Process for the preparation of reactive penicillanic acid and cephalosporanic acid derivatives

A process for the preparation of a compound of the formula ##STR15## or a pharmaceutically acceptable salt thereof wherein R.sup.1 is nitrophenacyl;

• R.sup.2 is hydrogen, alkyl, alkenyl, alkyl having a conventional penicillin aryl heterocyclic substituent, or a conventional penicillin aryl, aralkyl, or heterocyclic group;
• R.sup.3 is hydrogen, aryl, alkyl, cycloalkyl or aralkyl;
• and
• X is a group selected from the formulae consisting of ##STR16## by acylating a compound of the formula ##STR17## wherein R.sup.4 is nitrophenacyl, in which the acylation is performed at a temperature of -10.degree. C. to +30.degree. C. for a period of up to two hours using an ester of the formula ##STR18## wherein R.sup.5 is aryl, alkyl, cycloalkyl, or aralkyl;
• and wherein
• R.sup.3 is hydrogen, splitting off the substituent R.sup.5.

A process for the preparation of a compound of the formula ##STR19## or a pharmaceutically acceptable salt thereof wherein R.sup.1 is nitrophenacyl;

• R.sup.2 is hydrogen, alkyl, alkenyl, alkyl having a conventional penicillin aryl heterocyclic substituent, or a conventional penicillin aryl, aralkyl, or heterocyclic group;
• R.sup.3 is hydrogen;
• an aromatic group having a halogen, nitro, alkyl, alkoxy, acyl, carbamoyl or dialkylamino substituent;
• a C.sub.3 to C.sub.7 unsubstituted cycloalkyl or substituted by a halogen or an alkyl substituent, or being condensed with an aryl group;
• or a benzyl group or benzyl substituted by a halogen, alkyl, alkoxy, acyl, nitro or dialkylamino substituent;
• and
• X is a group selected from the formulae consisting of ##STR20## by acylating a compound of the formula ##STR21## wherein R.sup.4 is nitrophenacyl, in which the acylation is performed in the presence of a tertiary base selected from the group consisting of a trialkylamine, pyridine or N,N-dialkylaniline at a temperature of -10.degree. C. to +30.degree. C. using an ester of the formula ##STR22## wherein R.sup.6 is an aromatic group having a halogen, nitro, alkyl, alkoxy, acyl, carbamoyl or dialkylamino substituent;
• a C.sub.3 to C.sub.7 unsubstituted cycloalkyl or substituted by a halogen or an alkyl substituent, or being condensed with an aryl group;
• or a benzyl group or benzyl substituted by a halogen, alkyl, alkoxy, acyl, nitro, or dialkylamino substituent;
• and
• wherein
• R.sup.3 is hydrogen, splitting off the substituent R.sup.6.

A process for the preparation of a compound of the formula ##STR23## or a pharmaceutically acceptable salt thereof wherein R.sup.1 is hydrogen, trialkylamino, trialkylsilyl, trichloroethyl, acetoxymethyl, phenacyl, nitrophenacyl, phenyl or a benzyl group;

