Process for producing 6-aminopenicillanic acid or 7-aminocephalosporanic acid derivatives

A process for preparing a compound of the formula

• H.sub.2 N-A
• wherein A is a penicillin moiety represented by the formula ##STR19## wherein the carboxy group is unprotected or protected by a conventional protecting group, or A is a cephalosporin moiety represented by the formula ##STR20## wherein the carboxy group is unprotected or protected by a conventional protecting group and R.sup.3 is a group which does not take part in the reactions described below and is a member selected from the group consisting of
• 1. lower alkyl,
• 2. lower alkoxymethyl,
• 3. lower alkanoyloxymethyl,
• 4. a group represented by the formula
• -CH.sub.2 SR.sup.4
• wherein R.sup.4 is lower alkyl or a 5 or 6 membered nitrogen-containing heterocyclic group having 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, the nitrogen being in the oxide or non-oxide form, which nitrogen-containing heterocyclic group is unsubstituted or substituted by (a) lower alkyl, (b) trifluoromethyl, (c) lower alkoxy, (d) chlorine or bromine, (e) amino, (f) mercapto, (g) hydroxy, (h) carbamoyl, (i) carboxy, (j) lower alkyl substituted by hydroxy, mercapto, amino, morpholino, carboxy, sulfo, carbamoyl, alkoxycarbonyl having 2 to 13 carbon atoms, mono- or di-lower alkyl carbamoyl, alkoxy having 1 to 12 carbon atoms, alkylthio having 1 to 3 carbon atoms, alkylsulfonyl having 1 to 3 carbon atoms, acyloxy selected from the group consisting of acetoxy, propionyloxy, valeryloxy, caproyloxy, benzoyloxy and phenylacetoxy, morpholinocarbonyl or N-lower alkylamino, (k) mercapto substituted by lower alkyl wherein the lower alkyl is unsubstituted or substituted by hydroxy, mercapto, amino, morpholino, carboxy, sulfo, carbamoyl, alkoxycarbonyl having 2 to 13 carbon atoms, mono- or di- lower alkyl carbamoyl, alkoxy having 1 to 12 carbon atoms, alkylthio having 1 to 3 carbon atoms, alkylsulfonyl having 1 to 3 carbon atoms, acyloxy selected from the group consisting of acetoxy, propionyloxy, valeryloxy, caproyloxy, benzoyloxy and phenylacetoxy, morpholinocarbonyl or N-lower alkylamino, or (1) amino mono- or di- substituted by carboxy, carbamoyl, lower alkyl, alkoxycarbonyl having 2 to 13 carbon atoms, lower alkyl carbamoyl, or lower alkyl substituted by hydroxy, mercapto, amino, morpholino, carboxy, sulfo, carbamoyl, alkoxycarbonyl having 2 to 13 carbon atoms, mono- or di- lower alkyl carbamoyl, alkoxy having 1 to 12 carbon atoms, alkylthio having 1 to 3 carbon atoms, alkylsulfonyl having 1 to 3 carbon atoms, acyloxy selected from the group consisting of acetoxy, propionyloxy, valeryloxy, caproyloxy, benzoyloxy and phenylacetoxy, morpholinocarbonyl or N-lower alkylamino, and
• 5. an iminomethyl group of the formula
• -CH.dbd.NOR.sup.5
• wherein R.sup.5 is alkyl having 1 to 6 carbon atoms or cycloalkyl having up to 6 carbon atoms, which alkyl and cycloalkyl groups are unsubstituted or substituted by (a) allyl, (b) phenyl, (c) an unsubstituted 5 or 6 membered heterocyclic group having 1 or 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, (d) carboxy or (e) pyridinium,
• which comprises reacting a compound of the formula ##STR21## wherein R.sup.1 is an organic residue derived from an acylamido group in the 6- position of a penicillin or the 7- position of a cephalosporin by eliminating the -CONH- moiety of the acylamido group, which organic residue is capable of combination with a thiocarbonyl group to form a thioacyl group, and A has the same meaning as above,
• with a disulfidizing agent selected from the group consisting of (1) sulfenyl halides of the formula
• R.sup.2 X
• wherein R.sup.2 is (a) lower alkoxycarbonylthio, (b) halocarbonylthio wherein the halo is chloro or bromo, (c) lower alkylthio, (d) mono-, di- or tri-halo lower alkylthio wherein the halo is chloro or bromo, (e) mono- or di- lower alkylaminothio, (f) mercapto substituted by an unsubstituted nitrogen-containing 5 or 6 membered heterocyclic group, (g) halothio wherein the halo is chloro or bromo or (h) halodithio wherein the halo is chloro or bromo, and X is chlorine or bromine, (2) isothioureas of the formula ##STR22## wherein R.sup.2 has the same meaning as above, (3) imides of the formula ##STR23## wherein R.sup.2 has the same meaning as above, and (4) Bunte salts of the formula ##STR24## wherein R.sup.2 has the same meaning as above and Me represents alkali metal,
• to obtain a disulfide compound of the formula ##STR25## wherein R.sup.1, R.sup.2 and A have the same meanings as above, and reacting the disulfide compound with a solvolysis solvent selected from the group consisting of aliphatic alcohols having 1 to 4 carbon atoms, glycols having 2 to 4 carbon atoms, glycerine, acetic acid, propionic acid, methylmercaptan, ethylmercaptan and water.

