Note: Descriptions are shown in the official language in which they were submitted.
~ ~5-~39
X-5055-P -1-
Allylic Chlorination Process
and Compounds Prepared Thereby
This invention concerns a process for the
preparation of novel thiazolinoazetidinone compounds
which are intermediates of the cephalosporin series.
Thiazolinoazetidinones are now well known as
intermediates for preparing cephalosporins. A variety
of synthetic routes have been published. In general,
all of them proceed by first opening the 5-membered
ring of a penicillin to form a thiazolinoazetidinone.
- Modifications are made to the group on the nitrogen
atom of the azetidinone ring ~whether fused or not) and
the resulting compound is re-cyclized to form the
desired cephalosporin. The following publications are
representative of those which describe such processes:
Belgian Patent 864,321, Belgian Patent 832 t 174, Belgian
Patent 862,793, Belgian Patent 863,700, Belgian Patent
~ 863,998, V.S. Patent 4,079,181, U.S. Patent 4,013,653,
: 20 U.S. Patent 4,077,970, British Patents 1,472,863
-- through 1,472,870, and U.S. Patent 4,018,776.
Some previous publications show or suggest
halogenation of the butenoate group on a thiazolino-
;~ azetidinone. Particular attention is given to Belgian
25 Patent 862,793, where such a halogenation is performed
on a 3-methyl-2-but-3-enoate group. This patent teaches
generally that bromine, chlorine or iodine atoms may be
inserted with the use of fr~e radical initiators.
N-Bromosuccinimide in the presence of azobisisobutyro-
nitrile is emphasized in the patent, although sul~uryl
chloride and molecular chlorine are also used. The
patent shows that the oxazolinoazetidinones which are
,~'' .' - ' .
. .
X-5055-P -2-
its starting compounds frequently have the oxazoline
ring opened by the halogenation step, and that the
methylbutenoate group is isomerized so that a mixture
of products is obtained.
Belgian Patent 864,321 shows the chlorination
of a similar group on an o~azolinoazetidinone by
molecular chlorine and strong light. However, a
second chlorine atom is also added on the 3-carbon
atom.
U.S. Patent ~,077,970 and British Patents
1,472,863 through 1,472,870 suggest the halog~nation of
a methylbutenoate group on a thiazolinoazetidinone.
However, the halogenations which these patents show
cause the isomerization of the 3-butenoate group to a
2-butenoate group.
The invention described here provides a process
for preparing novel thiazolinoazetidinone compounds
prepared by an allylic chlorination process which
inserts a chlorine atom on the saturated methyl group
of a 3-methyl-2-but-3-enoate group on the ring nitrogen
atom of a thiazolinoazetidinone ring. The chloro-
substituted thiazolino compounds which are prepared by
the use of this process are novel intermediates which
are useful in preparing antibiotic compounds of the
cephalosporin series. The allylic chlorination of this
invention proceeds in economical yields at moderate
temperatures. The chlorinatir,g agents are molecular
chlorine or t-butyl hypochlorite in any of a range of
organic solvents, of which esters are preferred.
Specifically, the invention provides a process
for preparing novel compounds which were not accessible
prior to this invention. The novel compounds are of
the formula
,., ;
~ X-5055 -3-
,
;, ~
ÇH2CI
~ t /~CHz
ÇH
COzR~
wherein
: R is hydrogen,
methoxy,
~ Cl-C2 alkoxycarbonyl,
.~ Cl-C8 alkyl,
`:~ Cl-C8 alkyl monosubstituted with protected
: 15 hydroxy, Cl-C3 alkoxy or cyano,
C2-C8 alkenyl,
` C2-C8 alkenyl monosubstituted with protected
hydroxy, Cl-C3 alkoxy or cyano,
C3-C8 cycloalkyl,
-:, C3-C8 cycloalkyl substituted with protected
.~ 20
- hydroxy, Cl-C3 alkoxy or cyano,
, ~
-(CH2) -Y-(CH2) -
' 25
-ÇH- OR
RZ = ~ ~3
R ~ - ~/~~~ ;
. .
:,
,'.'~
.
. ", . . .
. . .
.. .
X-5055 ~4~
R2 is hydrogen, protected hydroxy, chloro, bromo,
Cl-C3 alkyl, Cl-C3 alkoxy, nitro or cyano;
Y is oxygen or a carbon-carbon bond;
R3 is protected hydroxy, C1-C4 alkyl, or pro-
tected amino;m is 0-2;
n is 0-2;
;~Rl is a carboxylic ~cid pxotecting group; provided
that the l- and 5-position C-H bonds in the thiazolino-
azetidinone are in the a-position.
-The novel compounds above are made hy a
;process which comprises reacting a compound of the
formula
~ : : I ~ CH2 II
C02R
' 20
,;wherein the l- and 5-positions are ln the configuration
described above, with molecular chlorine or t-butyl
hypochlorite in the presence of a C1-C3 carboxylic
acid; provided that when molecular chlorine is used, a
hydrochloric acid scavenger is also present.
The ring system which forms the nuclei of the
compounds discussed herein will be named according to
Chemical Abstracts nomenclature. The ring system is
numbered as follows.
.
"'
~, ., . ~
,
:' .,
.
",
.
:
~ X-5055 -5-
',' I
~s ~2
5 1
0~ _
Thus, the fused-ring nucleus of a compound of this
invention would be called a 2-thia-4,7-diazabicyclo-
~3.2.0]hept-3-en-6-one.
0 It must be noted that the thiazolinoazeti-
dinones of this invention, and their respective starting
compounds, have the Cl-H and C5-H bonds in the a con-
figuration. The thiazolinoazetidinone ring system is
shown graphically as follows.
The various terms used in the descriptions
above are used as they normally are in organic chem-
istry. For example, the term Cl-C2 alkoxycarbonyl
includes methoxycarbonyl and ethoxycarbonyl.
