Cephalosporin derivatives

7-{(Z)-2-(2-Aminothiazol-4-yl)-2-[(substituted)oxyimino]acetamido}-3-[3-(qu aternary ammonio)-1-propen-1-yl]-3-cephem-4-carboxylates and salts, esters and solvates thereof, having potent antibacterial activity, are provided. Processes for their preparation and intermediates in their preparation also are disclosed.

SUMMARY OF THE INVENTION 
This application relates to novel cephalosporin derivatives of the formula 
##STR1## 
wherein R.sup.1 is hydrogen or a conventional amino-protecting group, 
R.sup.2 is hydrogen, a straight or branched chain alkyl group containing 
from 1 to 4 carbon atoms or a group of the formula 
##STR2## 
in which R.sup.3 is hydrogen, (lower)alkyl or carboxyl, X is halogen, 
hydroxy or (lower)alkoxy, and R.sup.4 and R.sup.5 are each independently 
hydrogen, methyl or ethyl, or R.sup.4 and R.sup.5, taken together with the 
carbon atom to which they are attached, may be a cycloalkylidene ring 
containing from 3 to 5 carbon atoms, and 
##STR3## 
is a quaternary ammonio group, and to nontoxic pharmaceutically acceptable 
salts, physiologically hydrolyzable esters and solvates thereof. 
In another aspect this invention relates to a process for the preparation 
of the compounds of Formula I and to intermediates in their preparation. 
BACKGROUND AND PRIOR ART 
(A) Published European Patent Application No. 30,630 discloses a vast 
number of 7-acylamino-3-vinylcephalosporanic acid derivatives including, 
inter alia, those of the formula 
##STR4## 
wherein R inter alia may be (lower)alkyl, (lower)alkenyl, (lower)alkynyl 
or carboxy(lower)alkyl. The compounds are prepared, inter alia, by 
reaction of the corresponding 3-halomethyl compound with a 
triarylphosphine, followed by treatment with a base and reaction with 
formaldehyde. In each case, the final 3-substituent is the vinyl group. 
There is no disclosure or suggestion of a quaternary ammonio-substituted 
propenyl moiety for the 3-substituent. 
(B) U.K. Patent Specification No. 1,399,086 contains a generic disclosure 
encompassing a vast number of cephalosporins of the formula 
##STR5## 
wherein R is hydrogen or an organic group, R.sup.a is an etherifying 
monovalent organic group linked to the oxygen through a carbon atom, B is 
&gt;S or &gt;S.fwdarw.O, and P is an organic group. In one embodiment, P may be 
inter alia a vinyl group of the formula 
##STR6## 
in which R.sup.3 and R.sup.4 independently may be hydrogen, nitrile, 
(lower)alkoxycarbonyl, or substituted or unsubstituted aliphatic, 
cycloaliphatic, araliphatic or aromatic. However, the 2-aminothiazol-4-yl 
group is not identified as a possible R substituent and there is no 
disclosure or suggestion that P may be a quaternary ammonio-substituted 
propenyl group. U.S. Pat. No. 3,971,778 and its divisionals U.S. Pat. Nos. 
4,024,133, 4,024,137, 4,064,346, 4,033,950, 4,079,178, 4,091,209, 
4,092,477 and 4,093,803 have similar disclosures. 
(C) U.S. Pat. No. 4,307,233 discloses, inter alia, 3-vinyl cephalosporin 
derivatives of the formula 
##STR7## 
in which R.sup.5 inter alia may be alkyl, vinyl, cyanomethyl or a 
protective group such as 2-methoxyprop-2-yl, and R.sup.3 and R.sup.4 are 
alkyl groups (optionally substituted by hydroxy, alkoxy, amino, alkylamino 
or dialkylamino) or phenyl groups, or R.sup.3 and R.sup.4, taken together 
with the nitrogen to which they are attached, may form a saturated 
heterocyclic ring of 5 or 6 members, optionally containing another 
hetero-atom selected from N, O and S, and optionally substituted by an 
alkyl group. The compounds are useful as intermediates in the preparation 
of 3-thiovinyl cephalosporin derivatives. There is no disclosure or 
suggestion of a quaternary ammonio-substituted propenyl moiety for the 
3-substituent. Published United Kingdom Patent Application No. 2,051,062 
is concordant thereto and has a similar disclosure. 
(D) Published European Patent Application No. 53,537 discloses, inter alia, 
3-vinylcephalosporin derivatives of the formula 
##STR8## 
in which R.sub.5.sup.a and R.sub.5.sup.b are the same or different and are 
hydrogen or alkyl, or taken together, form an alkylene group containing 2 
or 3 carbon atoms, R.sub.5.sup.c is an acid protecting group, R.sub.2 is 
an acid protecting group such as an ester, R.sub.3 and R.sub.4 are the 
same or different and are hydrogen, alkyl (optionally substituted by 
hydroxy, alkoxy, amino, alkylamino or dialkylamino) or phenyl groups, or 
R.sub.3 and R.sub.4, taken together with the nitrogen to which they are 
attached, may form a saturated heterocyclic ring of 5 or 6 members, 
optionally containing another hetero-atom selected from N, O and S, and 
optionally substituted by an alkyl group. The compounds are useful as 
intermediates in the preparation of 3-thiovinyl cephalosporin derivatives. 
There is no disclosure or suggestion of a quaternary ammonio-substituted 
propenyl group for the 3-substituent. 
(E) U.S. Pat. No. 4,307,116 discloses 3-thiovinylcephalosporins of the 
formula 
##STR9## 
in which R.degree. is hydrogen, alkyl, vinyl or cyanomethyl, and R inter 
alia may be one of a vast number of heterocyclic rings such as 
##STR10## 
or the like. However, in each case, the heterocyclic ring is attached to 
the sulfur atom via a carbon atom of the heterocyclic ring. There is no 
disclosure or suggestion of a quaternary ammonio-substituted propenyl 
moiety for the 3-substituent. Although not formally related, published 
European Patent Application No. 53,961 has a similar disclosure, but 
includes 2-carboxyprop-2-yl, 1-carboxycyclobut-1-yl and the like as 
possible meanings of R.degree.. 
(F) Published European Patent Application No. 53,074 generically discloses 
a vast number of 3-vinylcephalosporin derivatives of the formula 
##STR11## 
wherein R.degree..sub.1a (in one of several embodiments) may be 
##STR12## 
in which R.sub.5 inter alia may be hydrogen, alkyl, vinyl, cyanomethyl, an 
oxime-protecting group such as trityl, etc., or a group of the formula 
##STR13## 
in which R.sup.a.sub.5 and R.sup.b.sub.5 are the same or different, and 
may be hydrogen, alkyl or, taken together, an alkylene radical of 2 or 3 
carbon atoms, and R.sup.c.sub.5 is hydrogen or an acid-protecting radical; 
R.degree..sub.2a is hydrogen or an acid-protecting radical such as 
methoxy-methyl; R.degree. (in one of several embodiments) may be a methyl 
group substituted by a 5- or 6-membered atomatic heterocyclic ring 
containing a single hetero atom, such as 2- or 3-pyridyl, or 2- or 
3-thienyl or 2- or 3-furyl; and R.sub.3 is a group of the formula 
##STR14## 
in which R.sub.4 may be alkyl, trihalomethyl or optionally substituted 
phenyl. 
These compounds are stated to be intermediates in the preparation of 
compounds in which the 3-substituent is a group of the formula 
##STR15## 
which are stated to have antibacterial activity. 
Although this patent includes the possibility of R.degree. being a methyl 
group substituted by an N-containing heterocyclic ring, in both the 
intermediates and final products (thus giving a heterocyclic-substituted 
propenyl moiety), it teaches only that the heterocyclic ring is attached 
via one of its carbon atoms. Thus, there is no suggestion of a quaternary 
ammonio-substituted propenyl group. The reference exemplifies R.degree. in 
the intermediates and final products only as methyl. Further, in both the 
intermediates and final product, the propenyl group must contain a second 
substituent (--O.sub.3 SR.sup.4 or --SR, respectively). 
(G) Published European Patent Application No. 53,538 discloses, inter alia, 
3-vinylcephalosporin intermediates of the formula 
##STR16## 
in which n is 0 or 1, R.sup.5 is hydrogen, alkyl, vinyl, cyanomethyl or an 
oxime-protecting group, and R.sup.3 is halogen. 
COMPLETE DISCLOSURE 
This application relates to novel cephalosporin derivatives which are 
potent antibacterial agents. More particularly, it relates to compounds of 
the formula 
##STR17## 
wherein R.sup.1 is hydrogen or a conventional amino-protecting group, 
R.sup.2 is hydrogen, a straight or branched chain alkyl group containing 
from 1 to 4 carbon atoms or a group of the formula 
##STR18## 
in which R.sup.3 is hydrogen, (lower)alkyl or carboxyl, X is halogen, 
hydroxy or (lower)alkoxy, and R.sup.4 and R.sup.5 are each independently 
hydrogen, methyl or ethyl, or R.sup.4 and R.sup.5, taken together with the 
carbon atom to which they are attached, may be a cycloalkylidene ring 
containing from 3 to 5 carbon atoms, and 
##STR19## 
is a quaternary ammonio group, and nontoxic pharmaceutically acceptable 
salts and physiologically hydrolyzable esters thereof. Also included 
within the scope of the invention are the solvates (including hydrates) of 
the compounds of Formula I, as well as the tautomeric forms of the 
compounds of Formula I, e.g. the 2-iminothiazolin-4-yl form of the 
2-aminothiazol-4-yl moiety. 
