CA1152513A - PROCESS FOR HALOGENATION OF .beta.-LACTAM COMPOUNDS - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Disclosed herein are novel thiazoline azetidinone vinyl halides are of the formula I

wherein X is Cl or Br;
R is hydrogen or a carboxylic acid protecting group; and R5 is (a) hydrogen, C1-C4 alkyl or halo(C1-C4)alkyl;
(b) a group R6 wherein R6 is phenyl which is either un-substituted or is substituted by 1 or 2 groups selected from the following: fluoro, chloro, bromo, iodo, nitro, cyano, C1-C4alkyl, C1-C4alkoxy, protected hydroxy, carbonyl, trifluoromethyl and methanesulfonamido;
(c) a group of the formula R6(O)mCH2 wherein m is 1 or 0 and R6 is as defined above;
(d) a group of the formula R6a CH2 wherein R6a is cyclohexadienyl, 2-furyl, 2-thienyl, ox 3-thienyl; or (e) a group of the formula COOR
wherein R is as defined above.
They are prepared by reacting compounds of the formula II

wherein R and R5 are as previously defined, with from about 1.0 to about 1.3 equivalents of a halogenating compound of the formula F?X2 IV

wherein Z is hydrogen, halo, C1-C4alkyl or C1-C4alkoxy, and X is Cl or Br.
The aforesaid novel thiazoline azetidinone vinyl halides are useful in the preparation of certain cephalosporin anti-biotics.

Description

L , il 52S13 X-5147A-Canada -1-Title PROCESS FOR HALOGENATION OF ~3-LACTAM COMPOUNDS
The present invention provides a process for preparing novel thiazoline aæetidinone vinyl halides useful in the preparation of certain cephem antibiotics.
An intensive research effort in the field of cephalosporin antibiotics has produced a number of clinically significant cephalosporin compounds. One of the more recent developments i~ this area has been the discovery of cephem compounds directly substituted with halogen at the C-3 position. A number of 3-halo-3-cephems have been described by Chauvette in U.S.
Patents Nos. 3,925,372, 4,064,343 and 3,962,227. These potent antibiotic compounds are prepared by halogena-tion of the corresponding 3-hydroxy-3-cephems.
U.S. Patent 4,079,181 describes the starting materials used in the process of this invention.
The novel thiazolineazetidinone vinyl halide compounds of the formula ~5 ~,CH3 ~:

2 5 0~t~ ~X
COOR

' -.::
.~
: - . . ~ , . , :; ;
':

~52S~L3 are prepared from the corresponding enols of theformula Rs N~
~ t ~3 II
0~
COOR
utilizing novel halogenating compounds of the general formula ¦ \0/

wherein 2 is hydrogen, halo, Cl-C4 alkyl or Cl C4 alkoxy, and X is Cl or Br, which halogenating com-pounds are the kinetically controlled products of the reaction of equivalent amounts of a triaryl phosphite of the formula ¦ \
and chlorine or bromine in a substantially 2nhydrous inert organ~c solvent.

:
, - :

~ _, . . . . . . ........... . . . . , . . ... ,,, ,, , _, .. .. .
~. :

-~L1~13 X-5147~ -3-Triaryl phosphites of the formula s l `o-,-o ~,,P V
wherein Z is hydrogen, halo, Cl-C~ alkyl or Cl-C4 alkoxy, have been found to react with equivalent amounts of chlorine or bromine in a substantially anhydrous inert organic solvent to provide, initially, kinetically controlled products having the empirical formula lS ~ \ O / ~ P~X~ IV
~-he,rein Z is as defined above and X is Cl or Br.
The term "halo" in the definition of Z
includes chloro, bromo or iodo. "Cl-C4 Alkyl"
includes methyl, ethyl, isopropyl, n-pro?yl, n-butyl, sec-butyl, tert-butyl and isobutyl. Repre-sentative "Cl-C4 alkoxy" groups are methoxy, ethoxy, sopropoxy, tert-butoxy and n-butoxy.
The dot (~) in the general formula used to represent the kinetically controlled products employed in the present processes is used simply to designate that equivalent amounts of halogen and triarylphosphite are combined chemically and in a way that can be distinsuished from that in the thermodynæmically stable derivatives which have been known in the art and which typically ha~e been drawn without the dot [e.g. (PhO)3PC12].

, . ..... .... ............. --.. -...... .............................. ..........................................................................
:. ~ - -, - ;
.: - - - , :
.: . - - . . . . . .
: . , ~ , ~ ~ , - ,.

~152~13 X-5147~ -4-The exact molecular form of the triaryl phosphite-halogen kinetic complexes described herein has not been established definitively; however, physical-chemical data do indicate that the kinetic product i~ one wherein the phosphorus center acquires some cationic character. Herein the terms "kinetic compound", "kinetic complex", "triarylphosphite-halogen complex (compound)", "kinetically controlled products and "kinetically controlled halogenating compounds" are used synonymously.
Suitable triarylphosphites for the prep-aration of the kinetically controlled halogenating compounds used in the present process include triphenyl phosphite, tri(p-methoxyphenyl)phosphite, tri(o-lS chlorophenyl)phosphite, tri(p-chlorophenyl)phosphite, tri(p-tolyl)phosphite, tri(o-tolyl)phosphite, tri(m-bromophenyl)phosphite, tri(p-bromophenyl)phosph~te, tri(p-iodophen~l)phos?hite, tri(p-n-propylphenyl)phosphite, tri(p-tert-butylphen~l)phosphite, tri(m-tolyl)phosphite, tri(p-isopropoxyphenyl)phosphite and the like. Triphenyl ; phosphite is preferre~, primarily because of commercial availability.
Any of a ~-ide variety of inert organic solvents may be em?loyed as the medium for the prep-aration of the kineticall~ controlled halogenatingcompounds and for the halogenation processes described below. By "inert organic solvent" is meant an organic solvent which, under the reaction conditions of the preparation, does not enter into any appreciable reaction with either the reactants or the procuc1:s.
Since the haloenatins co~pounds are suscep'ible to ..._ ~ = = ~?j????'j?????:??::?:??'j???jjj j:?~ = ~ ~ C== _ :,:,:',:.,,:.:1, -.:

