Carbapenems having the formula: ##STR1## are useful antibacterial agents.

BACKGROUND OF THE INVENTION 
The present invention relates to antibacterial agents of the carbapenem 
class, in which the 2-position sidechain is characterized by a phenyl 
moiety, optionally substituted, to which is attached, usually through an 
alkyl bridge, a 1,2,3-triazolyl group, optionally substituted, with 
attachment being only through a nitrogen atom of the triazolyl group, as 
described in more detail below. 
Thienamycin was an early carbapenem antibacterial agent having a broad 
spectrum; it has the following formula: 
##STR2## 
Later, N-formimidoyl thienamycin was discovered; it has the formula: 
##STR3## 
The 2-(1,2,3-triazolyl substituted)phenyl carbapenems of the present 
invention have an antibacterial potency equal to or greater than, in most 
cases, that of either thienamycin or N-formimidoyl thienamycin. The 
compounds of the present invention are also more resistant than 
thienamycin or N-formimidoyl thienamycin to degradation by the 
dehydropeptidase enzyme DHP-I, thus permitting greater therapeutic 
application of the compounds. 
More recently, carbapenem antibacterial agents have been described which 
have a 2-substituent which is an aryl moiety optionally substituted by, 
e.g., aminomethyl and substituted aminomethyl. These agents are described 
in U.S. Pat. Nos. 4,543,257 and 4,260,627 and have the formula: 
##STR4## 
However, these compounds belong to a different class from those of the 
present invention and are distinguished by different physiological 
properties. 
There is also described in EP-A-0 277 743 a particular class of carbapenems 
of the formula: 
##STR5## 
but the disclosure thereof is very limited and none of those compounds 
suggest the compounds of the present invention. 
SUMMARY OF THE INVENTION 
The present invention provides novel carbapenem compounds of the formula I: 
##STR6## 
wherein: R is H or CH.sub.3 ; 
R.sup.1 and R.sup.2 are independently H, CH.sub.3 --, CH.sub.3 CH.sub.2 --, 
(CH.sub.3).sub.2 CH--, HOCH.sub.2 --, (R)--CH.sub.3 CH(OH)--, 
(CH.sub.3).sub.2 C(OH)--, FCH.sub.2 --, F.sub.2 CH--, F.sub.3 C--, 
(R)--CH.sub.3 CH(F)--, CH.sub.3 CF.sub.2 --, or (CH.sub.3).sub.2 C(F)--; 
R.sup.a and R.sup.b are independently hydrogen or: 
a) a trifluoromethyl group: --CF.sub.3 ; 
b) a halogen atom: --Br, --Cl, --F, or --I; 
c) C.sub.1 -C.sub.4 alkoxy radical: --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, 
--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 or phenyl), 
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); 
d) a hydroxy group: --OH; 
e) a carbonyloxy radical: --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:--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)--, --S(O).sub.2 --or --NR.sup.3 --, to 
form a ring (where R.sup.e is hydrogen, C.sub.1 -C.sub.4 alkyl, and 
C.sub.1 -C.sub.4 alkyl mono-substituted with R.sup.q and the ring is 
optionally mono-substituted with Rq as defined above); 
g) a sulfur radical: --S(O).sub.n --R.sup.s where n=0-2, and R.sup.s is 
defined above; 
h) a sulfamoyl group: --SO.sub.2 N(R.sup.y)R.sup.z where R.sup.y and 
R.sup.z are as defined above; 
i) azido: N.sub.3 
j) a formamido group: --N(R.sup.5)(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: 
--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: 
--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: --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: --N(R.sup.t)SO.sub.2 R.sup.2, where R.sup.s and 
R.sup.t are as defined above; 
o) a cyano group: --CN; 
p) a formyl or acetalized formyl radical: --(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: --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: --(C.dbd.O)R.sup.s, where R.sup.s is as defined above; 
s) a hydroximinomethyl radical in which the oxygen or carbon atom is 
optionally substituted by a C.sub.1 -C.sub.4 alkyl group: 
--(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: --(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: --(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 in 
which the nitrogen atom may be additionally substituted by a C.sub.1 
-C.sub.4 alkyl group: --(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: --(C.dbd.S)N(R.sup.y)R.sup.z where R.sup.y and 
R.sup.z are as defined above; 
x) carboxyl: --COOM.sup.b, where M.sup.b is as defined above; 
y) thiocyanate: --SCN; 
z) trifluoromethylthio: --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 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 monosubstituted 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 monosubstituted 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; 
R.sup.c is R.sup.a as defined hereinabove, hydrogen, --NR.sup.y R.sup.z 
(where R.sup.y and R.sup.z are defined hereinabove), or 
##STR7## 
but independently selected from R.sup.a and from each other if more than 
one R.sup.c is present, and is attached to a ring carbon atom or a ring 
nitrogen heteroatom the valency of which is not satisfied by the ring 
bonds; 
R.sup.d is R.sup.a as defined hereinabove, hydrogen or --NR.sup.y R.sup.z 
(where R.sup.y and R.sup.z are defined hereinabove), 
##STR8## 
is a 5- or 6-membered monocyclic aromatic heterocycle or an 8-, 9- or 
10-membered bicyclic aromatic heterocycle, the heterocycle containing a 
first nitrogen in an aromatic 5- or 6-membered first ring, with said first 
nitrogen quaternary by virtue of attachment to A' in addition to the ring 
bonds thereto, with attachment of the heterocycle to A' by way of said 
first nitrogen atom, with the first ring containing zero or one of either 
of the atoms of O or S, with the first ring containing zero to two 
additional nitrogen atoms, with the first ring optionally fused to a 3- or 
4-membered moiety to form the optional second ring, with the moiety 
containing at least one carbon atom, with the moiety containing zero or 
one of either of the atoms of O or S, with the moiety containing zero to 
two nitrogen atoms, and with the moiety being saturated or unsaturated and 
the second ring aromatic or non-aromatic; 
A and A' are independently (CH.sub.2).sub.m --Q--(CH.sub.2).sub.n, where m 
is zero to 6 and n is zero to 6 and Q is a covalent bond, O, S, SO, 
SO.sub.2, NH, --SO.sub.2 NH--, --NHSO.sub.2 --, --CONH--, --NHCO--, 
--SO.sub.2 N(C.sub.1 -C.sub.4 alkyl)--, --N(C.sub.1 -C.sub.4 
alkyl)SO.sub.2 --, --CON(C.sub.1 -C.sub.4 alkyl)--, --N(C.sub.1 -C.sub.4 
alkyl)CO', --CH.dbd.CH--, --CO--, --OC(O)--, --C(O)O--or N(C.sub.1 
-C.sub.4 alkyl); provided when m=n=zero that Q is not a covalent bond; 
Y is selected from: 
i) COOH or a pharmaceutically acceptable ester, 
ii) COOR.sup.3 wherein R.sup.3 is a readily removable carboxyl covering 
group which is not a pharmaceutically acceptable ester, 
iii) COOM wherein M is an alkali metal, or 
iv) COO--; 
provided that when Y is other than iv) and a quaternary nitrogen 
heteroatom is present, a counterion Z.sup.- is provided, 
or the pharmaceutically acceptable salt thereof. 
The R.sup.a, R.sup.b and R.sup.c substituents optionally represent from 1 
to 2 substituents which may be the same or different and are selected on 
an independent basis While a single such substituent is clearly preferred, 
there is occasion to use up to three such substituents, e.g., where it is 
desired to enhance the effect of a particular substituent group by 
employing multiple substituents. Thus, two carboxymethyl substituents may 
be used. At other times it may be desired to employ a substituent known to 
enhance antibacterial activity of the overall molecule against a 
particular bacterium, for example, while also employing a substituent 
known to improve the duration of action of the overall molecule. 
The overall molecule must be electronically balanced. Since a quaternary 
nitrogen may be present in the compounds of the present invention, a 
balancing anion must, in that case, also be present. This is usually 
accomplished by having Y be COO.sup.-. However, where Y is, e.g., a 
pharmaceutically acceptable ester, and a quaternary nitrogen is present, a 
counterion (anion) Z.sup.- must be provided, or alternatively, an anionic 
substituent might be utilized Further, it is within the scope of this 
invention to utilize an anionic substituent where the quaternary nitrogen 
is already balanced by Y.dbd.COO.sup.-. In that case, it will be 
understood that it is necessary to provide a counterion (cation) for the 
anionic substituent. However, it is well within the skill of a medicinal 
chemist, to whom there is available many suitable anionic and cationic 
counterions, to make such choices. 
With reference to the above definitions, "alkyl" means a straight or 
branched chain aliphatic hydrocarbon radical. 
The term "heteroatom" means N, S, or O, selected on an independent basis. 
Under the definition of "Y", the term "pharmaceutically acceptable ester or 
salt" refers to those salt and ester forms of the compounds of the present 
invention which would be apparent to the pharmaceutical chemist, i.e., 
those which are non-toxic and which would favorably affect the 
pharmacokinetic properties of said compounds, their palatability, 
absorption, distribution, metabolism and excretion. Other factors, more 
practical in nature, which are also important in the selection, are cost 
of raw materials, ease of crystallization, yield, stability, 
hygroscopicity, and flowability of the resulting bulk drug. Since the 
compounds of the present invention may be carboxylates, the salts would be 
cations such as benzathine, chloroprocaine, choline, diethanolamine, 
meglumine and procaine. The metallic cations such as aluminum, calcium, 
lithium, magnesium and zinc are potential choices. The alkali metal 
cations sodium and potassium are specifically defined. It will also be 
noted that the compounds of the present invention are potentially internal 
salts or zwitterions, since under physiological conditions the carboxyl 
group may be anionic, and this electronic charge might then be balanced 
off internally against the cationic charge of a quaternary nitrogen atom. 
