# US 5,350,846 A · 2-biphenyl-carbapenems

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- Number: US 5,350,846 A
- Document ID: US5350846A
- Status: Granted
- Kind: A
- Application number: 08/007,934
- Filed: 1993-01-25
- Granted: 1994-09-27
- Earliest claimed: 1990-10-09
- Assignees: Merck & Co., Inc.
- Inventors: Frank P. DiNinno; Thomas N. Salzmann
- Web page: https://patentgrep.com/patent/US5350846A

## CPC

- C07D 477/14: with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 3
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Carbapenems of the formula: ##STR1## are useful intermediates to antibacterial agents.

## Claims

### Claim 1

A compound of the formula: ##STR68## wherein: R is H or CH.sub.3 ;
P' is a removable protecting group for hydroxy;
R.sup.a are independently selected from the group consisting of hydrogen and the radicals set out below:
a) a trifluoromethyl group which is --CF.sub.3 ;
b) a halogen atom selected from the group consisting of --Br, --Cl, --F, and --I;
c) C.sub.1 -C.sub.4 alkoxy radical which is --OC.sub.1-4 alkyl, wherein the alkyl is optionally mono-substituted by R.sup.q, where
R.sup.q is a member selected from the group consisting of --OH, OP', --OCH.sub.3, --CN, --C(O)NH.sub.2, --OC(O)NH.sub.2, CHO, --OC(O)N(CH.sub.3).sub.2, --SO.sub.2 NH.sub.2, --SO.sub.2 N(CH.sub.3).sub.2, --SOCH.sub.3, --SO.sub.2 CH.sub.3, --F, --CF.sub.3, --COOM.sup.a (where M.sup.a is hydrogen, alkali metal, methyl, phenyl or M defined below), tetrazolyl (where the point of attachment is the carbon atom of the tetrazole ring and one of the nitrogen atoms is mono-substituted by M.sup.a as defined above) and --SO.sub.3 M.sup.b (where M.sup.b is hydrogen or an alkali metal or M defined below);
d) a hydroxy or protected hydroxy which is --OH or --OP';
e) a carbonyloxy radical which is --O(C.dbd.O)R.sup.s, where
R.sup.s is C.sub.1-4 alkyl or phenyl, each of which is optionally mono-substituted by R.sup.q as defined above;
f) a carbamoyloxy radical which is --O(C.dbd.O)N(R.sup.y)R.sup.z where
R.sup.y and R.sup.z are independently H, C.sub.1-4 alkyl (optionally mono-substituted by R.sup.q as defined above), together a 3- to 5-membered alkylidene radical to form a ring (optionally substituted with R.sup.q as defined above) or together a 2- to 4-membered alkylidene radical, interrupted by --O--, --S--, --S(O)-- or --S(O).sub.2 --, to form a ring (where the ring is optionally mono-substituted with Rq as defined above);
g) a sulfur-containing radical which is --S(O).sub.n --R.sup.s where n=0-2, and R.sup.s is defined above;
h) a sulfamoyl group which is --SO.sub.2 N(R.sup.y)R.sup.z where R.sup.y and R.sup.z are as defined above;
i) azido which is N.sub.3
j) a formamido group which is --N(R.sup.t)(C.dbd.O)H, where
R.sup.t is H or C.sub.1-4 alkyl, and the alkyl thereof is optionally mono-substituted by R.sup.q as defined above;
k) a (C.sub.1 -C.sub.4 alkyl)carbonylamino radical which is --N(R.sup.t)(C.dbd.O)C.sub.1-4 alkyl, where R.sup.t is as defined above, and the alkyl group is also optionally mono-substituted by R.sup.q as defined above;
l) a (C.sub.1 -C.sub.4 alkoxy) carbonylamino radical which is --N(R.sup.t)(C.dbd.O)OC.sub.1-4 alkyl, where R.sup.t is as defined above, and the alkyl group is also optionally mono-substituted by R.sup.q as defined above;
m) a ureido group which is --N(R.sup.t)(C.dbd.O)N(R.sup.y)R.sup.z where R.sup.t, R.sup.y and R.sup.z are as defined above;
n) a sulfonamido group which is --N(R.sup.t)SO.sub.2 R.sup.s, where R.sup.s and R.sup.t are as defined above;
o) a cyano group which is --CN;
p) a formyl or acetalized formyl radical which is --(C.dbd.O)H or --CH(OCH.sub.3).sub.2 ;
q) (C.sub.1 -C.sub.4 alkyl)carbonyl radical wherein the carbonyl is acetalized which is --C(OCH.sub.3).sub.2 C.sub.1-4 alkyl, where the alkyl is optionally mono-substituted by R.sup.q as defined above;
r) carbonyl radical which is --(C.dbd.O)R.sup.s, where R.sup.s is as defined above;
s) a hydroximinomethyl radical which is --(C.dbd.NOR.sup.z)R.sup.y where R.sup.y and R.sup.z are as defined above, except they may not be joined together to form a ring;