- - ~ . `~, ~ '., . ' ' ~' , ' ' ~

1~ ~Z51~3 X-5147~ -5-reaction with protic compounds, such compounds, in-cluding water, alcohols, amines (other than tertiary), thiols, organic acids and othe:r such protic compounds should be excluded from the reaction medium.
A substantially anhydrous aprotic organic solvent is preferred. .he term '7substantially anhydrous"
as used in the present description means that, although anhydrous organic solvents are generally preferred, trace amounts of water, such as that often found in commercially available solvents, can be tolerated.
Although the kinetic products described herein will react with any water present in the solvent medium, additional amounts of reagents can easily be added to compensate for the loss due to hydrolysis. It is preferred that conventional laboratory techniques be employed to dry the solvents employed and to exclude moisture from the reaction mixtures.
Suitable solvents include hydrocarbons, both aliphatic and aromatic, including pentane, hexane, heptane, octane, cyclohexane, cyclopentane, benzene, toluene, o-, m- or p- xylene, mesitylene and the like;
ethers, cyclic and acyclic such as diethyl ether, butyl ethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxy-ethane and the like; carboxylic acid esters such as ethyl acetate, methylformate, methyl acetate, amyl acetate, n-butyl acetate, sec-butyl acetate, methyl propionate, methyl butyrate and the like; nitriles such as acetonitrile, propionitrile, butyronitrile and the like; halogenated hydrocarbons, both aromatic anà
aliphatic, such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane (ethylene .. . .
~ ; , --:
. -: ~ ~', . ' :' 115~

dichloride), 1,1,2-trichloroethane, 1,1-di~romo-2-chloroethane, 2-chloropropane, l-chlorobutane, chl~ro-ben2ene, fluorobenzene, o-, m-, or p- chl~ro~oluene, o-, m-, or p- bromotoluene, dic:hlorobenzene and the like; and nitro ~ompounds such as nitromethane, nitro-ethane, 1- or 2-nitropropane, nitrobenzene and the like.
The particular inert organic solvent employed as a medium for the preparation of the kinetical~y controlled triaryl phosphite-halogen compounds or as a medium for their use in the present halogenation processes is not critical, however, such solvent properties as polarity, melting or boiling point, and ease of isolation of halogenated products may be considered in selecting a most suitable solvent.
Preferred solvents for the preparation of the ~inetically controlled products and for the present processes described hereinbelow are hydrocarbons, especiall~ aroma'ic h~droc~rbons, and halo~enated hydrocarbons.
If a halogenatins compound derived from the kinetically controlled reaction of a triaryl phosphite and chlorine or bromine is allowed to stand in solution it converts or iscmerizes to the corresponding thermo-dynamicall~ stable compound at varying rates dependingon, among other things, the nature o' the triaryl phosphite, the solvent, the halogen and the solution temperature. EY.perimental data has also shown that the presence of an acid (HX) or an excess o_ triaryl phosphite will enhance the rate of conve-sion of the kinetic to the thermodynamic product.
, .. -............. ....................................... .............. ..... .......... .
'i '' .'.. ,'..... ........................
~, .- .. , .' ... ,. ' . ~ ' ~

- : : ~ . .
: - : : ;

f ~L~5~51~3 X-5147~ -7--~ sing 31p nuclear magnetic resonance spectro-scopy the half-life of the kinetically controlled product from the reaction of triphenyl phosphite and chlorine in methylene chloride at room temperature was determined to be about 8 hours. A half-life of about 39 hours was observed for the triphenyl phosphite-bromine kinetic complex under the same conditions. As mentioned above the observed half-life (rate of con~
version) for any given kinetic complex described herein can be affected by the solvent and by the presence of a hydrogen halide acid (HX) or excess triaryl phosphite.
Thus, for example, a shorter half-life will be observed where the solvent for the preparation of kinetic - complex has not been rigorously dried; the hydrogen 1~ halide acid produced from reaction of the kinetic complex with the moisture present in the solvent will enhance the rate of conversion to the stable form.
Table I presents a summary of several properties of the kinetically controlled product and the corresponding thermodynamically controlled product of the reaction of triphenyl phosphite and chlori~e.

---- .. --.--. . . ..
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o ~ m _~ m-- ~ ~ ~ c ~r~ l ~
E ~ --o _I u

3 ~ ~ ~
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. ~ ~ 5 t~ N ~ O`--a~ _ .~
, ~ ~u) ~ ~ a) 11 O ~ E ~o s~ ~ o ~ _ ~ O rl ~ :5 ~ +
r~ ~ o ` ~ C~ ` 3 .a ~
~ --I E~ ~ ~1 _ _ I _ + q~
rl ,~3 0 --I O ~ O ~
E ~ O ~1-- ~' 0 1: ,I S .Y
~: h _ r .C c: ~ ~ 0 ~5 ~ ~ ~ ` O ~q Q) ~ ~I) O . Q~
:~ ~ ~ _I _ cr~ C) S ~1 S ~ r~ ~ 3 a v 1~ N ~ 3 Cl. _~
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Ll ~ _ O ~ v --O ~ 4~ 3 a~ .a -- r~ 3 s~ O U O 3 0 O~
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r-t ~1 ~1 ~Lt ) U E
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3,t 3 rl _t O U~ 1 C ~ C
r-t r--l ~ O O ~ ~t ~1 0 O~ S ~D --co ~ _1 ~ ~t ~1 ~.1~ ~ _ ~ Ll~ * S r~ .C ~) ~~ co 3 ~ _ o *u~ ~J 3 o ~n D) --~ r-t U~ O rt ~ ~1 t) U 1~ _ _ N ~ 3 1 ~5 rt S~ ~ ~ E 3 ~ Ql _t Ell Q~ r t Q~ Q- O t~ O-- O C ~ ~ ~1rt C ~ E~ r~ r t ~ ~1 ~t ~~ a) S O ~ N ~
r t r t ~ ~J~.1 r-t ~ ~ _~ ~ Q) I r--~ 3 o u~
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~1~i2~
X-5147A ~9-The term kinetically controlled product is a term of art which when used in reference to reactions yielding two (~r m~re) products, re~ers to the product formed faster, regardless of its thermodynamic stability.
5 If such a reaction is stopped well before the products achieve thermodynamic equilibrium, the reaction is said to be kinetically controlled since more of the ~aster formed product will be present. In some cases, in-cluding the reaction of triaryl phosphites and chlorine or bromine, the rate of formation of the kinetic product and the rate of thermodynamic equilibrium is such that the kinetically controlled prod~ct can be prepared and utilized before any significant amount o~
the kinetically controlled product equilibrates or isomerizes to the thermodynamically stable product.
To maximize the production and stability of the kinetically controlled product, reaction conditions are selected so as to minimize the potential for thermodynamic equilibrium of the initial product of the reaction. Most simply conditions for kinetic control are achieved by lowerin~ the reaction tem-perature and the temperature of the kinetic product after it is formed, and by minimizing the time allowed for thermodynamic equilibrium, such as, by utilizing the kinetic product in a subsequent reaction shortly after it has been prepared.
Typically the reactants, a triaryl phos-phite and chlorine or bromine, are combined in a sukstantially anhydrous inert organic solvent at a temperature below about 30C. Although the kin-.