Where this is not the case, and a quaternary nitrogen heteroatom is 
present, it is provided in the definition of "Y" that a counterion 
"Z.sup.- " is present. This counterion is selected from the group of 
suitable pharmaceutical anions, e.g., chloride, phosphate and tartrate. 
The term "readily removable carboxyl covering group" means a conventional 
substituent which takes the place of the acidic hydrogen of the carboxyl 
group and thereby prevents said group from reacting with any of the 
reagents employed in the various steps of the overall synthesis. Such 
covering of the carboxyl group is often necessary to prevent unwanted 
competing reactions involving said carboxyl group from taking place. Thus, 
all of these compounds are intermediates. The conventional covering 
substituent must also be "readily removable", by which is meant that it is 
selectively removable, i.e., it is not likely to be removed during the 
course of ordinary procedures which are to be carried out on the 
carbapenem nucleus and sidechains, while, on the other hand, it is likely 
to be removed by procedures which are not so harsh as to disturb the basic 
ring structure of the carbapenem nucleus or unprotected substituents 
thereon. 
It is preferred that when one of R.sup.1 or R.sup.2 is H, the other is 
(R)'CH.sub.3 CH(OH)--or (R)--CH.sub.3 CH(F)--, and (R)--CH.sub.3 
CH(OH)--is most preferred. Further, it is preferred that the configuration 
at C-6 is (S), and that at C-5 is (R). 
Representative A groups are --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, 
--CH.sub.2 --N(CH.sub.3)--, --CH.sub.2 --S--, --CH.sub.2 --S--CH.sub.2 --, 
and --CH.sub.20 (C.dbd.O)--. 
Representative R.sup.c groups are --CH.sub.3, --CH.sub.2 CH.sub.3, 
--(CH.sub.2).sub.3 CH.sub.3, --OCH.sub.3, --SCH.sub.3, 
##STR9## 
--COOH, --NHCH.sub.2 COOH, --OH, --CH.sub.2 OH, --CH.sub.2 COOH, 
--CH.sub.2 CH.sub.2 COOH, --CH.sub.2 CONH.sub.2, --CH.sub.2 CH.sub.2 
S.sup.+ (CH.sub.3)2, --CH.sub.2 CH.sub.2 SO.sub.3 H, 
##STR10## 
--CONH.sub.2, --SO.sub.2 NH.sub.2, --SO.sub.3 H, --NH.sub.2, 
--N(CH.sub.3)2, --CON(CH.sub.3).sub.2, --NHCH.sub.3, --CH.sub.2 NH.sub.2, 
--CN, --CH.sub.2 CN, --CH.sub.2 SCH.sub.3, --CH.sub.2 SO.sub.3.sup.-, 
--CH.sub.2 SOCH.sub.3, --CH.sub.2 SO.sub.2 CH.sub.3, --SO.sub.2 CH.sub.3, 
--SOCH.sub.3, --CH.sub.2 OCH.sub.3, --CH.sub.2 P(O)(OH)OCH.sub.3, 
--CF.sub.3, --CH.sub.2 OC(O)NH.sub.2, --CH.sub.2 SO.sub.2 NH.sub.2, 
--SCH.sub.2 CH.sub.2 CN, Br, Cl, F, --SCF.sub.3, --CH.sub.2 SCF.sub.3, and 
--SCH.sub.2 CF.sub.3. 
The aromatic heterocycle moiety has been conveniently represented 
throughout by the following formula: 
##STR11## 
Useful examples of the nitrogen-containing aromatic heterocycle moiety are 
set out below. 
##STR12## 
The pyridyl group is preferred since it provides the desired properties of 
good antibacterial spectrum and potency combined with chemical stability 
and satisfactory resistance to hydrolysis by the dihydropeptidase (DHP-I) 
enzyme, together with ready availability and ease of handling as a 
starting material. However, any of the other groups set out above, as well 
as those falling within the definition of the heteroaryl moiety set out 
herein but not specifically described above, are also suitable, although 
perhaps in some cases less desirable in terms of one or more of the 
criteria mentioned above. With regard to all of the preferred substituents 
described above, the following compounds are preferred embodiments of the 
present invention. 
##STR13## 
where R' is a negative charge - or an alkali metal salt, a 
pharmaceutically acceptable carboxy covering group, or additionally a 
readily removable carboxyl covering group which is not a pharmaceutically 
acceptable carboxy covering group. 
The carbapenem compounds of the present invention are useful per se and in 
their pharmaceutically acceptable salt and ester forms in the treatment of 
bacterial infections in animal and human subjects. Conveniently, 
pharmaceutical compositions may be prepared from the active ingredients in 
combination with pharmaceutically acceptable carriers. Thus, the present 
invention is also concerned with pharmaceutical compositions and methods 
of treating bacterial infections utilizing as an active ingredient the 
novel carbapenem compounds of the present invention. 
The pharmaceutically acceptable salts referred to above include non-toxic 
acid addition salts The Formula I compounds can be used in the form of 
salts derived from inorganic or organic acids. Included among such salts 
are the following: acetate, adipate, alginate, aspartate, benzoate, 
benzenesulfonate, bisulfate, butyrate, citrate, camphorate, 
camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, 
ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, 
heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 
2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 
2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, 
persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, 
tartrate, thiocyanate, tosylate, and undecanoate. Also, the basic 
nitrogen-containing groups can be quaternized with such agents as lower 
alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides 
and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl 
sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl 
chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl 
bromides and others. Water or oil-soluble or dispersible products are 
thereby obtained. 
The pharmaceutically acceptable esters of the novel carbapenem compounds of 
the present invention are such as would be readily apparent to a medicinal 
chemist, and include, for example, those described in detail in U.S. Pat. 
No. 4,309,438, Column 9, line 61 to Column 12, line 51, which is 
incorporated herein by reference. Included within such pharmaceutically 
acceptable esters are those which are hydrolyzed under physiological 
conditions, such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl 
and methoxymethyl, and those described in detail in U.S. Pat. No. 
4,479,947, which is incorporated herein by reference. 
The novel carbapenem compounds of the present invention may also take the 
form where Y is COOR.sup.3, where R.sup.3 is a readily removable carboxyl 
protecting group. Such conventional blocking groups consist of known ester 
groups which are used to protectively block the carboxyl group during the 
synthetic procedures described further below. These conventional blocking 
groups are readily removable, i.e., they can be removed, if desired, by 
procedures which will not cause cleavage or other disruption of the 
remaining portions of the molecule. Such procedures include chemical and 
enzymatic hydrolysis, treatment with chemical reducing agents under mild 
conditions, and catalytic hydrogenation. Examples of such ester protecting 
groups include benzhydryl, p-nitrobenzyl, 2-naphthylmethyl, allyl, benzyl, 
trichloroethyl, silyl such as trimethylsilyl, phenacyl, p-methoxybenzyl, 
acetonyl, o-nitrobenzyl, 4-pyridylmethyl, and C.sub.1 -C.sub.6 alkyl such 
as methyl, ethyl or t-butyl. 
The compounds of the present invention are valuable antibacterial agents 
active against various Gram-positive and to a lesser extent Gram-negative 
bacteria and accordingly find utility in human and veterinary medicine. 
The antibacterials of the invention are not limited to utility as 
medicaments; they may be used in all manner of industry, for example: 
additives to animal feed, preservation of food, disinfectants, and in 
other industrial systems where control of bacterial growth is desired. For 
example, they may be employed in aqueous compositions in concentrations 
ranging from 0.1 to 100 parts of antibiotic per million parts of solution 
in order to destroy or inhibit the growth of harmful bacteria on medical 
and dental equipment and as bactericides in industrial applications, for 
example in waterbased paints and in the white water of paper mills to 
inhibit the growth of harmful bacteria. 
The compounds of this invention may be used in any of a variety of 
pharmaceutical preparations. They may be employed in capsule, powder form, 
in liquid solution, or in suspension. They may be administered by a 
variety of means; those of principal interest include: topically or 
parenterally by injection (intravenously or intramuscularly). 
Compositions for injection, a preferred route of delivery, may be prepared 
in unit dosage form in ampules, or in multidose containers. The 
compositions may take such forms as suspensions, solutions, or emulsions 
in oily or aqueous vehicles, and may contain formulatory agents. 
Alternatively, the active ingredient may be in powder form for 
reconstitution, at the time of delivery, with a suitable vehicle, such as 
sterile water. Topical applications may be formulated in hydrophobic or 
hydrophilic bases as ointments, creams, lotions, paints, or powders. 
The dosage to be administered depends to a large extent upon the condition 
and size of the subject being treated as well as the route and frequency 
of administration, the parenteral route by injection being preferred for 
generalized infections. Such matters, however, are left to the routine 
discretion of the therapist according to principles of treatment well 
known in the antibacterial art. Another factor influencing the precise 
dosage regimen, apart from the nature of the infection and peculiar 
identity of the individual being treated, is the molecular weight of the 
chosen species of this invention. 
The compositions for human delivery per unit dosage, whether liquid or 
solid, may contain from 0.1% to 99% of active material, the preferred 
range being from about 10-60%. The composition will generally contain from 
about 15 mg to about 1500 mg of the active ingredient; however, in 
general, it is preferable to employ a dosage amount in the range of from 
about 250 mg to 1000 mg. In parenteral administration, the unit dosage is 
usually the pure compound I in sterile water solution or in the form of a 
soluble powder intended for solution. 
The preferred method of administration of the Formula I antibacterial 
compounds is parenteral by i.v. infusion, i.v. bolus, or i.m. injection. 
For adults, 5-50 mg of Formula I antibacterial compounds per kg of body 
weight given 2, 3, or 4 times per day is preferred. Preferred dosage is 
250 mg to 1000 mg of the Formula I antibacterial given two (b.i.d.) three 
(t.i.d.) or four (q.i.d.) times per day. More specifically, for mild 
infections a dose of 250 mg t.i.d. or q.i.d. is recommended. For moderate 
infections against highly susceptible gram positive organisms a dose of 
500 mg t.i.d. or q.i.d. is recommended. For severe, life-threatening 
infections against organisms at the upper limits of sensitivity to the 
antibiotic, a dose of 1000 mg t.i.d. or q.i.d. is recommended. 