In another aspect, this application relates to a process for the 
preparation of the compounds of Formula I and to certain 
3-(3-halo-1-propen-1-yl)-substituted intermediates in their preparation. 
As shown in the structural formula, the compounds of Formula I have the 
"syn" or "Z" configuration with respect to the alkoxyimino group. Because 
the compounds are geometric isomers, some of the "anti" isomer may also be 
present. This invention comprises compounds of Formula I containing at 
least 90% of the "syn" isomer. Preferably the compounds of Formula I are 
"syn" isomers which are essentially free of the corresponding "anti" 
isomers. 
In addition to geometric isomers possible with respect to the alkoxyimino 
group, the compounds of Formula I (and the intermediates of Formulae IX 
and X) also form geometric (cis and trans) isomers about the double bond 
of the propenyl group. Both the cis ("Z") and trans ("E") isomers of these 
compounds are specifically included within the scope of this invention. 
The nontoxic pharmaceutically acceptable salts of the compounds of Formula 
I include salts with mineral acids such as hydrochloric, hydrobromic, 
phosphoric and sulfuric, or with organic carboxylic acids or sulfonic 
acids such as acetic, trifluoroacetic, citric, maleic, oxalic, succinic, 
benzoic, tartaric, fumaric, mandelic, ascorbic, malic, methanesulfonic, 
p-toluenesulfonic and other acids known and used in the penicillin and 
cephalosporin arts. Preparation of these acid addition salts is carried 
out by conventional techniques. 
Examples of physiologically hydrolyzable esters of the compounds of Formula 
I include indanyl, phthalidyl, methoxymethyl, acetoxymethyl, 
pivaloyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, and other 
physiologically hydrolyzable esters known and used in the penicillin and 
cephalosporin arts. Such esters are prepared by conventional techniques 
known in the art. 
The compounds of Formula I in which R.sup.1 is hydrogen exhibit high 
antibacterial activity against various Gram positive and Gram negative 
bacteria, and are useful in the treatment of bacterial infections in 
animals, including man. The compounds of Formula I may be formulated for 
parenteral use in a conventional manner utilizing known pharmaceutical 
carriers and excipients, and may be presented in unit dosage form or in 
multi-dosage containers. The compositions may be in the form of solutions, 
suspensions or emulsion in oily or aqueous vehicles, and may contain 
conventional dispersing, suspending or stabilizing agents. The 
compositions may also be in the form of a dry powder for reconstitution 
before use, e.g. with sterile, pyrogen-free water. The compounds of 
Formula I may also be formulated as suppositories utilizing conventional 
suppository bases such as cocoa butter or other glycerides. The compounds 
of this invention may, if desired, be administered in combination with 
other antibiotics such as penicillins or other cephalosporins. 
When provided in unit dosage forms the compositions will preferably contain 
from about 50 to about 1500 mg of the active ingredient of Formula I. The 
dosage of the compounds of Formula I is dependent on such factors as the 
weight and age of the patient as well as the particular nature and 
severity of the disease, and is within the discretion of the physician. 
However, the dosage for adult human treatment will usually be in the range 
of from about 500 to about 5000 mg per day, depending on the frequency and 
route of administration. When administered intramuscularly or 
intravenously to an adult human, a total dosage of from about 750 to about 
3000 mg per day, in divided doses, normally will be sufficient, although 
higher daily doses of some of the compounds may be desirable in the case 
of Pseudomonas infections. 
The quaternary ammonio group of the formula 
##STR20## 
may be acyclic, cyclic, or a combination of the two, and may contain one 
or more additional hetero atoms selected from nitrogen, sulfur and oxygen. 
An example of an acyclic quaternary ammonio group is a group of the formula 
##STR21## 
in which R.sup.6, R.sup.7 and R.sup.8 may be the same or different and 
may, for example, be (lower)alkyl or substituted (lower)alkyl in which the 
substituents are, for example, halogen, amino with the provision that the 
amino group may not be on an .alpha.-carbon, hydroxy with the provision 
that the hydroxy group may not be on an .alpha.-carbon, (lower)alkoxy with 
the provision that the alkoxy group may not be on an .alpha.-carbon, 
(lower)alkylthio, (lower)alkylamino, di(lower)alkylamino, carbamoyl, 
(lower)alkenyl, phenyl(lower)alkyl, phenyl or substituted phenyl (in which 
the substituents may be, for example, halogen, hydroxy, amino, 
(lower)alkylamino, di(lower)alkylamino, acylamino, (lower)alkyl, 
(lower)alkylthio, (lower)alkoxy, or the like). 
Examples of cyclic quaternary ammonio groups are fully unsaturated 
monocyclic heterocyclic ring systems, and bicyclic heterocyclic ring 
systems in which at least one N-containing ring is fully unsaturated. 
Suitable cyclic quaternary ammonio ring systems include, for example, 
those of the formulae 
##STR22## 
and the like, in which R.sup.9 and R.sup.10 are the same or different and 
may be, for example, hydrogen, halogen, amino, (lower)alkyl, 
(lower)alkenyl, (lower)alkylthio, hydroxy, (lower)alkoxy, 
(lower)alkoxy(lower)alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, 
amino(lower)alkyl, (lower)alkylamino(lower)alkyl, 
di(lower)alkylamino(lower)alkyl, (lower)alkylamino, di(lower)alkylamino, 
carboxy(lower)alkyl, carboxy(lower)alkylamino, carbamoyl, acylamino, 
acyloxy, phenyl, pyridyl, amidino, guanidino and the like. 
Examples of combined acyclic/cyclic quaternary ammonio groups include, for 
example, those of the formulae 
##STR23## 
and the like, in which R.sup.11 may be, for example, (lower)alkyl, 
(lower)alkoxy(lower)alkyl, hydroxy(lower)alkyl with the provision that the 
hydroxy may not be on an .alpha.-carbon, carboxy(lower)alkyl, 
amino(lower)alkyl with the provision that the amino may not be on an 
.alpha.-carbon, (lower)alkenyl, halo(lower)alkyl, allyl and the like, and 
R.sup.12 may be, for example, hydrogen, hydroxy, halogen, (lower)alkyl, 
hydroxy(lower)alkyl, (lower)alkoxy(lower)alkyl, halo(lower)alkyl, 
amino(lower)alkyl, (lower)alkoxy, (lower)alkylthio, (lower)alkenyl, amino, 
(lower)alkylamino, di(lower)alkylamino, acylamino, acyloxy, carbamoyl, 
amidino(lower)alkyl, phenyl, pyridyl, amidino, guanidino and the like. 
Preferred quaternary-ammonio groups are those of the formulae 
##STR24## 
wherein R.sup.13, R.sup.14 and R.sup.15 are the same or different and are 
(lower)alkyl, (lower)alkenyl, amino(lower)alkyl with the provision that 
the amino may not be on a .alpha.-carbon, or hydroxy(lower)alkyl with the 
provision that the hydroxy group may not be on an .alpha.-carbon; 
R.sup.16 is hydrogen, (lower)alkyl, (lower)alkoxy, (lower)alkylthio, amino, 
(lower)alkylamino, di(lower)alkylamino, formylamino, (lower)alkanoylamino, 
-hydroxy, hydroxy(lower)alkyl, halo(lower)alkyl, amino(lower)alkyl, 
(lower)alkoxy(lower)alkyl or carbamoyl; 
R.sup.17 is (lower)alkyl, (lower)alkoxy(lower)alkyl, halo(lower)alkyl, 
allyl, hydroxy(lower)alkyl with the provision that the hydroxy group is 
not on the .alpha.-carbon, amino(lower)alkyl with the provision that the 
amino group is not on the .alpha.-carbon, or phenyl(lower)alkyl; 
R.sup.18 is hydrogen, (lower)alkyl, (lower)alkoxy, 
(lower)alkoxy(lower)alkyl, (lower)alkylthio, amino, (lower)alkylamino, 
di(lower)alkylamino, hydroxy, hydroxy(lower)alkyl, amino(lower)alkyl, 
formylamino, (lower)alkanoylamino or carbamoyl; 
n is an integer of from 1 to 3, inclusive; 
Z is CH.sub.2 or, when n is 2, Z also may be S, O or N-R.sup.19, in which 
R.sup.19 is hydrogen or (lower)alkyl; and 
R.sup.20 and R.sup.21 are the same or different and are hydrogen, 
(lower)alkyl, (lower)alkoxy, (lower)alkylthio, amino, (lower)alkylamino, 
di(lower)alkylamino, hydroxy, hydroxy(lower)alkyl, amino(lower)alkyl, 
(lower)alkoxy(lower)alkyl, carboxy(lower)alkyl, carboxy(lower)alkylamino, 
(lower)alkanoylamino, carboxy(lower)alkanoylamino or carbamoyl. 
Particularly preferred quaternary ammonio groups are 
N-(lower)alkylpyrrolidinio (and especially N-methylpyrrolidinio), 
tri(lower)alkylammonio (and especially trimethylammonio), pyridinio, 
2-methylthiothiazolium and 2-methylthiazolio and 
2-amino-5-thiazolo[4,5-c]pyridinio. 