~.:
... . . . .

~ , , .
. . .

~ . .. . . ..

etically controlled products are formed at higher temperature, such conditions favor the formation of the thermodynamically contrclled products. Pref-erably the halogenating compounds are prepared at 5 temperatures at or below about 30C. Minimum re-action temperature are, of course, determined by the freezing point of the solvent employed for the preparation. Most preferred reaction temperatures are in the range of from about -70 to about 0C.
It has been found that the triaryl phos-phite itself reacts to some extent with its kinetic reaction product with chlorine or bromine, effectively increasing the rate of conversion to the corresponding thermodyna~ic product. It is preferred, therefore, but 1~ not reouired, that an excess of halogen be maintained in the reaction mixture during the formation of the halogenating compounds. This can be achieved prac-tically by adding the trizryl phosphite to a soluti~n of an eSuivalent amount of the halogen or by adding the halogen and the triaryl phosphite simultaneously $o a quantity of inert organic solvent at the desired te~?erature. The co-addition of reagents i5 conducted at such a rate that the color of the halogen persists in the reaction mixture until the last drop of t~iaryl;
2~ phos~hite discharges the color. Alternatively excess haiogen can be discharged using known halogen scavengers s~c;, as acetylenes, or olefins including alkenes, ~ienes, cycl~alXenes, or bicycloalkenes. ~ preferred scavenger is a C~ to C6 alkene, for example, ethylene, pro?ylene. ~utylene, or amylene.

:
.
.. , ~ . - , , . .
...

~152~1L3 X-5147~ -11-The kinetically controlled halogenating reagents used in the process of the present invention are stabilized in solution by l:he addition of about 10 to about 100 mole percent of a tertiary amine base having a PKb value of about 6 to about 10. If, for example, about 50 mole percent.of pyridine is added to a solution of the kinetically controlled product of the reaction of triphenyl phosphite and chlorine in methylene chloride, only trace amounts of the thermo-dynamic equilibrium product can be detected by 31pnmr, even after prolonged periods at room temperature.
The tertiary amine base can be added to a solution of - the freshly prepared chlorinating compound or, optionally, it can be employed in the reaction mixture of the triaryl phosphite and halogen to produce a stabilized solution of the kinetically controlled product of the present invention.
The novel thiazoline azetidinone vinyl halides of the formula ~ C~3 2; ~ X
. C002 are prepared by reacting a com~ound of the formula ,,,,,,, jjj ,;j, ,,,,,,,,jj,jjjjjjjjjjjjjjjjjj:jj jj:jjjjjjj.jjj.. j.. ,.-.. ,.. ,.. ,. j.j jj;

.
, ,~
; ~, ` ' ~52S13 X-~147A -12-s . I ~ ~H3 II
bH
I
COOR
with about 1.0 to about 1.3 equivalents of one of the aforedescribed halogenating compounds of the general formula 1~ \o.~ l~
wherein Z is hydrogen, halo, Cl-C4 alkyl or Cl-C4 alkoxy, and X is Cl or Br, in a substantially anhydrous inert organic solvent at a temperature below a~out 30DC., wherein R is a carboxy protecting group and R5 is (a) hydrogen, Cl-C4 alkyl or halo(Cl-C4 alkyl);
~b) a group R6 wherein R6 is phenyl or ~ ~
phenyi subst~ituted by 1 or.2 groups ~ :
-elected from the group consisting of fluoro~, chloro,:bromo, iodo, nitro, cyano, Cl-C4 alkyl, Cl-C4 alkoxy, protected hydroxy, carbamyl, trifluoro-methyl and~methanesulfonamido; ~ ~ :

.

.. . . . . . .. . . . . . ..

- ~ . . .
.
.:

1525~3 X-5147~ -13-(c) a group of the formula R6 () mCH2-. wherein m is 1 or 0 and R6 is as defined above;
(d) a group of the formula 6a 2 wherein R6a is cyclohexadienyl, 2-.
furyl, 2-thienyll or 3-thienyl; or (e) a group of the formula -COOR wherein R
is as defined above.
Both c~s and trans (halo with respect to carboxy) vinyl chloride products are produced in accordance with the present thiazoline enol halogenation process. The ratio of cls and trans products varies from substrate to substrate. Fox example, when RS is phenoxymethyl, X is chloro and R is 4-nitrobenzyl the ratio of cls and trans vinyl chloride products is about 1:1; however when R5 is benzyl and X is chloro the cis isomer is the major product. The isomers can be separated by conventional chromatographic proceduxes.
Exemplary of the R5 groups in accordance wlth the above definition are hydrogen, methyl, ethyl, sec-~:
2; butyl, t _ -butyl, chloromethyl, bromomethyl, 2 iodoethyl, 2-fluoropropyl, phenyl, 2-bromophenyl, 4 chlorophenyl, 4-methoxyphenyl, p-tolyl, o-tolylj

4-benzyioxyphenyl, 3-carbamylphenyl, 4-chloro-~-cyanophenyl, 4-methoxy-2-tolyl, 4-trifluoromethylphenyl,:
benzyl, 4-methoxybenzyl, 4-iodobenzyl, 3-methanesul-fonamidobenzyl, 3-nltrobenzyl, 3-chloro-4-benzyloxy-::

. . .

: ' : :' : ~ ~' ., :

.