For children, a dose of 5-25 mg/kg of body weight given 2, 3, or 4 timer 
per day is preferred; a dose of 10 mg/kg t.i.d. or q.i.d. is usually 
recommended. 
Antibacterial compounds of Formula I are of the broad class known as 
carbapenems or 1-carbadethiapenems. Naturally occuring carbapenems are 
susceptible to attack by a renal enzyme known as dehydropeptidase (DHP). 
This attack or degradation may reduce the efficacy of the carbapenem 
antibacterial agent. The compounds of the present invention, on the other 
hand, are significantly less subject to such attack, and therefore may not 
require the use of a DHP inhibitor. However, such use is optional and 
contemplated to be part of the present invention. Inhibitors of DHP and 
their use with carbapenem antibacterial agents are disclosed in the prior 
art [see European Patent Applications No. 79102616.4 filed Jul. 24, 1979 
(Patent No. 0 007 614); and No. 82107174.3, filed Aug. 9, 1982 
(Publication No. 0 072 014)]. 
The compounds of the present invention may, where DHP inhibition is desired 
or necessary, be combined or used with the appropriate DHP inhibitor as 
described in the aforesaid patents and published application. Thus, to the 
extent that the cited European patent applications 1.) define the 
procedure for determining DHP susceptibility of the present carbapenems 
and 2.) disclose suitable inhibitors, combination compositions and methods 
of treatment, they are incorporated herein by reference. A preferred 
weight ratio of Formula I compound: DHP inhibitor in the combination 
compositions is about 1 1. A preferred DHP inhibitor is 
7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2 
-heptenoic acid or a useful salt thereof.

DETAILED DESCRIPTION OF THE INVENTION 
The 2-(1,2,3-triazolyl substituted)phenyl carbapenem compounds of the 
present invention may be prepared in accordance with well known procedures 
in the art. Particularly useful are the following synthetic schemes in 
which the symbols R, R.sup.1, R.sup.2, R.sup.a, R.sup.b, R.sup.c, R.sup.d, 
R.sup.e, A, 
##STR14## 
are as defined above. 
Scheme A shows the synthetic steps leading to the intermediate A5. A 
benzene moiety, optionally substituted with R.sup.a, R.sup.b or suitable 
precursor substituents thereof, may be added to azetidin-2-one A1 in a 
Grignard reaction. The Grignard reaction requires that the Grignard 
reagent A2 be prepared by reaction of the corresponding bromobenzene 
derivative and magnesium with 1,2-dibromoethane initiation in a suitable 
polar aprotic solvent, such as THF, diethyl ether, or the like, from 
20.degree. C. to 60.degree. C., and subsequently contacting the Grignard 
reagent (A2) with A1 in a suitable polar aprotic solvent, such as THF, 
diethyl ether, or the like, at from -70.degree. C. to about 20.degree. C. 
to produce azetidin-2-one A3. Alternatively, the bromobenzene may be 
reacted with t-butyllithium, n-butyllithium, or the like in a suitable 
polar aprotic solvent, such as THF, diethyl ether, or the like, at from 
-78.degree. to -50.degree. C. followed by the addition of magnesium 
bromide to produce the same Grignard reagent A2. R.sup.i of A1 is in 
practice pyrid-2-yl but may clearly be a variety of substituents including 
aromatic and heteroaromatic substituents. Further R.sup.i might be for 
example phenyl, 2-pyrimidinyl or 2-thiazolyl. 
Azetidin-2-one A3 is an intermediate that may be ring closed to a 
carbapenem. It is on this intermediate that R.sup.a, R.sup.b or precursor 
substituent such as -butyldimethylsilyloxy-methyl may be modified where 
such modification is incompatible with the carbapenem nucleus. For 
example, a convenient reaction to remove the t-butyldimethylsilyl group of 
A3 is to expose it to a 2% solution of sulfuric acid in methanol at 
0.degree. C. for from a few minutes to several hours. Flow Sheet A 
(continued) shows the resulting compound A4. If a t-butyldimethylsilyl 
group were removed by exposing carbapenem A5 to tetra-n-butylammonium 
fluoride and acetic acid in THF, a substantial portion of carbapenem would 
be degraded and lost. Thus, modification of the precursor substituent in 
this instance and replacement with another precursor substituent or even 
-A-heterocycle is optionally performed before the intramolecular 
cyclization is carried out, provided the substituent is uncharged. 
Compound A3 or A4 may be ring closed to carbapenem A5 by refluxing in 
xylene with a trace of p-hydroquinone for about 1 to 2 hours in an inert 
atmosphere. It is on this intermediate A5 that final elaboration to 
generate the -A-triazole moiety from a precursor substituent, e.g. 
hydroxymethyl, may be accomplished, as will be described in detail 
hereinbelow. Removal of the protecting groups by methods known in the art, 
such as a palladium (0) catalyzed deallylation, then provides the final 
compound Formula I. Such final elaboration and deprotection is described 
in further detail below. 
##STR15## 
Flow Sheet B shows an alternative synthesis of an intermediate functionally 
equivalent to A5, i.e. attachment of the base benzene to the 2-position of 
the carbapenem. This synthesis involves a palladium catalysed 
cross-coupling reaction between a carbapenem triflate and a suitably 
substituted arylstannane, a process which is described in U.S. Pat. 
application Ser. No. 485,096 filed Feb. 26, 1990. Thus the 2-oxocarbapenam 
B1 is reacted with a suitable trifluoromethanesulfonyl source, such as 
trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride and 
the like, in the presence of an organic nitrogen base, such as 
triethylamine, diisopropylamine and the like, in a polar aprotic solvent, 
such as methylene chloride or tetrahydrofuran, at a reduced temperature, 
such as -78.degree. C. An organic nitrogen base, such as triethylamine and 
the like, is then added to the reaction solution followed immediately by a 
silylating agent, such as trimethylsilyl trifluoromethanesulfonate to 
provide intermediate 
An aprotic polar coordinating solvent, such as DMF, 
1-methyl-2-pyrrolidinone and the like, is added. This is followed by the 
addition of a palladium compound, such as 
tris(dibenzylideneacetone)dipalladium-chloroform, palladium acetate and 
the like, the stannane B3 and, optionally, a suitably substituted 
phenylphosphine, such as tris(4-methoxyphenyl)phosphine, 
tris(2,4,6-trimethoxyphenyl)phosphine and the like. A halide source, such 
as lithium chloride, zinc chloride or diisopropylammonium chloride and the 
like, is added and the reaction solution is quickly warmed to a suitable 
temperature, such as 0.degree. to 50.degree. C., and allowed to stir for a 
suitable amount of time. The carbapenem B4 is obtained by conventional 
isolation/purification methodology known in the art. Final elaboration of 
the -A-heterocycle moiety from a precursor substituent, e.g. 
hydroxymethyl, may be accomplished on carbapenem intermediate B4. Removal 
of protecting groups then provides the final compound of Formula I. Such 
final elaboration and deprotection is described in further detail below. 
##STR16## 
Scheme C shows the synthetic steps leading to the intermediate C2 which 
incorporates the triazole group characteristic of the instant invention. 
The scheme, which shows the synthesis wherein A is --CH.sub.2 --, is 
illustrative and is not meant to be limiting. Thus, the intermediate A5 
may be reacted with hydrogen azide in the presence of diethyl 
azodicarboxylate and triphenylphosphine in a suitable polar aprotic 
solvent, such as tetrahydrofuran (THF), diethyl ether, or the like, at 
from 0.degree. to 20.degree. C. to provide the azidocarbapenem C1. 
Alternatively, the hydroxyl group of A5 can be converted to a leaving 
group, such as a mesylate or iodide, which can then be reacted with an 
azide source, such as lithium azide or sodium azide to provide the 
azidocarbapenem C1 (as described in U.S. Pat. No. 4,543,257). The 
intermediate C1 is then contacted with a suitable substituted acetylene, 
such as allyl propiolate, propargyl alcohol, propargyl chloride and the 
like, in a suitable solvent, such as benzene, toluene, xylene and the 
like, at from 80.degree. to 150.degree. C. to provide the 
triazolylmethylphenylcarbapenem C2. The substituent R.sup.t on the 
triazole ring may be R.sup.c or may be further elaborated as described in 
detail hereinbelow to provide R.sup.c. Removal of the protecting groups by 
methods known in the art, such as a palladium(O) catalyzed deallylation, 
then provides the final compound of Formula I. Such deprotection is 
described in further detail below. 
##STR17## 
Azetidin-2-one A1 (R.sup.i =2-pyridyl), a pyridyl-thioester, is a well 
known compound in the Production of carbapenems. Diverse synthetic schemes 
useful to make A1 may be imagined by the skilled artisan. Particularly 
useful to the instant invention is a synthetic scheme set out further in 
Flow Sheet D below in which the symbol R.sup.i is as defined above. The 
steps for preparing intermediate A1 are analogous to the procedures 
described, for example, in U.S. Pat. Nos. 4,260,627 and 4,543,257; L. D. 
Cama et al., Tetrahedron, 39, 2531 (1983); R. N. Guthikonda et al., J. 
Med. Chem.,30, 871 (1987). 
##STR18## 
The R.sup.c substituents herein are intended to represent suitable further 
substituents on the triazole moiety, and optional heterocycle substituent. 
As seen above, the heterocycle moieties are monocyclic or bicyclic 
aromatic groups containing heteroatoms. Given this class of primary 
substituent, further suitable substituents may be readily discovered in 
the penem and carbapenem art. For example, suitable substituents for 
heterocycle moieties are generally taught in U.S. Pat. No. 4,729,993 
assigned to Merck and Co. or in U.S. Pat. No. 4,746,736 assigned to 
Bristol-Myers Co. 