In the compounds of Formula I, particularly preferred values of R.sup.2 are 
(lower)alkyl (and especially methyl), 1-carboxycycloalk-1-yl containing 
from 3 to 5 carbon atoms (and especially 1-carboxycyclobut-1-yl) and 
carboxy(lower)alkyl (and especially 2-carboxyprop-2-yl). The most 
preferred compounds of the invention are 
(1) 
7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[3-(1-methylpyrr 
olidinio)-1-propen-1-yl]-3-cephem-4-carboxylate, 
(2) 
7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(3-pyridinio-1-p 
ropen-1-yl)-3-cephem-4-carboxylate, 
(3) 
7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxy-2-propoxyimino)acetamido]-3-(3 
-pyridinio-1-propen-1-yl)-3-cephem-4-carboxylate, 
(4) 
7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxycyclobut-1-oxyimino)acetamido]- 
3-[3-(1-methylpyrrolidinio)-1-propen-1-yl]-3-cephem-4-carboxylate, 
(5) 
7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxycyclobut-1-oxyimino)acetamido]- 
3-(3-pyridinio-1-propen-1-yl)-3-cephem-4-carboxylate, 
(6) 
7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxycyclobut-1-oxyimino)acetamido]- 
3-[3-(2-amino-5-thiazolo[4,5-c]pyridinio)-1-propen-1-yl]-3-cephem-4-carboxy 
late, 
(7) 
7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[3-(trimethylamm 
onio)-1- propen-1-yl]-3-cephem-4-carboxylate, 
(8) 
7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[3-(3-aminopyrid 
inio)-1-propen-1-yl]-3-cephem-4-carboxylate, 
(9) 
7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[3-(1-methyl-3-p 
yrrolinio)-1-propen-1-yl]-3-cepehm-4-carboxylate, 
(10) 
7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxycyclobut-1-oxyimino)acetamido]- 
3-[3-(1-methyl-3-pyrrolinio)-1-propen-1-yl]-3-cephem-4-carboxylate, 
(11) 
7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxy-2-propoxyimino)acetamido]-3-[3 
-(1-methylpyrrolidinio)-1-propen-1-yl]-3-cephem-4-carboxylate, 
(12) 
7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxycyclobut-1-oxyimino)acetamido]- 
3-[3-(2-methylthio-3-thiazolio)-1-propen-1-yl]-3-cephem-4-carboxylate, 
(13) 
7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[3-(2-methyl-3-t 
hiazolio)-1-propen-1-yl]-3-cephem-4-carboxylate, 
(14) 
7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxy-2-propoxyimino)acetamido]-3-[3 
-(2-methylthio-3-thiazolio)-1-propen-1-yl]-3-cephem-4-carboxylate, 
(15) 
7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxycyclobut-1-oxyimino)acetamido]- 
3-[3-(4-aminopyridinio)-1-propen-1-yl]-3-cephem-4-carboxylate, 
(16) 
7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[3-(4-amino-1-py 
ridinio)-1-propen-1-yl]-3-cephem-4-carboxylate, 
(17) 
7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[3-(2-methylthio 
-3-thiazolio)-1-propen-1-yl]-3-cephem-4-carboxylate, 
(18) 
7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxycyclobut-1-oxyimino)acetamido]- 
3-[3-(3-amino-1-pyridinio)-1-propen-1-yl]-3-cephem-4-carboxylate, 
(19) 
7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[3-(4-carbamoyl- 
1-pyridinio)-1-propen-1-yl]-3-cephem-4-carboxylate, 
(20) 
7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[3-(2-amino-5-th 
iazolo[4,5-c]pyridinio)-1-propen-1-yl]-3-cephem-4-carboxylate and 
(21) 
7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxycyclobut-1-oxyimino)acetamido]- 
3-[3-(2-methyl-3-thiazolio)-1-propen-1-yl]-3-cephem-4-carboxylate. 
The numbering system utilized herein for the various reactants, 
intermediates and final products is as follows: 
##EQU1## 
The Roman Numeral designates whether the compound is a final product [I] 
or an intermediate or other reactant [all other Roman Numerals]. The 
Arabic Numerals and Letters are not used in those instances where the 
overall class (genus) of compounds is meant. 
The Arabic Numeral designates the particular meaning of substituent 
R.sup.2, and the assigned meanings may be seen, for example, in 
Preparation No. 1. If the particular R.sup.2 group contains a carboxyl 
group which is protected by a conventional carboxyl-protecting group, a 
"prime" (') is used after the Arabic Numeral to indicate this fact. No 
"prime" is used if the carboxyl group is unprotected. A "prime" also is 
used with the generic R.sup.2 substituent (i.e. R.sup.2') when generically 
referring to an R.sup.2 group containing a protected carboxyl group. 
The Letter at the end of the compound number refers to the particular 
meaning of the quaternary ammonio group 
##STR25## 
For convenience, the Arabic Numerals and Letters assigned to some of the 
preferred R.sup.2 groups and quaternary ammonio groups are set forth 
below. 
______________________________________ 
Arabic Numeral R.sup.2 
______________________________________ 
1 = methyl 
2 = ethyl 
3 = allyl 
4 = 2-carboxyprop-2-yl 
5 = 1-carboxycyclobut-1-yl 
6 = 1-carboxy-3-chlorocyclobut-1-yl 
7 = 2-propyn-1-yl 
______________________________________ 
Letter .sup..sym. --N.tbd.Q 
______________________________________ 
A = 1-methylpyrrolidinio 
B = pyridinio 
C = 2-amino-5-thiazolo[4,5-c]pyridinio 
D = trimethylammonio 
E = 3-aminopyridinio 
F = 1-methyl-3-pyrrolinio 
G = 2-(methylthio)thiazolio 
H = 2-methylthiazolio 
I = 4-aminopyridinio 
J = 4-carbamoylpyridinio 
______________________________________ 
In the primary evaluation of the compounds of this invention, the Minimum 
Inhibitory Concentrations (MIC's) of the compounds were determined by the 
two-fold serial agar dilution method in Mueller-Hinton agar against 32 
strains of test organisms in six groups. The geometric means of the MIC's 
determined in these tests are shown in Table 1. 
TABLE 1 
______________________________________ 
Com- Geometric Mean of MIC (mcg/ml) 
pound (G-)- (G-)- (G-)- 
Num- (G+)-Ia (G+)-Ib (G-)-Ia 
Ib II III 
ber (5) (5) (5) (5) (5) (7) 
______________________________________ 
I-1B 0.20 0.52 0.012 0.050 0.10 5.7 
I-4B 6.0 15 0.046 0.37 0.41 5.0 
I-1A 0.22 0.59 0.021 0.11 0.13 5.1 
I-5B 1.6 4.7 0.019 0.23 0.17 2.0 
I-5A 1.8 4.7 0.038 0.23 0.26 2.6 
I-5C 1.3 4.4 0.015 0.15 0.14 2.7 
I-1E 0.10 0.30 &lt;0.0053 
0.050 0.043 5.7 
I-1F 0.15 0.39 0.014 0.074 0.10 3.1 
I-5F 1.5 4.0 0.037 0.22 0.17 2.4 
I-4A 2.3 4.1 0.036 0.20 0.17 2.3 
I-1D 0.17 0.59 0.0093 0.074 0.10 3.1 
I-5G 0.84 2.8 0.014 0.13 0.13 1.9 
I-1H 0.10 0.30 0.0093 0.050 0.074 5.7 
I-4G 1.8 5.4 0.021 0.22 0.20 3.5 
I-5I 1.6 4.7 0.019 0.20 0.22 3.5 
I-1I 0.11 0.34 &lt;0.016 0.10 0.15 &gt;25 
I-1G 0.15 0.39 0.014 0.074 0.085 7.6 
I-5E 1.2 3.1 0.016 0.15 0.15 1.9 
I-1J 0.26 0.61 0.016 0.11 0.13 5.7 
______________________________________ 
(G+)Ia: Penicillinsensitive S. aureus (5 
(G+)Ib: Penicillinresistant S. aureus (5 
(G-)Ia: Cephalothinsensitive E. coli (2 strains), Kl. pneumoniae (1 
strain) and Pr. mirabilis (2 strains) 
(G-)Ib: Cephalothinresistant E. coli (3 strains) and Kl. pneumoniae (3 
strains) 
(G-)II: M. morganii (1 strain), Ent. cloacae (2 strains) andSer. 
marcescens (2 strains) 
(G-)III: Ps. aeruginosa (7 strains) 
In another aspect, this invention relates to processes for the preparation 
of the compounds of Formula I. The preferred procedure is shown below in 
Reaction Scheme 1, while alternative procedures are shown in Reaction 
Schemes 2, 3 and 4. In the reaction schemes, m may be 0 or 1. The 
abbreviation "Tr" represents the trityl (triphenylmethyl) group, which is 
a preferred amino-protecting group. The abbreviation "Ph" represents the 
phenyl group. Thus, the --CH(Ph).sub.2 moiety is the benzhydryl group, 
which is a preferred carboxyl-protecting group. When R.sup.2 contains a 
carboxyl group, it is desirable to protect the carboxyl group with a 
conventional carboxyl-protecting group such as the t-butyl moiety. 
##STR26## 
Reaction Scheme 1 shows two alternate means of going from Compound X to 
Compound XII. The direct route, utilizing a tertiary amine (XI), is 
applicable for the preparation of all compounds of Formula I. The indirect 
route, via Compound XXIX, utilizes a secondary amine as reactant, and is 
quaternized in the following step. The secondary amine RR'NH may be 
acyclic (e.g. dimethylamine) or cyclic (e.g. pyrrolidine), and this 
indirect procedure therefore is suitable for the preparation of compounds 
of Formula I in which the quaternary ammonio group is acyclic or "mixed" 
acyclic/cyclic. This indirect route is not suitable for the preparation of 
compounds of Formula I wherein the quaternary nitrogen is in a fully 
unsaturated heterocyclic ring (e.g. pyridinio, thiazolio, 
2-amino-5-thiazolo[4,5-c]pyridinio, and the like). 
