Note: Descriptions are shown in the official language in which they were submitted.
l~)S63'72
The present invention provides a novel process for
preparing 3-methylenecepham sulfoxides by the intramolecular
cyclization of penicillin sulfoxide derived azetidinone
sulfinyl chlorides and related sulfinic acid derivatives by
reaction with Friedel-Craft catalysts or metathetic cation
forming agents. The 3-methylenecepham compounds are useful
intermediates in the preparation of cephem antibiotics.
Penicillins and more recently cephalosporins have
been recognized for their high degree of antibacterial
10 activity and have been used extensively for the treatment of
infectious diseases in man. There has been a considerable
research effort directed toward the chemical modification of
these compounds in search of yet more active beta-lactam
antibiotics. Much emphasis has been placed specifically on
the variation of the C6-acylamino substituent on the peni-
cillin compounds and both the C7-acylamino substituent and
the C3-substituent on the cephem compounds.
Recently R. R. Chauvette and P. A. Pennington re-
ported the use of 3-methylenecephams both in the preparation
20 of 7-amino desacetoxycephalosporanic acid and biologically
active derivatives thereof [Journal of Organ c Chemistry,
38, 2994 (1973)], and in the preparation of novel 3-methoxy
and 3-halo cephems [Journal of the American Chemical Society,
96, 4986 (1974)]. In each case the 3-methylenecepham inter-
mediates were prepared from cephalosporanic acids by first
treating the cephalosporanic acids with selected sulfur
} nucleophiles such as thiourea, thiobenzoic acid, potassium
ethyl xanthate or sodium thiosulfate and then reducing the
respective product C3-(substituted)thiomethyl cephem deriva-
30 tives with either Raney nickel in aqueous ethanol or zinc in
X-4372A -2-
.~
.
lOS6~7'~
formic acid-dimethylformamide. The demonstrated versatility
of the 3-methylenecephams as intermediates to novel cephem
antibiotics has prompted a search for alternative procedures
for preparing such compounds from readily available, econom-
ical starting materials.
The present invention provides a novel process for
preparing 3-methylenecepham sulfoxides by the intramolecular
cyclization of penicillin sulfoxide derived monocyclic
azetidinone- 2-sulfinyl chlorides and sulfinic acid,
sulfinate ester, thiosulfinate ester, sulfinamide, and
sulfinimide derivatives thereof with Friedel-Crafts -~
catalysts or metathetic cation forming agents. Some of the
azetidinone sulfinic acid derivative starting materials are
themselves novel.
The present invention provides a process for
preparing 3-methylenecepham sulfoxides of the formula
O
---T
0~ CH2
~ OOR '
which comprises reacting a compound of the formula
O . .....
Rl ~SX
COOR
with a Lewis acid type Friedel-Crafts catalyst, a Bronsted
proton acid type Friedel-Crafts catalyst or a metathetic
X-4372A -3-
1~51~;3~Z
cation-forming agent in a dry inert organic solvent; or
dissolving such compound in an organic Bronsted acid;
wherein in the above formulae
R is a carboxylic acid protecting group;
R' is R or hydrogen;
Rl is (1) an imido group of the formula
O :'
~C\
R2 / N -
11 ~,
wherein R2 is C2-C4 alkenylene, C2-C4 alkylene, 1,2-
phenylene, 1,2-cyclohexenylene; or
(2) an amido group of the formula
O
R3CNH-
wherein R3 is (a) hydrogen, Cl-C3 alkyl, halomethyl, or
3-(2-chlorophenyl)-5-methylisoxazol-4-yl;
(b) benzyloxy, 4~nitrobenzyloxy, 2,2,2-
trichloroethoxy, tert-butoxy, or 4-
methoxybenzyloxy;
(¢) the group R" wherein R" is 1,4-cyclo-
hexadienyl, phenyl or phenyl substituted
with 1 or 2 substituents independently
selected from the group consisting of
halo, protected hydroxy, nitro, cyano,
trifluoromethyl, Cl-C3 alkyl, and Cl-C4
alkoxy;
(d) an arylalkyl group of the formula
R" ~ (O)m~CH2
X-4372A -4-
,
105637Z
wherein R" is as defined above, and m is
O or l; . .
(e) a substituted arylalkyl group of the
formula
R'''CH-
W
wherein R''' is R" as defined above and
W is protected hydroxy, or protected
amino;
~3) an imido group of the formula
O
R ' C>~
., R " -(O) CH C -
' .
wherein R" and m are as defined hereinabove :
and R2' is Cl-C3 alkyl, Cl-C6 haloalkyl, . -
Cl-C3 alkoxy or trichloroethoxy; or Rl is
(4) an imidazolidinyl group of the formula
O . ' '
R"\ / \
¦ ~/CH3 ~:
y,, \ '.
CH3
wherein R" is as defined above and Y is acetyl or
nitroso; and X is
(1) chloro or bromo;
(2) a group of the formula -OR4 wherein R4 is ~ ~
hydrogen, Cl-C10 alkyl, aryl(Cl-C3 alkyl) or ~-
Cl-C6 haloalkYl;
X-4372A -5-
."~ . .
,... . . : : . . . - :
: . . . . . . ~ . .. . . .
1056372
(3) a group of the formula -SR5 wherein R5 is
Cl-C6 alkyl, aryl or aryl(Cl-C3 alkyl); or
(4) a group of the formula -N\ 6
R7
wherein
(a). R6 is hydrogen and R7 is hydrogen, R" as
defined hereinabove, or a group of the
formula -NHR8 wherein R8 is aminocar-
bonyl, Cl-C3 alkylaminocarbonyl, Cl-C3
alkoxycarbonyl, Cl-C3 alkylcarbonyl or ::
tosyl; or wherein
(b) R6 is -COORg or -CORg and R7 is :
-NHCOORg or -NHCORg wherein Rg is Cl-C6
alkyl, or phenyl; or wherein
(c) R6, R7 and the nitrogen atom to which
they are bonded taken together form an
imido group of the formula
11
- ~ ~ R ~ .
C
O
wherein R2 is as defined hereinabove:
and when R6 is -COORg or -CORg and R7 is
-NHCOORg or -NHCORg, R3 is additionally a :
heteroarylmethyl group of the formula
R''''CH2- wherein R'''' is 2-thienyl, 3-
thienyl, 2-furyl, 3-furyl, 2-thiazolyl or
5-isoxazolyl;
X-4372A . -6-
105637Z
with the limitations that when X is bromo, Rl is only an
imido group of the formula
O
R ~
O
when a metathetic cation-forming agent or a Lewis acid is
employed, X is only chloro or bromo; and when R is an acid
labile carboxylic acid protecting group, the product is a
3-methylenecepham-4-carboxylic acid sulfoxide.
The present invention is also directed to com-
pounds of the formula
O
~ OOR
wherein Rl, R and X are as defined hereinabove with the
exception that X is other than chloro, bromo, or a group of
the formula -N\ 5 wherein R6 is -COORg or -CORg and R7
is -NHCOORg or -NHCORg.
