
A suspension of iodine [88.5g] in hexamethyldisilane at 20-300C was heated to 60-700C under nitrogen atmosphere and maintained for 3-6 hours. The above solution was cooled to O0C and added N-methylpyrrolidine in hexamethyldisilane.
The resultant slurry was stirred at 0-150C for 30 minutes.
Solution B:
To a suspension of 7-ACA (50 g) in hexamethyldisilane was added BSA (78 g) at 10-300C. The resulting mixture was stirred for 1-3 hours under nitrogen atmosphere.
Condensation:
The silylated 7-ACA solution [Solution B] was added to the Solution A at O0C.
The suspension was heated to 30-500C and maintained till completion of reaction.
After the completion of the reaction, reaction mixture was cooled to 3-50C. Cold aqueous methanol (50%) was added into the reaction mixture followed by concentrated hydrochloric acid. The aqueous phase was separated and combined with aqueous methanol extract of the organic phase. To the aqueous phase, methanol and activated carbon were added, stirred and filtered. The filtrate was diluted with aqueous methanol. The product was crystallized by adjusting the pH to 3.0 - 3.5 using triethylamine. The crystallized product was filtered and washed with cold aqueous methanol followed by cold methanol. Drying under vacuum at 35 -4O0C afforded pure title compound.

Claims

We Claim:
1) A process for the preparation of compound of formula (I) which comprises the steps of:
Figure imgf000009_0001
(I) wherein HX represents HI, HCl, H2SO4 i) reacting silylated 7-ACA of formula (III)
Figure imgf000009_0002
with its silylated derivative of formula (V)
Me- .SiMe,
N
O I in hexamethyldisilane to produce compound of formula (VI),
Figure imgf000009_0003
ii) treating the compound of formula (VI) with aqueous alcoholic solvent or alcoholic solvent or water, and iii) isolating the compound of formula (I); wherein the improvement consists of conducting the step (i) reaction only in hexamethyldisilane. 2) A process as claimed in claim 1, wherein silylated 7-ACA of formula (III)
Figure imgf000010_0001
prepared by reacting 7-ACA of formula (II) with silylating agent in hexamethyldisilane.
3) A process as claimed in claim 1, wherein silylated N-methylpyrrolidine of formula (V) is prepared by reacting N-methylpyrrolidine (NMP) of formula (IV) with iodotrimethylsilane in hexamethyldisilane.
4) A process as claimed in claim 2, wherein the silylating agent is selected from hexamethyldisilazane (HMDS), trimethylchlorosilane (TMCS), trimethylsilyl iodide (TMSI), N,O-bis-(trimethylsilyl)-acetamide (BSA), methyltrimethylsilyltrifluoroacetamide (MSTFA), and N,O-bis-
(trimethylsilyl)trifiuoroacetamide (BSTFA).
5) A process as claimed in claim 1, wherein the alcoholic solvent employed for the isolation of compound of formula (I) in step (ii) is selected from methanol, ethanol, isopropyl alcohol, or butanol.
6) A process as claimed in claim 1, further comprising converting compound of formula (I) to Cefepime or its salts by utilizing conventional technique.
7) Use of compound of formula (I) prepared according to the present invention in the preparation of Cefepime or its pharmaceutically acceptable salts.
8) A process for the preparation of compound of formula (I), which comprises treating the compound of formula (VI) in hexamethyldisilane with methanol, aqueous methanol and/or water.
PCT/IB2008/001734 2007-07-04 2008-07-02 Improved process for the preparation of cefepime intermediate Ceased WO2009004463A1 (en)

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IN1437CH2007 2007-07-04

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102276631A (en) * 2011-06-16 2011-12-14 哈药集团制药总厂 Preparation method of cefepime hydrochloride
CN102675345A (en) * 2012-06-01 2012-09-19 苏州中联化学制药有限公司 Method for preparing cefepime hydrochloride
CN104926851A (en) * 2015-07-17 2015-09-23 山东博苑医药化学有限公司 Iodotrimethylsilane preparing by dissolving and adding iodine
CN117003768A (en) * 2023-06-16 2023-11-07 国药集团威奇达药业有限公司 Preparation method of cefoperazone impurity A
CN117659046A (en) * 2023-12-07 2024-03-08 艾美科健（中国）生物医药有限公司 Synthesis method of cefpodoxime proxetil intermediate 7-AMCA

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 (en) * 2004-07-16 2006-01-26 Hetero Drugs Limited Process for preparing pure cephalosporine intermediates
WO2006075244A2 (en) * 2005-01-17 2006-07-20 Orchid Chemicals & Pharmaceuticals Ltd Improved process for the preparation of cephalosporin antibiotic intermediate

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 (en) * 2004-07-16 2006-01-26 Hetero Drugs Limited Process for preparing pure cephalosporine intermediates
WO2006075244A2 (en) * 2005-01-17 2006-07-20 Orchid Chemicals & Pharmaceuticals Ltd Improved process for the preparation of cephalosporin antibiotic intermediate

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102276631A (en) * 2011-06-16 2011-12-14 哈药集团制药总厂 Preparation method of cefepime hydrochloride
CN102675345A (en) * 2012-06-01 2012-09-19 苏州中联化学制药有限公司 Method for preparing cefepime hydrochloride
CN104926851A (en) * 2015-07-17 2015-09-23 山东博苑医药化学有限公司 Iodotrimethylsilane preparing by dissolving and adding iodine
CN104926851B (en) * 2015-07-17 2016-02-24 山东博苑医药化学有限公司 Dissolving adds iodine and prepares Iodotrimethylsilane
CN117003768A (en) * 2023-06-16 2023-11-07 国药集团威奇达药业有限公司 Preparation method of cefoperazone impurity A
CN117659046A (en) * 2023-12-07 2024-03-08 艾美科健（中国）生物医药有限公司 Synthesis method of cefpodoxime proxetil intermediate 7-AMCA

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