t) a (C.sub.1 -C.sub.4 alkoxy)carbonyl radical which is --(C.dbd.O)OC.sub.1-4 alkyl, where the alkyl is optionally mono-substituted by R.sup.q as defined above;
u) a carbamoyl radical which is --(C.dbd.O)N(R.sup.y)R.sup.z where R.sup.y and R.sup.z are as defined above;
v) an N-hydroxycarbamoyl or N(C.sub.1 -C.sub.4 alkoxy)carbamoyl radical which is --(C.dbd.O)--N(OR.sup.y)R.sup.z where R.sup.y and R.sup.z are as defined above, except they may not be joined together to form a ring;
w) a thiocarbamoyl group which is --(C.dbd.S)N(R.sup.y)(R.sup.z) where R.sup.y and R.sup.z are as defined above;
x) carboxyl which is --COOM.sup.b, where M.sup.b is as defined above;
y) thiocyanate which is --SCN;
z) trifluoromethylthio which is --SCF.sub.3 ;
aa) tetrazolyl, where the point of attachment is the carbon atom of the tetrazole ring and one of the nitrogen atoms is mono-substituted by hydrogen, an alkali metal or a C.sub.1 -C.sub.4 alkyl optionally substituted by R.sup.q as defined above;
ab) an anionic function selected from the group consisting of: phosphono [P.dbd.O(OM.sup.b).sub.2 ]; alkylphosphono {P.dbd.O(OM.sup.b)--[O(C.sub.1 -C.sub.4 alkyl)]}; alkylphosphinyl [P.dbd.O(OM.sup.b)--(C.sub.1 -C.sub.4 alkyl)]; phosphoramido [P.dbd.O(OM.sup.b)N(R.sup.y)R.sup.z and P.dbd.O(OM.sup.b)NHR.sup.x ]; sulfino (SO.sub.2 M.sup.b); sulfo (SO.sub.3 M.sup.b); acylsulfonamides selected from the structures CONM.sup.b SO.sub.2 R.sup.x, CONM.sup.b SO.sub.2 N(R.sup.y)R.sup.z, SO.sub.2 NM.sup.b CON(R.sup.y)R.sup.z ; and SO.sub.2 NM.sup.b CN, where
R.sup.x is phenyl or heteroaryl, where heteroaryl is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, in which a carbon atom is the point of attachment, in which one of the carbon atoms has been replaced by a nitrogen atom, in which one additional carbon atom is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 2 additional carbon atoms are optionally replaced by a nitrogen heteroatom, and where the phenyl and heteroaryl are optionally mono-substituted by R.sup.q, as defined above; M.sup.b is as defined above; and R.sup.y and R.sup.z are as defined above;
ac) C.sub.5 -C.sub.7 cycloalkyl group in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S, NH or N(C.sub.1 -C.sub.4 alkyl) and in which one additional carbon atom may be replaced by NH or N(C.sub.1 -C.sub.4 alkyl), and in which at least one carbon atom adjacent to each nitrogen heteroatom has both of its attached hydrogen atoms replaced by one oxygen thus forming a carbonyl moiety and there are one or two carbonyl moieties present in the ring;
ad) C.sub.2 -C.sub.4 alkenyl radical, optionally mono-substituted by one of the substituents a) to ac) above and phenyl which is optionally substituted by R.sup.q as defined above;
ae) C.sub.2 -C.sub.4 alkynyl radical, optionally mono-substituted by one of the substituents a) to ac) above;
af) C.sub.1 -C.sub.4 alkyl radical;
ag) C.sub.1 -C.sub.4 alkyl mono-substituted by one of the substituents a)-ac) above;
ah) a 2-oxazolidinonyl moiety in which the point of attachment is the nitrogen atom of the oxazolidinone ring, the ring oxygen atom is optionally replaced by a heteroatom selected from --S-- and >NR.sup.t (where R.sup.t is as defined above) and one of the saturated carbon atoms of the oxazolidinone ring is optionally mono-substituted by one of the substituents a) to ag) above; and
M is a removable carboxyl protecting group.

### Claim 2 (depends on 1)

The compound of claim 1 wherein M is selected from the group consisting of benzhydryl, p-nitrobenzyl, 2-naphthylmethyl, allyl, benzyl, trichloroethyl, trimethylsilyl, t-butyldiphenylsilyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl and 4-pyridylmethyl.

### Claim 3 (depends on 1)

The compound of claim 1 wherein P' is selected from the group consisting of trialkylsilyl, aryl(alkyl)silyl, diarylalkylsilyl, triorganosilyl, alkyloxycarbonyl and substituted alkyloxycarbonyl, benzyloxycarbonyl and substituted benzyloxycarbonyl and allyloxycarbonyl and substituted allyloxycarbonyl.

### Claim 4 (depends on 1)

The compound of claim 1 wherein P' is selected from the group consisting of methoxy-t-butylphenylsilyl, t-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and allyloxycarbonyl.