WO2010082108A1 - Improved process for preparation of key intermediate of cephalosporins - Google Patents

Improved process for preparation of key intermediate of cephalosporins Download PDF

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Publication number
WO2010082108A1
WO2010082108A1 PCT/IB2010/000036 IB2010000036W WO2010082108A1 WO 2010082108 A1 WO2010082108 A1 WO 2010082108A1 IB 2010000036 W IB2010000036 W IB 2010000036W WO 2010082108 A1 WO2010082108 A1 WO 2010082108A1
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Prior art keywords
formula
compound
acid
reaction mixture
reaction
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PCT/IB2010/000036
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French (fr)
Inventor
Prabhat Kumar Sahoo
Ajay Kumar Shrivastava
Chhannu Lal Yadav
Bipin Kumar Chaubey
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Nectar Lifesciences Ltd.
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Priority to IN78/DEL/2009 priority Critical
Priority to IN78DE2009 priority
Application filed by Nectar Lifesciences Ltd. filed Critical Nectar Lifesciences Ltd.
Publication of WO2010082108A1 publication Critical patent/WO2010082108A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D501/00Heterocyclic 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
    • C07D501/02Preparation
    • C07D501/04Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D501/00Heterocyclic 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
    • C07D501/14Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/207-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/227-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D501/00Heterocyclic 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
    • C07D501/14Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/207-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/247-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