The terms Cl-C8 alkyl, substituted Cl-C8
alkyl, C2-C8 alkenyl, substituted C2-C8 alkenyl,
Cl-C3 alkoxy~ Cl-C3 alkyl, Cl-C4 alkyl, C4-C6 t-alkyl
and C5-C8 t-alkenyl include such gr~ups as methyl,
ethyl, isopropyl, hexyl, 2-ethylbutyl, neopentyl,
- octyl, 3-methylheptyl, 4-octyl, t-butyl, 3-propyl-3-
,:
',':'
'''
,,
r
,,, ' I `
.
33~
.~ X-5055 -6-
'~
pentyl, formyloxymethyl, 3-benzyloxypentyl, 8-t-
butoxyoctyl, 2-methoxyethyl, 6-propoxyhexyl, 4-
ethoxyoctyl, 3-cyanopropyl, cyanomethyl, 7-cyano-
heptyl, vinyl, allyl, 5-hexenyl, l,l-dimethylallyl,
4-heptenyl, 2-octenyl, l-chloroacetoxyallyl, 5-
~ormyloxy-3-pentenyl, 8-benzyloxy-4-octenyl, 2-
.~ methoxyvinyl, 3-propoxyallyl, 8-ethoxy-2,6-octadienyl,
2-cyanoallyl, 3-cyano-2-pentenyl, 8-cyano-4-octenyl,
. ethyl, methoxy, isopropoxy, 2-butyl, l,l-dimethylbutyl,
ljl-dimethyl-2-propenyl, 1,1-dimethyl-3-hexenyl, and
~ 1,1-diethyl-2-butenyl.
- The terms C3-C8 cycloalkyl and substituted
`~ C3-C8 cycloalkyl include such groups as cyclopropyl,
~: cyclopentyl, cycloheptyl, cyclooctyl, 2-methoxymethoxy-
cyclobutyl, 3-~ormyloxycyclohexyl, 2-benzyloxycyclo-
octyl, 2-ethoxycyclopropyl, 2-methoxycyclohexyl,
` 4-isopropoxycyclooctyl, 2-cyanocyclohexyl, 3-cyano-
cyclooctyl and 2-cyanocyclopropyl.
The term protected amino refers to an amino
;~ 20 group substituted with one of the commonly employed
amino-protecting groups such as t-butoxycarbonyl,
benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-
nitrobenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl
and l-carbomethoxy-2-propenyl. Other accepted amino-
protecting groups such as are described by J. W.
Barton in Protective Groups in Organic Chemistry,
J.F.W. McOmie, Editor, Plenum Press, New York, 1973,
chapter 2 will be recognized by organic chemists as
: j
.. suitable ~or the purpose.
, .
'' ,
,,~
" .
3~
X-5055 -7-
:
:.
The term, a carboxyl-c acid protecting group~
refers to any group which is conventionally used to
block or protect the carboxylic acid functionality of
a cephalosporin or penicillin while reactions in-
5 volving other functional sites are carried out. Such
- carboxylic acid protecting groups are noted for their
ease of cleavage and for their ability to protect the
acid from unwanted reactions. Such groups are thoroughly
described by E. Haslam in Protective Groups in Organic
Chemistr~, Chapter 5. Any such group may be used, of
course. The preferred groups, however, are Cl-C4
alkyl, C4-C6 t-alkyl, C5-C8 t-alkenyl, benzyl, methoxy-
benzyl, nitrobenzyl, diphenylmethyl, phthalimidomethyl,
;~ succinimidomethyl or trichloroethyl.
Similarly, the term protected hydroxy refers
to groups formed with a hydroxy group such as formyloxy,
; 2-chloroacetoxy, benzyloxy, diphenylmethoxy, tri-
; phenylmethoxy, 4-nitrobenzyloxy, trimethylsilyloxy,
- phenoxycarbonyloxy, t-butoxy, methoxymethoxy and
tetrahydropyranyloxy. Other accepted hydroxy-pro-
- tecting groups, such as those described by C. B. Reese
in chapter 3 of Protective Groups in Organic Chemistry
` will be understood to be included in the term protected
hydroxy.
The novel compounds of this invention, are
made by a process which proceeds in a single step by
contacting and reacting the starting compounds described
above with either molecular chlorine or, preferably,
- t-butyl hypochlorite. A small amount of a Cl-C3
carboxylic acid in the reaction mixture is needed.
"' -
, . .
5~3~
- X-5055 -8-
.
The choice of solvent in which to run the
reaction i9 not critical. The preerred solvents are
the C2-C8 alkyl esters, such as ethyl acetate, ethyl
formate, methyl acetate, butyl acetate, methyl formate,
and the like. The esters are especially advantageous,
because they ordinarily contain a small amount of free
carboxylic acid which is sufficient to serve as the
reaction initiator. However, many other solvents
including ketones including acetone and methyl ethyl
ketone, halogenated solvents such as dichloromethane,
chloroform, 1,l-dichloroethane, chlorobenzene, bromo-
benzene and the like, acids including acetic acid and
propionic acid, nitriles such as acetonitrile, and
nitroalkanes such as nitromethane, are effectively
used.
When molecular ch~orine is used, it is
necessary to include a hydrochloric acid scavenger in
the reaction mi~ture, because free hydrochloric acid is
likely to cause chlorination at the 3-position.
Epoxides, especially propylene oxide and butylene
oxide, are the preferred acid scavengers. ~ther basic
compounds may also be used, however, especially basic
salts such as the alkali metal salts of carboxylic
acids, including sodium and potassium salts of formic
- 25 and acetic acids. Still other hases, including in-
organic bases such as the hydroxides, carbonates and
bicarbonates of sodium, potassium and lithium, may also
, be used as acid scavengers.
Ç' ~he process of this invention proceeds in
acceptable yields at convenient temperatures in the
range o f~om about ~20C. to about 50C.; the pre-
ferred temperature range is from about -10C. to the
; ambient temperature.
''
' '
~ ~ ~45
X-5055 -9-
The process of this invention gives excellent
yields of the novel compounds of this invention.
; However, a certain amount of the corresponding 3-
chloromethyl-2-butenoate is usually produced as a side
product. This process usually gives about 4 parts of
the desired novel compound and 1 part of the 2-
butenoate.
The starting compounds used in the process of
this invention are now known in the cephalosporin art.