In the foregoing definition of the process of the
present invention the term "Cl-C3 alkyl" refers to methyl,
ethyl, _~propyl, or isopropyl. The term "Cl-C10 alkyl" in-
cludes methyl, ethyl, propyl, isopropyl, cyclohexyl, sec-
butyl, heptyl, octyl, isooctyl, decyl, or menthyl. "Cl-C6
Haloalkyl" represents groups such as chloromethyl, bromo-
ethyl, iodoethyl, 2-chloropropyl, 2-chlorocyclohexyl, or
2-chlorobutyl. The term "aryl(Cl-C3alkyl)" includes benzyl,
X-4372A -7_
.
.. , : ,
1056;37Z
2-phenylethyl, 2-phenyl propyl, 4-chlorobenzyl, naphthyl-
methyl, or 3-(2-nitrophenyl) propyl. Exemplary of the term
Cl-C3 alkoxycarbonyl are methoxycarbonyl, ethoxycarbonyl,
and isopropoxycarbonyl. Exemplary of "halomethyl" groups
are chloromethyl, bromomethyl or iodomethyl. Imido groups
represented when R2 is C2-C4 alkenylene are maleimido,
3-ethylmaleimido, or 3,4-dimethylmaleimido. Imido groups
represented when R is 1,2-cyclohexenylene or 1,2-phenylene
are 3,4,5,6-tetrahydrophthalimido or phthalimido respec-
tively.
When in the above definition R" represents a sub-
stituted phenyl group, R" can be a mono or disubstituted
halophenyl group such as 4-chlorophenyl, 2,6-dichlorophenyl,
2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-
bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-
fluorophenyl, or 2-fluorophenyl; a protected hydroxy phenyl
group such as 4-benzyloxyphenyl, 3-benzyloxyphenyl, 4-tert-
butoxyphenyl, 4-tetrahydropyranyloxyphenyl, 4-t4-nitro-
benzyloxy)phenyl, 2-phenacyloxyphenyl, 4-benzhydroxyphenyl,
or 4-trityloxyphenyl; a nitrophenyl group such as 3-nitro-
phenyl or 4-nitrophenyl; a cyanophenyl group, for example,
4-cyanophenyl; a mono or dialkyl substituted phenyl group
such as 4-methylphenyl, 2,4-dimethylphenyl, 2-ethylphenyl,
4-isopropylphenyl, 4-ethylphenyl, or 3-n-propylphenyl;
a mono or dialkoxyphenyl group, for example, 2,6-dimethoxy-
phenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 4-isopropoxyphenyl,
4-tert-butoxyphenyl, or 3-ethoxy-4-methoxyphenyl. Also,
R" represents disubstituted phenyl groups wherein the
substituents can be different for example, 3-methyl-4-
methoxyphenyl, 3-chloro-4-benzyloxyphenyl, 2-methoxy-4-
X-4372A -8-
105637Z
bromophenyl, 4-ethyl-2-methoxyphenyl, 3-chloro-4-nitro-
phenyl, 2-methyl-4-chlorophenyl and like disubstituted
phenyl groups bearîng different substituents.
The term "protected amino" as employed in the
above definition has reference to an amino group substituted
with one of the commonly employed amino blocking groups such
as the tert-butoxycarbonyl group (t-BOC); the benzyloxy-
carbonyl group, the 4-methoxybenzyloxycarbonyl group, the
4-nitrobenzyloxycarbonyl group, the 2,2,2-trichloroethoxy-
carbonyl group, or the 1-carbomethoxy-2-propenyl group
formed with methyl acetoacetate. Like amino protecting
groups such as those described by J. W. Barton in "Pro-
tective Groups in Organic Chemistry," J. F. W. McOmie, Ed.,
Plenum Press, New York, N.Y., 1973, Chapter 2 also are
recognized as suitable.
The term "protected hydroxy" has reference to the
readily cleavable groups formed with an hydroxyl group such
as the formyloxy group, the chloroacetoxy group, the ben-
zyloxy group, the benzhydryloxy group, the trityloxy group,
the 4-nitrobenzyloxy group, the trimethylsilyloxy group, the
phenacyloxy group, the tert-butoxy group, the methoxymethoxy
group, or the tetrahydropyranyloxy group. Other hydroxy
protecting groups, including those described by C. B. Reese
in "Protective Groups in Organic Chemistry", supra, Chapter
3 also are considered as within the term "protected hydroxy"
as used herein.
The term "carboxylic acid protecting 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
X-4372A -9-
1~56;37Z
sites of the compound are carried out. Such carboxy pro-
tecting groups are noted for their ease of cleavage by
hydrolytic or by hydrogenolytic methods to the corresponding
carboxylic acid. Examples of carboxylic acid ester pro-
tecting groups include methyl, tert-butyl, benzyl, 4-
methoxybenzyl, C2-C6 alkanoyloxymethyl, 2-iodoethyl, 4-
nitrobenzyl, diphenylmethyl (benzhydryl), phenacyl, 4-
halophenacyl, dimethylallyl, 2,2,2-trichloroethyl, tri(Cl-
C3alkyl)silyl, or succinimidomethyl. Other known carboxy
protecting groups such as those described by E. Haslam in
"Protective Groups in Organic Chemistry", supra, Chapter 5,
also are recognized as suitable. The nature of such ester
forming groups is not critical.
When the azetidinone sulfinic acid derivative
starting material for the process of this invention is
protected with an acid labile carboxy protecting group such
as 4-methoxybenzyl, benzhydryl, tert-butyl or tri(Cl-
C3alkyl)silyl the product of the cyclization of the present
invention is an 3-exomethylenecepham sulfoxide acid. Like-
wise, if the starting materials have similar acid labilehydroxy or amino protecting groups, such groups will usually
be removed under the acidic conditions of the present
cyclization process. The removal of certain acid labile
protecting groups under the reaction conditions of the
present process is not a critical feature of the present
invention. The protecting groups on the azetidinone
starting materials for the process of this invention are
there present because of the necessity of protecting their
precursor penicillin sulfoxides during the preparation of
the intermediate azetidinone sulfinyl halides. Thus, the
X-4372A -10-
,~.. . . . , . . . . : -. , : - . . - , - : : , .
1~5637Z
primary purpose of the protecting groups is to protect the
reactive functional groups during the preparation of the
starting materials. The nature of the protecting group is
not critical to the present process. No significant
reduction in yield of exomethylenecepham sulfoxide is noted
when acid labile protecting groups are employed. In such
case, the only difference is that the products are typically
cepham acids instead of cepham esters. Since subsequent
conversions are usually contemplated for the exomethyl -
enecepham sulfoxide products of the present invention, it ispreferred that the reactive functional groups on these
products remain protected during the cyclization process of
this invention. Non-acid labile protecting groups are
therefore preferred. The preferred carboxylic acid ester
protecting groups are methyl, 2-iodoethyl, 4-nitrobenzyl,
4-halophenacyl and 2,2,2-trichloroethyl.
In the foregoing definitions, hydroxy, amino, and
carboxy protecting groups are not exhaustively defined. The
function of such groups is to protect the reactive func-
tional groups during the preparation of the startingmaterials and then be removed at some later point in time
without disrupting the remainder of the molecule. Many such
protective groups are well known in the art and the use of
other groups equally applicable to the process and compounds
of the present invention is recognized as suitable. Thus,
there is no novelty or inventiveness asserted with regard to
the "protecting groups" alluded to in this specification.