Alternate Reaction Scheme 2, shown below, also utilizes a tertiary amine as 
a reactant, and therefore is suitable for the preparation of all compounds 
of Formula I. Alternate Reaction Scheme 3, on the other hand, utilizes a 
secondary amine as a reactant, which is quaternized in the final step. 
Accordingly, like the indirect step of Reaction Scheme 1 (via Compound 
XXIX), Reaction Scheme 3 is suitable for the preparation of compounds of 
Formula I where the quaternary ammonio group is acyclic or mixed 
acyclic/cyclic, but not those compounds wherein the quaternary nitrogen is 
in a fully unsaturated heterocyclic ring. 
Reaction Scheme 4, shown below, is a shortened version of Reaction Scheme 
1, in that two steps are eliminated. That is, the direct route of Reaction 
Scheme 4 goes directly from Compound VIII to Compound XII (rather than 
VIII.fwdarw.IX.fwdarw.X.fwdarw.XII in the direct route of Reaction Scheme 
1), while the indirect route of Reaction Scheme 4 is two steps from 
Compound VIII to Compound XII (VIII.fwdarw.XXX.fwdarw.XII) rather than 
four steps in the indirect route of Reaction Scheme 1 
(VIII.fwdarw.IX.fwdarw.X.fwdarw.XXIX.fwdarw.XII). As discussed above, the 
direct route of Reaction Scheme 4 is suitable for the preparation of all 
compounds of Formula I, while the indirect route is suitable for the 
preparation of the compounds of Formula I in which the quaternary ammonio 
group is acyclic or mixed acyclic/cyclic. 
Intermediates of Formula XXI (3-formylcephalosporin derivatives) are known 
compounds or may be prepared by known procedures. See, for example, U.S. 
Pat. Nos. 3,351,596, 4,166,115, 4,279,818 and 4,331,664 which teach the 
preparation of 3-formylceph-3-em compounds by oxidation of the 
corresponding 3-hydroxymethylceph-3-em compounds. 
##STR27## 
Although Reaction Scheme 1, above, shows a preferred multi-step procedure 
for the preparation of the compounds of Formula I, it will be appreciated 
that other starting materials and procedures may be utilized to prepare 
the intermediates used in the key step. Thus, the key step in Reaction 
Scheme 1 is the reaction of Compound X with the tertiary amine of XI to 
produce the "protected" product XII (or the indirect reaction of Compound 
X with a secondary amine, followed by quaternization to produce product 
XII). Compound X may, of course, be prepared by various other procedures. 
The present invention provides a process for the preparation of compounds 
of the formula 
##STR28## 
wherein R.sup.1 is hydrogen or a conventional amino-protecting group, 
R.sup.2 is hydrogen, a straight or branched chain alkyl group containing 
from 1 to 4 carbon atoms, or a group of the formula 
##STR29## 
in which R.sup.3 is hydrogen, (lower)alkyl or carboxyl, X is halogen, 
hydroxy or (lower)alkoxy, and R.sup.4 and R.sup.5 are each independently 
hydrogen, methyl or ethyl, or R.sup.4 and R.sup.5, taken together with the 
carbon atom to which they are attached, may be a cycloalkylidene ring 
containing from 3 to 5 carbon atoms, and 
##STR30## 
is a quaternary ammonium group, and nontoxic pharmaceutically acceptable 
salts, physiologically hydrolyzable esters and solvates thereof, which 
process comprises reacting a compound of the formula 
##STR31## 
wherein R.sup.2' is the same as R.sup.2 or is a group of the formula 
##STR32## 
in which X, R.sup.4 and R.sup.5 are as defined above, B.sup.1 is a 
conventional carboxyl-protecting group, B.sup.2 is a conventional 
amino-protecting group and m is 0 or 1, with a tertiary amine, to produce 
a compound of the formula 
##STR33## 
and, if m is 1, reducing the sulfoxide by conventional means, and 
subsequently removing all protecting groups by conventional means. 
The present invention also provides a process for the preparation of 
compounds of the formula 
##STR34## 
wherein R.sup.1 is hydrogen or a conventional amino-protecting group, 
R.sup.2 is hydrogen, a straight or branched chain alkyl group containing 
from 1 to 4 carbon atoms, or a group of the formula 
##STR35## 
in which R.sup.3 is hydrogen, (lower)alkyl or carboxyl, X is halogen, 
hydroxy or (lower)alkoxy, and R.sup.4 and R.sup.5 are each independently 
hydrogen, methyl or ethyl, or R.sup.4 and R.sup.5, taken together with the 
carbon atom to which they are attached, may be a cycloalkylidene ring 
containing from 3 to 5 carbon atoms, and 
##STR36## 
is a quaternary ammonio group, and nontoxic pharmaceutically acceptable 
salts, physiologically hydrolyzable esters and solvates thereof, which 
process comprises reacting a compound of the formula 
##STR37## 
wherein R.sup.2' is the same as R.sup.2 or is a group of the formula 
##STR38## 
in which X, R.sup.4 and R.sup.5 are as described above, B.sup.1 is a 
conventional carboxyl-protecting group, B.sup.2 is a conventional 
amino-protecting group and m is 0 or 1, with an appropriate base such as 
hydroxyl ion and then with a compound of the formula 
##STR39## 
in which 
##STR40## 
is a quaternary ammonio group and A.sup..crclbar. is hydroxyl, chloro, 
bromo or iodo, to produce a compound of the formula 
##STR41## 
and, if m is 1, reducing the sulfoxide by conventional means, and 
subsequently removing all protecting groups by conventional means. 
The present invention also provides a process for the preparation of 
compounds of the formula 
##STR42## 
wherein R.sup.1 is hydrogen or a conventional amino-protecting group, 
R.sup.2 is hydrogen, a straight or branched chain alkyl group containing 
from 1 to 4 carbon atoms, or a group of the formula 
##STR43## 
in which R.sup.3 is hydrogen, (lower)alkyl or carboxyl, X is halogen, 
hydroxy or (lower)alkoxy, and R.sup.4 and R.sup.5 are each independently 
hydrogen, methyl or ethyl, or R.sup.4 and R.sup.5, taken together with the 
carbon atom to which they are attached, may be a cycloalkylidene ring 
containing from 3 to 5 carbon atoms, and 
##STR44## 
is a quaternary ammonium group, and nontoxic pharmaceutically acceptable 
salts, physiologically hydrolyzable esters and solvates thereof, which 
process comprises reacting a compound of the formula 
##STR45## 
wherein R.sup.2' is the same as R.sup.2 or is a group of the formula 
##STR46## 
in which X, R.sup.4 and R.sup.5 are as defined above, B.sup.1 is a 
conventional carboxyl-protecting group, B.sup.2 is a conventional 
amino-protecting group and m is 0 or 1, with a compound of the formula 
##STR47## 
in which X is chloro, bromo or iodo, to produce a compound of the formula 
##STR48## 
and, if m is 1, reducing the sulfoxide by conventional means, and 
subsequently removing all protecting groups by conventional means. 
The reactions are carried out in a non-aqueous organic solvent such as 
dimethyl sulfoxide, hexamethylphosphoramide, methylene chloride, 
chloroform, ethyl ether, hexane, ethyl acetate, tetrahydrofuran, 
acetonitrile and the like, or mixtures of such solvents. The reactions are 
conveniently carried out at a temperature of from about -10.degree. C. to 
about +50.degree. C.; we normally prefer to conduct the reactions at room 
temperature. In Reaction Scheme 1, at least one mole of the tertiary amine 
(or secondary amine) should be used per mole of Compound X; we normally 
prefer to utilize from about 25% to 100% excess of the tertiary amine. 
Similarly, at least one mole of Compound R"I should be used per mole of 
Compound XXIX. 
Carboxyl-protecting groups suitable for use as B.sup.1 in the above 
reactions are well-known to those skilled in the art and include aralkyl 
groups such as benzyl, p-methoxybenzyl, p-nitrobenzyl and diphenylmethyl 
(benzhydryl); alkyl groups such as t-butyl; haloalkyl groups such as 
2,2,2-trichloroethyl, and other carboxyl protecting groups described in 
the literature, e.g. in U.K. Pat. No. 1,399,086. We prefer to utilize 
carboxyl-protecting groups which are readily removed by treatment with 
acid. Particularly preferred carboxyl-protecting groups are the benzhydryl 
and t-butyl moieties. 
Amino-protecting groups suitable for use as B.sup.2 are also well-known in 
the art, and include the trityl group and acyl groups such as 
chloroacetyl, formyl and trichloroethoxycarbonyl. Amino-protecting groups 
which are readily removed by treatment with acid, e.g. the trityl group, 
are preferred. 
In Reaction Scheme 1, 2, 3, or 4, when the cephalosporin nucleus is 
utilized in the form of the 1-oxide (m=1), the 1-oxide is prepared by 
known procedures such as oxidation with m-chloroperbenzoic acid, peracetic 
acid, etc. The 1-oxide subsequently may be reduced by known procedures, 
e.g. reduction of the corresponding alkoxysulfonium salt with iodide ion 
in an aqueous medium. The alkoxysulfonium salt itself is readily prepared 
by treatment of the 1-oxide with, for example, acetyl chloride. 
As used herein, the terms acylamino and acyloxy refer to an acylated amino 
or acylated hydroxy group in which the acyl moiety is (lower)alkanoyl 
(e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, etc.), 
aroyl (e.g. benzoyl, etc.), (lower)alkanesulfonyl (e.g. mesyl, 
ethanesulfonyl, etc.) or arylsulfonyl (e.g. benzenesulfonyl, tosyl, etc.). 
