US4347183A — Process for the synthesis of penems and carbapene…

Claim 1

Independent Claim 229 words

The process for the preparation of a compound of Formula I: ##STR15## wherein R 1 is hydrogen, lower alkyl, acylamino or ##STR16## wherein R 4 is hydrogen, lower alkyl, aryl, heteroaryl and R 5 is an O-protecting group: R 2 is lower alkyl, aryl, alkylaryl, an N-protected amino-lower alkyl, an O-protected hydroxyalkyl, thioalkyl, thioaryl, thioheteroaryl, an α-(N-protected) amino acid ester or an alkylcarboxylic acid ester; R 3 is nitrile, tetrazole, or --COOR 6 wherein R 6 is lower alkyl, lower alkylthihalogenomethykl, aryl, allyl, or a metabolisable ester: X and Z are independently sulfur, oxygen, -NR 7 wherein R 7 is acyl, alkyl, aryl, or an N-protecting group; or --(CH 2 ) n --wherein n is 1 or 2; which comprises the reaction of an azetidinone of Formula A: ##STR17## wherein R 1 , R 2 , X and Z are as hereinabove defined, with an acid halide of Formula B: ##STR18## wherein in R 3 is as hereinabove defined, in an inert solvent in the presence of a tertiary amine and an alkaline earth metal carbonate; followed by reaction of the thereby produced imido derivative of Formula C: ##STR19## wherein in R 1 , R 2 , R 3 , X and Z are as hereinabove defined: with a trialkyl phosphite, said reaction being carried out at temperatures in the range of from about 20° to about 80° C.

Claim 2

Dependent Claim 229 words

The process for the preparation of a compound of Formula I: ##STR15## wherein R 1 is hydrogen, lower alkyl, acylamino or ##STR16## wherein R 4 is hydrogen, lower alkyl, aryl, heteroaryl and R 5 is an O-protecting group: R 2 is lower alkyl, aryl, alkylaryl, an N-protected amino-lower alkyl, an O-protected hydroxyalkyl, thioalkyl, thioaryl, thioheteroaryl, an α-(N-protected) amino acid ester or an alkylcarboxylic acid ester; R 3 is nitrile, tetrazole, or --COOR 6 wherein R 6 is lower alkyl, lower alkylthihalogenomethykl, aryl, allyl, or a metabolisable ester: X and Z are independently sulfur, oxygen, -NR 7 wherein R 7 is acyl, alkyl, aryl, or an N-protecting group; or --(CH 2 ) n --wherein n is 1 or 2; which comprises the reaction of an azetidinone of Formula A: ##STR17## wherein R 1 , R 2 , X and Z are as hereinabove defined, with an acid halide of Formula B: ##STR18## wherein in R 3 is as hereinabove defined, in an inert solvent in the presence of a tertiary amine and an alkaline earth metal carbonate; followed by reaction of the thereby produced imido derivative of Formula C: ##STR19## wherein in R 1 , R 2 , R 3 , X and Z are as hereinabove defined: with a trialkyl phosphite, said reaction being carried out at temperatures in the range of from about 20° to about 80° C.

Claim 3

Dependent Claim 18 words

The process of claim 1 including the subsequent step of isolating the thereby produced compound of formula I.

Claim 4

Dependent Claim 54 words

The process of claim 1 wherein to one mole of said azetidinone of formula A, there is added about a molar equivalent of each of said acid halide of formula B and said tertiary amine, at least a molar equivalent of said alkaline earth metal carbonate, and about two molar equivalents of trialkyl phosphite.

Claim 5

Dependent Claim 12 words

The process of claim 3 when carried out at about 60° C.

Claim 6

Dependent Claim 16 words

The process of claims 3 or 4 wherein said inert solvent is a halogeneated hydrocarbon solvent.

Claim 7

Dependent Claim 51 words

The process of claims 1 or 3 wherein said acid chloride of formula B is allyloxalyl chloride, said-tertiary amine is di-isopropylethylamine, said alkaline earth metal carbonate is calcium carbonate, said inert solvent is a halogenated hydrocarbon, and said trialkyl-phosphite is triethylphosphite, and said process is carried out at about 60° C.