Broadly, when two R.sup.c 's are present they may be the same or different 
and may be selected on an independent basis from the group as defined 
above. While a single such substitution is preferred, there is occasion to 
use up to two such substituents on a triazole moiety, where it is desired 
to enhance the effect of a particular substituent group by employing 
multiple substituents. The particular choice of R.sup.c will depend upon 
the situation. For instance, a specific R.sup.c may lend particular 
stability to a nitrogen cation on a heterocycle moiety. At other times it 
may be desired to employ a substituent known to enhance antibacterial 
activity of the overall molecule against a particular bacterium, for 
example, while also employing a substituent known to improve some other 
property such as water solubility or the duration of action of the overall 
molecule. 
Preferred R.sup.c substituents attached to ring carbon atoms are 
--NH.sub.2, --SCH.sub.3, --SOCH.sub.3, --CH.sub.2 OH, --CH.sub.2 NH.sub.2, 
--(CH.sub.2).sub.2 OH, --OCH.sub.3, --COOM.sup.b, --CH.sub.2 COOM.sup.b, 
--CH.sub.2 CH.sub.2 COOM.sup.b, --CH.sub.2 SOCH.sub.3, --CH.sub.2 
SCH.sub.3, --CH.sub.2 O(C.dbd.O)NH.sub.2, --CHO, --CH.sub.2 --(heterocycle 
aromatic ring), --SO.sub.3 M.sup.b, --CH.sub.2 SO3M.sup.b, --CH.sub.2 
CH.sub.2 SO.sub.3 M.sup.b, --CH.sub.2 Br, --CH.sub.2 Cl, --CH.sub.2 F, 
--CH.sub.2 I, --CH.sub.3, CH.sub.2 CH.sub.3, CH.sub.2 CONH.sub.2 and 
CH.sub.2 CON(C.sub.1 -C.sub.4 alkyl where M.sup.b is defined above. 
It is preferred that the triazole moiety and optional heterocycle moiety 
have no more than two R.sup.c substituents which are other than hydrogen. 
The previously listed more specific structures should be interpreted to 
have no more than two R.sup.c substituents for each monocyclic group. 
Suitable A spacer moieties include --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, 
--CH.sub.2 CH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --, 
--OCH.sub.2 CH.sub.2 --, --SOCH.sub.2 --, --SO.sub.2 CH.sub.2 --, 
--SCH.sub.2 CH.sub.2 --, --SOCH.sub.2 CH.sub.2 --, --SO.sub.2 CH.sub.2 
CH.sub.2 --, --NHCH.sub.2 CH.sub.2 --, --N(CH.sub.3)CH.sub.2 CH.sub.2 --, 
--CH.sub.2 N(CH.sub.3)CH.sub.2 CH.sub.2 --, --CONHCH.sub.2 CH.sub.2 --, 
--SO.sub.2 NHCH.sub.2 CH.sub.2 --, --COCH.sub.2 --, --CH.dbd.CHCH.sub.2 
--and --CH.sub.2 OCH.sub.2 CH.sub.2 --. Preferably, where Q is O, S, NH or 
N(C.sub.1-4 alkyl), then n is 2-6 and m is as previously described. 
Conveniently, the triazole moiety should be synthesized with a precursor 
substituent which may be elaborated into the desired cationic substituent. 
The identity of the precursor substituent will vary according to the 
particular R.sup.c desired. For example, one such precursor substituent is 
hydroxymethyl. 
Such a hydroxymethyl precursor substituent may be elaborated into the 
-A'-heterocycle moieties by converting the hydroxyl into an active leaving 
group such as an iodide followed by reaction with a desired nitrogen 
containing aromatic compound. More particularly, two alternative 
procedures may be utilized to produce a leaving group on the precursor to 
moiety -A'-heterocycle and subsequently to replace such a leaving group 
with moieties of the type just described. 
For a first procedure, the hydroxyl group of the precursor substituent may 
be converted to a methanesulfonate group by treating with methanesulfonyl 
chloride in the presence of triethylamine. A suitable solvent, e.g., 
dichloromethane, is employed, and the reaction is carried out at reduced 
temperatures. In turn, the methanesulfonate intermediate may be converted 
to the reactive iodide derivative by treatment with sodium iodide in a 
suitable solvent, e.g., acetone, at reduced or ambient temperatures. 
Alternatively, the hydroxyl group may be directly converted into the 
iodide group by common methods known to the art. For example, treatment of 
the hydroxyl group with methyl triphenoxyphosphonium iodide in a suitable 
solvent, such as dimethylformamide, at reduced or ambient temperatures, 
directly provides the desired iodide. The iodide is then reacted in a 
nucleophilic displacement reaction with an aromatic compound which has a 
nucleophilic side-chain substituent such as mercapto or amino. In this 
displacement reaction, it is the side-chain substituent that is the 
reacting nucleophile and not the aromatic ring nitrogen. Suitable 
substrates for this reaction include 2-(mercaptomethyl)pyridine, 
2-aminopyridine, 2-(aminomethyl)pyridine or 4-(mercaptomethyl)pyridine. 
The reaction is carried-out in an inert organic solvent, e.g. methylene 
chloride, at from about 0.degree. C. to room temperature in the presence 
of a non-nucleophilic base such as triethylamine or diisopropylethylamine. 
Quaternization or protonation as described above then gives the cationic 
heterocycle substituent. 
For a second procedure, the hydroxyl group of the precursor substituent may 
be converted into the reactive trifluoromethanesulfonate (triflate) group. 
However, such an activating group may not be isolable by conventional 
techniques. In such a case, the activating group may be formed and used in 
situ. Thus, treatment of the hydroxyl group with trifluoromethanesulfonic 
(triflic) anhydride in the presence of a hindered, non-nucleophilic base 
such as 2,6-lutidine, 2,4,6- collidine, or 
2,6-di-tert-butyl-4-methylpyridine in a suitable solvent, such as 
dichloromethane, at reduced temperatures provides the triflate activating 
group. Alternatively, the iodide described above may be treated in situ 
with silver trifluoromethanesulfonate in a suitable solvent such as 
acetonitrile at reduced temperatures to provide the triflate activating 
group. The triflate is then treated as described hereinabove for the 
iodide. 
Where the cationic substitution has a substituent R.sup.c, the most facile 
method of providing such a substituent is to employ as the reactant in the 
preparation methods described above a nitrogen containing compound which 
already has the desired substituent. Such substituted compounds are 
readily available starting materials or may be prepared in a 
straight-forward manner using known literature methods. 
The steps for preparing the 2-phenyl carbapenem intermediate are well known 
in the art and are explained in ample detail in U.S. Pat. Nos. 4,260,627 
and 4,543,257. 
In the preparation methods described above, the carboxyl group at the 
3-position remains blocked by a carboxyl covering group until the final 
product is prepared. Then, if the anionic carboxylate is desired so as to 
form a zwitterionic internal salt, deblocking may be carried out in a 
conventional manner, with care being taken to avoid a procedure which is 
so harsh as to disrupt other portions of the final product molecule. 
The general synthetic description above and the particular examples which 
follow show the 6-(1-hydroxyethyl) moiety, which is preferred in most 
cases. However, it has been found that with certain 2-sidechain 
selections, the ultimate balance of favorable biological properties in the 
overall molecule may be enhanced by selection of the 6-(1-fluoroethyl) 
moiety instead. Preparation of this and other 6-fluoroalkyl compounds 
within the scope of the present invention may be carried out in a 
straightforward manner using techniques well know in the art of preparing 
carbapenem antibacterial compounds. See, e.g., J. G. deVries et al., 
Heterocycles, 23 (8), 1915 (1985); BE 900 718 A (Sandoz). 
The invention is further defined by reference to the following examples, 
which are intended to be illustrative and not limiting. All temperatures 
are in degrees Celsius. For .sup.1 H-NMR spectra run in CDCl.sub.3, 
tetramethylsilane (TMS) was used as an internal standard, and chemical 
shifts are expressed in ppm downfield from TMS. In the case of spectra run 
in D.sub.2 O, no internal standard was used; the DOH peak was assigned at 
4.80 ppm. 
EXAMPLE I 
Dipotassium (5R,6S)-2-[4-(4'-carboxylate-1',2', 
3'-triazol-1'-ylmethyl)phenyl]-6-[1R-hydroxyethyl]-carbapen-2-em-3-carboxy 
late and 
Dipotassium (5R, 6S)-2-[4-(5'-carboxylate-1',2', 
3'-triazol-1'-ylmethyl)phenyl]-6-[1R-hydroxyethyl]-carbapen-2-em-3-carboxy 
late 
##STR19## 
Step A: Allyl 
(5R,6S)-2-(4-azidomethylphenyl)-6-[1R-(allyloxycarbonyloxy)ethyl]carbapen- 
2-em-3-carboxylate 2 
To a solution of 265 mg (0.62 mmol) of carbapenem 1 and triphenylphosphine 
(192 mg, 0.73 mmol) in 6.8 mL of ether at 0.degree. C. was added 
simultaneously diethyl azodicarboxylate 107 .mu.L, 0.68 mmol) and 0.44 mL 
of a solution of hydrogen azide in benzene (ca. 0.68 mmol) [prepared from 
sodium azide and sulfuric acid in a water/benzene mixture]. The solution 
was stirred for 5 minutes at 0.degree. C. At the end of this time the 
light yellow solution was treated with 13 mL of 0.5M pH7 phosphate buffer. 
The layers were separated, and the aqueous layer was extracted with ether. 
The combined ether layers were then dried over MgSO.sub.4, filtered and 
concentrated under vacuum. The residue was purified by thin layer 
chromatography (6-1000.mu. silica gel plates; 5% EtOAc in CH.sub.2 
Cl.sub.2) to provide 215 mg (77% yield) of the title compound 2. 