As used herein, the terms "(lower)alkyl", "(lower)alkoxy", 
"(lower)alkylthio" (or the like) mean straight or branched chain alkyl, 
alkoxy, alkylthio (or the like) groups containing from 1 to 6 carbon 
atoms, inclusive. 
In another embodiment, this invention relates to novel intermediates of the 
formula 
##STR49## 
wherein Z is chloro, bromo or iodo, m is 0 or 1 and R.sup.2 is hydrogen, a 
straight or branched chain alkyl group containing from 1 to 4 carbon 
atoms, or a group of the formula 
##STR50## 
in which R.sup.3 is hydrogen, (lower)alkyl or carboxyl, X is halogen, 
hydroxy or (lower)alkoxy, and R.sup.4 and R.sup.5 are each independently 
hydrogen, methyl or ethyl, or R.sup.4 and R.sup.5, taken together with the 
carbon atom to which they are attached, may be a cycloalkylidene ring 
containing from 3 to 5 carbon atoms, and salts and esters thereof. Also 
included are compounds of Formula XXVIII in which the amino and/or 
carboxyl groups are protected by conventional amino-protecting or 
carboxyl-protecting groups. 
Preparation No. 1 
##STR51## 
Ethyl (Z)-2-Methoxyimino-2-(2-tritylaminothiazol-4-yl)acetate (III-1) 
A mixture of ethyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl) acetate 
(II) (5.00 g, 10.9 mmoles), CH.sub.3 I (2.04 mL, 32.8 mmoles) and K.sub.2 
CO.sub.3 (4.54 g, 32.8 mmoles) in dry dimethylsulfoxide (DMSO) (100 mL) 
was stirred at room temperature overnight and then poured into water (250 
mL). The precipitate which formed was collected by filtration, washed with 
water and dried to give the title compound (5.15 g, quantitative yield). 
Mp. 115.degree. C. (dec.). 
NMR: .delta..sup.CDCl.sbsp.3 ppm 1.32 (3H, t), 3.98 (3H, s), 4.30 (2H, q), 
6.42 (1H, s), 7.2 (1H, s), 7.25 (15H, s). 
Compounds III-2, III-3, III-4', III-5', III-6' and III-7 were prepared by 
the general procedure set forth above, but replacing the methyl iodide 
with the appropriate iodide or bromide. 
__________________________________________________________________________ 
Literature 
Compound 
R.sup.2 (or R.sup.2') 
Yield (%) 
Mp (.degree.C.) 
Mp (.degree.C.) 
__________________________________________________________________________ 
III-1 methyl 100 115 (dec.) 
120 (dec.).sup.(1) 
III-2 ethyl 67 97-98 
* 
III-3 allyl * * * 
III-4' 
C(CH.sub.3).sub.2 COOtButyl 
100 125-126 
123.5-125.sup.(2) ; 134.sup.(3) 
III-5' 
##STR52## 68 81-83 
not reported.sup.(3) 
III-6' 
##STR53## 36 75-85 
(new compound) 
III-7 CH.sub.2 CCH 
94 70-73 
not reported.sup.(4) 
__________________________________________________________________________ 
*The ester was hydrolyzed without isolation 
.sup.(1) Tetrahedron, 34, 2233 (1978) 
.sup.(2) U.S. Pat. No. 4,258,041 
.sup.(3) U.S. Pat. No. 4,288,434 
.sup.(4) U.S. Pat. No. 4,294,960 
Preparation No. 2 
##STR54## 
(Z)-2-Methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (IV-1) 
The ethyl ester III-1 prepared in Preparation No. 1 (6.00 g, 12.7 mmoles) 
in ethanol (120 mL) was treated with 2N NaOH (12.7 mL) at room temperature 
overnight. The reaction mixture was adjusted to pH 8 by the addition of 
powdered dry ice and the solvent was evaporated under reduced pressure. 
The residue was dissolved in water (100 mL) and the solution was acidified 
with 1N HCl to pH 2 and then extracted with ethyl acetate (3.times.50 mL). 
The combined extracts were washed with a saturated aqueous NaCl solution, 
dried and evaporated. The residue was crystallized from ethyl 
acetate-hexane to afford 5.56 g (yield 98%) of the title product. Mp. 
138.degree.-143.degree. C. (dec.). 
NMR: .delta..sup.CDCl.sbsp.3 ppm 3.89 (3H, s), 6.52 (1H, s), 7.2 (15H, s). 
Compounds IV-2, IV-3, IV-4', IV-5', IV-6' and IV-7 were prepared by the 
general procedure set forth above. 
______________________________________ 
Literature 
Com- Yield Mp (.degree.C., 
Mp 
pound R.sup.2 (or R.sup.2') 
(%) dec.) (.degree.C., dec.) 
______________________________________ 
IV-1 methyl 98 138-143 
ca. 140.sup.1 
IV-2 ethyl 85 140-145 
not reported.sup.1 
IV-3 allyl 66 170-178 
ca. 170.sup.1 
IV-4' C(CH.sub.3).sub.2 COOtButyl 
77 174-175 
152-156.sup.2 ; 190.sup.3 
IV-5' 
##STR55## 78 163-164 
not reported.sup.3 
IV-6' 
##STR56## 51 125-135 
new compound 
IV-7 CH.sub.2 CCH 88 136-138 
.sup.4 
______________________________________ 
.sup.1 Tetrahedron, 34, 2233 (1978) 
.sup.2 U.S. Pat. No. 4,258,041 
.sup.3 U.S. Pat. No. 4,288,434 
.sup.4 The corresponding NH.sub.2 compound is described in U.S. Pat. No. 
4,294,960 
Preparation No. 3 
Benzhydryl 3-Hydroxymethyl-7-phenylacetamido-3-cephem-4-carboxylate 
To a stirred suspension of phosphate buffer (pH 7, 162.5 ml) and wheat bran 
(20 g, dry) at room temperature was added 7-phenylacetamidocephalosporanic 
acid sodium salt (5 g, 12.1 mmoles) in one portion. The progress of the 
reaction was monitored by HPLC until the hydrolysis was complete (5 
hours). The suspension was filtered to remove the wheat bran and the 
filtrate was cooled to 5.degree.-10.degree. C. for extractive 
esterification. To the cooled solution was added methylene chloride (32 
mL) followed by a 0.5M solution of diphenyldiazomethane in methylene 
chloride (24 mL). The pH was then adjusted to 3.0 with 28% phosphoric 
acid. After 1 hour the reaction mixture was allowed to rise to 20.degree. 
C. Heptane (56 mL) was slowly added and the resulting crystalline title 
product was recovered by filtration. Yield of the title product was 3.0 g 
(50%). 
Preparation No. 4 
Benzhydryl 7-Amino-3-chloromethyl-3-cephem-4-carboxylate (V) 
To a slurry of PCl.sub.5 (8.3 g, 40 mmoles) in CH.sub.2 Cl.sub.2 (100 mL) 
was added pyridine (3.2 g, 40 mmoles) and the mixture was stirred for 20 
minutes at 20.degree. C. To the mixture was added benzhydryl 
3-hydroxymethyl-7-phenylacetamido-3-cephem-4-carboxylate prepared in 
Preparation No. 3 (5.1 g, 10 mmoles) with stirring at -40.degree. C., in 
one portion. The mixture was stirred at -10.degree. C. for 15 minutes and 
allowed to stand at -10.degree. C. to -15.degree. C. for 7 hours. To the 
cooled solution (-20.degree. C.) was added propane-1,3-diol (10 mL) and 
the mixture was allowed to stand at -20.degree. C. for 16 hours and then 
at room temperature for 20 minutes with stirring. The resulting solution 
was washed with ice-water (2.times.20 mL) and saturated aqueous NaCl (10 
mL), dried over MgSO.sub.4 and concentrated in vacuo. The gummy residue 
(12 g) was dissolved in a mixture of CHCl.sub.3 and n-hexane (2:1), and 
subjected to chromatography using a silica gel column (200 g) and the same 
solvent as eluant. Fractions containing the title compound were evaporated 
in vacuo and the residue triturated with n-hexane to give the title 
product (2.1 g, 51%), melting at &gt;110.degree. C. (dec.). 
IR: .nu..sub.KBr 3400, 2800, 1785, 1725 cm.sup.-1. 
UV: .lambda..sub.max.sup.EtOH 265 nm (E.sub.1 cm.sup.1% 160). 
NMR: .delta..sub.ppm.sup.DMSO-d.sbsp.6.sup.+CDCl.sbsp.3 3.69 (2H, s), 4.43 
(2H, s), 5.09 (1H, d, J=4.5 Hz), 5.24 (1H, d, J=4.5 Hz), 6.87 (1H, s), 7.3 
(10H, m). 
Preparation No. 5 
Benzhydryl 
3-Chloromethyl-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamid 
o]-3-cephem-4-carboxylate (VI-1) 
Benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate prepared in 
Preparation No. 4 (2.29 g, 5.52 mmoles) in CH.sub.3 CN (57 mL) was treated 
with bis(trimethylsilyl)acetamide (BSA, 4.09 mL, 16.6 mmoles) at room 
temperature for 50 minutes to give a clear solution. To the solution was 
added an acid chloride solution, which was prepared from 
(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (IV-1) (2.04 
g, 4.60 mmoles) and PCl.sub.5 (1.15 g, 5.52 mmoles) in methylene chloride 
(20 mL). The mixture was stirred at room temperature for 30 minutes, 
poured into cold water (200 mL) and extracted with ethyl acetate 
(3.times.100 mL). The combined extracts were washed with aqueous NaCl, 
dried and evaporated. The residual syrup (4 g) was chromatographed on a 
silica gel (150 g) column by eluting with 10:1 and 3:1 mixtures of toluene 
and ethyl acetate successively. The fractions containing the desired 
compound were combined and evaporated to afford 2.61 g (68%) of VI-1 as an 
amorphous powder. 