11 5~S~

X-5147~ -14-benzyl, 2-ethylbenzyl, phenoxymethyl, 4-bromophenoxy-methyl, 2-methoxyphenoxymethyl, 4-tolyloxymethyl, 4-chlorophenoxymethyl, 4-carb~mylphenoxymethyl, 3-chloro-4-ethoxyphenoxymethyl and like groups. R~ can also be 2-furylmethyl, 2-thienylmethyl, 3-thienylmethyl, cyclohex~dienylmethyl, carbomethoxy, 4-nitro~enzy-loxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxy-carbonyl, benzhydryloxycarbonyl and the like.
The carboxylic acid protecting group (R) can be remo~red from the abo~-e-described thiazoline azeti-dinone vinyl halides by conventional procedures to provide the novel corresponding carboxylic acid derivatives of the formula 1~- R
.\
t7I I
rCH3 ~ X
COOH
which compounds and their alkaii metal ~alts exhibit acti~ity against~ a number of microorgani9m8, including B . Subti lis, Sarcina lutea, E. coli and Candida - 2~ albicans among others. Accordincly these compounds find utility.and a number of antibiotic applications.
For e~ample., they may be employed in aqueous composi-tions ir. concentrations ranging fro~ lOD to 1000 parts per million parts of solution, alone, or in - 30 conjunction with other antibiotic compounds to destroy and inhibit the srowth of harmful bacteria on, ~ .
. _ . . . _ . _ . . .. ..

~ ' ~

~lS~513 for example, medicinal and dental equipment and as bactericides in industrial applications. Alter-natively these compounds may be used alone or in com-bination with other antibiotics in any one of a number of pharmaceutical applications. These anti-biotics and their alkali metal salts may be employed for human or veterinary use in capsule form or as tablets, powders or liquid solutions, or as sus-pensions or elixirs. They may be administered orally, intravenously or intramuscularly.
It is preferred that the enol-halogenation process described above be conducted in the presence of a tertiary amine base. Typically from about 1.0 to about 1.2 equivalents and preferably about 1.0 equivalents of a tertiary amine base is employed for each equivalent of halogenating agent used in the enol-halogenation process. Preferred tertiary amine bases for this process are those having a PKb value of about 1 to about 10. More preferred are those tertiary amine bases having a PKb value of about 6 to about 10.
Exemplary of suitable tertiary amine bases for use in the present invention are trialkylamines such as trimethylamine, triethylamine, tri-n-propylamine, ethyldimethylamine, benzyldiethylamine and the like;
dialkylarylamines such as dimethylaniline, diethyl-aniline, N,N-diethyl-4-methylaniline, N-methyl-N-ethylaniline, N,N-dimethyltoluidine and the like;
cyclic and bicyclic tertiary amines such as pyridine, collidine, quinoline, isoquinoline, 2,6-lutidine, 2,4-lutidine, 1,5-diazabicyclo [4.3.0] nonene-5 (DBN), 1,5-diazabicyclo [5.4.0] undecene-5 (DBUI, triethylenediamine , : , ': - ' ~

;i13 x-5147A -16-and the like; and polymeric tertiary amine bases such as the copolymer formed from divinylbenzene and vinyl-pyridine described by Hallensleben and Wurm in An~ew.
Chem. Intl. Ed. Engl., 15, 163 (1976). Pyridine is a preferred tertiary amine base.
The term "protected hydroxy" has reference to the readily cleavable groups formed with an hydroxyl group such as the formyloxy group, the chloro-acetoxy group, the benzyloxy group, the-benzhydryIoxy group, the trityloxy group, the 4-nitrobenzyloxy group, the trimethylsilyloxy ~roup, the phenacyloxy group, the tert-butoxy group, the methoxymethoxy group, the tetrahycropyranyloxy sroup, and the like. Other - hydroxy pro~ecting groups, including those described by C. B. Reese in Protective Groups ln Organic Chemistry, supra, Cha?ter 3 shail be considered as ~ithin the term "protected hydroxy" as used herein.
The term "carboxylic acid protectins group"
has reference to the commonly used carboxylic acid protecting groups employed to block or protect the carboxylic acid functionality while reactions involving other functional sites of the compound ~re carried out.
Such carboxy protecting sroups are noted for their ease of cleavage by hydrolytic or by hydrogenolytic methods to the corresponding carboxylic acid. Examples of carboxylic acid ester protecting groups include methyl, tert-b~tyl, benzyl, 4-methoxybenzyl, C2-C~ alkanoyl-oxymethyl, 2-iodoethyl, 4-nitrobenzyl, diphenylmethyl (benzhydryI), phenacyl, 4-halophenacyl, dimethylall~
2,2,2-trichloroethyl, tri(Cl-C3 alkyl)silyl, succinimido-methyl and like ester- ~orming moieties. In addition to .. ,. =................ ...........

- .

- ~
. ' , .

X-5147A-Canada -17-ester protection o~ carboxy groups, such groups can also be prot~cted as the mixed anhydride, such as that formed with acetyl chloride, propionyl chloride, isobutyryl chloride and like acid chlorides in the presence of a tertiary amine base. Other known carboxy protecting groups such as those described by E. Haslam in Protective Groups in Organic Chemistry, supra, Chapter 5, shall be recognized as suitable. The nature of such ester forming groups is not critical.
In the foregoing definitions hydroxy, amino and carboxy protecting sroups are not exhaustively defined. The function of such groups is to protect the reactive functional groups during the present process and then to be removed at some later point in time without disrupting the remainder of the molecule. Many protecting groups are known in the art, and the use of other protecting groups not specifically referred to hereinabove are equally applicable to the substrates used in the processes of the present invention.
The triphenyl phosphite-halogen complexes (Z=H) are the preferred halogenating agents in the halogenation processes of this invention. The tri-phenyl phosphite-chlorine kinetic complex is most preferred for the present processes. Best results are seen when about l.l to about 1.2 equivalent of halo-genating reagent are used for each equivalent of enol substrate.

.

:
: . ,: : .

., : . -. , , ~ : .
.

`` 1152~i~3 The halogenation processes of this invention are preferably carried out at a temperature of about 0 or below~ A reaction temperature of about -10 or below is more preferred. Usually the present processes are not conducted at a temperature below about -70C.
Most preferred is a reaction temperature of about -10 to about -70C. It should be noted that the present chlorination processes can be conducted, although not advantageously, at temperatures above 30 and below -70. The freezing point of the reaction medium and substrate solubility are limiting factors at low temperatures while the ability of the thermodynamically uns,able halogenating agent is the main consideration in selection of higher reaction temperatures. Of course, if the halogenating agent has been stabilized in solution with a tertiary amine base as described hereinabove, the upper temperature range for the present process becomes even a less critical variable; higher temperatures could easily be employed without signifi-cant loss of the halogenating agent and without detrimentto the halogenation process itself.
Solvents which may be employed are the same as those described hereinabove for the preparation of the triaryl phosphite-halogen kinetic complexes.
Preferred solvents are aromatic hydrocarbons or halo-genated hydrocarbons.
The thiazolineazetidinone enol starting mate-ials of the formula ~.