The thiazolinoazetidinones are most easily prepared as
described by Cooper, U.S. Patent 3,705,892, which
illustrates the reaction of a penicillin sulfoxide with
a trialkylphosphite or triphenylphosphine to prepare
' the desired starting thiazolinoazetidinone in a single
step, in the la, 5a epimeric form. The reaction is also
-~ discussed by Cooper and Spry in chapter 5 of Cephalo-
sporins and Penicillins, Flynn, Editor, Academic Press,
; New York, 1972, at page 235.
- The R groups of the starting compound are
~, 20 derived from the corresponding 6-amido groups of the
~` penicillin which is the ultimate starting compound. It
:~ will be recognized that the R groups are those which
have been commonly seen on penicillin and cephalosporin
antibiotics of the prior art. Antibiotic chemists will
understand that the R groups of the starting compounds
used in this invention are provided, in many cases, by
deacylating the penicillin which is the ultimate
starting compound, and reacylating with the desired
group. Such steps are very old in the antibiotic art,
of course, and have been well discussed by Kaiser and
; Kukolja in Chapter 3 of Cephalosporins and Penicillins,
~ cited supra.
.'"`'
' ''
,
39
X-5055 -10-
The following preparative examples are
presented to assure that organic chemists can easily
obtain any compound of this invention, and can carry
out any process of this invention. The products of the
examples were identified by various instrumental
analytical techniques, as will be explained in the
individual examples. When a given product was made
repeatedly by different embodiments of the process of
this invention, the product was often identified by
thin-layer chromatography (TLC) or nuclear magnetic
resonance analysis (NMR) as identical to the original
sample, and was therefore not isolated or further
analyzed.
Example 1
- 4-nitrobenzyl (la,5~)-2-(3-phenoxymethyl-2-
thia-6-oxo-4,7-diazabicyclo~3.2.0]hept-3-en-7-yl)-3-
chloromethyl-3-butenoate
A 5.83 g. portion of 4-nitrobenzyl (la,5a)-
2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]-
hept-3-en-7-yl)-3-methyl-3-butenoate was dissolved in
100 ml. of chloroform, and 4.1 g. of sodium acetate and
;~ 4.3 ml. of acetic acid were added. The mixture was
stirred and cooled to -10C. A 2.71 g. portion of
t-butyl hypochlorite was dissolved in 5 ml. of chloro-
form and added to the reaction mixture over a period of
10 minutes. The reaction mixture was stirred at
constant temperature for 2 hours, and was then poured
into saturated aqueous sodium chloride solution. The
organic layer was sepaxated, extracted twice with
portions of fresh brine and dried over magnesium
.' ,
; X-5055 -11-
sulfate. The dry organic layer was then evaporated
under vacuum to obtain 6.5 g. of a light yellow oil
which was purified by high pressure liquid chroma-
tography, using a mixture of 15 parts of dichloro-
methane and 1 part of ethyl acetate as the eluting
solvent. The product-containing fractions were com-
bined and heated in methanol, whereupon crystallization
began. A total of 2.34 g. of the desired product, m.p.
105.5-107C., was obtained.
, 10 Infrared analysis of the product, as a
potassium bromide compact, showed maxima at 1795, 1787,
1770, 1755 and 1740 cm 1. Ultraviolet analysis in
methanol showed a lambda-maximum at 262 nm, s 11,742.
- Nuclear magnetic resonance analysis in CDC13
on a 360 megacycle instrument showed the following
values: 3.9 (q, J=12Hz); 4.94 (q, J=14Hz); 5.12(s);
5.23(s); 5.461s); 5.88(d,J=4Hz); 6.04 (d, J=4Hz); 5.29
~q, J=14Hz); 6.~8-7.33(m); 7.48(d, J=8Hz); 8023(d,
J=8Hz)
Example ~
~i 4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-2-
thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-
chloromethyl-3-butenoate
~ 4.67 g. portion of (la,5a)-2-(3-phenoxy-
methyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-
en-7-yl)-3-methyl-3-butenoate was dissolved in 250 ml.
of ethyl acetate, and 10 ml. of propylene oxide was
added. The mixture was stirred at room temperature
while a solution of 0.35 g~ of chlorine in carbon
tetrachloride was added, and the mixture was stirred
.
~ ,
"
;
5 ~
X-5055 -12-
for 1 hour more. Successively, two additional 0.35 g.
portions of chlorine were added, and the mixture was
then cooled to 0C. A fourth portion of chlorine was
added, and the mixture was allowed to stand for 16
hours. The reaction mixture was then evaporated, and
the resulting oil was purified by preparative thin-
layer chromatography. The product-containing fractions
were combined and evaporated to dryness to isolate the
~ desired product as a pale yellow foam, which was
- 10 identified as identical to the product of Example 1.
Example 3
4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-
2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-
3-chloromethyl-3-butenoate
A 920 mg. portion of 4-nitrobenzyl (la,5a)-
2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo-
[3.2.01hept-3-en-7-yl)-3-methyl-3-butenoate was
, dissolved in 50 ml. of t-butyl acetate, and 0.07 g. of
chlorine ~nd 1 ml. of propylene oxide were added. The
` reaction was stirred at room temperature for 1 hour,
and the reaction mixture was examined by nuclear
magnetic resonance analysis. Signals indicating the
presence of the desired product were observed.
Example 4
4-nitrobenzyl (1,5a)-2-(3-phenoxymethyl-
, 2-thia-6-oxo-4,7-diazabicyclo[3,2.0]hept-3-en-7-yl)-
; 3~chloromethyl-3-butenoate
The process of Example 3 was followed,
except that methyl formate was used as the solvent.
. : i
,,,: ' .
, ~
~,
.,
X-5055 -13-
N~R analysis of the reaction mixture indicated the
presence of the desired product, which was not
isolated.
Example 5
4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-
2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-
_ 3-chloromethyl-3-butenoate
The process of Example 3 was repeated again,
using dichloromethane as the solvent. Again, NMR
analysis of the reaction mixture showed that the
desired product was obtained, although it was not
- isolated.