.sup.1 H-NMR (300 MHz, CDCl.sub.3): 1.49 (d, J=6 Hz, CH.sub.3 CHO--), 3.19 
(dd, J=10, 18 Hz, H.sub.1a), 3.29 (dd, J=8, 18 Hz, H.sub.1b), 3.42 (dd, 
J=3, 8Hz, H.sub.6), 4.29 (m, H5), 4.35 (s, CH.sub.2 N.sub.3), 4.59-4.76 
(m, CO.sub.2 CH.sub.2), 5.12-5.40 (m, CH.sub.3 CHO and CH.dbd.CH.sub.2), 
5.79-6.01 (m, CH.dbd.CH.sub.2), 7.30, 7.38 ppm (2d, phenyl protons). 
IR (CH.sub.2 Cl.sub.2) 2120 (N.sub.3), 1780 (.beta.-lactam carbonyl); 1740 
and 1725(other carbonyls)cm-1. 
##STR20## 
Step B: 
Allyl-(5R,6S)-2-[4-(4'-(allyloxycarbonyl)-1',2',3'-triazol-1'-ylmethyl)phe 
nyl]-6-[1R-(allyloxycarbonyloxy)ethyl]-carbapen-2-em-3-carboxylate and 
Allyl-(5R,6S)-2-[4-(5'-(allyloxycarbonyl)-1',2',3'-triazol-1'-ylmethyl)phen 
yl-6-[1R-(allyloxycarbonyloxy)ethyl]carbapen-2-em-3-carboxylate 
To a solution of 88 mg (0.19 mmol) of the azidocarbapenem 2 from Step A in 
1.8 mL of benzene was added 700 .mu.L of allyl propiolate (7 mmol) 
[prepared as described by C. D. Heaton, J. Am. Chem. Soc.,71, 2948 
(1949)]. The reaction solution was stirred at room temperature (RT) for 4 
days, then concentrated under vacuum. The residue was partitioned between 
methylene chloride and an aqueous K.sub.2 HPO.sub.4 solution. The 
separated aqueous layer was extracted with methylene chloride, and the 
combined methylene chloride layers were washed with brine. The methylene 
chloride layer was then dried, filtered and concentrated under vacuum. 
The residue was purified by thin layer chromatography (2-1000.mu. silica 
gel plates; 1:1 EtOAc: hexanes) to provide 77 mg (72% yield) of one of the 
regioisomers 3a and 15 mg (14% yield) of the other regioisomer 3b. 
3a 
.sup.1 H-NMR (200 MHz, CDCl.sub.3): .delta.1.48 d, J=6 Hz, CH.sub.3 CHO--), 
3.18 (dd, J=10, 18Hz, H.sub.1a), 3.30 (dd, J=9, 18 Hz, H.sub.1b), 3.43 
(dd, J=3, 8Hz, H.sub.6), 4.30 (m, H.sub.5), 4.57-4.88 (m, CO.sub.2 
CH.sub.2), 5.09-5.46 (m, CH.sub.3 CHO and CH.dbd.CH.sub.2), 5.58 
(s,--CH.sub.2 --triazole), 5.76-6.12 (m, CH.dbd.CH.sub.2), 7.27 and 7.39 
(2d, phenyl protons), 8.0 ppm (s, triazole proton). 
3b 
.sup.1 H-NMR (200 MHz, CDCl.sub.3): .delta.1.47 (d, J=6Hz, CH.sub.3 CHO--), 
3.15 (dd, J=10, 18 Hz, H.sub.1a), 3.27 (dd, J=9, 18 Hz, H.sub.1b), 4.21 
(dd, J=3, 8Hz, H.sub.6), 4.27 (m, H.sub.5), 4.55-4.80 (m, CO.sub.2 
CH.sub.2), 5.11-5.43 (m, CH.sub.3 CHO and CH.dbd.CH.sub.2), 5.73-6.06 (m, 
CH.dbd.CH.sub.2); 5.91(s on top of previous m, --CH.sub.2 --triazole), 
7.31 (s, phenyl protons), 8.15 ppm (s, triazole proton). 
IR (CH.sub.2 Cl.sub.2) 1775 (.beta.-lactam carbonyl), 1740 and 1720 (other 
carbonyls)cm-1. 
##STR21## 
Step C: Dipotassium 
(5R,6S)-2-[4-(4'-carboxylate-1',2',3'-triazol-1'-ylmethyl)-phenyl]-6-[1R-h 
ydroxyethyl]-carbapen-2-em-3-carboxylate 
Dipotassium 
(5R,6S)-2-[4-(5'-carboxylate-1',2',3'-triazol-1'-ylmethyl)phenyl]-6-[1R-hy 
droxyethyl]-carbapen-2-em-3-carboxylate 
To a stirred solution of 77 mg (0.14 mmol) of carbapenem isomer 3a in 2.5 
mL of methylene chloride and 2.5 mL of EtOAc at room temperature (RT) was 
added a solid mixture of triphenylphosphine (11 mg, 0.042 mmol and 
tetrakis(triphenylphosphine)-palladium (14 mg, 0.012 mmol). A solution of 
0.5M potassium 2-ethylhexanoate in EtOAc (0.62 mL, 0.31 mmol) and 25 1 
2-ethylhexanoic acid (0.16 mmol) were then added, and the reaction mixture 
was stirred 2 hours at room temperature. The mixture was then concentrated 
under a N.sub.2 stream and then under vacuum. The solid was slurried in 
ether, and the mixture was centrifuged. The supernatant was decanted and 
the ether addition/centrifuge procedure repeated twice. The solid residue 
was then purified by RPS-F silica gel thin layer chromatography 
(2-1000.mu. plates; 2.5% EtOH in H.sub.2 O) to provide 33 mg (50% yield) 
of the title compound 4a as a white lyophilizate. 
.sup.1 H-NMR (300 MHz, D.sub.2 O): .delta.1.28 (d, J=6 Hz, CH.sub.3 CHO--), 
3.03 (dd, J=10, 18 Hz, H.sub.1a), 3.40 (dd, J=8, 18 Hz, H.sub.1b), 3.50 
(dd, J=3, 6 Hz, H.sub.6), 4.17-4.32 (m, H.sub.5 and CH.sub.3 CH), 5.6 (s, 
--CH.sub.2 --triazole), 7.26 and 7.34 (2d, phenyl protons), 8.23 ppm (s, 
triazole proton). 
UV (H.sub.2 O): .lambda..sub.max =301 nm (.epsilon.=13,000). 
Employing the procedure described above, but substituting the carbapenem 
isomer 3b from Example 1, Step B for the carbapenem isomer 3a provided the 
other regioisomer 4b. 
.sup.1 H-NMR (300 MHz, D.sub.2 O): .delta.1.27 (d, J=6 Hz, CH.sub.3 CHO--), 
3.02 (dd, J=10, 18 Hz, H.sub.1a), 3.38 (dd, J=9, 18 Hz, H.sub.1b), 3.47 
(dd, J=2, 6 Hz, H6), 4.17-4.29 (m, H.sub.5 and CH.sub.3 CH), 5.90 
(s,--CH.sub.2 --triazole), 7.15, 7.30 (2d, phenyl protons), 7.98 ppm (s, 
triazole proton). 
UV (H.sub.2 O): .lambda..sub.max =301 (.epsilon.=12,000). 
EXAMPLE 2 
Potassium 
(5R,6S)-2[4-(4'-azidomethyl-1',2',3'-triazol-1'-ylmethyl)phenyl]-6-[1R-hyd 
roxyethyl]-carbapen-2-em-3-carboxylate and 
Potassium 
(5R,6S)-2-[4-(5'-azidomethyl-1',2',3'-triazol-1'-ylmethyl)phenyl]-6-[1R-hy 
droxyethyl]-carbapen-2-em-3-carboxylate 
##STR22## 
Step A: Allyl 
(5R,6S)-2-[4-(4'-chloromethyl-1',2',3'-triazol-1'-ylmethyl)phenyl]-6-[1R-( 
allyloxycarbonyloxy)ethyl]carbapen-2-em-3-carboxylate and 
Allyl 
(5R,6S)-2-[4-(5'-chloromethyl-1',2',3'-triazol-1'-ylmethyl)phenyl]-6-[1R-( 
allyloxycarbonyloxy)ethyl]carbapen-2-em-3-carboxylate 
A solution of carbapenem 2 from Example 1, Step A (154 mg, 0.34 mmol) and 
propargyl chloride (430 .mu.L, 5.9 mmol) in 860 .mu.L of toluene was 
heated in a sealed tube at 90.degree. C. for 5 hours. The reddish brown 
solution was then concentrated under a nitrogen stream, and the residue 
was dissolved in CH.sub.2 Cl.sub.2. The solution was again concentrated 
and the residue purified by thin layer chromatography (4-1000.mu. silica 
gel plates, 15% EtOAC in CH.sub.2 Cl.sub.2) to provide two products 
carbapenem 5a (65 mg, 36% yield) and carbapenem 5b (38 mg, 21% yield). 
5a 
.sup.1 H-NMR (300 MHz, CDCl.sub.3): .delta.1.49 (d, J=6 Hz, CH.sub.3 
CHO--), 3.17 (dd, H.sub.1a), 3.28 (dd, H.sub.1b), 3.42 (dd, H.sub.6), 4.28 
(m, H5), 4.58-4.74 (m, CO.sub.2 CH.sub.2), 4.68 (s on top of previous m, 
CH.sub.2 Cl), 5.10-5.38 (m, CH.sub.3 CHO and CH.dbd.CH.sub.2), 5.50 (s, 
phenyl-CH.sub.2 -triazole), 5.79-6.00 (m, CH.dbd.CH.sub.2), 7.24, 7.37 
(2d, phenyl protons), 7.51 ppm (s, triazole proton). p IR (CH.sub.2 
Cl.sub.2): 1780 (.beta.-lactam carbonyl); 1750 and 1730 (other 
carbonyls)cm.sup.-1. 