O
Representative of the acylamino group, R3CNH-,
as defined hereinabove are formamido, acetamido, propion-
X-4372A -11-
.
~OS637Z
amidO, butyramido, 2-pentenoylamino, chloroacetamido,
bromoacetamido, or 5-tert-butoxycarbonylamino-5-tert-
butoxycarbonylvaleramido.
Illustrative of the particular acylamino group,
R"CNH-, are benzamido, 2,6-dimethoxybenzamido, 4-chloro-
benzamido, 4-methylbenzamido, 3,4-dichlorobenzamido, 4-
cyanobenzamido, 3-bromobenzamido, or 3-nitrobenæamido.
o
Exemplary of the acylamino group R3CNH, when R3 is
a group of the formula R"~O)mCH2- and m is O, are cyclo-
hexa-1,4-dienylacetamido, phenylacetamido, 4-chlorophenyl-
acetamido, 3-methoxyphenylacetamido, 3-cyanophenylacetamido,
3-methylphenylacetamido, 4-bromophenylacetamido, 4-ethoxy-
phenylacetamido, 4-nitrophenylacetamido, or 3,4-dimethoxy-
phenylacetamido; and when m is 1, representative acylamino
groups are phenoxyacetamido, 4-cyanophenoxyacetamido,
4-chlorophenoxyacetamido, 3,4-dichlorophenoxyacetamido,
2-chlorophenoxyacetamido, 4-methoxyphenoxyacetamido, 2-
ethoxyphenoxyacetamido, 3,4-dimethylphenoxyacetamido, 4-
isopropylphenoxyacetamido, 3-cyanophenoxyacetamido, or
3-nitrophenoxyacetamido.
Illustrative of the acylamino groups when R3 i5 a
substituted arylalkyl group of the formula R'''-CH- and
when W is protected hydroxy are 2-formyloxy-2-phenylacet-
amido, 2-benzyloxy-2-(4-methoxyphenyl)acetamido, 2-(4-
nitrobenzyloxy)-2-(3-chlorophenyl)acetamido, 2-chloroacet-
oxy-2-(4-methoxyphenyl)acetamido, 2-benzyloxy-2-phenyl-
acetamido, 2-trimethylsilyloxy-2-(4-chlorophenyl)acetamido,
or 2-benzhydryloxy-2-phenylacetamido. Representative of
such groups when W is protected amino are 2-(4-nitrobenzyl-
X-4372A -12-
10563~
oxycarbonylamino)-2-phenylacetamido, 2-(2,2,2-trichloro-
ethoxycarbonylamino)-2-phenylacetamido, 2-chloroacetamido-
2-(1,4-cyclohexadien-l-yl)acetamido, 2-(4-methoxybenzyloxy-
carbonylamino)-2-(4-methoxyphenyl)acetamido, 2-benzhydryl-
oxycarbonylamino-2-phenylacetamido, or 2-(l-carbomethoxy-
2-propenyl)amino-2-phenylacetamido.
Representative of Rl wherein Rl is an imido group
of the formula
o
R '>~
) m 2 Ic~
O
are N-acetyl-N-phenylacetylamino, N-trichloroethoxycar-
bonyl-N-phenoxyacetylamino, N-propoxycarbonyl-N-(4-chloro-
phenoxy)acetylamino, or N-(2-bromoacetyl)-N-phenoxyacetyl-
amino.
O
"
Exemplary of the acylamino group R3CNH- when R3 is
a heteroarylmethyl group of the formula R""-CH2- are 2- ;
thienylacetam:ido, 3-thienylacetamido, 2-furylacetamido, a
2-thiazolylacetamido group of the formula
_____
O
\S CH2CNH- ,
or a 3-(2-chlorophenyl)-5-methylisoxazol-4-ylamido group of
the formula
X-4372A -13-
~OS637Z
.~ -
\.= ./
\CI
-CNH-
Representative of Rl when Rl is an imidazolidinyl
group of the formula
R"\ / ~ ;.
: :
CH3
are the 2,2-dimethyl-3-nitroso-5-oxo-4-phenyl-1-imidazoli-
dinyl group, the 2,2-dimethyl-3-nitroso-5-oxo-4-(4-benzyl- ~ :~
oxyphenyl)-l-imidazolidinyl group, the 2,2-dimethyl-3- ~ :
acetyl-5-oxo-4-(1,4-cyclohexadien-1-yl)-1-imidazolidinyl
group, or the 2,2-dimethyl-3-nitroso-5-oxo-4-(2-thienyl)-
l-imidazolidinyl group.
In general, the process of this invention is ~ :
directed to the cyclization of penicillin sulfoxide derived
. azetidinone sulfinic acid derivatives by the Friedel-Crafts-
catalyst induced intramolecular reaction of the sulfinyl and
olefinic functionalities on the azetidinone ring. This .
¦ internal alkylsulfination reaction can be regarded as an
analog of a Friedel-Crafts acylation reaction, in which a
o . ,.
I sulfinyl group (-S-) is substituted for a carbonyl group
' ~,. .
~: .
l~ X-4372A -14-
t ~
..~.. ....
.
10563~Z
(-C-), and the product is a sulfoxide instead of a ketone.
The literature contains at least three reports of Friedel-
Crafts type sulfinylation reactions. Specifically, the
intermolecular arenesulfinylation of aromatics giving diaryl
sulfoxides has been described [C. Courtot and J. Frenkiel,
C. R. Acad. Sci., 199, 557 (1934); George A. Olah and Jun
Nishimura, J. Org. Chem., 39, 1203 (1973); and Irwin B.
Douglass and Basil Said Farah, J. Org. Chem., 23, 805 (1958)].
In an analogous reaction alkyl or arylsulfenyl chlorides
react with aromatic hydrocarbons in the presence of aluminum
chloride catalyst to give thioethers with good yields [H.
Britzinger and M. Langheck, Ber., 86, 557 (1953)]. The
reaction of alkyl or arylsulfonic acid chlorides with
aromatics to provide sulfones has been more extensively
investigated. See e.g., George A. Olah, "Friedel-Crafts
Chemistry," John Wiley and Sons, Inc., New York, N.Y., 1973,
pp. 122-123, 146, 507. There have been no previous reports
of intramolecular alkylsulfinylation of the sort described
hereinbelow. The intramolecular cyclization of carboxylic
acids and derivatives thereof with Friedel-Crafts catalysts
to prepare cyclic ketones is, however, well documented in
the chemical literature. See William S. Johnson in "Organic
Reactions," Roger Adams et al., Eds., John Wiley and Sons,
Inc., New York, N.Y., 1944, Chapter 4, pp. 130-177 and
"Friedel-Crafts Chemistry", supra. It has been found in
this invention that conventional Friedel-Crafts acylation
procedures, including reaction conditions, solvents, and
catalytic reagents are successfully applied generally to the
intramolecular cyclization of the azetidinone sulfinyl
chlorides and derivatives thereof of this invention.
X-4372A -15-
:,
, ~ ~, . .
: : ' ' ' .
~ .
~- .