Example 6
4-nitrobenzyl (la,Sa)-2-(3-phenoxymethyl-
2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-
3-chloromethyl-3-butenoate
A 920 mg. portion of 4-nitrobenzyl (la,5a)-
2 (3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo-
[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoate was dis-
solved in 50 ml. of methyl formate, and 1 ml. of
~, propylene oxide and 0.2 g. of t-butyl hypochlorite
were added. The reaction mixture was stirred for 1
hour at room temperature, at which time the reaction
~ mixture was examined by NMR analysis, which showed the
;~j presence of a large amount of the desired product.
The reaction mixture was evaporated under vacuum, and
~' the residue was crystallized from methanol/diethyl
ether to obtain 350 mg. of the desired product,
--~ identical to the product of Example 1.
'
' .
-,
''
,'
" ;
,s
' .
X-5055 -14-
Example 7
4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-2-
thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-
;-~ chloromethyl-3-butenoate
The process of Example 3 waC foliowed,
except that sodium carbonate was used as the hydro-
chloric acid scavenger instead of propylene oxide.
- NMR analysis of the reaction mixture after 1 hour
showed the presence of the desired product, which was
not isolated.
Example 8
4-nitrobenzyl (1,5~)-2~(3-benzyl-2-thia-
6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-
chloromethyl-3-butenoate
- A 450 mg. portion of 4-nitrobenzyl (la,5a)-
2-(3-benzyl-2-thia-6-oxo-4j7-diazabicyclo[3.2.0]hept-
3-en-7-yl)-3-methyl-3-butenoate was dissolved in
` 20 50 ml. of methyl ~ormate, and 0.5 ml. of propylene
~- oxide was added. An 0.15 ml. portion of t-butyl
hypochlorite was added, and the reaction mixture was
~ stirred for 1 hour at room temperature. NMR analysis
- of the reaction mixture in CDC13 on a 60 megacycle
instrument showed the presence of the desired product,
which was not isolated.
3.6 ~q, J=14Hz); 3.84(s); 5.1(s); 5.25(s); 5.4(s);
~j 5.86 (broad s); 7.28(s); 7.48 (d, J=8Hz); 8.16 (d,
J=8Hz~
, !.',
, '~',' ': .
,, ",
. ...
''",'',''
, . .... .
/, , ,
:, ,
' ' ' ,
, ~", . . .
1:" ' , ~ ' ` '
.;
.' , , '
....
. .
. . .
X-5055 -15-
.
;~ Example 9
4-nitrobenæyl (la,5a)-2-(3-phenoxyme~hyl-2-
thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-
chloromethyl-3-butenoate
A 9.6 g. portion of 4-nitrobenzyl (la,5a3-
2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo-
[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoate was dis-
solved in 250 ml. of methyl formate and a 10 ml.
; 10 portion of propylene oxide was added. The reaction
; mixture was stirred at 0C., while a total of 4 ml. of
t-butyl hypochlorite was added in 5 portions at
~ intervals of approximately 5 minutes. Analysis of the
,; reaction mixture by high pressure liquid chromatography
lS showed that the amount of the desired product in tha
- reaction mixture increased steadily with each addition
;~ of the hypochlorite, and that essentially complete
conversion to the desired product occurred. The
` product was iden~ifi~d as identical to the product of
Example l.
Example 10
4-nitrobenzyl (la,Sa)-2-(3-phenoxymethyl-2-
; thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en~7-yl)-3-
; chloromethyl-3-butenoate
~ A 1.17 g. portion of 4-nitrobenzyl ~la,5a)-
i~ 2-~3-phenoxymethyl-2-thia-6~oxo-4,7-diazabicyclo-
[3.2.0]hept-3~en-7-yl)-3-methyl-3-butenoate was
dissolved in 25 ml. of methyl formate and 2 ml. of
propylene oxide at room temperature. A 2.5 ml.
, portion of l-molar chlorine solution in carbon tetra-
,~, .
.
:',,
.f .
, . ,;~
'
:,
r, ,
'; '
. --
X-5055 -16-
chloride was added dropwise over a 30 minute period.
After the mixture had stood for 1.5 hours, an additional
2.5 ml. of the chlorine solution was added, and the
reaction mixture was checked by thin-layer chroma-
tography. An additional 1 ml. of chlorine solutionwas added, and the mixture was allowed to stand at
room temperature for 16 hours. The mixture was then
evaporated to dryness, and the residue was taken up in
dichloromethane and precipitated by the addition of
heptane. Analysis of the product by NMR showed that
it was identical to the product of Example 1, although
some impurities were present.
Exam~le 11
4-nitro~enzyl (la,5a)-2-(3-phenoxymethyl-2- -
thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-
chloromethyl-3-butenoate
A 1.17 g. portion of 4-nitrobenzyl (la,5a)-
2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicycls-
[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoate was
dissolved in 25 ml. of methyl formate, 170 mg. of
sodium formate was added, and the mixture was cooled
; to -13C. Six 0.1 ml. portions of t-butyl hypochlorite
;; were added at intervals of about 5 minutes, while the
temperature of the mixture rose to -3C. NMR analysis
, of the reaction mixture showed that the reaction had
; gone essentially to completion and that the desired
product was the major component of the-reaction
mixture.
,
.
.
,
X-5055 -17-
Example 12
4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-
2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-
yl)-3-chloromethyl-3-butenoate
The process of Example 11 was followed,
except that 210 mg. of potassium formate was used as
the base, and a few milligrams of 18-crown-6 was also
added. The temperature of the reaction was from
-1C. to 8C. Again, NMR analysis of the reaction
mixture showed that the reaction had given an essentially
complete yield of the desired product, identical to
the product of Example 1.
Example 13
4-nitrobenzyl (1~,5a)-2-(3-phenoxymethyl-
2-thia-6-oxo-4,7-diazabicyclo[3.2.0~hept-3-en-7-
yl)-3-chloromethyl-3-butenoate
A 1.17 g. portion of 4-nitrobenzyl (la,5a)-
20 2-~3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo-
[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoate was
dissolved in 25 ml. of methyl formate and cooled in an
ice-methanol bath. A 680 mg. portion of sodium
formate and 0.18 ml. of formic acid were added, and
0 6 ml. of t-butyl hypochlorite was added in 0.1 ml.
portions while the temperature of the reaction mixture
rose from -8C to -2C. The mixture was stirred for a
total of about 1.5 hours, while the temperature rose
to 6C. NMR analysis of the reaction mixture showed
the presence of the desired product, identical to the
product of Example 1.