NMR: .delta..sup.CDCl.sbsp.3 ppm 3.50 (2H, s), 4.02 (3H, s), 4.33 (2H, s), 
4.98 (1H, d), 5.87 (1H, q), 6.65 (1H, s), 6.90 (1H, s), 7.3 (25H, m). 
Preparation No. 6 
Benzhydryl 
3-Iodomethyl-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido] 
-3-cephem-4-carboxylate (VII-1) 
A mixture of the 3-chloromethyl derivative prepared in Preparation No. 5 
(VI-1) (1.50 g, 1.79 mmoles) and NaI (1.34 g, 8.93 mmoles) in methyl ethyl 
ketone (30 mL) was stirred at room temperature for 1 hour. After 
evaporation of the solvent the residue was dissolved in ethyl acetate (100 
mL) and washed with water, aqueous Na.sub.2 S.sub.2 O.sub.3 and aqueous 
NaCl, dried and evaporated to give the title compound VII-1 (1.47 g, 89%) 
as an amorphous powder. 
NMR: .delta..sup.CDCl.sbsp.3 ppm 3.55 (2H, ABq), 4.00 (3H, s), 4.25 (2H, 
s), 4.97 (1H, d), 5.80 (1H, q), 6.65 (1H, s), 6.90 (1H, s), 7.3 (25H, m). 
Preparation No. 7 
Benzhydryl 
3-Chloromethyl-7-[(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido 
]-3-cephem-4-carboxylate (VI-2) 
To a solution of (Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid 
(IV-2) (1.095 g, 2.4 mmoles) in dichloromethane (20 mL) was added 
phosphorous pentachloride (500 mg). After stirring for 1 hour at room 
temperature, the mixture was added in one portion to an ice-cooled 
solution of Compound V (1.083 g, 2.4 mmoles) and BSA (1 mL) in 
dichloromethane (20 mL). After stirring for 0.5 hour the reaction mixture 
was poured into 10% aqueous NaHCO.sub.3 (200 mL) and extracted with 
CHCl.sub.3 (100 mL). The extract was washed with water, dried over 
MgSO.sub.4, and evaporated under reduced pressure. The residue was 
chromatographed on a silica gel column. Elution with CHCl.sub.3 gave VI-2 
as an amorphous powder, 1.76 g (86%). 
NMR: .delta..sup.CDCl.sbsp.3 ppm 1.40 (3H, t, CH.sub.2 CH.sub.2), 3.53 (2H, 
ABq, 2-H), 4.37 (2H, s, --CH.sub.2 Cl), 4.60 (2H, q, --CH.sub.2 CH.sub.3), 
4.90 (1H, d, 6-H), 5.89 (1H, d, 7-H), 6.88 (1H, s, thiazole-H), 6.91 (1H, 
s, benzhydryl-CH). 
Preparation No. 8 
Diphenylmethyl 
7-[(Z)-2-Ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl- 
3-cephem-4-carboxylate (VII-2) 
A mixture of VI-2 prepared in Preparation No. 7 (1.07 g, 1.25 mmoles) and 
NaI (562 mg, 2.75 mmoles) in acetone (20 mL) was stirred for 1 hour. The 
mixture was filtered and the filtrate was poured into water and extracted 
with ethyl acetate. The organic layer was washed successively with 5% 
aqueous Na.sub.2 S.sub.2 O.sub.3, water and saturated aqueous NaCl, dried 
over MgSO.sub.4 and evaporated to give 1.04 g (89%) of Compound VII-2. 
NMR: .delta..sup.CDCl.sbsp.3 ppm 3.55 (2H, q, 2-H), 4.27 (2H, s, CH.sub.2 
I), 5.02 (1H, d, 6-H), 5.87 (1H, d, 7-H), 6.68 (1H, s, thiazole ring H), 
6.93 (1H, s, benzhydryl-CH). 
Preparation No. 9 
Benzhydryl 
7-[(Z)-2-Allyloxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromet 
hyl-3-cephem-4-carboxylate (VI-3) 
To a suspension of Compound V (1.35 g, 3 mmoles) in methylene chloride (20 
mL) was added BSA (1.1 mL, 4.5 mmoles), and the mixture was stirred for 30 
minutes at room temperature to become a clear solution. A mixture of 
(Z)-2-allyloxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (IV-3) (1.40 
g, 3.0 mmoles) and phosphorous pentachloride (690 mg, 3.3 mmoles) in 
methylene chloride (20 mL) was stirred for 15 minutes at room temperature 
and poured in one portion into the solution of the trimethylsilylated 
Compound V. The mixture was stirred for 20 minutes at room temperature and 
diluted with ethyl acetate (200 mL), washed with aqueous sodium 
bicarbonate and water, dried and evaporated under reduced pressure. The 
oily residue was purified by silica gel column chromatography (Wako-gel, 
C-200, 30 g). The column was eluted with chloroform and the fractions 
containing the desired product were combined. Evaporation under reduced 
pressure afforded the title compound (VI-3) as an amorphous powder, yield 
2.32 g (89%). Mp. 100.degree.-115.degree. C. (dec.). 
IR: .nu..sub.max.sup.KBr cm.sup.-1 3390, 1790, 1730, 1680, 1530, 1380, 
1250, 1160, 1020. 
NMR: .delta..sup.CDCl.sbsp.3 ppm 3.50 (2H, 2-H), 4.32 (2H, s, 3-CH.sub.2), 
4.6-6.1 (7H, m, CH.sub.2 CH.dbd.CH.sub.2 and 6,7-H), 6.70 (1H, s, 
thiazole-H), 6.90 (1H, s, Ph.sub.2 CH), 7.1-7.6 (30H, m, phenyl protons). 
Anal. Calc'd. for C.sub.48 H.sub.40 N.sub.5 O.sub.5 S.sub.2 
Cl.1/3CHCl.sub.3 : C, 64.05; H, 4.45; N, 7.73; S, 7.08; Cl, 7.82. Found: 
C, 64.13; 63.99; H, 4.61, 4.64; N, 7.50, 7.30; S, 6.85, 6.85; Cl, 7.55, 
7.46. 
Preparation No. 10 
Benzhydryl 
7-[(Z)-2-Allyloxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethy 
l-3-cephem-4-carboxylate (VII-3) 
A mixture of Compound VI-3 (2.30 g, 2.65 mmoles) and sodium iodide (2 g, 
13.3 mmoles) in acetone (15 mL) was stirred for 1 hour at room temperature 
and then evaporated under reduced pressure. A solution of the oily residue 
in ethyl acetate (200 mL) was washed with 10% sodium thiosulfate and 
water, evaporated under reduced pressure to afford Compound VII-3 as an 
amorphous powder, which was used in the subsequent step without further 
purification. Yield 2.52 g (99%). 
Preparation No. 11 
Benzhydryl 
3-Chloromethyl-7-[(Z)-2-(2-t-butoxycarbonylprop-2-oxyimino)-2-(2-tritylami 
nothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (VI-4') 
Procedure 1 
A mixture of 
(Z)-2-(2-t-butoxycarbonylprop-2-oxyimino)-2-(2-tritylaminothiazol-4-yl)ace 
tic acid (IV-4') (1.94 g, 3.6 mmoles) DCC (742 mg, 3.6 mmoles) and 
N-hydroxybenztriazole (486 mg, 3.6 mmoles) in tetrahydrofuran (THF) (45 
mL) was stirred at room temperature for 45 minutes, during which 
dicyclohexylurea separated. The dicyclohexylurea was removed by filtration 
and the filtrate was mixed with V (1.5 g, 3.6 mmoles). The mixture was 
stirred overnight at room temperature and then evaporated in vacuo. The 
residual oil was dissolved in CHCl.sub.3 (20 mL), washed with saturated 
aqueous NaHCO.sub.3 and saturated aqueous NaCl, dried over MgSO.sub.4 and 
evaporated to dryness. The residue (3.9 g) was dissolved in 
n-hexane:CHCl.sub.3 (1:2) and passed through a silica gel column (40 g) 
using the same solvent system. Fractions containing the title compound 
were evaporated in vacuo to give 1.3 g (39%) of VI-4' melting at 
&gt;100.degree. C. (dec.). 
IR: .nu..sub.max.sup.KBr cm.sup.-1 3390, 1790, 1715, 1690. 
UV: .lambda..sub.max.sup.EtOH nm 240 (E.sub.1 cm.sup.1% 280), 265 (E.sub.1 
cm.sup.1% 190). 
NMR: .delta..sup.CDCl.sbsp.3 ppm 1.45 (9H, s), 1.63 & 1.66 (6H, each s), 
3.49 (2H, broad s), 4.34 (2H, s), 4.96 (1H, d, J=4.5 Hz), 5.90 (1H, d-d, 
J=4.5 & 7.5), 6.66 (1H, s), 6.86 (1H, s), 7.0-7.5 (25H, m), 8.23 (1H, d, 
J=7.5 Hz). 