~0563'7Z
The azetidinone sulfin~l chloride starting materials
for the process of the present invention are derived from
the corresponding known penicillin sulfoxide esters by
reacting such esters at elevated temperatures with a reagent
serving as a source of positive halogen, preferably an
N-haloimide such as N-chlorosuccinimide (NCS). The con-
version of 6-imido penicillin sulfoxide esters to the
corresponding sulfinyl chlorides with sulfuryl chloride has ;
been described in the literature [S. Kukolja and S. R.
Lammert, Angew. Chem., 12, 67-68 (1973~]. Generally the
sulfinyl chloride starting materials for the process of this
invention are prepared by reacting a penicillin sulfoxide
ester with about 1.1 equivalents of N-chlorosuccinimide in a
dry inert organic solvent, preferably 1,1,2-trichloroethane
or toluene at a temperature of about 70 to 120C., the
preferred temperature being dependent primarily on the
nature of the C6-substituent. The conversion of C6-imido -~
penicillin sulfoxides is usually accomplished at 70-100C.,
while slightly higher temperatures (100-120C.) are pre-
'i 20 ferred for the sulfinyl chloride preparation from C6-
acylamino penicillin sulfoxides. The reaction is usually
complete in 45-90 minutes at the preferred reaction tempera- -~
ture. The penicillin sulfoxide ester precursors to the
sulfinyl chlorides are either known or readily available
compounds, many of which have been used in the preparation
of cephem compounds. They are prepared from known 7-acyl-
amino and 7-imido penicillin acids by (1) esterification and
' (2) subsequent oxidation, usually with metachloroperbenzoic
i acid or sodium periodate.
,
X-4372A -16-
I
,,
.
, . -, - -~ ., ~ , . . .. . . .
lOSf~37Z
Exemplary of the preparation of the azetidinone
sulfinyl chloride starting materials of the present in-
vention is the following brief description of the prepara-
tion of 4'-nitrobenzyl 3-methyl-2-(2-chlorosulfinyl-4-oxo-
3-acetamido-1-azetidinyl)-3-butenoate: A solution of 5
mmoles of 4'-nitrobenzyl 6-acetamidopenicillanate l-oxide
in 200 ml. of toluene is heated to reflux and dried aze- -
otropically by allowing approximately 20 ml. of toluene to
be distilled from the mixture. After cooling the mixture
briefly, 5.5 mmoles of N-chlorosuccinimide is added. The
mixture is refluxed for 90 minutes after which time the
solution is cooled to room temperature and filtered.
Evaporation in vacuo of the filtrate provides 4'-nitrobenzyl
3-methyl-2-(2-chlorosulfinyl-4-oxo-3-acetamido-1-azetidinyl)-
3-butenoate as a froth. The product azetidinone sulfinyl
chlorides thus obtained can be employed in the cyclization
process of this invention directly without purification.
; Indeed, it is often the case that the Friedel-Crafts
catalyst reagent is added directly to the final reaction
mixture of the preparation of the azetidinone sulfinyl
chloride.
In a reaction analogous to the reaction of peni-
' cillin sulfoxide esters with NCS to provide azetidinone
sulfinyl chlorides, penicillin sulfoxide esters having an
imido group at C-6 can be reacted with N-bromosuccinimide
; (NBS) to provide the corresponding azetidinone sulfinyl
bromides. The reaction conditions for this conversion are
; identical to those employed in the aforedescribed sulfinyl
"
X-4372A ~ -17-
~ i .
; .
.
~ .
.~ .
. - . .. i . .. . , .- .. , , . -, - . :
. ~ . . . .. ~ .... . .. - .: .
105637Z
chloride preparation using NCS. The aforedescribed azetidi-
none sulfinyl chlorides and the corresponding sulfinyl
bromides exhibit similar chemical reactivity in regard to
the cyclizing agents described in detail hereinbelow.
The azetidinone sulfinic acids of the formula
I l .
lo `I~
~OOR
wherein R and Rl are as defined hereinabove, are generally
prepared from the corresponding sulfinyl chlorides by slur-
rying an ethyl acetate solution of the sulfinyl chloride
with an aqueous sodium bicarbonate solution at room tem-
perature for about one hour. The aqueous layer containing
the sulfinic acid salt is separated, washed with ethyl
acetate, layered with another portion of ethyl acetate and
then acidified. The organic layer is separated, washed with
brine, dried over anhydrous sodium sulfate, and then evapo-
.... .
rated ln vacuo to dryness. The sulfinic acids thereby
isolated are generally obtained as colorless amorphous
.... .... . .
solids.
Representative of the sulfinic acids of this in-
vention are the following:
4'-nitrobenzyl 3-methyl-2-(2-sulfino-4-oxo-3-
phenylacetamido-l-azetidinyl)-3-butenoate,
2',2',2'-trichloroethyl 3-methyl-2-(2-sulfino-4-
oxo-3-acetamido-1-azetidinyl)-3-butenoate,
X-4372A -1~- -
.` ' . :
.',
.
lOS6~7Z
- 2'-iodoethyl 3-methyl-2-(2-sulfino-4-oxo-3-
chloroacetamido-l-azetidinyl)-3-butenoate,
4'-methoxybenzyl 3-methyl-2-(2-sulfino-4-oxo-
3-phthalimido-1-azetidinyl)-3-butenoate,
tert-butyl 3-methyl-2-[2-sulfino-4-oxo-3-(2-
bromoacetamido)-l-azetidinyl]-3-butenoate,
benzhydryl 3-methyl-2-[2-sulfino-4-oxo-3-(4-
chlorophenoxyacetamido)-l-azetidinyl]-3-butenoate,
4'-nitrobenzyl 3-methyl-2-[2-sulfino-4-oxo-3- .
(4-nitrobenzyloxycarbonylamino)-1-azetidinyl]-3-butenoate,
2',2',2'-trichloroethyl 3-methyl-2-[2-sulfino-4-
oxo-3-(2,2-dimethyl-3-nitroso-5-oxo-4-phenyl-1-imidazoli-
dinyl)-l-azetidinyl]-3-butenoate,
2'-iodoethyl 3-methyl-2-[2-sulfino-4-oxo-3-acet-
amido-l-azetidinyl]-3-butenoate, and
4-nitrobenzyl 3-methyl-2-[2-sulfino-4-oxo-3-
(4- chlorobenzamido)-1-azetidinyl]-3-butenoate.
' It is recognized that other derivatives of the
azetidinone sulfinyl chlorides, including sulfinate esters,
thiosulfinate esters, mixed carboxylic and sulfonic an-
hydrides, and sulfinamide and sulfinimide derivatives
thereof, can be prepared from the sulfinic acids and from
their precursor sulfinyl chlorides. Such derivatives can be
prepared by well-known conventional procedures employed in
, the preparation of carboxylic acid derivatives e.g. esters,
thioesters, anhydrides, amides and imides from carboxylic
acids and carboxylic acid chlorides. Some azetidinone
sulfinamide derivatives have been prepared directly from
; penicillin sulfoxides [S. Terao, T. Matsuo, S. Tsushima, N.
X-4372A -19-
lQS637Z
Matsumoto, T. Miyawaki, and M. Miyamoto, J. Chem. Soc (C),
1304 (1972)]. It further recognized that such derivatives
can be cyclized to 3-methylenecepham sulfoxide compounds by
the procedures and conditions set forth hereinbelow.