X-5055 -18-
Example 14
4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-
2-thia-6-oxo-4,7-diazabicyclo~3.2.0]hept-3-en-7-
yl)-3-chloromethyl-3-butenoate
The proc~ss of Example 13 was followed,
except that the solvent was dichloromethane instead of
methyl formate. The final reaction temperature was
-1C. in this instance. NMR analysis of the reaction
mixture showed that somewhat less of the desired
product was obtained and that the reaction mixture
still contained some starting compound.
Example 15
4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-
2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3 en-7-
yl)-3-chloromethyl-3-butenoate
A 1.17 g. portion of 4-nitrobenzyl (la,5a)-
2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diaza~icyclo-
[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoate was dis-
solved in 25 ml. of dichloromethane and cooled. An
0.38 ml. portion of formic acid and 0.81 ml~ of
pyridine were added to the reaction mixture, and
0.6 ml. of t-butyl hypochlorite was added portionwise
while the temperature of the reaction mixture rose
from -14C. to -2C. Analysis of the reaction mixture
after about 1.5 hours showed that a moderate yield of
the desired product, identical to the product of
Example 1, was obtained.
X-5055 -19-
Example 16
4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-
2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-
yl)-3-chloromethyl-3-butenoate
The process of Example 13 was followed,
except that the solvent was a mixture of 10 ml. of
dichloromethane and 10 ml. of methyl acetate. The
initial reaction temperature was -14C., rising to
-3C. The mixture was stirred for about 1 hour, and
was then evaporated under vacuum to dryness. The
residue was purified over silica gel, using as solvent
a mixture of 15 parts of dichloromethane and 1 part
ethyl acetate. Analysis of the fractions removed from
the column showed that the major product was the
desired one, and that the corresponding 3-chloro-
methyl-2-butenoate was a minor product.
Example 17
4-nitrobenzyl ( la,Sa) - 2-(3-phenoxymethyl-
20 2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-
yl)-3-chloromethyl-3-butenoate
A 1.17 g. portion of 4-nitrobenzyl (la,5a)-
2-(3-phenox~methyl-2-thia-6-oxo-4,7-diazabicyclo-
25 [3.2.0~hept-3-en-7-yl)-3~methyl-3-butenoate was
dissolved in 10 ml. of methyl acetate and 10 ml. of
dichloromethane, and the solution was cooled. An
0.5 ml. portion of acetic acid and 0.8 g. of sodium
acetate were added to the rsaction mixture, followed
by 0.6 ml. of t-butyl hypochlorite in 0.1 ml. portions.
The temperature of the mixture ranged from -5C. to
X-5055 -20-
3C. during the addition. After 1 hour of stirring,the reaction mixture was evaporated to dryness under
vacuum, and the residue was purified by chromatography
ovar an 8-cm. column of silica gel, using the same
eluting solvent as used in Example 16. The major
product was the desired one, identical to the product
of Example 1.
Example 18
4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-
2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-
yl)-3-chloromethyl-3-butenoate
The process of Example 13 was carried out
again, but without the formic acid, in order to
ascertain the importance of the acid. Analysis of the
reaction mixture by thin-layer chromatography at
intervals showed that the reaction produced the
desired product, but at a slower rate. Even after 5
days of standing at ambient temperature, the reaction
was not complete.
Example 19
4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-
2-thia-6-oxo-4~7-diazabicyclo[3.2.0]hept-3-en-7-
yl)-3-chloromethyl-3-butenoate
An 0.26 ml. portion of S0 percent aqueous
sodium hydroxide solution was added to 30 ml. of
methyl formate with stirring. After about 20 minutes,
1.17 g. of 4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-
2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-
yl)-3-methyl-3-butenoate and 3 ml. of dichloromethane
3~
X-5055 -21-
were added, and the reaction mixture was cooled. An
0.6 ml. portion of t-butyl hypochlorite was added in
0.1 ml. portions while the temperature rose from -5C.
to 0C. After the mixture had stirred for 1 hour, it
S was analyzed by NMR and TLC, which analysis indicated
that the desired product, identical to the product of
Example l, had been obtained.
Example 20
4-nitrobenzyl (la,5~)-2-(3-phenoxymethyl-2-
thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-
chloromethyl-3-butenoate
The process of Example 17 was repeated,
except that the solvent was 20 ml. of acetone, and the
lS reaction temperature ranged from -10C. to 1C.
Analysis by NMR and TLC showed that the desired
product, identical to the product of Example 1, was
obtained.
Example 21
4-nitrobenzyl (la,S~)-2-(3-phenoxymethyl-
2-thia-6-oxo-4,7-diazabicyclo[3.2.03hept-3-en-7-
yl)-3-chloromethyl-3-butenoate
The process o~ Example 20 was repeated,
except that the solvent was 25 ml. or 1,2-dichloro-
ethane. Analysis of the reaction mixture by TLC and
NMR methods showed that a yield of the desired product,
identical to the product of Example 1, was obtained.
5 ~33~
X-5055 -22-
Example 22
4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-2-
thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-
chloromethyl~3-butenoate
A 1.17 g. portion of 4-nitrobenzyl (la,5~)-2-
(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]-
hept-3-en-7-yl)-3-methyl-3-butenoate was dissolved in
20 ml. of 1,2-dichloroethane and the solution was cooled.
A 1.14 ml. portion of acetic acid and 0.53 g. of sodium
carbonate were added to the mixture, and 0.6 ml. of
t-butyl hypochlorite was added in 0.1 ml. portions
over a period of 1 hour while the temperature varied
from -8C. to 4C. TLC analysis indicated that a good
15 yield of the desired product, identical ~o the product
of Example 1, was obtained.