,. .

__ __ -- _ _ _ ............ _................................ .

, ~ ~
:: : - : . . ..
' ~
.
- .: .: - : ~ , , , - ~.

1~5~3 X-5147~ -19-COOR
are prepared by mild ozonolysis of the correspondin~
compounds of the formula IR

¦ ~ VIII

~ \CH
COOR
described in ~.S. Patent 3,705,892 issued December 12, 2C 1972. The thiazoline azetidinone enols are described as intermediates to 3-hydroxycephems in V.S. Patent No.
4,079,181 issued March 14, 1978.
The thiazolineazetidinone vinyl halide products from the enol-halogenation processes of the present 2~ invention can be isolate~ and~purified by conventional~
laboratory techniques including for example extraction,: .
crystallization and recrystallization , trituration and chromatography.
The following examples are provided to furtner illustrate the pr~sent invention. It is not intended that this invention be limited in scope by ,: , . .. . . . .

~52S~3 X-5147A . 20-reason of any of these examples. In the following examples and preparations nuclear magnetic resonance spectra are abbreviated nmr. The chemical shifts are expressed in ~ values in parts per million (ppm) and coupling constants (J) are expressed in Hz (cycles per second).
Example 1 4'-Nitrobenzyl ~-[3-phenoxymethyl-7-oxo-2,6-diaza-4-thiabicyclo[3.2.0]hept-2-en-6-yl]-~-(1-chloroethyli-dene)acetate.
To a solution of chlorine in a mixture of 16 ml of carbon tetrachloride and 20 ml of methylene dichloride at -10C was added 3.14 ml l12 mmol) of triphenyl phosphite at such a rate that the temperature did not rise above -5C until a colorless endpoint was reached. After coolins the reaction mixture to 10C
2.54 gm (5.41 mmol) of 4`-nitrobenzyl -[3-phenoxy-methyl-7-oxo-2,6-diaza-4-thiabicyclo[3.2.0]hept-2-en-6-yl]-~ hydroxyethylidene~acetate was added. After most of the substrate had dissolved in the reaction mixture, 1~45 ml (13 mmol) of pyridine in 10 ml of methylene chloride was added over a 50 minute period.
Following the pyridine addition the reaction mixture 2; was removed from the coolins bath and stirred at room temperature for about 70 minutes. After this time the reaction mixture was diluted with ethyl acetate and washed successively with two 50 ml-portions of lN. HCl, 50 ml of saturated sodium bicar~onate solution, and 100 ml of saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and ' ~ :
' ' ', ': ','. ~ :

..
' ~

ij ~15:~5~3 evaporated in vacuo to dryness to provide abcut 1.4 grams of the title product as a mixture of the cis and trans chloro isomers. The isomers were separated by hroma-tography over 40 ~rams of silica gel using 10~ ethyl acetate/toluene as the eluent.
First isomer off column: nmr tCDC13) ~ 2.63 (s, 3), 4.65 (ABq, 2), 5.2 (s, 2), 6.01 (s, 2, ~-lactam ~), and 6.7-8.3 (ArH).
Second isomer off column: nmr (CDC13) ~
2.16 (s, 3), 4.93 (s, 2), 5.33 ~s, 2~, 5.87 (s, 1, J=4 ~z), 6.1 (bd, 1, J=4 Hz) and 6.7-8.3 (ArH).
Examples 2-10 Following the experimental procedure described in Example 1 the following conversions are carried out employing chlorinating compounds derived from the indicated triaryl phosphite and chlorine.
Example 2. 4'-~ethoxybenzyl ~-13-benzyl-7-oxo-2,6-diaza-4-thiabicyclol3.2.0]hept-2-en-6 yl]~
chloroethylidene)acetate from 4'-methoxybenzyl -[3-benzyl-7-oxo-2,6-diaza-4-thiabicyclo[3.2.0]hept~2-en-6-yl]-~-(1-hydroxyethylidene3acetate; triphenyl phosphite.
Example 3. 4'-Nitrober.zyl ~-,13-methyl-7-ox~-2,6-diaza-2~ 4-thiabicyclo~3.2.0]he~t-2-en-6-yl3-~-~1-chloroethyl-idene)acetate from 4'-nitrobenzyl ~-~3-methyl-7-~xo-2,6-diaza-4-thiabicyclo~3.2.0]hept-2-en-6-yl]-~-~l-hydroxyethylidene)acetate; tri(4-methoxyphenyl) phosphite.

. . . . _ .............................................. .~ , - ~ . ~ . . .

, ~

( : . .

X-5147~ -22-Example 4. tert-Butyl Q- [3-phenyl-7-oxo-2,6-diaza-4-thiabicyclo[3.2.0]hept-2-en-6-yl]-~-(l-chloroethyl-idene)acetate from tert-butyl ~-13-phenyl-7-oxo-2,6-diaza-4-thiabicyclo~3.2.0]hept-~-en-6-yl]--(l-hydroxyethylidene)acetate; tri(o-tolyl) phosphite.
Example 5. Benzhydryl Q- 13-(4-chlorophenyl)-7-oxo-2,6-diaza-4-thiabicyclo[3.2.0]hept-2-en-6-yl]-Q- (l-chloroethylidene)acetate from benzhydryl ~-[3-(4-chlorophenyl)-7-oxo-2,6-diaza-4-thiabicyclo-[3.2.0]hept-2-en-6-yl]-Q-(l-hydroxyethylidene)acetate;
triphenyl phosphite.
Exam?le 6. 2'-Iodoethyl c-[3-(4-tolyl)-7-oxo-2,6-diaza-4-thiabicyclol3.2.0]hept-2-en-6-yl] -Q- (l-chloro-eth~lidene)acetate from 2'-iodoethyl Q- [3-(4-tolyl)-7-oxo-2,6-diaza-4-thiabic~clo[3.2.0]hept-2-en-6-yl~-~-(l-hydroxyethylidene)acetate; tri(4-tert-butoxyphenyl) phosphite.
Exa~ple 7. 4'-~itrobenzyl Q- [3-cyclohexadienylmethyl-7-oxo-2,6-diaza-4-thiabicyclo[3.2.0]hept-2-en-6-~'1] -Q- tl-chloroethylidene)aceta~e from 4'-nitrobenzyl Q- [ 3-cyclohexadienylmethyl-7-oxo-2,6-diaza-4-thia-bicyclo[3.2.0]hept-2-en-6-yl]--(l-hydroxyethylidene)-ace_ate; triphenyl phosphite.
Exæ-.?'e 8. Benzyl Q- 13-ethyl-7-oxo-2,6-diaza-4-thi2~icyclo[3.2.0]hept-2-en-6-yl] -Q- (l-chloroethyl-ide..e)acetate from benz~l c-[3-ethyl-7-oxo-2,6-di2z2-4-thiabicyclo[3.2.0]hept-2-en-6-yl] -Q- (1-hyc-oxyethylidene)acet2te; triphenylphosphite.