Azetidinone sulfinic acid esters (sulfinates)
of the formula
O : ~
R ~ / 4
o~
~ OOR
wherein R and Rl are as defined hereinabove and R4 is
Cl-C10 alkyl, aryl(Cl-C3alkyl) or Cl-C6 haloalkyl are prepared
from the aforedescribed penicillin sulfoxide derived azetidi-
none sulfinyl chlorides by reacting the sulfinyl chloride
with the corresponding Cl-C10 alkanol, aryI(Cl-C3 alkanol)
or Cl-C6 haloalkanol respectively. Typically the sulfinic
acid esters are prepared by adding the desired alcohol
directly to the reaction mixture in which the azetidinone
sulfinyl chloride has been generated from a penicillin
sulfoxide. The product sulfinic acid ester is then isolated
using standard isolation techniques including evaporation,
crystallization and chromatography.
Exemplary of alcohols which can be employed in the
preparation of the sulfinic acid esters of this invention
are methanol, ethanol, isopropanol, cyclohexanol, 4-chloro-
cyclohexanol, sec-butanol, n-heptanol, menthol, benzyl
alcohol, 2-phenylethanol, 3-phenylpropanol, 2-chlorobenzyl
alcohol, 4-methoxybenzyl alcohol, 2-(4-nitrophenyl) ethanol,
. ~
X-4372A -20-
,:,
,
,, , . , . , ,- , ,- . ,
l~S637Z
2-chloroethanol, 2-bromoethanol, 3-bromocyclohexanol, 4-
chlorobutano~, or 3-chloropropanol.
Representative of the azetidinone sulfinic acid
esters are
4'-nitrobenzyl 3-methyl-2-(2-isobutoxysulfinyl-
4-oxo-3-acetamido-1-azetidinyl)-3-butenoate,
benzhydryl 3-methyl-2-[2-(2-chloropropoxysulfinyl)-
4-oxo-3-phenoxyacetamido-1-azetidinyl]-3-butenoate,
2',2',2'-trichloroethyl 3-methyl-2-[2-(2-bromo-
ethoxysulfinyl)-4-oxo-3-(2-formyloxy-2-phenylacetamido)-1-
azetidinyl]-3-butenoate,
2'-iodoethyl 3-methyl-2-[2-(4-bromobenzyloxy-
sulfinyl)-4-oxo-3-phthalimido-1-azetidinyl]-3-butenoate,
tert-butyl 3-methyl-2-(2-methoxysulfinyl-4-oxo-
3-benzyloxycarbonylamino-1-azetidinyl)-3-butenoate,
4'-chlorophenacyl 3-methyl-2-[2-(2-phenylisopro-
poxysulfinyl)-4-oxo-3-(2-chlorobenzamido)-1-azetidinyl]-3-
butenoate,
4'-methoxybenzyl 3-methyl-2-~2-cyclohexyloxysul-
finyl-4-oxo-3-(2,2-dimethyl-3-nitroso-5 oxo-4-phenyl-
l-imidazolidinyl)-l-azetidinyl]-3-butenoate, and
methyl 3-methyl-2-[2-(3-phenylpropoxysulfinyl)-
4-oxo-3-(4-chlorophenoxyacetamido)-1-azetidinyl]-3-butenoate.
Azetidinone thiosulfinate esters of the formula
O .: :.
Il .
R ~~S 5
o~
~OOR ~ :
X-4372A -21-
105637Z
wherein R and Rl are as defined hereinabove and R5 is Cl-C6
alkyl, aryl, or aryl(Cl-C3 alkyl) are prepared from the
aforedescribed azetidinone sulfinyl chlorides by their
reaction with the corresponding Cl-C6 alkylthiol, arylthiol
or aryl(Cl-C3 alkyl)thiol respectively. The thiosulfinate
esters are prepared and isolated using standard experimental ~ -
techniques. Their preparation is directly analogous to the
preparation of carboxylic acid thioesters from carboxylic
acid chlorides.
Representative of thiols or mercaptans which can
be employed in the preparation of the azetidinone thiosul-
finate esters are methanethiol, ethanethiol, 2-propanethiol,
2-methyl-2-propanethiol, cyclohexanethiol, 2-pentanethiol,
l-butanethiol, thiophenol, 4-chlorothiophenol, 2-phenyl-
ethanethiol, and benzylmercaptan.
, Representative of the azetidinone thiosulfinate
esters of this invention are
4'-nitrobenzyl 3-methyl-2-(2-methylthiosulfinyl
4-oxo-3-formamido-1-azetidinyl)-3-butenoate,
2'-iodoethyl 3-methyl-2-[2-(2-methyl-1-propane-
thiosulfinyl)-4-oxo-3-(4-methoxybenzyloxycarbonylamino)-1-
azetidinyl]-3-butenoate,
2',2',2'-trichloroethyl 3-methyl-2-[2-(1-hexane-
thiosulfinyl)-4-oxo-3-(4-trifluoromethylbenzamido)-1-
azetidinyl]-3-butenoate,
, benzhydryl 3-methyl-2-[2-benzylthiosulfinyl-4-
oxo-3-(4-methylphenoxyacetamido)-1-azetidinyl]-3-butenoate,
and
X-4372A -22-
.'~ ' ''~
, .
~ .
.... : : ~ . . . ,, ., . ;
lOS637Z
tert-butyl 3-methyl-2-[2-phenylthiosulfinyl-4-
oxo-3-(4-nitrobenzyloxycarbonylamino)-1-azetidinyl]-3-
butenoate.
The sulfinamide and sulfinimide derivatives of the
penicillin sulfoxide derived azetidinone sulfinyl chlorides
are represented by the formula
o
Il ,R
10~I 1 ,.~
OOR
wherein R and Rl are as defined hereinabove and wherein
(a) R6 is hydrogen and R7 is hydrogen, R" as defined here-
inabove, or a group of the formula -NHR8 wherein R8 is
; aminocarbonyl, Cl-C3 alkylaminocarbonyl, Cl-C3 alkoxycar-
bonyl, Cl-C3 alkylcarbonyl or tosyl; or wherein (b) R6 and
R7 and the nitrogen atom to which they are bonded taken
together form an imido group of the formula
O :'
., 11 :
O
wherein R2 is as defined hereinabove.
Generally the azetidinone sulfinamides and sul- :
finimides are prepared from the corresponding sulfinyl
chlorides in the same manner carboxamides and carboximides
are prepared from carboxylic acid chlorides; that is, by
reacting the acid chloride with from about 1 to about 2
equivalents of an appropriate amine base. Typ1cally this
X-4372A -23-
' . . .
~L05f~37Z
reaction, like the aforedescribed preparation of sulfinic
acid esters and thioesters, is carried out in an inert
organic solvent such as benzene, toluene, methylene chloride,
chloroform, or ethyl acetate. The following table illus-
trates the particular bases employed to prepare individual
sulfinamides and sulfinimides:
,fll\
OOR
X Amine base
O
-SNH2 4
O
-SNHR" R"-NH2
O O O '.
- ........................... ...
. -SNHNHCNH 2 H2NNHCNH2
O O O
" " "
-SNHNHCNH(Cl-C3)alkyl H2NNHCNH(C1-C3alkyl)
O O O . '
.. .. ..