Abstract

An improved process for the preparation of 7-phenylacetamido-3-vinyl cephalosporanic acid-p-methoxybenzyl ester of formula (I), which is a key intermediate of cephalosporin antibiotics and is extremely useful in their synthesis, is provided. More particularly, an improved process for the preparation of a compound of formula (I) by using a compound of formula (A) is provided, wherein, R represents hydrogen, alkyl, aryl or arylalkyl, which may be same or different and may be further substituted, making it a substantially cost effective and eco-friendly procedure.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF A KEY INTERMEDIATE FOR CEPHALOSPORINS
Field of the invention
The present invention relates to an improved process for the preparation of 7-phenylacetamido-3-vinyl cephalosporanic acid-p-methoxybenzyl ester of formula (I) using a compound of formula (A); wherein R represents hydrogen, alkyl, aryl or arylalkyl, which may be same or different and may be further substituted.
Figure imgf000002_0001
Background of the invention The cephalosporin compounds referred to in this specification are generally named with reference to cepham which is described in J. Am. Chem. Soc. 1962, 84, 3400. The term "cephem" refers to the basic cepham structure with a single double bond.
Compounds referred to in this specification are useful for the manufacturing of cephalosporins having antibacterial activity against a range of gram-positive and gram-negative organisms and are of value in human and veterinary medicine. They may also be of value in the preparation of other 3-substituted cephalosoporin compounds. The compound of formula (I) is one of the key intermediate of cephalosporin antibiotics such as Cefixime and Cefdinir and is extremely useful in their synthesis.
According to the product patent of Cefixime US 4,409,214 (henceforth '214), the route of synthesis of 7-phenylacetamido-3-vinyl cephalosporanic acid-p- methoxybenzyl ester of compound of formula (I) is generically disclosed. The preparation of compound of formula (I) is specifically neither disclosed nor described in the said patent '214. According to the general disclosure of '214 a compound of formula (I) may be prepared by Wittig reaction using the alkali metal halide such has sodium iodide, potassium iodide, sodium bromide and the like in a conventional solvent which does not adversely influence the reaction such as N,N-dimethylformamide, dimethylsulfoxide, methylene chloride, tetrahydrofuran, ethyl acetate, etc., or a mixture thereof. The said patent '214 further discloses that the reaction temperature is not critical and the reaction is usually carried out under cooling to warming. When we have carried out the general procedures described in the said patent '214 for equivalent compound(s) of a compound of formula (I) we have got substantially low yield and low purity of the products. Hence the present inventors attempted to do the experiment in a substantially different way, which has resulted in a good yield and purity of the compound of formula (I) by using a compound of formula (A) in a simple and economical process.
Patent IN 961 /MUM/2004 (henceforth '961) discloses and claims an improved process for the preparation of 7-Amino-3-vinyl-3-cephem-4-carboxylic acid (7-AVCA) and for (Z)-isomer enriched (7-amino-8-oxo-3-[(lZ)-prop-l-enyl]-5-thia-l- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (7-APCA) by carrying out multi-step reactions in one pot and utilizing sodium bromide in Wittig reaction. The said patent
'961 discloses in example 3 the process for the preparation of a compound of formula (I) which is a complex manufacturing procedure, and therefore commercially not preferred.
According to the disclosure of example 3 of the said patent '961 , the process makes use of a suspension of the reagents in a reaction, because of which the reaction goes slow and it takes more time to complete. Moreover, the use of additional hydrobromic acid and aqueous sodium thiosulfate in Wittig reaction makes the procedure complex in larger commercial scale. During the isolation of Wittig product, the role of temperature and addition of methanol is very critical and crucial. The procedure disclosed according to example 3 of the said patent '961 results in low yields and surprisingly the said patent is silent about the purity of a compound of formula (I). Because the process disclosed in the said patent '961 may be suffering from unwanted by-products or is accompanied by impurity formation during the formation of Wittig product; this ultimately results in the low yield mentioned. Accordingly therefore, there is an urgent need to develop a process for the preparation of a compound of formula (I), which is readily amenable to scale-up. Hence, we focused our research to simplify the process for the preparation of a compound of formula (I) with greater yield and higher chemical purity by using a compound of formula (A) in a substantially cost effective and eco-friendly manner and to obviate the problems associated with the prior art process(s).
Objective of the invention
The main object of the present invention is to provide a process for the preparation of a compound of formula (I), which is simple, economical, user- friendly and commercially viable.
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),which makes the present invention eco-friendly as well.
Yet another objective of the present invention is to provide a process for the preparation of a compound of formula (I) in a greater yield with higher chemical purity.
Still another objective of the present invention is to provide a process for the preparation of a compound of formula (I), wherein the byproduct formed during the reaction can be reusable and thereby recyclable, which makes the process industrially more suitable.
Summary of the invention
Accordingly, the present invention provides a process for the preparation of compound of formula (I), which comprises the steps of:
Figure imgf000004_0001
M (i) dissolving 7-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylic acid-p- methoxybenzyl ester of formula (II) in an organic solvent to get a solution;
(ii) reacting triphenylphosphine and a compound of formula (A) with a solution obtained from step (i) to get a compound of formula (III); (Hi) adding an organic solvent after the completion of reaction;
(iv) filtering the reaction mixture;
(v) treating the filtrate with aqueous formaldehyde and a base;
(vi) adjusting the pH of reaction mixture with acid;
(vii) separating and concentrating the organic layer; (viii) precipitating the reaction mixture by using an alcoholic solvent;