Claim 8

Dependent Claim 28 words

The process of claim 6 wherein said azedtidinone is a compound of the following formula A": ##STR20## whereby is produced a compound of formula I" as follows: ##STR21##

Claim 9

Dependent Claim 23 words

The process of claim 7 wherein the azetidinone of formula A" is (3S, 4R, 5R)-3-[(1-trichlorethoxycarbonyloxyethyl)]-4-[(ethylthio) carbonothioylthio]azetidin-2-one whereby is produced allyl (5R, 6S, 8R)-6-(1-trichloroethoxycarbonyloxyethyl)-2-ethylthiopenem-3-carboxylate.

Claim 10

Dependent Claim 25 words

The process of claim 7 where in the azetidinone of formula A is (3S, 4R, 4R)-3-(1-trichlorethoxy-carbonyloxyethyl)-4-[(methylthio) carbonothioylthio] azetidin-2-one whereby is produced allyl (5R, 6S, 8R)-6-(1-trichloroethoxycarbonyloxy-2-methylthioethyl)penem-3-carboxylate.

Claim 11

Dependent Claim 173 words

The process for the preparation of a compound represented by formula I: ##STR22## wherein R 1 is hydrogen, lower alkyl, acylamino or ##STR23## wherein R 4 is hydrogen, lower alkyl, aryl or heteroaryl and R 5 is an O-protecting group: R 2 is lower alkyl, aryl, alkylaryl, an N-protected amino-lower alkyl, an O-protected hydroxyalkyl, thioalkyl, thioaryl, thioheteroaryl, an α-(N-protected) amino acid ester or an alkylcarboxylic acid esters R 3 is nitrile, tetrazole, or --COOR 6 wherein R 6 is lower alkyl, lower alkyltrihalogenomethyl, aryl, allyl, or a metabolisable ester; X and Z are independently sulfur, oxygen, --NR 7 --wherein R 7 is acyl, alkyl, aryl, or an N-protecting group; or 13 (CH 2 ) n --wherein n is 1 or 2; which comprises the reaction of an imido derivative of formual C: ##STR24## wherein R 1 , R 2 , R 3 , X and Z are as hereinabove defined; with a trialkyl phosphite, said reaction being carried out at temperatures in the range of from about 20° C. to about 80° C.

Claim 12

Dependent Claim 173 words

The process for the preparation of a compound represented by formula I: ##STR22## wherein R 1 is hydrogen, lower alkyl, acylamino or ##STR23## wherein R 4 is hydrogen, lower alkyl, aryl or heteroaryl and R 5 is an O-protecting group: R 2 is lower alkyl, aryl, alkylaryl, an N-protected amino-lower alkyl, an O-protected hydroxyalkyl, thioalkyl, thioaryl, thioheteroaryl, an α-(N-protected) amino acid ester or an alkylcarboxylic acid esters R 3 is nitrile, tetrazole, or --COOR 6 wherein R 6 is lower alkyl, lower alkyltrihalogenomethyl, aryl, allyl, or a metabolisable ester; X and Z are independently sulfur, oxygen, --NR 7 --wherein R 7 is acyl, alkyl, aryl, or an N-protecting group; or 13 (CH 2 ) n --wherein n is 1 or 2; which comprises the reaction of an imido derivative of formual C: ##STR24## wherein R 1 , R 2 , R 3 , X and Z are as hereinabove defined; with a trialkyl phosphite, said reaction being carried out at temperatures in the range of from about 20° C. to about 80° C.

Claim 13

Dependent Claim 75 words

The process of claim 10 wherein the compound represented by Formula C is prepared by the reaction of an azetidinone represented by Formula A: ##STR25## wherein R 1 , R 2 , X and Z are as defined in claim 13, with an acid halide represented by Formula B: ##STR26## wherein R 3 is as defined in claim 13; in an inert solvent in the presence of a tertiary amine and alkaline earth metal carbonate.

Claim 14

Dependent Claim 9 words

The process of claim 10 wherein X is sulfur.

Claim 15

Dependent Claim 9 words

The process of claim 10 wherein X is oxygen.

Claim 16

Dependent Claim 18 words

The process of claim 10 wherein X is ##STR27## and R 7 is as defined in claim 13.

Claim 17

Dependent Claim 20 words

The process of claim 10 wherein X is --(CH 2 ) n --and n is as defined in claim 10.

Claim 18

Dependent Claim 18 words

The process of claim 15 wherein n is 1, Z is sulfur, and R 2 is N-protected aminoethyl.

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	1985-08-30	1986-03-01	1986-08-31	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	1989-08-30	1990-03-01	1990-08-31	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	1993-08-30	1994-03-01	1994-08-31	$7700.00	Window Closed / Lapsed

Process for the synthesis of penems and carbapenems

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