-SNHNHCO(C1-C3alkyl) 2N CO(Cl C3alkyl)
O O O
ll ll ll
-SNHNHC(Cl-C3alkyl) H2NNHC(C1-C3alkyl)
-SNHNHS-~ CH3 H2NNHS--~ ~-CH3
O o :
N~ ~R2 K I~R
U U
Succinimidosulfinyl azetidinones can also be
; prepared in accordance with the following reaction sequence.
X-4372A -24-
.
.
.
lOS637Z
~`I C/~ I t
HOAC DMF ~ O~ N\ /O\
~OOR IOOR
1 O ~OOR
The penicillin sulfoxide ester is heated in dimethylform-
amide at about 105C. with an excess of N-trimethylsilyl-
succinimide in the presence of acetic acid. The azetidinone
sulfenimide thereby derived is then oxidized with m-chloro-
perbenzoic acid to provide the corresponding sulfinimide
derivative.
Representative of the azetidinone sulfinamides and
sulfinimides are:
4'-nitrobenzyl 3-methyl-2-(2-phthalimidosulfinyl-
4-oxo-3-phenylacetamido-l-azetidinyl)-3-butenoate,
2'-iodoethyl 3-methyl-2-[2-(4-chloroanilinosul-
finyl)-4-oxo-3-phenoxyacetamido-l-azetidinyl]-3-butenoate,
benzhydryl 3-methyl-2-[2-carbamylhydrazosulfinyl-
4-oxo-3-(4-nitrobenzyloxycarbonylamino)-l-azetidinyl]-3-
butenoate,
4'-chlorophenacyl 3-methyl-2-(2-ethylcarbamyl-
hydrazosulfinyl-4-oxo-3-formamido-1-azetidinyl)-3-butenoate,
X-4372A -25-
.
:105637Z
tert-butyl 3-methyl-2-[2-carboethoxyhydrazosul-
finyl-4-oxo-3-(2-formyloxy-2-phenylacetamido)-1-azetidinyl]-
3-butenoate,
- 2',2',2'-trichloroethyl 3-methyl-2-(2-propionyl-
hydrazosulfinyl-4-oxo-3-phthalimido-1-azetidinyl)-3-butenoate,
methyl 3-methyl-2-[2-(4-tolylsulfonylhydrazo-
sulfinyl)-4-oxo-3-(2-chlorobenzamido)-1-azetidinyl]-3-
butenoate,
4'-methoxybenzyl 3-methyl-2-(2-succinimidosulfinyl-
4-oxo-3-propionamido-1-azetidinyl)-3-butenoate,
4'-nitrobenzyl 3-methyl-2-[2-(4-methoxyanilino-
sulfinyl)-4-oxo-3-phenoxyacetamido-1-azetidinyl]-3-butenoate,
2'-iodoethyl 3-methyl-2-(2-carbomethoxyhydraæo-
sulfinyl-4-oxo-3-chloroacetamido-1-azetidinyl)-3-butenoate,
and
2',2',2'-trichloroethyl 3-methyl-2-[2-acetylhydra-
zosulfinyl-4-oxo-3-(2-tert-butoxycarbonylamino-2-phenyl-
acetamido)-l-azetidinyl]-3-butenoate.
In addition to the aforedescribed sulfinamides,
: 20 other sulfinamides can be employed as starting materials in
the cyclization process of this invention~ In particular,
: azetidinone sulfinamides of the formula
O NHCOOR O NHCOR
Il 'I ~ 11 1
I~ o r
OOR OOR
wherein R and Rl are as defined hereinabove, and Rg is
Cl-C6 alkyl or phenyl, can by cyclized under the acidic
X-4372A -26-
.
105637Z
conditions of the present process to provide the corre-
sponding 3-methylenecepham sulfoxides. Such azetidinone
sulfinamides are known compounds. [S. Terao et al., supra].
They are prepared directly from penicillin sulfoxides by
their reaction with azodicarboxylates or diacyldiimides.
With the somewhat milder reaction conditions (verses those
reaction conditions for sulfinyl halide preparation) for the
preparation of these azetidinone sulfinamides, a wider range
of penicillin sulfoxide starting materials may be employed. -
Thus Rl in the sulfinamide formula immediately hereinabove
can represent, in addition to those groups described herein-
O
before, an amide group of the formula R''''CH2CNH- wherein
R'''' is a heteroaryl group including among others, 2-
thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-thiazoyl, or 4-
isoxazolyl.
Exemplary of the sulfinamide starting materials
derived directly from penicillin sulfoxides and azodicar-
boxylates or diacyldiimides, for the process of this in-
vention are
4'-nitrobenzyl 3-methyl-2-[2-(N,N'-dicarbotert-
butoxyhydrazosulfinyl)-4-oxo-3-(2-thienylacetamido)-1-
azetidinyl]-3-butenoate,
2'-iodoethyl 3-methyl-2-[2-(N,N'-dibenzoylhydrazo-
sulfinyl)-4-oxo-3-phenoxyacetamido-1-azetidinyl]-3-butenoate,
2',2',2'-trichloroethyl 3-methyl-2-[2-(N,N'-
dicarboethoxyhydrazosulfinyl)-4-oxo-3-phenylacetamido-1-
azetidinyl]-3-butenoate,
' ~
X-4372A -27-
lOS637Z
benzhydryl 3-methyl-2-[2-(N,N'-dicarbomethoxyhy-
drazosulfinyl)-4-oxo-3-(2-formyloxy-2-phenylacetamido)-1-
azetidinyl]-3-butenoate, and
4'-chlorophenacyl 3-methyl-2-[2-(N,N'-dicarbo-
propoxyhydrazosulfinyl)-4-oxo-3-acetamido-1-azetidinyl]-3-
butenoate.
The scope of reagents suitable for effecting the
intramolecular sulfinylation of the process of this in-
vention is essentially coextensive with that of those
reagents which have been recognized as capable of effectu-
ating acylation reactions of the Friedel-Crafts type. An
extensive survey of Friedel-Crafts acylations, related
reactions, and catalysts therefor is presented by George A.
Olah in "Friedel-Crafts Chemistry," John Wiley and Sons, New
York, N.Y., 1973.
Suitable reagents which can be employed in the
process of this invention to effect intramolecular cycliza-
tion of the aforedescribed azetidinone sulfinyl chlorides
and sulfinyl bromides are the conventional Friedel-Crafts
catalyst reagents, including Lewis acid type catalysts,
Bronsted proton acid type catalysts, and metathetic cation-
forming agents. Preferred of the Lewis acid type Friedel-
Crafts catalysts are the metal halide Lewis acid type
catalysts. The Bronsted proton acid type catalysts include
acidic chalcides (particularly acidic oxides), conjugate
Friedel-Crafts catalysts of the formula HMA4 6' and both the
organic and the inorganic Bronsted proton acids themselves.
Cyclization of the aforedescribed azetidinone
sulfinic acids, esters, thioesters, amides, and imides,
X-4372A -28-
~05637Z
is accomplished with Bronsted proton acid type catalysts.