(ix) adding water to the reaction mixture; and
(x) isolating the 7-phenylacetamido-3-vinyl cephalosporanic acid-p-methoxybenzyl ester of formula (I).
The above process is illustrated in the following synthetic scheme
Formation of trlphenylohosphonlum halide step
Figure imgf000005_0001
Organic sohfent(s)
[W [III]
Aqueous formaldehyde
Vinylation step Base
Organic solvent(s)
Figure imgf000005_0002
R = Hydrogen, alkyl, aryl or arylalkyl, which may be same or different and may be further substituted II] X = Any halogen 1
Detailed description of the invention
Accordingly in an embodiment of the present invention, the triphenylphosphonium halide formation and vinylation steps are carried out in an in-situ manner without isolating the compound of formula (III), which makes the process easier.
In another embodiment of the present invention, the organic solvent used in step (i) is preferably N,N-dimethylformamide or N, N-dimethylacetamide or mixture thereof.
In another embodiment of the present invention, in a compound of formula (A). R is represented hydrogen, alkyl, aryl or arylalkyl, which may be same or different and may be further substituted, more preferably R is hydrogen.
In another embodiment of the present invention, in a compound of formula (III) and formula (A). X is represented by any halogen, preferably bromine or iodine, more preferably bromine.
In another embodiment of the present invention, the step (ii) of said reaction is carried out preferably in the range of 0.2 to 5 equivalents of a compound of formula (A).
In another embodiment of the present invention, the step (ii) of said reaction is preferably with 1 to 2 equivalents of triphenylphosphine.
In another embodiment of the present invention, the step (ii) of said reaction is completed in the range of 1 hr to 6 hrs, preferably in 2 hrs.
In another embodiment of the present invention, the organic solvent used for the preparation of compound of formula (I) in step (iii) is preferably methylene chloride.
In another embodiment of the present invention, the formaldehyde used in step (v) is preferably in the range of 3 to 50 equivalents.
In another embodiment of the present invention, the base used in step (v) is preferably an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide and the like, more preferably sodium hydroxide. In another embodiment of the present invention, the acid used in step (vi) is preferably hydrochloric acid or sulfuric acid and the like, more preferably hydrochloric acid.
In another embodiment of the present invention, the alcoholic solvent used in step (viii) is preferably methanol.
In another embodiment of the present invention, the role of addition of water in step (ix) is a very essential and crucial feature of the present invention. By doing this way it results in better quality of a compound of formula (I) along with good yield. The addition of water during this step takes care of the inorganics or by-products formed during the reaction.
In another embodiment of the present invention, all the steps are preferably performed at a temperature in the range of (-) 100C to reflux temperature of the solvent used.
In yet another embodiment of the present invention, process for preparation of a compound of formula (I) can be extended further in the making of cephalosporin antibiotics such as Cefixime and Cefdinir by conventional methods.
In the present invention starting material(s) for the preparation a compound of formula (I), were prepared according to the known processes in the prior art.
The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.
Example
Preparation of 7-phenylacetamido-3-vinyl cephalosporanic acid-p-methoxy benzyl ester of formula (T)
T-phenylacetamido-S-chloromethyl-S-cephem^-carboxylic acid-p-methoxybenzyl ester (10Og, 0.205mol) was dissolved in N,N dimethylformamide (15OmL) in a four necked round bottom flask at room temperature and triphenylphosphine (55g, 0.21 mol), ammonium bromide (19.46g, 0.205 mol) were added under stirring and the temperature raised slightly to facilitate the reaction. After the completion of reaction in 2.5 hrs, methylene chloride (50OmL) was added and the reaction mixture was cooled to 120C to 140C. The reaction mixture was filtered and washed with methylene chloride (10OmL). After 10 minutes of stirring, 36% aqueous formaldehyde solution (108.0 g, 1.29 mol) and sodium hydroxide solution (lOg/lOOmL, 0.25 mol) were added. After 40 mins of further stirring of the reaction mixture, water (80OmL) and hydrochloric acid (5 mL, 36%) were added to this, so that the pH becomes less than 2.0. The organic layer was separated and aqueous layer was extracted with methylene chloride (2 x 100mL).The mixed organic layer was concentrated by distilling out methylene chloride. Methanol (120OmL) was added to the concentrated mass and stirred for one hour to complete the precipitation. Remaining methylene chloride was distilled out and water (35OmL) was added. The reaction mixture was cooled down to 1O0C, stirred for one hour and the solid was filtered and washed with aqueous methanol and dried at temperature 37 0C to yield 78g of 7-phenylacetamido-3-vinyl cephalosporanic acid-p-methoxy benzyl ester, with a chemical purity of more than 96.46 % by HPLC.
Substantial Advantages
(1) The process of the present invention provides higher yield with greater purity of Wittig product. (2) The use of alkali metal iodides such as sodium iodide in Wittig reaction leads to tendency of product to pick up color for which it requires additional purification procedures. Therefore, the present invention uses substantially cheaper reagent(s) in substantially lower amounts and less organic solvent(s) thereby achieving better quality Wittig product that is substantially free of colored impurities forming in the said reaction.
(3) The process of the present invention avoids excessive use of reagents like sodium bromide, sodium iodide, triphenylphosphine, formaldehyde and large amounts of organic solvent(s) such as N,N-dimethylformamide and methylene chloride, thereby reducing the reaction bulk that facilitates scaling up for an industrial production. (4) The process has effectively less number of steps that result in shortening of reaction time and lowering of labour. (5) The process of the present invention avoids excess usages of reagent(s) and organic solvent(s),and thereby promotes green chemistry and ensures a cleaner surrounding by putting less load on environment.
(6) In the process of the present invention, the by-products formed during the reaction can be reusable and recyclable, which makes the process industrially and commercially viable.