Procedure 2 
A solution of V (1.86 g, 4.49 mmoles) in CH.sub.3 CN (46.5 mL) was treated 
with BSA (3.33 mL, 13.5 mmoles) at room temperature for 50 minutes to give 
a clear solution. To the solution was added an acid chloride solution 
which had been prepared from IV-4' (2.56 g, 4.49 mmoles) and PCl.sub.5 
(1.12 g, 5.38 mmoles) in methylene chloride (26 mL). The mixture was 
stirred at room temperature for 30 minutes, poured into cold water (100 
mL) and extracted with ethyl acetate (3.times.50 mL). The combined 
extracts were washed with aqueous NaCl, dried and evaporated. The residual 
syrup (5 g) was chromatographed on a silica gel (100 g) column by eluting 
with 10:1 mixture of toluene and ethyl acetate. The fractions containing 
the desired compound were combined and evaporated to afford 2.84 g (65%) 
of VI-4'. 
Preparation No. 12 
Benzhydryl 7-[(Z)-2-(2-t-Butoxycarbonylprop- 
2-oxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem- 
4-carboxylate (VII-4') 
A mixture of VI-4' (500 mg, 0.53 mmole) and NaI (240 mg, 1.6 mmoles) in 
acetone (3 mL) was stirred for 2 hours at room temperature and then 
evaporated in vacuo. To the residue were added CH.sub.2 Cl.sub.2 (20 mL) 
and water (10 mL). The organic layer was washed with 10% w/v sodium 
thiosulfate (5 mL) and aqueous NaCl (5 mL), dried over MgSO.sub.4 and 
evaporated to dryness to give 540 mg (99%) of VII-4' as an amorphous 
powder melting at 106.degree. C. (dec.). 
IR: .nu..sub.max.sup.KBr cm.sup.-1 3350, 1790, 1690. 
UV: .lambda..sub.max.sup.EtOH nm 240 (E.sub.1 cm.sup.1% 270), 265 (E.sub.1 
cm.sup.1% 190). 
NMR: .delta.CDCl.sbsp.3 ppm 1.44 (9H, s), 1.65 (6H, s), 3.54 (2H, ABq), 
4.28 (2H, s), 4.98 (1H, d, J=4.5 Hz), 5.85 (1H, d-d, J=4.5 & 7.5 Hz), 6.70 
(1H, s), 6.90 (1H, s), 7.1-7.5 (25H, m). 
Preparation No. 13 
Diphenylmethyl 
7-[(Z)-2-(1-t-Butoxycarbonylcyclobut-1-oxyimino)-2-(2-tritylaminothiazol-4 
-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (VI-5') 
Phosphorus pentachloride (1.46 g, 7 mmoles) was added to a suspension of 
(Z)-2-(1-t-butoxycarbonylcyclobut-1-oxyimino)-2-(2-tritylaminothiazol-4-yl 
)acetic acid [IV-5'] (4.09 g, 7 mmoles) in 70 mL of dry methylene chloride, 
and the mixture was stirred for 1 hour at room temperature. The acid 
chloride solution was added at -20.degree. C. to a solution of silylated 
7-ACA ester, which was prepared by adding BSA (5.6 mL, 21 mmoles) to a 
stirred suspension of benzhydryl 
7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride [V] (3.16 g, 7 
mmoles) in dry methylene chloride (70 mL). The mixture was stirred for 20 
minutes at -10.degree. C. and then at room temperature for 40 minutes. The 
reaction mixture was evaporated and diluted with ethyl acetate (300 mL), 
and the organic layer was washed with 5% aqueous sodium bicarbonate, water 
and a saturated sodium chloride solution. After drying over sodium 
sulfate, the solvent was evaporated and the residue was purified by silica 
gel column chromatography (Wako gel C-200, 60 g); elution with chloroform. 
The fractions containing the desired product were combined and evaporated 
to obtain 5.88 g (86%) of VI-5' as a yellow powder. 
IR: .nu..sub.max.sup.KBr cm.sup.-1 1790, 1725, 1690, 1525. 
UV: .lambda..sub.max.sup.EtOH nm 240 (E.sub.1 cm.sup.1% =232), 265 (E.sub.1 
cm.sup.1% =181). 
Preparation No. 14 
Diphenylmethyl 
7-[(Z)-2-(1-t-Butoxycarbonylcyclobut-1-oxyimino)-2-(2-tritylaminothiazol-4 
-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate (VII-5') 
To a stirred solution of VI-5' (5.4 g, 5.5 mmoles) in acetone (108 mL) was 
added sodium iodide (2.48 g, 16.5 mmoles), and the mixture was stirred at 
room temperature for 3 hours. The reaction mixture was then filtered and 
evaporated to dryness, and the residue was dissolved in ethyl acetate (200 
mL). The solution was washed with water (100 mL), 10% w/v sodium 
thiosulfate (40 mL) and saturated sodium chloride (3.times.70 mL). After 
drying over magnesium sulfate, the solvent was removed under reduced 
pressure to give 5.38 g (91%) of VII-5' as a yellow powder. 
IR: .nu..sub.max.sup.KBr cm.sup.-1 1790, 1725, 1690, 1525. 
UV: .lambda..sub.max.sup.EtOH nm 240 (E.sub.1 cm.sup.1% =197), 265 (E.sub.1 
cm.sup.1% =154). 
NMR: .delta.CDCl.sbsp.3 ppm 1.45 (9H, s), 1.8-2.8 (6H, m), 3.52 (2H, ABq), 
4.25 (2H, s), 4.98 (1H, d, J=5.3 Hz), 5.87 (1H, dd, J=9 & 5.3 Hz), 6.70 
(1H, s), 6.88 (1H, s), 6.90 (1H, s), 7.28 (25H, s), 8.41 (1H, d, J=9 Hz). 
Preparation No. 15 
Diphenylmethyl 
3-chloromethyl-7-[(Z)-2-propargyloxyimino-2-(2-tritylaminothiazol-4-yl)ace 
tamido]-3-cephem-4-carboxylate [VI-7] 
Phosphorus pentachloride (910 mg) was added to a solution of 
(Z)-2-propargyloxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (IV-7) 
(1.7 g, 3.6 mmoles) in dichloromethane (30 mL). After stirring for 1 hour 
at room temperature the mixture was added in one portion to an ice-cooled 
solution of (V) (1.98 g, 4.4 mmoles) and N,O-bis(trimethylsilyl)acetamide 
(1.5 mL) in dichloromethane (30 mL). After stirring for 1 hour, the 
reaction mixture was poured into 10% aqueous NaHCO.sub.3 (300 mL) and 
extracted with ethyl acetate (300 mL). The extract was washed with water, 
dried over MgSO.sub.4 and evaporated under reduced pressure. The residue 
was chromatographed on a silica gel column. Elution with CHCl.sub.3 gave 
the title compound [VI-7] as an amorphous powder weighing 2.1 g (66%). 
NMR: .delta..sup.CDCl.sbsp.3 ppm 2.45 (1H, t, CH), 3.53 (2H, d, 
2-CH.sub.2), 4.37 (2H, s, --CH.sub.2 Cl), 4.83 (2H, d, O--CH.sub.2 
C.tbd.CH), 5.03 (1H, d, 6-H), 5.90 (1H, q, 7-H), 6.70 (1H, s, thiazole-H), 
6.92 (1H, s, benzhydryl-CH). 
Preparation No. 16 
Diphenylmethyl 
7-[(Z)-2-propargyloxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodom 
ethyl-3-cephem-4-carboxylate [VII-7] 
A mixture of diphenylmethyl 
3-chloromethyl-7-[(Z)-2-propargyloxyimino-2-(2-tritylaminothiazol-4-yl)ace 
tamido]-3-cephem-4-carboxylate (VI-7) (2.0 g, 2.3 mmoles) and NaI (1.04 g, 
6.9 mmoles) in acetone (40 mL) was stirred for 1 hour. The mixture was 
filtered and the filtrate was poured into water and extracted with ethyl 
acetate. The organic layer was washed with 5% aqueous Na.sub.2 S.sub.2 
O.sub.3, water and a saturated aqueous NaCl, successively. It was then 
dried over MgSO.sub.4 and evaporated to give 2.2 g (98%) of the title 
compound [VII-7]. 
NMR: .delta..sup.CDCL.sbsp.3 ppm 2.45 (1H, t, CH), 3.53 (2H, d, 
2-CH.sub.2), 4.25 (2H, s, CH.sub.2 I), 4.83 (2H, d, O--CH.sub.2), 5.0 (1H, 
d, 6-H), 5.80 (1H, q, 7-H), 6.70 (1H, s, thiazole-H), 6.92 (1H, s, 
benzhydryl-CH). 
Preparation No. 17 
Diphenylmethyl 
7-[(Z)-2-Methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-triphenylp 
hosphoniomethyl-3-cephem-4-carboxylate Iodide (VIII-1) 
A mixture of diphenylmethyl 
7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-iodomethyl 
-3-cephem-4-carboxylate (VII-1, 7.8 g, 8.4 mmoles) and triphenylphosphine 
(4.4 g, 16.8 mmoles) in benzene (160 ml) was stirred at room temperature 
for 1 hour. The resulting precipitate was collected by filtration to 
afford 8.0 g of the title compound VIII-1. The mother liquor was 
concentrated and the residue was triturated with n-hexane to yield an 
additional amount (1.3 g) of VIII-1. Total yield 9.3 g (93%). 
IR: .nu..sub.max.sup.KBr cm.sup.-1 1770, 1700, 1660, 1510. 