The Lewis acid type catalysts are characterized by
the presence of a vacant orbital which can accept an avail- -
able electron pair, either unshared. e.g. on an oxygen,
sulfur, or halide atom, or in a ~ orbital, of a Lewis base
type compound to form a covalent bond. Exemplary of suitable
Lewis acid type metal halide catalysts are aluminum chloride,
stannic chloride, stannic bromide, zinc chloride, zinc
bromide, antimony pentachloride, titanium tetrachloride,
ferric chloride, gallium trichloride, zirconium tetrachloride,
mercuric chloride, chromium trichloride and like metal
halide agents exhibiting Friedel-Crafts type catalytic
activity. Preferred of such catalysts are stannic chloride,
zinc chloride, zinc bromide, zirconîum tetrachloride and
titanium tetrachloride. Stannic chloride is most preferred.
The Bronsted proton acid type catalysts differ
from the acidic halide Lewis acid type Friedel-Crafts
catalysts in that, in the proton acid case, the electron
acceptor quality is due to a positively charged entity, a
proton. Exemplary of suitable organic Bronsted proton acid
catalysts are methanesulfonic acid, ethanesulfonic acid,
trifluoroacetic acid, trichloroacetic acid, dichloroacetic
acid and like organic acid compounds. Suitable inorganic
Bronsted proton acid catalysts for the process of this
invention include sulfuric acid, phosphoric acid, poly-
phosphoric acid, perchloric acid, chlorosulfonic acid,
fluorosulfonic acid and like proton acid catalysts. Pre-
ferred of the Bronsted proton acid catalysts are methane-
sulfonic acid, trifluoroacetic acid, phosphoric acid,
sulfuric acid, and polyphosphoric acid.
X-4372A -29-
lOS637Z
The chalcide catalysts include a wide variety of
solid oxides and sulfides. Olah, in "Friedel-Crafts Chemistry"
supra, reported that as far as Friedel-Crafts acylations are
concerned, acidic solid chalcide catalysts "seem to be the
most attractive catalysts of the future." Of the acidic
chalcides, acidic oxides or mixed acidic oxides are pre-
ferred for the process of this invention. Representative of
such acidic oxides are alumina, silica, Cr203, P205, Tio2,
A1203 CoO and A1203 MnO. Phosphorus pentoxide is most
preferred. Generally for Friedel-Crafts acylations de-
hydrated chalcides are inactive as catalysts; the addition
of small amounts (about 1-5~ by weight) of water, however,
activates the catalytic activity of these catalysts.
Absorbed protons seem to be essential to the catalytic
activity of acid chalcide catalysts. The effect of water
suggests that Bronsted acidity is responsible for the
catalyst activity of the acid chalcides [F. E. Condon in
"Catalysts," Vol. VI, ed. P. H. Emmet, Reinhold Publ. Corp.,
New York, N.Y. (1953), p 43]. Thus for the purpose of this
2~ invention acid chalcides are classified as Bronsted proton
type catalysts.
It should also be noted that, as is sometimes the
case in Friedel-Crafts type acylations, a metal halide Lewis
acid catalyst can be used in conjunction with a Bronsted
proton acid catalyst, the effective catalyst agent being a
conjugate Friedel-Crafts acid catalyst of the type HMA4 6
wherein M is a cation and A is an anion with a valence of -1.
Bronsted acid type activity is presumed to be responsible
for the effectiveness of this type of catalyst reagent.
Thus, for the purpose of this invention it is intended that
3~
.
1~ . ,
.. ., ~ , . ,. . : -
. -
105~;372
such conjugate catalysts be classified as Bronsted type
catalysts. Exemplary of such conjugate acid catalysts are
HBF4, HAlC14, HAsF6, and HAlBr4.
Although their activity in the real sense is not
catalytic (because they are generally consumed in the cation-
forming reaction), metathetic cation-forming agent~, par-
ticularly anhydrous silver salts, such as silver _-toluene-
sulfonate, silver perchlorate, silver phosphate, silver
tetrafluoroborate, silver trifluoroacetate and like silver
compound5 are effective "cataIysts" in the Friedel-Crafts
type cyclization of azetidinone sulfinyl halides in the
process of this invention. These silver salts act as
metathetic cation-forming substances when reacted with
halide reagents and not as acids. Thus the proposed inter-
mediate sulfinium type cation is generated from the sulfinyl
chloride by chloride abstraction with the silver cation and
not by an acid-base type reaction as is the case with the
aforedescribed acid catalyst reagents. The insoluble by-
product silver chloride precipitates. Silver p-toluene-
sulfonate is a preferred metathetic cation-forming agent for
the process of this invention.
The metathetic cation-forming agents are effective
only with azetidinone sulfinyl halide starting materials;
such reagents are not suitable for the cyclization of any of
the other corresponding sulfinic acid derivatives. Such
other sulfinic acid derivatives are cyclized using a Bronsted
proton acid type catalyst.
The azetidinone sulfinyl halide starting materials
for the process of the present invention can thus be cyclized
X-4372A -31-
~ .
1~5tj37Z
by their reaction with a Lewis acid type metal halide
catalyst, a Bronsted proton acid type catalyst, or a meta-
thetic cation-forming agent. The best yields of 3-methylene-
cepham sulfoxides from azetidinone sulfinyl chlorides, pre-
ferred starting materials for the process of this invention,
are achieved when Lewis acid type metal halide catalysts are
employed. However, good yields of the product sulfoxides
from sulfinyl halide starting materials have been achieved
with Bronsted proton acid type catalysts and metathetic
cation-forming agents. Lewis acid type metal halide catalysts
are preferred in the process of the present invention when
azetidinone sulfinyl chlorides and sulfinyl bromides are
employed as starting materials. Bronsted proton acid type
catalysts are preferred in the process of this invention
when the azetidinone sulfinic acids, and the corresponding
sulfinate esters, thiosulfinate esters, sulfinamides and
sulfinimides are employed as starting materials.
Any of a wide variety of dry inert organic sol-
vents may be employed as the medium for ~he cyclization
process of this invention. By "inert organic solvent" is
meant an organic solvent which, under the conditions of the
process, does not enter into any appreciable reaction with
either the reactants or the products. Since the sulfinyl
chloride starting materials, like other acid halide type
' reagents, are susceptible to hydrolysis and to attack by
other protic compounds, e.g. alcohols and amines, moisture
and other such protic compounds in the reaction medium
should be rigorously excluded. A dry aprotic organic
, ~
X-4372A -32-
"
:
:~, .
lOS637;~
solvent is thus preferred. Trace amounts of water such as
that found in commercially dried solvents, can be tolerated;
however, it is generally preferred that the process of this
invention be carried out under anhydrous conditions. Suitable
solvents include, for example, aromatic hydrocarbons, such
as, benzene, toluene, xylene, chlorobenzene, nitrobenzene,
or nitromesitylene; halogenated aliphatic hydrocarbons, such
as chloroform, methylene chloride, carbon tetrachloride,
1,2-dichloroethane (ethylene chloride), 1,1,2-trichloro-
ethane, 1,1-dibromo-2-chloroethane; and other solvents
recognized by those skilled in the art as suitable for
Friedel-Crafts type reactions, including among others,
carbon disulfide and nitromethane. The preferred solvents
are aromatic hydrocarbons and halogenated aliphatic hydro- ~;
carbons. Most preferred aromatic hydrocarbon solvents are
benzene and toluene. Most preferred of the halogenated
aliphatic hydrocarbons are methylene chloride, ethylene
chloride, and 1,1,2-trichloroethane.