• R.sup.2 is hydrogen, alkyl, alkenyl, alkyl having a conventional penicillin aryl heterocyclic substituent, or a conventional penicillin aryl, aralkyl, or heterocyclic group;
• R.sup.3 is hydrogen;
• an aromatic group having a halogen, nitro, alkyl, alkoxy, acyl, carbamoyl or dialkylamino substituent;
• a C.sub.3 to C.sub.7 unsubstituted cycloalkyl or substituted by a halogen or an alkyl substituent, or being condensed with an aryl group;
• or a benzyl group or benzyl substituted by a halogen, alkyl, alkoxy, acyl, nitro or dialkylamino substituent;
• and
• X is a group selected from the formulae consisting of ##STR24## wherein the compound is selected from the group consisting of:
• 6-(.alpha.[5-indanyloxy-carbonyl]-phenylacetamido)-2,2-dimethyl-penam-3-ca rboxylic acid;
• 6-(.alpha.-[2,4-dimethylphenoxy-carbonyl]-phenylacetamido)-2,2-dimethyl-pen am-3-carboxylic acid;
• 6-(.alpha.-[3,4-dimethylphenoxy-carbonyl]-phenylacetamido)-2,2-dimethyl-pen am-3-carboxylic acid;
• 6-(.alpha.-phenoxy-carbonyl-phenylacetamido)-2,2-dimethyl-penam-3-carboxyli c acid;
• 6-(.alpha.-carboxy-p-chlorophenylacetamido)-2,2-dimethyl-penam-3-carboxylic acid;
• 6-(.alpha.-carboxy-o-bromophenylacetamido)-2,2-dimethyl-penam-3-carboxylic acid;
• 7-(.alpha.-phenoxy-carbonyl-phenylacetamido)-3-methyl-ceph-3-em-4-carboxyli c acid;
• 7-(.alpha.-[5-indanyloxy-carbonyl]-phenylacetamido)-3-methyl-ceph-3-em-4-ca rboxylic acid;
• 7-(.alpha.-phenoxy-carbonyl-phenylacetamido)-3-methyl-ceph-3-em-4-carboxyli c acid triethylammonium salt;
• 7-(.alpha.-carboxy-3-thienyl-acetamido)-3-methyl-ceph-3-em-4-carboxylic acid;
• 7-(.alpha.-[5-indanyloxy-carbonyl]-phenylacetamido)-3-methyl-ceph-3-em-4-ca rboxylic acid trichloroethyl ester;
• 7-(.alpha.-phenoxy-carbonyl-phenylacetamido)-3-methyl-ceph-3-em-4-carboxyli c acid trichloroethyl ester;
• 7-(.alpha.-pentachlorophenoxy-carbonyl-phenylacetamido)-3-methyl-ceph-3-em- 4-carboxylic acid trichloroethyl ester;
• 7-(.alpha.-benzyloxy-carbonyl-phenylacetamido)-3-methyl-ceph-3-em-4-carboxy lic acid trichloroethyl ester;
• 7-(.alpha.-pentachlorophenoxy-carbonyl-phenylacetamido)-3-methyl-ceph-3-em- 4-carboxylic acid p-nitro-phenacylester;
• 7-(.alpha.-phenoxy-carbonyl-phenylacetamido)-3-methyl-ceph-3-em-4-carboxyli c acid trichloroethyl ester;
• 7-(.alpha.-phenoxy-carbonyl-phenylacetamido)-3-methyl-ceph-3-em-4-carboxyli c acid;
• 7-(.alpha.-carboxy-propylacetamido)-3-methyl-ceph-3-em-4-carboxylic acid;
• 7-(.alpha.-carboxy-propylacetamido)-3-methyl-ceph-3-em-4-carboxylic acid trichloroethyl ester;
• 7-(.alpha.-carboxy-p-chlorophenylacetamido)-3-methyl-ceph-3-em-4-carboxylic acid;
• and
• 7-(.alpha.-carboxy-o-bromophenylacetamido)-3-methyl-ceph-3-em-4-carboxylic acid, or a pharmaceutically acceptable salt thereof, which comprises the step of acylating a compound of the formula ##STR25## wherein R.sup.4 is an easily removable ester-forming group selected from the group which consists of trialkylamino, trialkylsilyl, trichloroethyl, acetoxymethyl, phenacyl, nitrophenacyl, phenyl and benzyl or a salt formed with an alkali metal or a trialkylamine in which the acylation is performed in the presence of a tertiary base selected from the group consisting of a trialkylamine, pyridine or N,N-dialkylaniline at a temperature of -10.degree. C. to +30.degree. C. using an ester of the formula ##STR26## wherein R.sup.6 is an aromatic group having a halogen, nitro, alkyl, alkoxy, acyl, carbamoyl or dialkylamino substituent;
• a C.sub.3 to C.sub.7 unsubstituted cycloalkyl or substituted by a halogen or an alkyl substituent, or being condensed with an aryl group;
• or a benzyl group or benzyl substituted by a halogen, alkyl, alkoxy, acyl, nitro, or dialkylamino substituent;
• and
• wherein
• R.sup.1 and R.sup.3 are hydrogen, splitting off the substituents R.sup.4 and R.sup.6.