Example 23
4-nitrobenzyl ( la, 5a) - 2-(3-phenoxymethyl-2-
thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-
chloromethyl-3-butenoate
A 1.17 g. portion of 4-nitrobenzyl (la,5~)-
2-~3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo-
~3.2.0]hept 3-en-7-yl)-3-methyl-3-butenoate was
dissolved in 20 ml. of chloroform, and the solution
was cooled. Then 0.34 g. of sodium formate and
0.19 ml. of formic acid were added, followed by six
0.1 ml. aliquots of t-butyl hypochlorite over a
period of 70 minutes while the temperature rose
from -10C. to -1C. TLC indicated that the reaction
produced the desired compound, identical to the
product of Example 1.
3~
X-5055 -23-
Example 24
4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-2-
thia-6-oxo-4,7-diazabicyclol3.2.0]hept-3-en-7-yl)-3-
chloromethyl-3-butenoate
A 1.17 g. portion of 4-nitrobenzyl (la,5a)-
2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo-
[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoate was -
dissolved in chloroform and the solution was cooled.
An 0.82 g. portion of sodium acetate and 0.57 ml. of
acetic acid were added, followed by 0.6 ml. of t-
butyl hypochlorite in six 0.1 ml. portions over a
period of 70 minutes while the temperature rose
from -14C. to -1C. TLC analysis after 3 hours
showed that the desired product, identical to the
product of Example 1, was obtained.
Example 25
4-nitrobenzyl (la,Sa)-2-(3-phenoxymethyl-
2-thia-6-oxo-4,7-diazabicyclo~3.2.0]hept-3-en-7-
yl)-3-chloromethyl-3-butenoate
A 1.17 g. portion of 4-nitrobenzyl (la,5)-
2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo-
~3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoate was
dissolved in chloroform and the mixture was cooled.
Then 0.38 ml. of propionic acid and 0.48 g. of sodium
propionate were added, and 0.6 ml. of t-butyl hypo-
chlorite was added in the usual manner. The tem-
perature varied from -15C. to -3C. over the l-hour
period of the additions. TLC analysis showed that the
reaction produced a relatively small yield of the
desired product after 75 minutes.
33~
X-5055 -24-
Example 26
4-nitrobenæyl (la,5a)-2-(3-phenoxymethyl-
2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-
yl)-3-chloromethyl-3-butenoate
The process of Example 24 was repeated,
except that the hypochlorite was added in one portion,
when the temperature of the reaction mixture was
-12C. After 100 minutes, the temperature had risen
to 9C., and the course of ~he reaction was checked by
TLC and NMR analysis, which indicated that the reaction
was not complete but that the desired compound was
obtained.
Example 27
4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-
2-thia-6-oxo-4,7~diazabicyclo[3.2.0]hept-3-en-7-
yl)-3-chloromethyl-3-butenoate
A 1.17 g. portion of 4-nitrobenzyl (la,5a)-
20 2-~3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo-
[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoate was dis-
solved in 20 ml. of chloroform and the solution was
cooled. A 1.14 ml. portion of acetic acid and 0.82 g.
of sodium acetate were added, and 3.5 ml. of l-molar
chlorine solution in carbon tetrachloride was added
dropwise over a period of 5 minutes. The reaction
temperature was -14C. The mix~ure was stirred for 2
hours, and was then analyzed by TLC and NMR methods.
An approxima~ely 50 percent yield of the desired
product, identical to the product of Example 1, was
obtained.
3~
X-5055 -25-
Example 28
4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-
2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-
yl)-3-chloromethyl-3-butenoate
A 4.68 g. portion of 4-nitrobenzyl (la,5a)-
2-~3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo-
[3.2.0~hept-3-en-7-yl)-3-methyl-3-butenoate was dis-
solved in 100 ml. of methyl formate and 5 ml. of
butylene oxide was added, followed by 1.09 g. of t-
butyl hypochlorite. The mixture was stirred at
ambient temperature for 1 hour, after which an additional
0.3 ml. of the hypochlorite was added, and the mixture
was stirred Eor 1 hour more. The reaction mixture was
then poured into heptane, and was evaporated to an oil
under vacuum. The residue was taken up in dichloro-
methane, filtered, and evaporated to dryness. The
residue was then taken up in dichloromethane again,
and purified by chromatography over silica gel. The
product-containing fractions were analyzed by ~LC and
NMR methods, which indicated that the desired product,
identical to the product o~ Example 1, was obtained.
Example 29
.
4-nitrobenzyl ~la,5a)-2-(3-phenoxymethyl-2-
25 thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-
chloromethyl-3-butenoatQ
An 0.46 g. ~ortion of 4-nitrobenzyl (la,5a)-
2-~3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo-
30 ~3.2.0~hept-3-en-7-yl)-3-methyl-3-butenoate was dis-
solved in 25 ml. of acetonitrile at ambient temper-
-
3~
X-5055 -26-
ature, and 0.12 ml. of t-butyl hypochlorite was added.
The mixture was allowed to stand for 4 hours, after
which analysis by TLC and NMR indicated that a yield
of about 20 percent of the desired product, identical
to the product in Example 1, had been obtained.
Example 30
4-nitroben~yl (la,5a)-2-(3-phenoxymethyl-2-
thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-
chloromethyl-3-butenoate
The process of Example 29 was repeated,
using nitromethane as the solvent. After one-half
hour of standing, the reaction produced about 25
percent of the desired product, as indicated by TLC
and NMR analysis.
Example 31
4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-
2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-
yl)-3-chloromethyl-3-butenoate
A 0.46 g. portion of 4-nitrobenzyl (la,5a)-
2-~3-phenox~methyl-2-thia-6-oxo-4,7-diazabicyclo-
[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoate was dis-
solved in 50 ml. of t-butyl acetate and 2 drops of
formic acid was added. A 1 ml~ portion of t-butyl
hypochlorite was added in 1 portion and the mixture
was stirred at room temperature for 1~ hours. Analysis
by TLC and NMR showed that a yield of the desired
product was obtained.
~s~
X-5055 -27-
Example 32
4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-
2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-
yl)-3-chloromethyl-3-butenoate
A 1.17 g. portion of 4-nitrobenzyl (la,5a)-
2-(3-pheno~ymethyl-2-thia-6-oxo-4,7-diazabicyclo-
[3.2.0~hept-3-en-7-yl)~3-methyl-3-butenoate was dis-
solved in 35 ml. of methyl formate, and the reaction
mixture was cooled to -10C. Then 0.6 ml. of t-butyl
hypochlorite was added in 0.05 ml. aliquots at intervals
of 5 minutes, while the temperature rose to -3C.