...................... ii.. i. iii .iiii - iiiiiiiiii iiiiiiiiiiiiii i.. iiiiiiii-riii.. ii .. - . .. i.. i.

.
:.

1~525~3 Example 9. Phenacyl G- [ 3-(2-carbomethoxy)-7-oxo-2,6-diaza-4-thiabicyclo[3.2.0]hept-2-en-6-yl]-~chloroethylidene)acetate from phenacyl ~-[3-(2-carbomethoxy)-~-oxo-2,6-diaza-4-thiabicyclol3.2.0]-hept-2-en-6-yl]--(1-hydroxyethylidene)acetate; tri-phenyl phosph~te.
Examplé 10. 4'-~itrobenzyl ~-[3-(2-thienylmethyl)-7-oxo-2,6-diaza-4-thiabicyclol3.2.0]hept-2-4n-6-, yl]-~-(l-chloroethylidene)acetate from 4'-nitrobenzyl-a-[3-(2-thienylmethyl)-7-oxo-2,6-diaza-4-thiabicyclo-l3.2.0]hept-2-en-6-yl]--(1-hydroxyethylidene)acetate;
triphenyl phosphite.
~xample 1' 15 Q- l3-Phenoxymethyl-7-oxo-2,6-diaza-4-thiabicyclo-[3 ~ O]hept-2-en-6-yl]-a-(1-bromoethylidene)acetic -acid.
(A) Under anhydrous conditions, 1.1 ml of bromine was added to a solution of 0.5 ml of pyridine in 70 ml of methylene chloride at -20C. Triphenyl phosphite (5.7 ml) was added to, the reaction mixture to a colorless end point. To the resulting solution was added 7.04 gm of 4'-nitrobenzyl -l3-PhenoxYmethYl-7 oxo-2,6-diaza-4-thiabicyclo[3.2.0]he?t-2-en-6-yl]--(1-hydroxyethylidene)acetate. Over a 30-minute period, a solution of 1.12 ml of py~idine in 15 ml of methylene chloride was added. The reaction mixture was allowed to warm to 0C and stirred for about 15 hours. The mixture was then diluted with ethyl acetate and washed successively with 1~. HCl and saturated sodium bicarbonate ,............... ................ ~ .. ;... . ............................... ..........
' .

.. ~ ~' ` : . , 25~3 solution. The ethyl acetate solution was then dried over anhydrous magnesium sulfate and concentrated ln vacuo. Chromatography of the crude product over silica gel using a 15 percent ethyl acetate/toluene eluent provided 3.2 gm of the titl~d product as a mixture of the cis and trans isomers.
nmr (CDC13) ~ 2.66 (s, 3, CH3 trans to COO~); 2.80 (s, 3, CH3 cis to COOH); 4.58 (s, 2, C6H5OCH2); 5.35 (s, 2, ester CH2); 6.06 (m, 2, ~-lactam H) and 6.8-8.4 (ArH).
(B) A slurry of 3 gm of a 5% palladium/-carbon catalyst in ethanol was hydrogenated at 60 psi for 1/2 hour. A solution of the product from Paragraph A above in a l l-methanol tetrahydrofuran mixture was added-to the hydroge~ated catalyst. ~he mixture was then hydrogenated at 60 psi for 1 1/2 hours. The catalyst was filtered and the filtrate concentrated ln vacuo to a red oil. This product was dissolved in ethyl acetate and extracted with aqueous sodium ~i-carbonate. The aqueous layer was separated and afterthe pH was adjusted to 6.8, it was extracted with ethyl acetate. The pH of the aqueous layer was then adjusted to 2.0 after which the aqueous layer was extracted with chloroform. Evaporation in vacuo of the chloroform extract gave 1.4 gm of the titled product.
nmr (CDC13) ~ 2.3 (s, 3, CH3 tra~s to COOH), 2.83 (s, 3, CH3 cis to COOH), 5.0 (s, 2, C6H~OCH2), 6.04 (m, 2, p,-lactam ~) and 6.8-7.4 (ArH).

'' ' : . ' ~J ~ 13 Example 12 -[2-Benzyl-7-oxo-2,6-diaza-4-thiabicyclol3.2.0~-hept-2-en-6-yl~ bromoethylidene)acetic acid.
(A) A 250 ml 3-neck round-bottom flask equipped with a magnetic stirrer, serum cap, claisen head, gas inlet and thermometer was flame dried under a nitrogen current. The flask was charged with dry methylene chloride (175 ml) and dry pyridine (3.1 ml, 10 38.5 mmol) and cooled to -23C. Bromine (2.0 ml, 38.5 mmol) was added, and the color was discharged by the dropwise addition o~ triphenyl phosphite (10.1 ml, 38.5 mmol). The substrate, 4'-nitrobenzyl ~-13-benzYl-7-oxo-2,6-diaza-4-thiabicyclo13.2.0]hept-2-en-6-yl] -G-(l-hydroxyethylidene)acetate (35 mmol), was added in one portion. After one hour at -20C the reaction mixture was warmed to 0C and stirred for 24 hours.
The mixture was then extracted sequentially with dilute HCl, saturated sodium bicarbonate solution, and brine.
The organic phase was dried (magnesium sulfate) and concentrated ln vacuo. A portion of the -esidual oil was chromatographed on a short silica gel column to afford 1.98 grams of the corresponding l-bromoethylidene acetic acid 4'-nitrobenzyl este_ as a mixture af 2; isomers.
nmr (CHC13) ~ 2.15 (s), 2.77 (s), 3.75 (br, s), 3.87 (br~ s~, 5.28 (s), 5.78 (d, J=3), 5.96 (s) and 6.00 (d; J=3).
tB) A 250 ml pressure bottle was charged witA
30 2.0 gm of 5~ palladium on carbon and 20 ml of ethanol.
TAe suspension was shaken under hydrogen pressure ~60 ........ . . . .. .. j ., j .. j . j .. j.. , ... . . . , ,,,,,, ~ , :; ` : . ~ ..