5b 
.sup.1 H-NMR (300 MHz, CDCl.sub.3): .delta.1.49 (d, J=6 Hz, CH.sub.3 
CHO--), 3.16 (dd, J=10, 18 Hz, H.sub.1a), 3.28 (dd, J=8, 18 Hz, H.sub.1b), 
3.41 (dd, 2.5, 8 Hz, H.sub.6), 4.27 (m, H.sub.5), 4.43 (s, CH.sub.2 Cl), 
4.58-4.75 (m, CO.sub.2 CH.sub.2), 5.10-5.38 (m, CH.sub.3 CHO and 
CH.dbd.CH.sub.2), 5.66 (s, phenyl-CH.sub.2 -triazole), 5.78-6.00 (m, 
CH.dbd.CH.sub.2), 7.20 and 7.36 (2d, phenyl protons), 7.70 ppm (s, 
triazole proton). 
##STR23## 
Step B: Allyl 
(5R,6S)-2-[4-(4'-azidomethyl-1',2',3'-triazol-1'-ylmethyl)phenyl]-6-[1R-(a 
llyloxycarbonyloxy)ethyl]carbapen-2-em-3-carboxylate and 
Allyl (5R,6S)-2-[4-(5'-azidomethyl-1', 
2',3'-triazol-1'-ylmethyl)phenyl]-6-[1R-(allyloxy-carbonyloxy)ethyl]carbap 
en-2-em-3-carboxylate 
Lithium azide (2.1 mg, 0.042 mmol) was added to a solution of carbapenem 5a 
(19 mg, 0.036 mmol) in 250 .mu.L of dimethylsulfoxide (DMSO), and the 
mixture was stirred 24 hours at room temperature. The reaction mixture was 
then partitioned between methylene chloride and H.sub.2 O. The separated 
organic layer was washed twice with brine, dried and filtered. The organic 
solution was concentrated under a nitrogen stream and then under vacuum. 
The residue was purified by thin layer chromatography (1-1000.mu. silica 
gel plate, 10% EtOAc in methylene chloride) to provide 12.8 mg (66% yield) 
of carbapenem 6a. 
.sup.1 H NMR (200 MHz, CDCl.sub.3): .delta.1.49 (d, J=6 Hz, CH.sub.3 
CHO--), 3.18 (overlapping dd, J=10, 18 Hz, H.sub.1a), 3.31 (overlapping 
dd, J=9, 18 Hz, H.sub.1b), 3.45 (dd, J=3, 8 Hz, H.sub.6), 4.30 (m, 
H.sub.5); 4.50 (s, CH.sub.2 N.sub.3), 4.58-4.79 (m, CO.sub.2 CH.sub.2), 
5.08-5.47 (m, CH.sub.3 CHO and CH.dbd.CH.sub.2); 5.56 (s, phenyl--CH.sub.2 
--triazole); 5.79-6.06 (m, CH.dbd.CH.sub.2); 7.27 and 7.41 (2d, phenyl 
protons), 7.51 ppm (s, triazole proton) 
IR(CH.sub.2 Cl.sub.2) 2090(N.sub.3), 1780(.beta.-lactam carbonyl); 1750 and 
1725(other carbonyls) cm-.sup.1. 
Employing the procedure described above, but substituting the carbapenem 
isomer 5b from Example 2, Step B for the carbapenem isomer 5a provided the 
other regioisomer 6b. An ene-lactam by-product is observed in both the NMR 
and IR spectra. 
.sup.1 H-NMR (300 MHz, CDCl.sub.3): .delta.1.47 (d, J=6 Hz, CH.sub.3 
CHO--), 3.15 (dd, J=10, 18 Hz, H.sub.1a), 3.26 (dd, J=9, 18 Hz, H.sub.1b), 
3.40 (dd, J=3, 8 Hz, H.sub.6), 4.27 (s, CH.sub.2 N.sub.3), 4.55-4.73 (m, 
CO.sub.2 CH.sub.2), 5.03-5.43 (m, CH.sub.3 CHO and CH.dbd.CH.sub.2); 5.60 
(s, phenyl--CH.sub.2 --triazole); 5.77-5.99 (m, CH.dbd.CH.sub.2); 7.23 and 
7.35 (2d, phenyl protons), 7.70 ppm (s, triazole proton) 
IR(CH.sub.2 Cl.sub.2): 2075(N.sub.3), 1770(.beta.-lactam carbonyl); 1725 
and 1710(other carbonyls) cm.sup.-1. 
##STR24## 
Step C: Potassium 
(5R,6S)-2-[4-(4'-azidomethyl-1',2',3'-triazol-1'-ylmethyl)phenyl]-6-1R-hyd 
roxyethyl carbapen-2-em-3-carboxylate and 
Potassium 
(5R,6S)-2-[4-(5'-azidomethyl-1',2',3'-triazol-1'-ylmethyl)phenyl]-6-[1R-hy 
droxyethyl]-carbapen-2-em-3-carboxylate 
To a solution of carbapenem 6a (12.8 mg, 0.024 mmol) in 0.44 mL of CH.sub.2 
Cl.sub.2 and 0.44 mL EtOAc was added 2.4 mg (0.002 mmol) of tetrakis 
(triphenylphosphine) palladium and 2.0 mg (0.008 mmol) of triphenyl 
phosphine. A 0.5M solution of potassium 2-ethyl-hexanoate in EtOAc (52 
.mu.L, 0.026 mmol) and 2-ethyl hexanoic acid (4.1 .mu.L, 0.026 mmol) were 
then added, and the mixture was stirred at room temperature for 2 hours. 
The reaction mixture was then concentrated under a nitrogen stream, then 
under vacuum, and the residue was slurried in Et.sub.2 O. The slurry was 
centrifuged, and the supernatant was decanted. The Et.sub.2 O insoluble 
residue was dissolved in H.sub.2 O and purified by reverse phase thin 
layer chromatography (1-500.mu. RPS-F plate, 10% EtOH in H.sub.2 O) to 
provide 4 mg (35% yield) of carbapenem 7a. No ene-lactam by-product is 
observed by NMR. 
.sup.1 H-NMR (300 MHz, D.sub.2 O): 1.27 (d, J=6 Hz, CH.sub.3 CHO--), 3.01 
(dd, J=10, 18 Hz, H.sub.1a), 3.38 (dd, J=8, 18 Hz, H.sub.1b), 3.46 (dd, 
J=3, 6 Hz, H.sub.6), 4.16-4.28 (m, H.sub.5 and CH.sub.3 CHO--), 4.46 (s, 
CH.sub.2 N.sub.3), 5.58 (s, phenyl-CH.sub.2 -triazole), 7.24, 7.32 (2d, 
phenyl protons), 8.01 ppm (s, triazole proton). UV (H.sub.2 O) : 
.lambda..sub.max =300nm (.epsilon.=11,500) 
Employing the procedure described above, but substituting the carbapenem 
isomer 6b from Example 2, Step B for the carbapenem isomer 6a provided the 
other regioisomer 7b. 
.sup.1 H-NMR (300 MHz, D.sub.2 O): 1.26 (d, J=6 Hz, CH.sub.3 CHO--), 3.01 
(dd, J=10, 18 Hz, H.sub.1a), 3.38 (dd, J=8, 18 Hz, H.sub.1b), 3.46 (dd, 
J=2, 6 Hz, H.sub.6), 4.16-4.28 (m, H.sub.5 and CH.sub.3 CHO--), 4.51 (s, 
CH.sub.2 N.sub.3), 5.64 (s, phenyl-CH.sub.2 -triazole), 7.15, 7.31 (2d, 
phenyl protons), 7.82 ppm (s, triazole proton). UV (H.sub.2 O) : 
.lambda..sub.max =301nm (.epsilon.=10,000). 
EXAMPLE 3 
Potassium (5R, 6S)-2-[4-(4'- or 5'-aminomethyl-1',2', 
3'-triazol-1'-ylmethyl)phenyl]-6-[1R-hydroxyethyl]-carbapen-2-em-3-carboxy 
late 
##STR25## 
A mixture of carbapenem 7a from Example 2, Step C (7.5 mg, 0.017 mmol) and 
1.5 mg 10% palladium on carbon (Pd/C) in 2 mL of D.sub.2 O and 0.34 mL of 
0.1M pH7 phosphate buffer was stirred under a H.sub.2 atmosphere (balloon 
pressure) for 1 hour. The system was then purged, and another 1.5 mg 
charge of 10% Pd/C was added. The mixture was again stirred under a 
H.sub.2 atmosphere for 1 hour. The system was then purged with N.sub.2, 
and the mixture was centrifuged. The supernatant was filtered through a 
millipore filter disk and the residue rinsed twice with H.sub.2 O. The 
filtrates were concentrated and purified by reverse phase thin layer 
chromatography (1-500.mu. RPS-F plate, 10% EtOH in H.sub.2 O ) to provide 
1.7 mg (24% yield) of carbapenem 8a. 
.sup.1 H-NMR (300 MHz, D.sub.2 O): 1.28 (d, J=6 Hz, CH.sub.3 CHO--), 3.02 
(dd, J=10, 19 Hz, H.sub.1a), 3.39 (dd, J=8, 19 Hz, H.sub.1b), 3.47 (br dd, 
H.sub.6), 4.18-4.28 (m, CH.sub.2 NH.sub.2, H.sub.5 and CH.sub.3 CHO--, 
5.60 (phenyl-CH.sub.2 -triazole), 7.26, 7.34 (2d, phenyl protons), 8.06 
ppm (br. s, triazole proton). 