Analysis by TLC and ~MR showed that a good yield of
the desired product was obtained.
Example 33
4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-2-
thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-
chloromethyl-3-butenoate
The process of Example 32 was repeated,
except that the solvent was ethyl formate. ~he result
of this experiment was similiar to the result of the
experiment of Example 32, in that a good yield o~ the
de3ired product, identical to the product of Example
1, was obtained.
4-~itrobenzyl (la,5a)-2-(3-phenoxymethyl-2-
thia-6-ox.o-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-
chloromethyl-3-butenoate
A 1.17 g. portion of 4-nitrobenzyl (la,5a)-
2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]-
39
X-5055 -28-
hept-3-en-7-yl)-3-methyl-3-butenoate was dissolved in
35 ml. of distilled methyl acetate. An 0.6 ml.
portion of t-butyl hypochlorite was added in the same~
portionwise fashion used in Example 32, while the
temperature varied from -20C. to -6C. Analysis by
TLC and NMR showed that no reaction had occurred.
One drop of formic acid was added, followed
by a further 0.6 ml. of the hypochlorite in 0O05 ml.
aliquots at 5 minute inter~als at temperatures from
-5C. to 2C. Analysis by TLC and NMR showed this
time that the desired product, identical to the
product of Example 1, was obtained.
Example 35
4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-2-
thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-
chloromethyl-3-butenoate
A 1.17 g. portion of 4-nitrobenzyl (la,5a)-
2-(3-phenoxymethyl-2-thia-5-oxo-4,7-diazabicyclo-
[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoate was dis-
solved in 30 ml. of distilled methyl acetate and
cooled. Then a few drops of trifluoroacetic acid were
added, followed by 1.2 ml. of t-butyl hypochlorite
over a ~eriod of 2 hours at temperatures from -5C.
to 1C. Analysis by TLC and NMR showed approximately
a 50 percent yield of the desired product, identical
to the product of Example 1.
r3
X-5055 -29-
Example 36
4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-2-
thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-
chloromethyl-3-butenoate
A 1.17 g. portion of 4-nitrobenzyl (la,5a)-
2-(3-phenoxymethyl-2-thia~6-oxo-4,7-diazabicyclo-
~3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoate was dis-
solved in 25 ml. of distilled methyl formate, and the
solution was cooled. An 0.1 ml. portion of formic
acid was added, followed hy 0.6 ml. of t-butyl hypo-
chlorite in 0.05 ml. aliquots over a period of 1 hour -
at temperatures from -13C. to -3C. Analysis by TLC
and NMR showed that the desired product, identical to
the product of Example 1, was obtained.
Example 37
4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-2-
thia-6-oxo-4,7-diazabicyclo~3.2.0]hept-3-en-7-yl)-3-
chloromethyl-3-butenoate
A 1.17 g. portion of 4-nitrobenzyl ~la,5a)-
2-~3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo-
[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoate was dis-
solved in 25 ml. of methyl formate, 0.1 ml. of dimethyl-
formamide was added, and the solution was cooled. An0.6 ml. portion of t-butyl hypochlorite was added in
the s~me manner used in Example 36, while the tem-
perature varied from -3C. to 1C. The desired product
~as obtained as indicated by T1C and NMR analysis.
,3~
X-5055 ~30-
Example 38
4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-2-
thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-
chloromethyl-3-butenoate
The process of Example 37 was repeated,
except that an 0.1 ml. portion of formic acid was
added, and the temperature varied between -11C. and
2C~ TLC and NMR analysis indicated that the desired
product, identical to the product of Example 1, was
obtained.
Example 39
4-nitrobenzyl (la,5a)-2-(3-phenoxymethyl-2-
thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3~en-7-yl)-3-
chloromethyl-3-butenoate
A 1.17 g. portion of 4-nitrobenzyl (la,5~)-
2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo-
[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoate was dis-
solved in 25 ml. of methyl formate and 1 ml. oftrimethyl orthoformate. The solution was cooled, and
five 0.1 ml. aliquots of t-butyl hypochlorite were
added over a period of 40 minutes at temperatures
from 4C to 1C. After 80 minutes, the mixture was
analyzed by TLC and NMR methods, which showed that the
desired product, identical to the product of Example
1, had been obtained.
3~
X-5055 -31-
Example 40
4-nitrobenzyl (la,5a)-2-(3-benzyl-2-
thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-
yl)-3-chloromethyl-3-butenoate
A 0.45 g. portion of 4-nitrobenzyl (la,5a)-
2-(3-benzyl-2-thia-6~oxo-4,7-diazabicyclo[3.2.0]-
hept-3-en-7-yl)-3-methyl-3-butenoate was dissolved in
50 ml. of methyl formate, and 0.1 ml. of t-butyl
hypochlorite was added. The mixture was allowed to
stand at ambient temperature for 3 hours, and was then
analyzed by NMR, which showed that the desired pro-
duct, identical to the product of Example 8, had been
obtained.
Example 41
benæyl (la,5a)-2-(3-phenoxymethyl-2-
thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-
yl)-3-chloromethyl-3-butenoate
A 0.42 g. portion of benzyl (la,5a)-2-
(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]-
hept-3-en-7-yl)-3-methyl-3-butenoate was dissolved in
50 ml. of methyl formate, and l ml. of propylene oxide
was added. The mixture was cooled to 0C., and
0.15 ml. of t-butyl hypochlorite was added in 1 portion.
The mixture stood for 30 minutes at 0C., at which time
analysis by nuclear magnetic resonance in CDC13 on a
60 m~gacycle instrument showed that the desired product
had been obtained. 3.95(s); 4.85(s); 5.2 (broad s);
30 5.4(s); 5.8 (d, J-4Hz); 5.92 (d, J=4Hz); 6.8-7.5(m)
3~
X-5055 -32-
The thiazolinoazetidinones are used in
various processes, one of which ~as described by
Masi et al., U.S. Patent 4,035,362. The compound is
first treated with mild base, such as pyridine in an
organic solvent, to convert the 3-butenoate group to
a 2-butenoate group. The compound is then reacted with
an azoderivative such as ethyl azodicarboxylate, which
opens the thiazoline ring and forms an azetidinone
having a 4-hydrazinothio group. That intermediate is
reacted with a strong base in an anhydrous organic
solvent to form a 3-chloromethyl-3-cephem, a useful
intermediate for preparing cephalosporin antibiotics.