S~3 psi) for 1/2 hour. The product from Paragraph A
immediate above was dissolved in a THF~methanol-70:10 (80 ml) and added to the pre-reduced catalyst suspension.
After shaking under hydrogen pressure (60 psi) for one hour, the cAtalyst was removed by filtration. The filtrate was concentrated to an ~il and the partitioned between`ethyl acetate and saturated sodium bicarbonate solution. The aqueous phase was adjusted to p~ 6.8 and extracted with ethyl acetate. The aqueous phase was then brought to pH 2.2, and the product crystallized.
The crystals were collected on a filter, washed with water, and dried in vacuo to yield 814 mg (56 percent) of the title product.
ir (KBr) 1760, 1705, 159i, 1358, 1220, 1028 and 695 cm 1.
nmr (CDC13) ~ 2.00 (s), 2.62 (s), 3.81 (s), 3.83 (s), 5.87 (d, J=3), 5.96 (s), 6.05 (d, J=3) and 7.20 (s) .
Example 13 ~
~-13-Phenoxymethyl-7-oxo-2,6-diaza-4-thiabicyclo-[3.2.0]hept-2-en-~-yl]~ chloroethylidene)acetic .
acid.
(A) A 250 ml 3-neck round-bottom lask equipped with a magnetic stirrer, serum cap, stopper, claisen head, gas inlet tube and thermometer W25 flame dried under a nitrogen current and cooled to room temperature. Chlorine gas was bubbled through dry methylene chloride (100 ml) at -25~C and the yellow color was titrated to a colorless endpoint with tri-, phenyl phosphite (7.2 ml, 25 ~ol). The substrate, ~'-......................................................................................... :........................... .....

.
.. . .

, - llS;;~:5~ 3 nitrobenzyl ~-~3-phenoxymethyl-7-oxo-2,6-diaza-4-thiabicycloL3.2.0]hept-2-en-6 yl]--(l-hydroxyethyl-idene)acetate (9.39 gm, 20 mmol), was added in one portion with S ml of dry methylene chloride to aid the transfer. ~he reaction mixture was warmed to -10C, and dry pyridine (2.02 ml, 25 mmol) was added dropwise over 1/2 hour in dry methylene chloride. The system was warmed to 0 over 35 minutes and then poured into 1:1 (v/v) of .5N HCl:saturated sodium chloride. The aqueous phase was washed with methylene chloride and the combined organic extracts were dried ~magnesium sulfate) and concentrated to afford a mixture of the desired 4'-nitrobenzyl ester of the title product and triphenyl phosphite.
(B) The unpurified vinyl chloride 4'-nitrobenzyl ester from Paragraph A was hydrogenated at 60 psi in a Parr apparatus with 9 gm of 5% palladium on charcoal ~pre-reduced) in 200 ml of l:l-methanol:-ethanol. The catalyst W25 filtered, and the resulting clear solution was concentrated to an orange oil. This oil was taken up in ethyl acetate and layered with a saturated sodium bicarbonate solution. The aqueous phase was extracted with a second portion of ethyl acetate. The pH of the aqueous phase was adjusted to 2~ 5.8 with concentrated HCl, and the aqueous phase was then extracted with ethyl acetate. The aqueous phase was~carefully acidified to pH 2 at which point the product oiled from solution. The mixture was parti-tioned between methylene chloride and its aqueous phase. The organic phase was separated, dried (mag-,, ~

, ~' ' , '' 3lS2:5~L3 nesium sulfate), and concentrated in vacuo. The resulting yellow oil was crystallized from ethyl acetate to yield the titled product~
ir (KBr~ 1770, 1700, 1620, 1602, 149~, 1243, 1010,

5 and 750 cm nmr (D~lSO-d6) ~ 2.00 (s, 3), 5.02 (br, s, 2), 5.95 (d, lj J=2 Hz), 6.16 (br, d, 1, J=2), 6.7-7.4 (m, 5).
Mass spectrum (EI) P m/e = 352, 3~4.
Anal calcd r C15H13~2O4SC:
C, 51.07; H, 3.71; N, 7.94; S, 9.09; Cl, 10.05.
Pound: C, ~0.85; H, 3.69; N, 7.92; S, 8.86; Cl, 10.28.
Example 14~
a-[3-Benzyl-7-oxo-2,6-diaza-4-thiabicyclol3.2.0]hept-15 2-en-6-yll-Q-(l-chloroethylidene)acetic acid.
(A) A 250 ml three-neck round-bottom flask equipped with a magnetic stirrer, claisen-head, ther-mometer, gas inlet stopper, and serum cap was flame dried under a nitrogen current and then cooled to room 20 temperature. Chlorine gas was bubbled through dry methylene chloride (50 ml) at .20~C, and the yellow color was titrated with tri?henyl phosphite (3.7 ml, 13 mmol). The substrate, 4'-nitrobenzyl ~- [3-benzyl-7-oxo-2,6-diaza-4-thiabicyclo[3.2.0]hept-2-en-6-yl]--2~ (l-hydroxyethylidene)acetate (4.54 gm, 10 mmol) was added with methylene chloride (5 ml) to aid the transfer.
After warming to -10C, dry pyridine (1.1 ml, 13 mmol) was added in me~hylene chloride (10 ml) over the course of 40 minutes. ~he system was warmed to 0~ over 20 30 minutes, and then it was extr~cted with .lN HCl. The ....... ... ........ . ............................... . . ;. ~. ~,.
..... ......... . .
, . ~...... ...... ................. ::: -::.:

.: , .. . .