UV (H.sub.2 O) .lambda..sub.max =300nm (.epsilon.=12,000) 
EXAMPLE 4 
Potassium 
(5R,6S)-[4-(4'-hydroxymethyl-1',2',3'-triazol-1'-ylmethyl)phenyl-6-[1'-hyd 
roxyethyl]-carbapen-2-em-3-carboxylate and 
Potassium 
(5R,6S)-[4-(5'-hydroxymethyl-1',2',3'-triazol-1'-ylmethyl)phenyl-6-[1R-hyd 
roxyethyl]-carbapen-2-em-3-carboxylate 
##STR26## 
Step A: Allyl 
(5R,6S)-2-[4-(4'-(t-butyldimethylsilyloxymethyl)-1',2',3'-triazol-1'-yl-me 
thyl)phenyl]-6-[1R-(allyloxycarbonyloxy)ethyl]-carbapen-2-em-3-carboxylate 
and 
Allyl-(5R,6S)-2-[4-(5'-(t-butyldimethylsilyloxymethyl)-1',2',3'-triazol-1'- 
ylmethyl)phenyl]-6-[1R-(allyloxycarbonyloxy)ethyl]carbapen-2-em-3-carboxyla 
te 
A solution of carbapenem 2 (prepared as described in Example 1) (85 mg, 
0.19 mmol) and 3-(t-butyldimethylsilyloxy)propyne (240 .mu.L, 1.41 mmol) 
in 470 .mu.L of toluene was heated in a sealed tube at 70.degree. C. for 1 
hour. The cooled solution was analyzed by thin layer chromatography, which 
showed that the reaction was incomplete. An additional 450 .mu.L of the 
propyne was added in two portions, and the reaction solution was heated a 
total of 10 hours at 80.degree. C. The solution was then cooled and 
concentrated under vacuum. The residue was purified by thin layer 
chromatography (2-1000.mu. silica gel plates, 1:1;EtOAc:hexanes) to 
provide a mixture of carbapenems 9a and 9b (45 mg, 38% yield). 
.sup.1 H-NMR (300 MHz, CDCl.sub.3): .delta.0.05, 0.1 (2s, 
Si(CH.sub.3).sub.3), 0.89, 0.91 (2s, C(CH.sub.3).sub.3), 1.49 (d, J=6 Hz, 
CH.sub.3 CHO--), 3.11-3.22 (2dd, J=10, 18 Hz, 2.times.H.sub.1a), 3.22-3.32 
(2dd, J=9, 18 Hz, 2.times.H.sub.1b), 3.39-3.44 (2t, 2.times.H.sub.6), 
4.23-4.32 (m, 2.times.H.sub.5), 4.55-4.74 (m, CO.sub.2 CH.sub.2), 4.59 (s, 
CH.sub.20 Si of one regioisomer), 4.83 (s, CH.sub.2 OSi of other 
regioisomer), 5.07-5.39 (m, CH.sub.3 CHO--and CH.dbd.CH.sub.2), 5.52 (s, 
phenyl-CH.sub.2 -triazole of major isomer), 5.62 (s, phenyl-CH.sub.2 
-triazole of minor isomer), 5.78-6.00 (m, CH.dbd.CH.sub.2), 7.17-7.37 (4d, 
phenyl protons), 7.43, 7.57 ppm (2s, triazole protons). 
IR (CH.sub.2 Cl.sub.2): 1780 (.beta.-lactam carbonyl); 1740 and 1725 (other 
carbonyls) cm.sup.-1. 
##STR27## 
Step B: 
Allyl-(5R,6S)-2-[4-(4'-(hydroxymethyl)-1',2',3'-triazol-1'-ylmethyl)phenyl 
]-6-[1R-(allyloxycarbonyloxy)ethyl]-carbapen-2-em-3-carboxylate and 
Allyl-(5R,6S)-2-[4-(5'-(hydroxymethyl)-1',2',3'-triazol-1'-ylmethyl)phenyl- 
6-[1R-(allyloxycarbonyloxy)ethyl]carbapen-2-em-3-carboxylate 
Acetic acid (6 .mu.L, 0.10 mmol) and a 1N solution of tetrabutylammonium 
fluoride in THF (35 .mu.L, 0.035 mmol) were added to a solution of 22 mg 
(0.035 mmol) of the mixture of regioisomeric carbapenems 9a and 9b from 
Step A in 0.4 mL of THF. The solution was stirred for 4.5 hours at RT and 
then partitioned between 0.5 mL 1N K.sub.2 HPO.sub.4 /l mL H.sub.2 O/l mL 
EtOAc. The layers were separated and the aqueous layer again extracted 
with EtOAc. The combined EtOAc layers were washed with brine, dried, 
filtered and concentrated under vacuum. The residue was purified by thin 
layer chromatography (1-500.mu. silica gel plate, EtOAc) to provide 
approximately equal quantities of the separated regioisomers, carbapenem 
10a and carbapenem 10b. 
10a 
.sup.1 H-NMR (300 MHz, CDCl.sub.3): .delta.1.47 (d, J=6 Hz, CH.sub.3 
CHO--), 3.14 (dd, J=10, 18 Hz, H.sub.1a), 3.25 (dd, J=9, 18 Hz, H.sub.1b), 
3.39 (dd, J=3, 8 Hz, H.sub.6), 4.26 (m, H.sub.5), 4.54-5.38 (m, CO.sub.2 
CH.sub.2), 4.6 (s, CH.sub.20 H), 5.08-5.38 (m, CH.sub.3 CHO--and 
CH.dbd.CH.sub.2), 5.62 (s, phenyl-CH.sub.2 -triazole), 5.76-5.98 (m, 
CH.dbd.CH.sub.2), 7.21, 7.32 (2d, phenyl protons), 7.58 ppm (s, triazole 
proton). 
IR (CH.sub.2 Cl.sub.2): 1780 (.beta.-lactam carbonyl); 1740 and 1725 (other 
carbonyls) cm.sup.-1. 
.sup.1 H-NMR (300 MHz, CDCl.sub.3): .delta.1.48 (d, J=6 Hz, CH.sub.3 
CHO--), 3.15 (dd, J=10, 18 Hz, H.sub.1a), 3.27 (dd, J=8, 18 Hz, H.sub.1b), 
3.40 (dd, J=3, 8 Hz, H.sub.6), 4.27 (m, H.sub.5), 4.57-4.80 (m, CO.sub.2 
CH.sub.2), 4.77 (s, CH.sub.20 H), 5.09-5.38 (m, CH.sub.3 CHO--and 
CH.dbd.CH.sub.2), 5.51 (s, phenyl-CH.sub.2 -triazole), 5.79-6.01 (m, 
CH.dbd.CH.sub.2), 7.22, 7.45 (2d, phenyl protons), 7.45 ppm (s, triazole 
proton). 
IR (CH.sub.2 Cl.sub.2): 1780 (.beta.-lactam carbonyl); 1750 and 1720 (other 
carbonyls) cm.sup.-1. 
##STR28## 
Step C: Potassium (5R,6S)-2-[4-(4'-(hydroxymethyl)-1', 
2',3'-triazol-1'-ylmethyl)phenyl]-6-[1R-hydroxyethyl]carbapen-2-em-3-carbo 
xylate and 
Potassium 
(5R,6S)-2-[4-(5'-(hydroxymethyl)-1',2',3'-triazol-1'-ylmethyl)phenyl]-6-[1 
R-hydroxyethyl]-carbapen-2-em-3-carboxylate 
Employing the procedure described in Example 2, Step C but substituting 
carbapenem 10a (prepared as described in Step B) for carbapenem 6a 
provided carbapenem 11a. 
.sup.1 H-NMR (300 MHz, D.sub.2 O): .delta.1.28 (d, J=6 Hz, CH.sub.3 CHO--), 
3.02 (dd, J=10, 18 Hz, H.sub.1a), 3.39 (dd, J=8, 18 Hz, H.sub.1b), 3.47 
(m, H.sub.6), 4.18-4.29 (m, H.sub.5 and CH.sub.3 CHO--), 4.65 (s, CH.sub.2 
O H), 5.63 (s, phenyl--CH.sub.2 --triazole), 7.15 and 7.32 (2d, phenyl 
protons), 7.76 ppm (s, triazole proton) 
UV (H.sub.2 O): .lambda..sub.max =302 nm 
Employing the procedure described in Example 2, Step C but substituting 
carbapenem 10b (prepared as described in Step B) for carbapenem 6a, and 
using 8% CH.sub.3 CN in H.sub.2 O as the chromatography eluant, provided 
carbapenem 11b. 
.sup.1 H-NMR (300 MHz, D.sub.2 O): .delta.1.30 (d, J=6 Hz, CH.sub.3 CHO--), 
3.05 (dd, J=11, 17 Hz, H.sub.1a), 3.42 (dd, J=8, 17 Hz, H.sub.1b), 3.49 
(dd, J=3, 6 Hz, H.sub.6), 4.10-4.32 (m, H.sub.5 and CH.sub.3 CHO--), 4.68 
s, CH.sub.2 O H), 5.60 (s, phenyl--CH.sub.2 --triazole), 7.26 and 7.36 
(2d, phenyl protons), 7.97 ppm (s, triazole proton) 
UV (H.sub.2 O): .lambda..sub.max =302 nm 
EXAMPLE 5 
(5R,6S)-2-[4-(4'-N-Pyridinium 
methyl-1',2',3'-triazol-1'-ylmethyl)phenyl]-6-[1R-hydroxyethyl]-carbapen-2 
-em-3-carboxylate 
(5R,6A)-2-[4-(5'-N-Pyridinium 
methyl-1',2',3'-triazol-1'-ylmethyl)phenyl]-6-[1R-hydroxyethyl]-carbapen-2 
-em-3-carboxylate 
##STR29## 
Step A: Allyl (5R,6S)-2-[4-(4'-N-pyridinium 
methyl-1',2',3'-triazol-1'-ylmethyl)phenyl]-6-[1R-(allyloxycarbonyloxy)-et 
hyl]carbapen-2-em-3-carboxylate chloride . and 
Allyl 
(5R,6S)-2-[4-(5'-N-pyridiniummethyl-1',2',3'-triazol-1'-ylmethyl)phenyl]-6 
-[1R-(allyloxycarbonyloxy)-ethyl]carbapen-2-em-3-carboxylate chloride 
A solution of carbapenem 5a (prepared as described in Example 2, Step A) 
(58 mg, 0.11 mmol) and pyridine (100 .mu.l, 1.24 mmol) in 1 mL of 
acetonitrile was heated at 90.degree. C. under a N.sub.2 atmosphere for 90 
minutes. Another 0.9 mL (11 mmol) of pyridine was added, and the solution 
was heated for another 3.5 hours. The solution was then cooled and 
concentrated under vacuum. The residue was purified by thin layer 
chromatography (2-1000.mu. silica gel plates, 20% methanol in methylene 
chloride) to provide 13.6 mg (21% yield) of carbapenem 12a. 
