Preparation of beta-methyl carbapenem intermediates

A process for synthesizing a compound of formula 6:

• ##STR20## wherein:
• R.sup.a is:
• (1) hydrogen,
• (2) C.sub.1-4 alkyl or
• (3) a hydroxy protecting group;
• and
• R.sup.b and R.sup.c are independently:
• tri-C.sub.1-6 alkyl silyl, phenyl di-C.sub.1-6 alkyl silyl, and diphenyl mono C.sub.1-6 alkyl silyl including tert-butyl-dimethylsilyl, hexyldimethylsilyl and isopropyl dimethylsilyl;
• straight and branched lower alkyl having from 1 to 10 carbon atoms;
• alkenyl or alkynyl, having from 2 to 10 carbon atoms;
• cycloalkyl having from 3 to 6 carbon atoms;
• cycloalkylalkyl wherein the cycloalkyl moiety comprises 3 to 6 carbon atoms and the alkyl moiety comprises 1 to 10 carbon atoms;
• alkylcycloalkyl wherein the alkyl moiety comprises 1 to 6 carbon atoms and the cycloalkyl moiety comprises 3 to 6 carbon atoms;
• aryl, selected from phenyl and naphthyl;
• aralkyl selected from benzyl and phenethyl;
• heterocyclyl (saturated and unsaturated) comprising structures having from 5 to 10 ring atoms, wherein one or more of the heteroatoms is selected from oxygen, nitrogen, or sulfur, wherein the structure is selected from thiophene, imidazolyl, tetrazolyl and furyl;
• heterocycloalkyl which comprises the immediately preceding heterocyclyl moieties and the alkyl moiety comprises from 1-10 carbon atoms;
• substituted species of the above named radicals wherein the substituents are selected from the group consisting of amino, hydroxyl, cyano, carboxyl, nitro, chloro, bromo, or fluoro;
• perhaloloweralkyl selected from trifluoromethyl;
• guanidino;
• amidino;
• sulfamoyl;
• N-substituted sulfamoyl, amidino, and guanidino wherein the N-substituent is lower alkyl having from 1 to 6 carbon atoms or aryl having 6-10 carbon atoms;
• COR or CO.sub.2 R, wherein R is lower alkyl having from 1 to 6 carbon atoms or aryl having 6-10 carbon atoms;
• wherein lower alkyl is C.sub.1-6 alkyl and wherein R.sup.b and R.sup.c may be the same or different, but R.sup.b must be removable in the presence of R.sup.c ;
• comprising:
• reacting the ketoester of formula 4:
• ##STR21## wherein R.sup.a, R.sup.b, and R.sup.c are defined above and R.sup.1 is an alkylsilyl protecting group;
• with an acid and a first catalyst selected from Pd/C, Pd(OH).sub.2 /C and (Ra)Ni at a temperature of about 0.degree. C. to about 50.degree. C. with about 0-500 psi H.sub.2 to give a compound of formula 5:
• ##STR22## and selectively desilylating with a desilylating agent selected from NaOH, KOH, tetrabutylammonium fluoride and 2-mercaptopyridine N-oxide at a temperature of about --10.degree. C. to about 50.degree. C. to yield the compound of formula 6.

A process for synthesizing a compound of formula I:

• ##STR23## wherein:
• R.sup.a is:
• (1) hydrogen,
• (2) C.sub.1-4 alkyl or
• (3) a hydroxy protecting group;
• and P is hydrogen, comprising:
• (a) reacting a ketoester of formula 1:
• ##STR24## wherein R.sup.b is selected from H, tri-C.sub.1-6 alkyl silyl, phenyl di-C.sub.1-6 alkyl silyl, and diphenyl mono C.sub.1-6 alkyl silyl including tert-butyl-dimethylsilyl, hexyldimethylsilyl and isopropyl dimethylsilyl;
• straight and branched lower alkyl having from 1 to 10 carbon atoms;
• alkenyl or alkynyl, having from 2 to 10 carbon atoms;
• cycloalkyl having from 3 to 6 carbon atoms;
• cycloalkylalkyl wherein the cycloalkyl moiety comprises 3 to 6 carbon atoms and the alkyl moiety comprises 1 to 10 carbon atoms;
• alkylcycloalkyl wherein the alkyl moiety comprises 1 to 6 carbon atoms and the cycloalkyl moiety comprises 3 to 6 carbon atoms;
• aryl selected from phenyl and naphthyl;
• aralkyl selected from benzyl and phenethyl;
• heterocyclyl (saturated and unsaturated) comprising structures having from 5 to 10 ring atoms, wherein one or more of the heteroatoms is selected from oxygen, nitrogen, and sulfur, wherein the structure is selected from thiophene, imidazolyl, tetrazolyl and furyl;
• heterocycloalkyl which comprises the immediately preceding heterocyclyl moieties and the alkyl moiety comprises from 1-10 carbon atoms;
• substituted species of the above named radicals wherein the substituents are selected from the group consisting of amino, hydroxyl, cyano, carboxyl, nitro, chloro, bromo, or fluoro;
• perhaloloweralkyl selected from trifluoromethyl;
• guanidino;
• amidino;
• sulfamoyl;
• N-substituted sulfamoyl, amidino, and guanidino wherein the N-substituent is lower alkyl having from 1 to 6 carbon atoms or aryl having 6-10 carbon atoms;
• COR or CO.sub.2 R, wherein R is lower alkyl having from 1 to 6 carbon atoms or aryl having 6-10 carbon atoms;
• and
• R.sup.c is selected from the group consisting of tri-C.sub.1-6 alkyl silyl, phenyl di-C.sub.1-6 alkyl silyl, and diphenyl mono C.sub.1-6 alkyl silyl including tert-butyl-dimethylsilyl, hexyldimethylsilyl and isopropyl dimethylsilyl;
• straight and branched lower alkyl having from 1 to 10 carbon atoms;
• alkenyl or alkynyl, having from 2 to 10 carbon atoms;
• cycloalkyl having from 3 to 6 carbon atoms;
• cycloalkylalkyl wherein the cycloalkyl moiety comprises 3 to 6 carbon atoms and the alkyl moiety comprises 1 to 10 carbon atoms;
• alkylcycloalkyl wherein the alkyl moiety comprises 1 to 6 carbon atoms and the cycloalkyl moiety comprises 3 to 6 carbon atoms;
• aryl selected from phenyl and naphthyl;
• aralkyl selected from benzyl and phenethyl;
• heterocyclyl (saturated and unsaturated) comprising structures having from 5 to 10 ring atoms, wherein one or more of the heteroatoms is selected from oxygen, nitrogen, and sulfur, wherein the structure is selected from thiophene, imidazolyl, tetrazolyl and furyl;
• heterocycloalkyl which comprises the immediately preceding heterocyclyl moieties and the alkyl moiety comprises from 1-10 carbon atoms;
• substituted species of the above named radicals wherein the substituents are selected from the group consisting of amino, hydroxyl, cyano, carboxyl, nitro, chloro, bromo, or fluoro;
• perhaloloweralkyl selected from trifluoromethyl;
• guanidino;
• amidino;
• sulfamoyl;
• N-substituted sulfamoyl, amidino, and guanidino wherein the N-substituent is lower alkyl having from 1 to 6 carbon atoms or aryl having 6-10 carbon atoms;
• COR or CO.sub.2 R, wherein R is lower alkyl having from 1 to 6 carbon atoms or aryl having 6-10 carbon atoms;
• wherein R is lower alkyl having from 1 to 6 carbon atoms or aryl having 6-10 carbon atoms;
• wherein lower alkyl is C.sub.1-6 alkyl and wherein R.sup.b and R.sup.c may be the same or different, but R.sup.b must be removable in the presence of R.sup.c ;
• with a compound of formula 2:
• ##STR25## wherein R.sub.a is defined above, and R.sup.d is C.sub.1-4 alkyl;
• in the presence of a first base selected from potassium and calcium carbonates, diazabicycloundecane, diisopropylethylamine, triethylamine, dimethylethylamine and dimethylpentylamine at a temperature of about 25.degree. C. to about 60.degree. C. to produce a ketoester adduct of formula 3:
• ##STR26## (b) reacting the compound of formula 3 with a silylating agent and a second base to produce the ketoester of formula 4:
• ##STR27## wherein R.sup.a, R.sup.b, and R.sup.c are defined above and R.sup.1 is an alkylsilyl protecting group;
• (c) reacting the isolated ketoester of formula 4 with an acid and a first catalyst at a temperature of about 0.degree. C. to about 50.degree. C. with about 0-500 psi H.sub.2, to give a compound of formula 5:
• ##STR28## (d) selectively desilylating with a desilylating agent at a temperature of about -10.degree. C. to about 50.degree. C. to yield the compound of formula 6:
• ##STR29## (e) dissolving the compound of formula 6 in an alcohol and hydrogenating at about 30 to about 55 psi with H.sub.2 in the presence of a second catalyst selected from Pd/C, Pd(OH).sub.2 /C and (Ra)Ni at a temperature of about 0.degree. C. to about 100.degree. C., to yield the compound of formula 1;
• and
• (f) purifying and isolating the compound of formula.