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US 3,941,779 AGranted
Method for producing 2-(substituted thio)-3-cephem derivatives
AssigneeE. R. Squibb & Sons, Inc.
InventorsWilliam A. Slusarchyk, Joseph Edward Dolfini, Marian G. Young
Life of this patent
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Abstract
Treatment of a 7-imido-3-cephem carboxylic acid ester with a thiolating agent in the presence of a strong base yields a 4-(substituted thio)-2-cephem derivative which can be made to rearrange by use of a strong acid to obtain a 2-substituted thio-2-cephem derivative which has antimicrobial activity.
Claims20
A process for the production of a compound of the formula ##SPC9##
- wherein R.sub.1 and R.sub.2 each is lower alkanoyl, benzoyl, halo-lower alkanoyl, lower alkyl-lower alkanoyl, lower alkoxy-lower alkanoyl, halobenzoyl, lower alkylbenzoyl or lower alkoxybenzoyl, or R.sub.1 and R.sub.2 taken together with the nitrogen form an alkyl dicarboxylic acid imide of the group consisting of maleimide, succinimide, phthalimide and naphthalene-1,2-dicarboxylic acid imide;
- R.sub.3 is hydrogen or a protecting ester group of the group consisting of lower alkyl, lower alkoxybenzyl, halo-lower alkyl and lower alkylsilyl;
- R.sub.4 is lower alkyl, halo-lower alkyl, lower alkoxy-lower alkyl, phenyl, halophenyl, lower alkoxyphenyl, nitrophenyl, cyanophenyl or carboalkoxyphenyl;
- and X is hydrogen or acetoxy,
- which comprises reacting a compound of the formula ##SPC10##
- wherein R.sub.1, R.sub.2 and X have the meaning already defined and R.sub.3 is a protecting ester group as defined above,
- with a thiolating agent R.sub.4 SY or (R.sub.4 S).sub.2
- wherein R.sub.4 has the meaning defined above and Y is halogen, lower alkoxycarbonylthio, lower alkylthio or --SO.sub.2 --Z wherein Z is lower alkyl or phenyl,
- at a temperature in the range of about -78.degree. to +30.degree.C. in the presence of a strong base of the group consisting of alkali metal lower alkoxide, triphenylmethyl lithium, lithium lower alkylamide and lower metal hydride, to yield a product of the formula ##SPC11##
- wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and X have the meaning defined above,
- and effecting the rearrangement of said product with a hydrohalic acid, trifluoroacetic acid, benzenesulfonic acid, toluenesulfonic acid, or mercury, silver or copper salt.
8 more elements
A compound of the formula ##SPC12##
- wherein R.sub.3 is hydrogen or a protecting ester group of the group consisting of lower alkyl, lower alkoxybenzyl, halo-lower alkyl and lower alkylsilyl;
- R.sub.4 is lower alkyl, halo-lower alkyl, lower alkoxy-lower alkyl, phenyl, halophenyl, lower alkoxyphenyl, nitrophenyl, cyanophenyl or carboalkoxyphenyl;
- and X is hydrogen or acetoxy.
A process for the production of a compound of the formula ##SPC16##
- wherein R.sub.1 is an acyl group R.sub.5 --CO-- wherein R.sub.5 is lower alkyl, phenyl, phenyl-lower alkyl, .alpha.-aminophenyl-lower alkyl, phenoxy-lower alkyl, lower alkoxymethyl, lower alkylthiomethyl, pyridyl-lower alkyl, thenyl, furylmethyl, ozazolylmethyl, isoxazolylmethyl, .beta.-lower alkoxy-lower alkenyl, (C.sub.4 -C.sub.6 -cyclo-lower alkyl)-lower alkyl, .alpha.-amino-(C.sub.4 -C.sub.6 -cyclo-lower alkadiene)-lower alkyl, and said aromatic and cycloaliphatic groups bearing one or two lower alkyl, lower alkoxy, halo, nitro, amino or trifluoromethyl groups;
- R.sub.2 is hydrogen;
- R.sub.3 is hydrogen or a protecting ester group of the group consisting of lower alkyl, lower alkoxybenzyl, halo-lower alkyl and lower akylsilyl;
- R.sub.4 is lower alkyl, halo-lower alkyl, lower alkoxy-lower alkyl, phenyl, halophenyl, lower alkoxyphenyl, nitrophenyl, cyanophenyl or carboalkoxyphenyl;
- and X is hydrogen or acetoxy,
- which comprises selectively cleaving with hydrazine a compound of the formula ##SPC17##
- to obtain an intermediate of the formula ##SPC18##
- wherein R.sub.3, R.sub.4 and X have the meaning defined above,
- acylating said intermediate with an acid halide of the formula R.sub.5 --CO--Y or acid anhydride of the formula (R.sub.5 --CO).sub.2,
- wherein R.sub.5 has the meaning defined above and Y is halo, azide, p-nitrophenyl or ethoxycarbonyl,
- and rearrangng the acylated product with hydrohalic acid, trifluoroacetic acid, benzenesulfonic acid, toluenesulfonic acid, or mercury, silver or copper salt.
8 more elements
Dependencies are inferred from the claim text.