Preparation No. 18 
Diphenylmethyl 
3-(3-Chloro-1-propen-1-yl)-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4 
-yl)acetamido]-3-cephem-4carboxylate (IX-1) 
The phosphonium iodide VIII-1 (20 g, 17 mmoles) in chloroform (130 ml) was 
shaken with aqueous sodium hydroxide (10 ml 2N NaOH plus 70 ml water) and 
the chloroform layer was washed with water and dried over sodium sulfate. 
To the chloroform solution was added chloroacetaldehyde (2 g, 25 mmoles) 
and the mixture was stirred at room temperature for 1.5 hours. The 
reaction mixture was concentrated in vacuo and the residue was 
chromatographed on a silica gel column (200 g), eluted with toluene (1.5 
L) and toluene-ethyl acetate (10:1). The desired fractions were combined 
and concentrated to yield 10.3 g (71%) of the title compound IX-1. 
Rf: 0.34 (chloroform/ethyl acetate=20/1; silica gel plate) 
IR: .nu..sub.max.sup.KBr cm.sup.-1 1780, 1710, 1660, 1510. 
NMR: .delta..sup.CDCl.sbsp.3.sup.+D.sbsp.2.sup.O ppm 3.53 (2H, s, 2-H), 
3.96 (2H, d, 7 Hz, --CH.sub.2 Cl), 4.05 (3H, s, --OCH.sub.3), 5.03 (1H, d, 
4.5 Hz, 6-H), 5.87 (1H, d, 4.5 Hz, 7-H), 6.70 (1H, s, thiazole-H), 6.96 
(1H, s, --CHPh.sub.2), 7.30 (25H, s, phenyl-H). 
Preparation No. 19 
Diphenylmethyl 
3-(3-Iodo-1-propen-1-yl)-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-y 
l)acetamido]-3-cephem-4-carboxylate (X-1) 
A mixture of the chloropropenyl derivative IX-1 (1.9 g, 2.3 mmoles) and 
sodium iodide (1.0 g, 6.9 mmoles) in acetone (40 ml) was stirred at room 
temperature for 1 hour. The reaction mixture was concentrated in vacuo and 
the residue was dissolved in ethyl acetate (50 ml). The ethyl acetate 
solution was washed with 10% aqueous sodium thiosulfate (50 ml) and 
aqueous sodium chloride (50 ml), dried over sodium sulfate and 
concentrated to give 2.0 g (94%) of the title compound X-1. 
Rf: 0.34 (chloroform/ethyl acetate=20/1; silica gel plate). 
IR: .nu..sub.max.sup.KBr cm.sup.-1 1770, 1710, 1660, 1500. 
NMR: .delta..sup.CDCl.sbsp.3.sup.+D.sbsp.2.sup.O ppm 3.50 (2H, s, 2-H), 
3.84 (2H, d, 7 Hz, --HC.dbd.CH--CH.sub.2 I), 4.03 (3H, s, --OCH.sub.3), 
5.05 (1H, d, 4.5 Hz, 6-H), 5.90 (1H, d, 4.5 Hz, 7-H), 6.75 (1H, s, 
thiazole-H), 6.98 (1H, s, --CHPh.sub.2), 7.30 (25H, s, phenyl-H). 
Preparation No. 20 
Diphenylmethyl 
7-[(Z)-2-(2-t-Butoxycarbonyl-2-propoxyimino)-2-(2-tritylaminothiazol-4-yl) 
acetamido]-3-triphenylphosphoniomethyl-3-cephem-4-carboxylate Iodide 
(VIII-4') 
A mixture of diphenylmethyl 
7-[(Z)-2-(2-t-butoxycarbonyl-2-propoxyimino)-2-(2-tritylaminothiazol-4-yl) 
acetamido]-3-iodomethyl-3-cephem-4-carboxylate (VII-4', 5.3 g, 5 mmoles) 
and triphenylphosphine (2.6 g, 10 mmoles) in benzene (100 ml) was stirred 
at room temperature for 1 hour and diluted with diisopropyl ether. The 
resulting precipitate was collected by filtration to yield 6.0 g (91%) of 
the title compound VIII-4'. 
IR: .nu..sub.max.sup.KBr cm.sup.-1 1780, 1705, 1670, 1500. 
Preparation No. 21 
Diphenylmethyl 
7-[(Z)-2-(2-t-Butoxycarbonyl-2-propoxyimino)-2-(2-tritylaminothiazol-4-yl) 
acetamido]-3-(3-chloro-1-propen-1-yl)-3-cephem-4-carboxylate (IX-4') 
The phosphonium iodide (VIII-4', 5.7 g, 4.3 mmoles) in chloroform (100 ml) 
was treated with aqueous sodium hydroxide (0.34 g NaOH in 100 ml of water) 
at room temperature. The mixture was washed with water (150 ml) and dried 
over sodium sulfate. To the chloroform solution was added 
chloroacetaldehyde (0.5 g, 6.5 mmoles) and the mixture was stirred at room 
temperature for 1 hour. The reaction mixture was concentrated in vacuo and 
the residue was chromatographed on a silica gel column (120 g), eluted 
with benzene (500 ml) and benzene-ethyl acetate (10:1). The desired 
fractions were combined and concentrated to yield 2.6 g (61%) of IX-4'. 
Rf: 0.18 (benzene/ethyl acetate=20/1; silica gel plate). 
IR: .nu..sub.max.sup.KBr cm.sup.-1 1785, 1720, 1690, 1520. 
UV: .lambda..sub.max.sup.EtOH nm(.epsilon.) 240 (sh, 23400), 278 (16000). 
Preparation No. 22 
Diphenylmethyl 
7-[(Z)-2-(2-t-Butoxycarbonyl-2-propoxyimino)-2-(2-tritylaminothiazol-4-yl) 
acetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (X-4') 
A mixture of the chloropropenyl derivative IX-4' (2.4 g, 2.4 mmoles) and 
sodium iodide (1.1 g, 7.2 mmoles) in acetone (50 ml) was stirred at room 
temperature for 1 hour. The reaction mixture was concentrated in vacuo and 
the residue was dissolved in ethyl acetate (50 ml). The ethyl acetate 
solution was washed with 10% aqueous sodium thiosulfate (50 ml), water (50 
ml) and aqueous NaCl solution (50 ml), dried over sodium sulfate and 
concentrated to yield 2.4 g (93%) of X-4'. 
IR: .nu..sub.max.sup.KBr cm.sup.-1 1775, 1710, 1670, 1500. 
Preparation No. 23 
Diphenylmethyl 
7-[(Z)-2-(1-t-Butoxycarbonylcyclobut-1-oxyimino)-2-(2-tritylaminothiazol-4 
-yl)acetamido]-3-triphenylphosphoniomethyl-3-cephem-4-carboxylate Iodide 
(VIII-5') 
A mixture of diphenylmethyl 
7-[(Z)-2-(1-t-butoxycarbonylcyclobut-1-oxyimino)-2-(2-tritylaminothiazol-4 
-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate (VII-5', 6.4 g, 6 
mmoles) and triphenylphosphine (2.4 g, 9 mmoles) in benzene (120 ml) was 
stirred at room temperature for 2 hours and diluted with n-hexane (ca. 500 
ml). The resulting precipitate was collected by filtration to afford 7.5 g 
(94%) of the title compound VIII-B 5'. 
IR: .nu..sub.max.sup.KBr cm.sup.-1 1780, 1710, 1670, 1510. 
Preparation No. 24 
Diphenylmethyl 
7-[(Z)-2-(1-t-Butoxycarbonylcyclobut-1-oxyimino)-2-(2-tritylaminothiazol-4 
-yl)acetamido]-3-(3-chloro-1-propen-1-yl)-3-cephem-4-carboxylate (IX-5') 
The phosphonium iodide VIII-5' (7.4 g, 5.5 mmoles) in chloroform (150 ml) 
was treated with aqueous sodium hydroxide (0.44 g NaOH in 150 ml of water) 
at room temperature. The mixture was washed with water and dried over 
sodium sulfate. To the chloroform solution was added chloroacetaldehyde 
(863 mg, 11 mmoles) and the mixture was stirred at room temperature for 
1.5 hours. The reaction mixture was concentrated in vacuo and the residue 
was chromatographed on a silica gel column (150 g), eluted with benzene 
(500 ml) and benzene-ethyl acetate (10:1). The desired fractions were 
combined and concentrated to give 2.95 g (53%) of the title compound 
IX-5'. M.p. 22 110.degree. C. (dec.). 
Rf: 0.61 (chloroform/ethyl acetate=20/1; silica gel plate). 
IR: .nu..sub.max.sup.KBr cm.sup.-1 1780, 1720, 1685, 1520. 
UV: .lambda..sub.max.sup.EtOH nm(.epsilon.) 240 (24700), 296 (15200). 
Preparation No. 25 
Diphenylmethyl 
7-[(Z)-2-(1-t-Butoxycarbonylcyclobut-1-oxyimino)-2-(2-tritylaminothiazol-4 
-yl)acetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (X-5'). 
A mixture of the chloropropenyl derivative IX-5' (3.5 g, 3.5 mmoles) and 
sodium iodide (1.0 g, 7.0 mmoles) in acetone (70 ml) was stirred at room 
temperature for 1 hour. After evaporation of the solvent, the residue was 
dissolved in ethyl acetate (100 ml) and the solution was washed with 10% 
aqueous sodium thiosulfate (100 ml) and aqueous NaCl solution (100 ml), 
dried over sodium sulfate and concentrated under reduced pressure to 
afford 3.3 g (86%) of X-5'. 
IR: .nu..sub.max.sup.KBr cm.sup.-1 1780, 1720, 1680, 1520. 
UV: .lambda..sub.max.sup.EtOH nm(.epsilon.) 308 (17900).