A process for preparing a compound of the formula

• H.sub.2 N-A
• wherein A is a penicillin moiety represented by the formula ##STR26## wherein the carboxy group is unprotected or protected by a conventional protecting group, or A is a cephalosporin moiety represented by the formula ##STR27## wherein the carboxy group is unprotected or protected by a conventional protecting group and R.sup.3 is a group which does not take part in the reaction described below and is a member selected from the group consisting of
• 1. lower alkyl,
• 2. lower alkoxymethyl,
• 3. lower alkanoyloxymethyl,
• 4. a group represented by the formula
• --CH.sub.2 SR.sup.4
• wherein R.sup.4 is lower alkyl or a 5 or 6 membered nitrogen-containing heterocyclic group having 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, the nitrogen being in the oxide or non-oxide form, which nitrogen-containing heterocyclic group is unsubstituted or substituted by (a) lower alkyl, (b) trifluoromethyl, (c) lower alkoxy, (d) halogen, (e) amino, (f) mercapto, (g) hydroxy, (h) carbamoyl, (i) carboxy, (j) lower alkyl substituted by hydroxy, mercapto, amino, morpholino, carboxy, sulfo, carbamoyl, alkoxycarbonyl selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl and dodecyloxycarbonyl, mono- or di- lower alkyl carbamoyl, alkoxy selected from the group consisting of methoxy, ethoxy, propoxy, butoxy, isobutoxy, hexyloxy, octyloxy, decyloxy and dodecyloxy, alkylthio selected from the group consisting of methylthio, ethylthio and isopropylthio, alkylsulfonyl selected from the group consisting of methylsulfonyl, ethylsulfonyl and isopropylsulfonyl, acyloxy selected from the group consisting of acetoxy, propionyloxy, valeryloxy, caproyloxy, benzoyloxy and phenylacetoxy, morpholinocarbonyl or N-lower alkylamino, (k) mercapto substituted by lower alkyl wherein the lower alkyl is unsubstituted or substituted by hydroxy, mercapto, amino, morpholino, carboxy, sulfo, carbamoyl, alkoxycarbonyl selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl and dodecyloxycarbonyl, mono- or di- lower alkyl carbamoyl, alkoxy selected from the group consisting of methoxy, ethoxy, propoxy, butoxy, isobutoxy, hexyloxy, octyloxy, decyloxy and dodecyloxy, alkylthio selected from the group consisting of methylthio, ethylthio and isopropylthio, alkylsulfonyl selected from the group consisting of methylsulfonyl, ethylsulfonyl and isopropylsulfonyl, acyloxy selected from the group consisting of acetoxy, propionyloxy, valeryloxy, caproyloxy, benzoyloxy and phenylacetoxy, morpholinocarbonyl or N-lower alkylamino, or (1) amino mono- or di- substituted by carboxy, carbamoyl, lower alkyl, alkoxycarbonyl selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl and dodecyloxycarbonyl, lower alkyl carbamoyl, or lower alkyl substituted by hydroxy, mercapto, amino, morpholino, carboxy, sulfo, carbamoyl, alkoxycarbonyl selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl and dodecyloxycarbonyl, mono- or di- lower alkyl carbamoyl, alkoxy selected from the group consisting of methoxy, ethoxy, propoxy, butoxy, isobutoxy, hexyloxy, octyloxy, decyloxy and dodecyloxy, alkylthio selected from the group consisting of methylthio, ethylthio and isopropylthio, alkylsulfonyl selected from the group consisting of methylsulfonyl, ethylsulfonyl and isopropylsulfonyl, acyloxy selected from the group consisting of acetoxy, propionyloxy, valeryoxy, caproyloxy, benzoyloxy and phenylacetoxy, morpholinocarbonyl or N-lower alkylamino, and
• 5. an iminomethyl group of the formula
• -CH.dbd.NOR.sup.5
• wherein R.sup.5 is alkyl having 1 to 6 carbon atoms or cycloalkyl having up to 6 carbon atoms, which alkyl and cycloalkyl groups are unsubstituted or substituted by (a) allyl, (b) phenyl, (c) an unsubstituted 5 or 6 membered heterocyclic group having 1 or 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, (d) carboxy or (e) pyridinium,
• which comprises reacting a compound of the formula ##STR28## wherein A has the same meaning as above, R.sup.1 is an organic residue derived from an acylamido group in the 6- position of a penicillin or the 7- position of a cephalosporin by eliminating the -CONH- moiety of the acylamido group, which organic residue is capable of combination with a thiocarbonyl group to form a thioacyl group, and R.sup.2 is a member selected from the group consisting of (1) lower alkoxycarbonylthio, (2) halocarbonylthio wherein the halo is chloro or bromo, (3) lower alkylthio, (4) mono-, di- or tri-halo lower alkylthio wherein the halo is chloro or bromo, (5) mono- or di- lower alkylamino thio, (6) mercapto substituted by an unsubstituted nitrogen containing 5 or 6 membered heterocyclic group, (7) halothio wherein the halo is chloro or bromo and (8) halodithio wherein the halo is chloro or bromo,
• with a solvolysis solvent selected from the group consisting of aliphatic alcohols having 1 to 4 carbon atoms, ethylene glycol, propylene glycol, 1,3-butanediol, glycerine, acetic acid, propionic acid, methylmercaptan, ethylmercaptan and water.

