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US 2004/0002600 A1Published application
Process for the conversion of penam ring system to cepham ring system
AssigneeOrchid Chemicals & Pharmaceuticals Limited
InventorsPandurang Balwant Deshpande, Senthilkumar Udayampalayam Palanisamy, Padmanabhan Ramar
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Abstract
The present invention relates to a new process for the preparation of cephalosporin derivative of formula (I) 1 wherein R1 represents p-methoxybenzyl, p-nitrobenzyl, o-chlorobenzyl or diphenylmethyl; R2 represents CH3 or CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (C1-C6) alkyl; R3 represents hydrogen, acyl, phenacyl, formyl or trityl group.
Claims32
A new process for the preparation of cephalosporin derivatives of formula (I)
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- wherein R1 represents p-methoxybenzyl, p-nitrobenzyl, o-chlorobenzyl or diphenylmethyl;
- R2 represents CH3 or CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (C1-C6)alkyl;
- R3 represents hydrogen, acyl, phenacyl, formyl or trityl, the said process comprising steps of:
- (i) condensing the compound of formula (IV)
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- wherein R2, R3 are as defined above and R6 represents hydroxy or an activation group with penam moiety of formula (III)
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- using a base in presence of a solvent at a temperature in the range of 0° C. to 50° C. to produce a compound of formula (V),
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- wherein R2 and R3 are as defined above,
- (ii) esterifying the compound of formula (V) using an esterifying agent in the presence of a solvent and a base at a temperature in the range of 25° C. to 50° C. followed by oxidation using an axidising agent in the presence of a solvent at a temperature in the range of −10° C. to 10° C. to produce a compound of formula (VI)
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- wherein R1, R2 and R3 are as defined above,
- (iii) opening the penam ring of formula (VI) using a mercaptan in the presence of a solvent at a temperature in the range of 80° C. to 120° C. to produce a compound of formula (VII)
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- wherein R7 represents a heteroaryl ring system and all other symbols are as defined above,
- (iv) converting a compound of formula (VII) to a compound of formula (VIII)
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- using a metal salt of aryl or alkyl sulfinic acid and a solvent at a temperature in the range of 25° C. to 40° C., wherein R8 represents (C1-C6)alkyl or aryl group and all other symbols are as defined above
- (v) chlorinating the compound of formula (VIII) using electrochemical method in a biphasic solvent system at a temperature in the range of 15° C. to 40° C. to produce a compound of formula (IX),
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- wherein R8 represents (C1-C6)alkyl or aryl group and all other symbols are as defined above,
- (vi) cyclizing the compound of formula (IX) using a base in the presence of a solvent at a temperature in the range of −10° C. to −50° C. to produce a compound of formula (I) where R1, R2, and R3 are as defined above.
21 more elements
A process for the conversion of the compound of formula (VI)
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- wherein R3 represents hydrogen;
- R1 represents p-methoxybenzyl, p-nitrobenzyl, o-chlorobenzyl or diphenylmethyl;
- R2 represents CH3 or CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (C1-C6)alkyl to a compound of formula (VI) where R3 represents acyl, phenacyl, formyl or trityl and all other symbols are as defined above using acetic anhydride, formic acetic anhydride, acid chloride or trityl chloride in the presence of a solvent.
1 more element
An intermediate of formula (VI)
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- wherein R1 represents p-methoxybenzyl, p-nitrobenzyl, o-chlorobenzyl or diphenylmethyl;
- R2 represents CH3 or CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (C1-C6)alkyl;
- R3 represents hydrogen, acyl, phenacyl, formyl or trityl group.
1 more element
An intermediate of formula (VII)
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- wherein R1 represents p-methoxybenzyl, p-nitrobenzyl, o-chlorobenzyl or diphenylmethyl;
- R2 represents CH3 or CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (C1-C6)alkyl;
- R3 represents hydrogen, acyl, phenacyl, formyl or trityl group;
- R7 represents a heteroaryl ring system.
2 more elements
An intermediate of formula (VIII)
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- wherein R1 represents p-methoxybenzyl, p-nitrobenzyl, o-chlorobenzyl or diphenylmethyl;
- R2 represents CH3 or CRaRbCOORc where, Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (C1-C6)alkyl;
- R3 represents hydrogen, acyl, phenacyl, formyl or trityl;
- R8 represents (C1-C6)alkyl or aryl group.
2 more elements
An intermediate of formula (IX)
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- wherein R1 represents p-methoxybenzyl, p-nitrobenzyl, o-chlorobenzyl or diphenylmethyl;
- R2 represents CH3 or CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (C1-C6)alkyl;
- R3 represents hydrogen, acyl, phenacyl, formyl or trityl group;
- R8 represents (C1-C6)alkyl or aryl group.
2 more elements
A process for the preparation of cephalosporin antibiotics of formula (II)
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- wherein R4 is carboxylate ion or COORd, where Rd represents hydrogen or ester which form a prodrug or a counter ion, resulting a salt;
- R2 represents CH3 or CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (C1-C6)alkyl;
- R5 represents CH3, CH2OCH3, CH2OCOCH3, CH═CH2, or
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- from a compound of formula (I)
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- prepared by a process as claimed in any of the preceding claims.
5 more elements
Dependencies are inferred from the claim text.