.sup.1 H-NMR (300MHz, CDCl.sub.3): .delta.1.41 (d, CH.sub.3 CHO--), 3.09 
(dd, H.sub.1a) 3.22 (dd, H.sub.1b), 3.36 (dd, H.sub.6), 4.21 (m, H.sub.5), 
4.50-4.65 (m, CO.sub.2 CH.sub.2), 5.03-5.31 (m, CH.sub.3 CHO--and 
CH.dbd.CH.sub.2), 5.42 (s, phenyl--CH.sub.2 --triazole), 5.71-5.93 (m, 
CH.dbd.CH.sub.2), 6.39 (s, CH.sub.2 -pyridinium), 7.20, 7.27 (2d, phenyl 
protons), 7.93(t), 8.32(t), and 9.76(d) (pyridinium protons), 8.74 ppm(s, 
triazole proton). 
IR (CH.sub.2 Cl.sub.2): 1775(.beta.-lactam carbonyl); 1735 and 720(other 
carbonyls) cm.sup.1. 
Employing the procedure described above, but substituting the carbapenem 
isomer 5b from Example 2, Step A for the carbapenem isomer 5a provided the 
other regioisomer 12b. 
.sup.1 H-NMR (300MHz, CDCl.sub.3): .delta.1.40 (d, J=6 Hz, CH.sub.3 CHO--), 
2.96 (dd, J=10 and 18 Hz, H.sub.1a) 3.15 (dd, J=9 and 18 Hz, H.sub.1b), 
3.35 (dd, J=2 and 8 Hz, H.sub.6), 4.17 (m, H.sub.5), 4.48-4.72 (m, 
CO.sub.2 CH.sub.2), 5.02-5.44 (m, CH.sub.3 CHO--and CH.dbd.CH.sub.2), 5.18 
(s, phenyl--CH.sub.2 --triazole), 5.77-5.94 (m, CH.dbd.CH.sub.2), 6.13 
(broad s, CH.sub.2 --pyridinium), 6.92 (broad s, phenyl protons), 7.58 
(broad s), 7.98 (broad d), and 9.10 (broad s) (pyridinium protons), 8.19 
ppm(s, triazole proton). (minor impurities from other regioisomer appear 
in the spectrum) 
IR (CH.sub.2 Cl.sub.2): 1780(.beta.-lactam carbonyl); 1740 and 1715(other 
carbonyls) cm.sup.-1. 
##STR30## 
Step B: (5R, 
6S)-2-[4-(4'-N-Pyridiniummethyl-1',2',3'-triazol-1'-ylmethyl)phenyl-6-[1R- 
hydroxyethyl]-carbapen-2-em-3-carboxylate and 
(5R, 
6S)-2-[4-(5'-N-Pyridiniummethyl-1',2',3'-triazol-1'-ylmethyl)phenyl]-6-(1R 
-hydroxyethyl)-carbapen-2-em-3-carboxylate 
Employing the procedure described in Example 2, Step C, but substituting 
carbapenem 12a from Step A for carbapenem 6a and using 25% CH.sub.3 CN in 
H.sub.2 O as the chromatography eluant, provided carbapenem 13a. 
.sup.1 H-NMR (300MHz, D.sub.2 O): .delta.1.29 (d, J=6 Hz, CH.sub.3 CHO--), 
3.03 (dd, J=10, 17 Hz, H.sub.1a), 3.40 (dd, J=8, 17 Hz, H.sub.1b), 3.48 
(dd, J=3, 6 Hz, H.sub.6), 4.19-4.31 (m, H.sub.5, CH.sub.3 CHO--) 5.62 (s, 
phenyl--CH.sub.2 --triazole), 5.93 (s, CH.sub.2 --pyridinium) 7.27 and 
7.34 (2d, phenyl protons), 8.06 (t), 8.55 (t), and 8.90 (d)(pyridinium 
protons), 8.25 ppm (s, triazole proton). 
Employing the procedure described in Example 2, Step C, but substituting 
carbapenem 12b from Step A for carbapenem 6a and using 25% CH.sub.3 CN in 
H.sub.2 O as the chromatography eluant, provided carbapenem 13b. 
.sup.1 H-NMR (300 MHz, D.sub.2 O): .delta.1.30 (d, J=6 Hz, CH.sub.3 CHO--), 
2.99 (dd, J=10, 16 Hz, H.sub.1a), 3.31 (dd, J=8, 16 Hz, H.sub.1b), 3.49 
(dd, J=3, 6 Hz, H.sub.6), 4.20-4.33 (m, H.sub.5, CH.sub.3 CHO--) 5.80 (s, 
phenyl--CH.sub.2 --triazole), 6.00 (s, CH.sub.2 --pyridinium) 6.77 and 
7.06 (2d, phenyl protons), 7.73 (t), 8.36 (t), and 8.45 (d)(pyridinium 
protons), 8.23 ppm (s, triazole proton). 
UV (H20): .lambda..sub.max =301 nm; sl. shoulder at 260 nm. 
EXAMPLES 6-53 
The following examples are prepared by a method analogous to that described 
in Examples 1-4 using the appropriate starting materials readily available 
or readily prepared by techniques known in the art. It is understood that 
in the synthesis of the following examples protecting groups known in the 
art may need to be employed. It is also understood that synthesis of an 
example compound may require functional group manipulation well known in 
the art. 
______________________________________ 
EXAMPLE R.sup.c 
______________________________________ 
##STR31## 
6 4-CH.sub.2 NH.sub.2 
7 5-CH.sub.2 NH.sub.2 
8 4-CH.sub.2 Cl 
9 5-CH.sub.2 Cl 
10 4-CH.sub.2 Br 
11 5-CH.sub.2 Br 
12 4-CH.sub.2 OC(O)NH.sub.2 
13 5-CH.sub.2 OC(O)NH.sub.2 
14 4-CHO 
15 5-CHO 
16 4-CN 
17 5-CN 
18 4-CHNOH 
19 4-CH.sub.2 I 
20 5-CH.sub.2 I 
21 4-CO.sub.2 CH.sub.3 
22 5-CHNOH 
23 4-C(O)NH.sub.2 
24 5-C(O)NH.sub.2 
25 4-C(O)CH.sub.3 
26 5-C(O)CH.sub.3 
27 4-CH.sub.2 SCH.sub.3 
28 5-CH.sub.2 SCH.sub.3 
29 4-CH.sub.2 S(O)CH.sub.3 
30 5-CH.sub.2 S(O)CH.sub.3 
31 4-CH.sub.2 S(O).sub.2 CH.sub.3 
32 5-CH.sub.2 S(O).sub.2 CH.sub.3 
33 4-CH.sub.2 NHC(NH)H 
34 5-CH.sub.2 NHC(NH)H 
35 4-CH.sub.2 OCH.sub.3 
36 5-CH.sub.2 OCH.sub.3 
37 5-CO.sub.2 CH.sub.3 
##STR32## 
38 4-CH.sub.2 NH.sub.2 
39 5-CH.sub.2 NH.sub.2 
40 4-CO.sub.2 K 
41 5-CO.sub.2 K 
42 4-CH.sub.2 N.sub.3 
43 5-CH.sub.2 N.sub.3 
44 4-CH.sub.2 OH 
45 5-CH.sub.2 OH 
##STR33## 
46 4-CH.sub.2 NH.sub.2 
47 5-CH.sub.2 NH.sub. 2 
48 4-CO.sub.2 K 
49 5-CO.sub.2 K 
50 4-CH.sub.2 N.sub.3 
51 5-CH.sub.2 N.sub.3 
52 4-CH.sub.2 OH 
53 5-CH.sub.2 OH 
______________________________________ 
EXAMPLES 54-87 
The following examples are prepared by a method analogous to that described 
in Examples 5 using the appropriate starting materials readily available 
or readily prepared by techniques known in the art. It is understood that 
in the synthesis of the following examples protecting groups known in the 
art may need to be employed. It is also understood that synthesis of an 
example compound may require functional group manipulation well known in 
the art. 
______________________________________ 
EXAMPLE R.sup.c 
______________________________________ 
##STR34## 
54 
##STR35## 
55 
##STR36## 
56 
##STR37## 
57 
##STR38## 
58 
##STR39## 
59 
##STR40## 
60 
##STR41## 
61 
##STR42## 
62 
##STR43## 
63 
##STR44## 
##STR45## 
64 
##STR46## 
65 
##STR47## 
66 
##STR48## 
67 
##STR49## 
68 
##STR50## 
69 
##STR51## 
70 
##STR52## 
71 
##STR53## 
72 
##STR54## 
73 
##STR55## 
74 
##STR56## 
75 
##STR57## 
##STR58## 
76 
##STR59## 
77 
##STR60## 
78 
##STR61## 
79 
##STR62## 
80 
##STR63## 
81 
##STR64## 
82 
##STR65## 
83 
##STR66## 
84 
##STR67## 
85 
##STR68## 
86 
##STR69## 
87 
##STR70## 
______________________________________