A process for preparing a compound of the formula

• H.sub.2 N-A
• wherein A is a penicillin moiety represented by the formula ##STR29## wherein the carboxy group is unprotected or protected by a conventional protecting group, or A is a cephalosporin moiety represented by the formula ##STR30## wherein the carboxy group is unprotected or protected by a conventional protecting group and R.sup.3 is a group which does not take part in the reactions described below and is a member selected from the group consisting of
• 1. lower alkyl,
• 2. lower alkoxymethyl,
• 3. lower alkanoyloxymethyl,
• 4. a group represented by the formula
• -CH.sub.2 SR.sup.4
• wherein R.sup.4 is lower alkyl or a 5 or 6 membered nitrogen-containing heterocyclic group having 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, the nitrogen being in the oxide or non-oxide form, which nitrogen-containing heterocyclic group is unsubstituted or substituted by (a) lower alkyl, (b) trifluoromethyl, (c) lower alkoxy, (d) chlorine or bromine, (e) amino, (f) mercapto, (g) hydroxy, (h) carbamoyl, (i) carboxy, (j) lower alkyl substituted by hydroxy, mercapto, amino, morpholino, carboxy, sulfo, carbamoyl, alkoxycarbonyl selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl and dodecyloxycarbonyl, mono- or di- lower alkyl carbamoyl, alkoxy selected from the group consisting of methoxy, ethoxy, propoxy, butoxy, isobutoxy, hexyloxy, octyloxy, decyloxy and dodecyloxy, alkylthio selected from the group consisting of methylthio, ethylthio and isopropylthio, alkylsulfonyl selected from the group consisting of methylsulfonyl, ethylsulfonyl and isopropylsulfonyl, acyloxy selected from the group consisting of acetoxy, propionyloxy, valeryloxy, caproyloxy, benzoyloxy and phenylacetoxy, morpholinocarbonyl or N-lower alkylamino, (k) mercapto substituted by lower alkyl wherein the lower alkyl is unsubstituted or substituted by hydroxy, mercapto, amino, morpholino, carboxy, sulfo, carbamoyl, alkoxycarbonyl selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl and dodecyloxycarbonyl, mono- or di- lower alkyl carbamoyl, alkoxy selected from the group consisting of methoxy, ethoxy, propoxy, butoxy, isobutoxy, hexyloxy, octyloxy, decyloxy and dodecyloxy, alkylthio selected from the group consisting of methylthio, ethylthio and isopropylthio, alkylsulfonyl selected from the group consisting of methylsulfonyl, ethylsulfonyl and isopropylsulfonyl, acyloxy selected from the group consisting of acetoxy, propionyloxy, valeryloxy, caproyloxy, benzoyloxy and phenylacetoxy, morpholinocarbonyl or N-lower alkylamino, or (1) amino mono- or di- substituted by carboxy, carbamoyl, lower alkyl, alkoxycarbonyl selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl and dodecyloxycarbonyl, lower alkyl carbamoyl, or lower alkyl substituted by hydroxy, mercapto, amino, morpholino, carboxy, sulfo, carbamoyl, alkoxycarbonyl selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl and dodecyloxycarbonyl, mono- or di- lower alkyl carbamoyl, alkoxy selected from the group consisting of methoxy, ethoxy, propoxy, butoxy, isobutoxy, hexyloxy, octyloxy, decyloxy and dodecyloxy, alkylthio selected from the group consisting of methylthio, ethylthio and isopropylthio, alkylsulfonyl selected from the group consisting of methylsulfonyl, ethylsulfonyl and isopropylsulfonyl, acyloxy selected from the group consisting of acetoxy, propionyloxy, valeryloxy, caproyloxy, benzoyloxy and phenylacetoxy, morpholinocarbonyl or N-lower alkylamino, and
• 5.