A preferred use of this invention is the
preparation of 3-hydroxycephalosporins from the
thiazolinoazetidinones of this invention. The reaction
which prepares the 3-hydroxycephalosporins is readily
performed as follows. The thiazolinoazetidinone is
first reacted with ozone, in an inert solvent. The
reaction is carried out at a temperature from about
-100C. to about 0C., preferably at a temperature
from about -80C. to about -20C. The ozonolysis may
be done in any of many solvents including the halo-
genated hydrocarbons, such as chloroform, dichloro-
methane, 1,2-dichloroethane, bromoethane, carbon
tetrachloride and the like. Ethers such as diethyl
ether, tetrahydrofuran, diethylene glycol dimethyl
ether, methyl ethyl ether and the like are likewise
suitablQ Further, alkanes such as hexane and octane,
amides such as dimethylformamide and dimethylacetamide
alcohols including methanol and ethanol, and esters
including ethyl acetate and methyl acetate, and
mixtures of such solvents, may be used as solvents for
the ozonolysis.
3~ 3~
X-5055 -33-
Reaction with ozone provides an ozonide
involving the C3-C4 double bond of the 3-butenoate
group. The ozonide is then reduced with a mild
reducing agent to form the corresponding 4-chloro-
3-oxobutyrate. The reduction is carried out with any
of the agents commonly used for the decomposition of
ozonides, including such agents as zinc or magnesium
in the presence of water or acetic acid, alkali metal
bisulfites, sulfur dioxide, trimethylphosphite,
stannous chloride, Raney nickel, dialkyl sulfides and
the like. Decomposition of the ozonide is accomplished
hy simply adding an excess of the reducing agent to
the mixture containing the ozonide at a temperature
from about -80C to about 0C.
Finally, the desired 3-hydroxycephalosporin
is obtained by reacting the oxobutyrate obtained above
with mild mineral acid. Acids such as hydrochloric
acid, sulfuric acid, sulfonic acids such as methane-
sulfonic acid and toluenesulfonic acid, and aqueous
perchloric acid may be used, at temperatures from
about 0C. to about 50C. The product has the R and
Rl groups of the thiazolinoazetidinone of this in-
vention as its side chain and acid protecting group,
respectively.
Thus, it will be understood ~hat the range
of 3-hydroxycephalosporins prepared by the exercise of
this invention is defined by the range of thiazolino-
azetidinones which has been discussed above. It is
accordingly unnecessary to elaborate further on the
3-hydroxycephalosporin products.
33~
X-5055 -34-
3-Hydroxycephalosporins obtained by the
above process have been well discussed in U.S. Patent
3,917,587, of Chauvette, which thoroughly explains the
use of such compounds as intermediates in preparing a
number of useful antibiotics.
It will be understood that the cephalosporins
which are prepared from the novel compounds of this
invention have their carboxy groups, and any amino or
hydroxy groups which may be on the amido side chains,
in the blocked or protected form. Antibiotic chemists
will of course understand that protecting groups must
be removed before antibiotic use is made of such
compounds.
The following preparative examples are shown
to assure that the reader can use the thiazalino-
azetidinones of this invention in the process of this
invention for preparing 3-hydroxycephalosporins.
Example A
4-nitrobenzyl 3-hydroxy-7-phenylacetamido-
3-cephem-4-carboxylate
A portion of 4-nitrobenzyl (la,5a)-2-
(3-benzyl-2-thia-6-oxo-4,7-diazabicyclo~3.2.0]hept-
3-en-7-yl)-3-chloromethyl-3-butenoate, prepared from
0.5 g. of the corresponding 3-methyl-3-butenoate,
was dissolved in 20 ml. of dichloromethane and 10 ml.
of methanol. The solution was cooled to -78C., and
ozone was bubbled slowly through the solution until it
turned blue. The tempexature was held constant, and
0.5 g. of trimethylphosphite was added wi~h stirring.
The reaction mixture was then allowed to warm to
1~533~
- X-5055 -35-
ambient temperature, and was evaporated under vacuum
to obtain a foam. Twenty ml. of methanol and 10 ml.
of l-normal hydrochloric acid were added to the foam,
and the mixture was stirred for 5 minutes at 40C.
The mixture was then evaporated to dryness under
vacuum, producing a foam which was analyzed by TLC
and NMR, and found to consist in large part of the
desired product. The following ~ values were observed
on the NMR spectrum.
2.53-1.70(q); 2.7(m); 4.4(q); 6.66(d); 5.03(d);
6.37(s); 6.6~2d)
Infrared analysis as a"Nujol"mull showed
absorptions at 3.04, 5.60 and 6.0 microns.
Example B
4-nitrobenzyl 3-hydroxy-7-phenoxyacetamido-
3-cephem-4-carboxylate
A 4B0 mg. portion of 4-nitrobenzyl (la,5a)-
2-(3-phenoxymethyl-~-thia-6-oxo-4,7-dia~abicyclo-
[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate was
dissolved in 25 ml. of dichloromethane and 25 ml. of
methanol and cooled to -78C. Ozone was bubbled
through the solution with stirring until a blue color
was observed, and then 1 g. of dimethyl sulfide was
addedO The reaction mixture was allowed to warm to
ambient temperature, and was washed three times with
saturated brine and dried over magnesium sulfate. Ten
ml. of methanol and 5 ml. of l-normal hydrochloric
acid were added, and the mixture was stirred for 5
minutes at 40C. It was then evaporated under vacuum
to obtain a foam, which was analyzed and found to
consist in large part of the desired compound.
*Trademark for a highly refined liquid paraffin; it is a transparent,
colorless, almost odorless, oily liquid which is a mixture of
hydrocar~ons,