organic phase was dried (magnesium sulfate) and con-centrated in vacuo to give an orange oil. ~his crude material, shown by nmr and thin~layer chromatographic analysis to contain a mixture of the desired product and triphenyl phosphate, was used directly in the ester removal described in parasraph B below.
nmr ~CDC13) ~ 1.97 (s, 3); 3.85 (s, 2); 5.25 (s, 2); 5.80 (d, 1, J=2 Hz); 5.98 (br, d, 1, J=2 HZ).
(B) A Parr apparatus pressure bottle was charged with methanol (40 ml) and 5% palladium on charcoal (4.0 gm). The system was shaken to equili-brium with hydrogen at 60 psi for one hour. The crude vinyl chloride 4'-nitrober;zyl ester from Paragraph A
immediately above was added to the catalyst slurry, and the system was hydrogenated at 60 p~i for 1 1/2 hours.
The catalyst was filte_ed, and the filtrate was con-centrated in vacuo. The resulting bright yellow oil was dissolved in eth~l acetate and layered with water.
After adjusting pH to 6.6 with 1~. sodium hydroxide solution, the organic phase was separated. The pH was adjusted to 2, and a yellow s~lid precipitated. The solid was collected on a filter, washed with water, and dried in ~acuo to afford 2.4 gm (71~) of the cis-isomer of the titled acid.
i ir (~Br) 3020, 1760j 1722, 1498, 1459, 1362, 1225, 1148, 1071, and 1027 cm 1.
nmr (~ SO-d6~ ~ 1.87 (s, 3); 3.90 (s, 2); 5.93 (d, 1, J=2 Hz), 6.11 (br, d, 1, J=2 ~z) and 7.24 (s, S).

::~

-: .: :: ,:
: , , . - ,. ~, .. -

Claims (20)

X-5147A-Canada -30-The embodiments of the invention for which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a compound of the formula I

which comprises reacting a compound of the formula II

with about 1.0 to about 1.3 equivalents of a halogenat-ing compound of the formula P?x2 IV

which is the kinetically controlled product of the reaction, in a substantially anhy-drous inert organic solvent, of equivalent amounts of a triaryl phosphite of the formula X-5147A-Canada -31- P V

and chlorine or bromine, in a substantially anhydrous inert organic solvent at a temperature below about 30°C, wherein in the above formulas:
X is Cl or Br;
z is hydrogen, halo, C1-C4 alkyl or C1-C4 alkoxy;
R is hydrogen or carboxylic acid protecting group;
R5 is (a) hydrogen, C1-C4 alkyl or halo(C1-C4 alkyl);
(b) a group R6 wherein R6 is phenyl or phenyl substituted by 1 or 2 groups selected from the group consisting of fluoro, chloro, bromo, iodo, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, protected hydroxy, carbamyl, tri-fluoromethyl and methanesulfonamido;
(c) a group of the formula R6(O)mCH2-wherein m is 1 or 0 and R6 is as defined above;
(d) a group of the formula R6aCH2-X-5147A-Canada -32-wherein R6a is cyclohexadienyl, 2-furyl, 2-thienyl, or 3-thienyl; or (e) a group of the formula -COOR wherein R
is as defined above.

2. The process of claim 1 for preparing a compound of the formula IX

which comprises reacting a compound of the formula II

wherein R and R5 are as defined in claim 1, with a halogenating compound of formula IV as defined in claim 1 wherein Z is hydrogen and X2 is Cl2.

3. The process of claim 1 wherein Z is hydrogen, methoxy, methyl or chloro.

4. The process of claim 1, 2 or 3 wherein Z
is hydrogen.

5. The process of claim 1 wherein X is Cl.

X-5147A-Canada -33-

6. The process of claim 1 wherein X is Br.

7. The process of claim 1 or 2 wherein R1 is hydrogen, X is Cl and Z is hydrogen.

8. The process of claim 1 or 2 wherein X is Cl and Z is hydrogen.

9. The process of claim 1 wherein the reaction is carried out in the presence of about 1.0 to about 1.2 equivalents of a tertiary amine base per equivalent of halogenating agent.

10. The process of claim 9 wherein the tertiary amine base has a pKb value of about 6 to about 10.

11. The process of claim 10 wherein the tertiary amine base is pyridine.

12. The process of claim 1 or 2 wherein the temperature is from about 0° to about -70°C.

13. The process of claim 1 or 2 wherein the inert organic solvent is an aromatic hydrocarbon or a halogenated hydrocarbon.

14. The process of claim 1 or 2 wherein the halogenating compound employed is stabilized with a tertiary amine base.

15. The process of claim 2 wherein the triphenyl phosphite-chlorine complex is of the formula P?Cl2 III

which (a) has a 31P nuclear magnetic resonance signal in methylene chloride at -3.7 X-5147A-Canada -34-ppm relative to that of phosphoric acid;
(b) has in methylene chloride an infrared spectrum which has the following characteristic absorptions: 1120-1190 (very strong), 1070 (very strong), 1035 (strong), 1010 (very strong), 990 (very strong), 640 (medium) 625 (medium), 580 (weak), 510 (strong) and 465 (weak);
(c) reacts with water to give HCl and triphenyl phosphate; and (d) reacts with n-butanol to give HCl, n-butyl chloride, and triphenyl phosphate.

16. The process of claim 1 wherein R5 is benzyl or phenoxymethyl.

17. A compound of the formula I

when prepared by the process of claim 1, or by an obvious chemical equivalent thereof, wherein X is Cl or Br;
R is hydrogen or a carboxylic acid protecting group; and R5 is (a) hydrogen, C1-C4 alkyl or halo(C1-C4 alkyl);

X-5147A-Canada -35-(b) a group R6 wherein R6 is phenyl or phenyl substituted by 1 or 2 groups selected from the group consisting of fluoro, chloro, bromo, iodo, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, protected hydroxy, carbamyl, trifluoro-methyl and methanesulfonamido;
(c) a group of the formula R6(O)mCH2-wherein m is 1 or 0 and R6 is as defined above;
d) a group of the formula R6aCH2-wherein R6a is cyclohexadienyl, 2-furyl, 2-thienyl, or 3-thienyl; or (e) a group of the formula -COOR wherein R
is as defined above.

18. The compound of claim 17 wherein X is chloro, when produced by the process of claim 5 or by an obvious chemical equivalent thereof.

19. The compound of claim 17 wherein X is bromo, when prepared by the process of claim 6 or by an obvious chemical equivalent thereof.

20. The compound of claim 17 wherein R5 is benzyl or phenoxymethyl, when prepared by the process of claim 16 or by an obvious chemical equivalent thereof.