Claims

We claim:
(I) A process for the preparation of a compound of formula (I), comprising the steps of;
Figure imgf000010_0001
[U
(i) dissolving 7-phenylacetamido-3-chloromethyl-3-cephern-4-carboxylic acid-p- methoxybenzyl ester of formula (II) in an organic solvent to get a solution;
Figure imgf000010_0002
[II]
(ii) reacting triphenylphosphine and a compound of formula (A), with a solution obtained from step (i) to get a compound of formula (III);
Figure imgf000010_0003
t∞] [A1
Wherein R is preferably represented by hydrogen, alkyl, aryl or arylalkyl, which may be same or different and may be further substituted and X is represented by any halogen selected from bromine or iodine
(iii) adding an organic solvent after the completion of reaction; (iv) filtering the reaction mixture;
(v) treating the filtrate with aqueous formaldehyde and a base;
(vi) adjusting the pH of reaction mixture with acid;
(vii) separating and concentrating the organic layer; (viii) precipitating the reaction mixture by using an alcoholic solvent; (ix) adding water to the reaction mixture; and
(x) isolating the 7-phenylacetamido-3-vinyl cephalosporanic acid-p-methoxybenzyl ester of formula (I).
(2) A process according to claim no. 1 wherein, the said organic solvent in step (i) is N,N-dimethylformamide or N, N-dimethylacetamide or mixture thereof.
(3) A process according to claim no.l wherein, the said compound of formula (A) is ammonium bromide or ammonium iodide.
(4) A process according to claim no. 1 wherein, the said organic solvent in step (iii) is methylene chloride.
(5) A process according to claim no. 1 wherein, the said base in step (v) is preferably an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide and the like, more preferably sodium hydroxide.
(6) A process according to claim no. 1 wherein, the pH of reaction mixture in step (vi) is adjusted below 2.0.
(7 A process according to claim no. 1 wherein, the said acid in step (vi) is preferably hydrochloric acid or sulfuric acid and the like, more preferably hydrochloric acid.
(8) A process according to claim no. 1 wherein, the said alcoholic solvent in step (viii) is methanol.
(9) A process according to claim no. 1 wherein, all the steps are preferably performed at a temperature in the range of (-) 100C to reflux temperature of the solvent used.
PCT/IB2010/000036 2009-01-16 2010-01-12 Improved process for preparation of key intermediate of cephalosporins WO2010082108A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102898440A (en) * 2012-10-11 2013-01-30 南通康鑫药业有限公司 Technology for preparing 7-phenylacetylamino-3-vinyl cephalosporanic acid p-methoxybenzyl ester
CN105440053A (en) * 2015-12-24 2016-03-30 湖北凌晟药业有限公司 Method for recycling GCLE (7-phenylacetamido-3-chloromethylcephalosporanic acidp-methoxybenzyl ester) crystallization barren liquor
CN103923104B (en) * 2014-04-25 2016-04-13 湖北凌晟药业有限公司 7-phenylacetylamino-3-vinyl-4-cephemcarboxylic acid is to the preparation method of methoxy benzyl ester

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5401841A (en) * 1991-03-08 1995-03-28 Sandoz Ltd. Process for the production of cephalosporines
US6417351B1 (en) * 1997-06-04 2002-07-09 Otsuka Kagaku Kabushiki Kaisha Process for producing 3-alkenylcephem compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5401841A (en) * 1991-03-08 1995-03-28 Sandoz Ltd. Process for the production of cephalosporines
US6417351B1 (en) * 1997-06-04 2002-07-09 Otsuka Kagaku Kabushiki Kaisha Process for producing 3-alkenylcephem compounds

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
WANG, YONGJIN ET AL.: 'Synthesis of Intermediate of Cefixime: 7-Amino-3-Vinyl Cephalosporanic Acid-p-Methoxybenzyl Ester Hydrochloride.' SHANDONG HUAGONG vol. 34, no. 4, August 2005, pages 9 - 10, 13 *
YOUSUKE KATSURA ET AL.: 'A Convenient Protective Method for the 7-Amino Function on a Cephem Derivative in Wittig Vinylation.' TETRAHEDRON LETTERS vol. 35, no. 51, 1994, pages 9601 - 9604 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102898440A (en) * 2012-10-11 2013-01-30 南通康鑫药业有限公司 Technology for preparing 7-phenylacetylamino-3-vinyl cephalosporanic acid p-methoxybenzyl ester
CN103923104B (en) * 2014-04-25 2016-04-13 湖北凌晟药业有限公司 7-phenylacetylamino-3-vinyl-4-cephemcarboxylic acid is to the preparation method of methoxy benzyl ester
CN105440053A (en) * 2015-12-24 2016-03-30 湖北凌晟药业有限公司 Method for recycling GCLE (7-phenylacetamido-3-chloromethylcephalosporanic acidp-methoxybenzyl ester) crystallization barren liquor

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