The temperature at which the process of the
present invention is carried out is dependent on the par-
ticular catalyst or agent employed; the temperature must be
sufficient to effect the cyclization of the starting material.
It is well known by those skilled in the art that different
Friedel-Crafts reagents are effective at different tem-
peratures in accomplishing, for example, a given acylation.
Moreover, such is known to be true even within a particular
class of Friedel-Crafts reagents. The process of the present
invention can be carried out generally at a temperature
ranging from 5 to 150C.
;
X-4372A -33-
-.
105637Z
The cyclization of both the azetidinone sulfinic
acid derivatives and the sulfinyl halides can be carried out
with Bronsted proton acid type catalysts in an inert organic
solvent at a temperature of about 70 to about 115C.,
typically the reflux temperature of the medium in which the
cyclization is being carried out.
Alternatively, any one of the aforedescribed
azetidinone sulfinyl derivatives can be cyclized to the
corresponding exomethylenecepham sulfoxide by its dissolution
in a neat organic Bronsted proton acid such as methane-
sulfonic acid, trifluoromethanesulfonic acid, trifluoro-
acetic acid, trichloroacetic acid or dichloroacetic acid.
The time required for cyclization under such conditions is
dependent upon the nature of the sulfinyl derivative, the
particular acid employed and the temperature of the reaction.
Typically azetidinone sulfinamide and sulfinimide deri-
vatives are cyclized within 5 to 10 minutes at room tem-
perature in methane sulfonic acid while cyclizati~n of the
sulfinic acids, esters, and thioester derivatives thereof,
is complete after about 30 minutes at room temperature.
The cyclization of the aforedescribed azetidinone
sulfinyl halides is preferably carried out at a temperature
ranging from about 10 to about 115C. More preferably the
reaction is accomplished at a temperature between about 20
and about 85C., the most preferred temperature being
dependent primarily upon the solubility and the catalytic
activity of the particular cyclizing agent employed. When a
Bronsted proton acid type catalyst (including acid chalcide
catalysts and conjugate Friedel-Crafts acid catalysts) is
'
X-4372A -34-
- -: . . . .
: .
lOS637Z
employed as the catalyst reagent to cyclize a sulfinyl
halide derivative in an inert organic solvent, the preferred
reaction temperature ranges from about 70 to about 115,
typically the reflux temperature of the medium in which the
cyclization is being carried out. However, cyclization of
methyl 3-methyl-2-(2-chlorosulfinyl-4-oxo-3-phthalimido-
1-azetidinyl)-3-butenoate was effected in neat polyphos-
phoric acid at room temperature. The intramolecular sul-
finylation, when effected by a metathetic cation-forming
agent, is preferably carried out at a temperature between
about 20 and about 80; most preferred is room temperature.
When a metal halide Lewis acid type catalyst, preferred for
the cyclization of the sulfinyl halides, is employed, the
preferred temperature at which the process can be carried
out is particularly dependent on the individual metal halide
catalyst reagent. Thus, when stannic chloride, stannic
bromide or antimony pentachloride, which reagents are
usually soluble in the solvents for the process, are em-
ployed, the cyclization is carried out preferably at a
temperature from about 10 to about 40C.; the most pre-
ferred temperature when such reagents are used is about room
temperature. E~owever, when titanium tetrachloride, a liquid -
which is also soluble in most of the reaction solvents, is
employed, an elevated temperature of about 40 to about 100C.
is preferred for the conversion. When metal halide Lewis
acid type catalysts, other than those few specifically
referred to immediately hereinabove, are employed in the
process of this invention, an elevated temperature of about
40 to about 115 is generally preferred; a temperature of
about 40 to about 85 is most preferred.
X-4372A _35_
'
1056372 :
When stannic chloride is employed as the cyclizing
agent in the process of the present invention in a toluene
medium, an intermediate stannic chloride-sulfinyl halide
complex can be isolated simply by filtering the reaction
mixture. The complex can be dried and stored or it can be
dissolved in ethyl acetate and washed successively with
hydrochloric acid, water, and brine to provide the cor-
responding exomethylenecepham sulfoxide.
In order to ensure completion of the cyclization
reaction of a sulfinyl halide, at least a stoichiometric
(mole per mole) amount of a Lewis acid type Friedel-Crafts
catalyst or of a metathetic cation-forming agent is em-
ployed. Using less than one molar equivalent of such
reagents results in lower yields of the product 3-methylene-
cepham sulfoxide and leaves a portion of the sulfinyl
chloride unreacted. Typically the amount of catalyst
reagent employed will range from slightly over one equivalent
to about two equivalents per mole of sulfinyl chloride.
Preferably about 1.1 equivalents of metal halide Lewis acid
or of metathetic cation-forming agent are employed for each
mole of azetidinone sulfinyl halide starting material.
Although less than a stoichiometric amount of a Bronsted
proton acid type Friedel-Crafts catalyst can be employed to
effect complete cyclization of either a sulfinyl chloride or
other sulfinic acid derivative, approximately an equivalent
amount or more of such acid catalysts is typically employed.
As stated hereinabove, the cyclization can also be effected
in a neat protic acid; such is a preferred method~
The time of the reaction under the aforedescribed
conditions will range generally from 5 minutes to about 2
X-4372A -36-
.
-
10563~
hours with the reaction time being dependent to some extent
upon the particular reactants, the solvents employed and the
temperature at which the reaction is carried out. Usually,
the reaction will be completed after the reactants have been
maintained in contact at the preferred temperatures for
about 45 to 90 minutes; however, as indicated hereinabove,
shorter reaction times are appropriate under certain con-
ditions. The reaction mixture can easily be monitored for
example, by comparative thin-layer chromatography, to
determine when the cyclization reaction has reached completion.
The mechanism by way of which the process of the
present invention accomplishes the desired results has not
been established with certainty, but the intermediacy of a
sulfinium ion
O :~
+ 1 1 .
R1\ / S~ Rl\l / S
\ H ~ CH~
~OOR OOR
or a complex thereof, wherein the C-2 substituent on the
azetidinone ring is
X X:M
I ................... I
S=O: M or -- S=O
::: '
(M = H or metal halide Lewis acid) is highly probable.
Cyclization of the deuterated sulfinyl chloride prepared -
from methyl 6-phthalimido
X-4372A -37-
. .
~05637Z
o o
Il o 11 o
5 Cl ~ D
I~OOCH3 ~OOCH3
3~-methyl-3a-trideuteriomethylpenam-3-carboxylate la-oxide
[R.D.G. Cooper, Journal of the American Chemical Society,
92, 5010 (1970)], with stannic chloride provided methyl 7-
phthalimido-2,2-dideuterio-3-methylenecepham-4-carboxylate
l-oxide.
The following are representative of the conver-
sions which can be accomplished by the process of the
present invention: :
tert-Butyl 3-methyl-2-(2-chlorosulfinyl-4-oxo-3-
phthalimido-l-azetidinyl)-3-butenoate, derived from tert-
butyl 6-phthalimidopenicillanate sulfoxide, is cyclized to
7-phthalimido-3-methylenecepham-4-carboxylic acid sulfoxide;
Benzyl 3-methyl-2-(2-chlorosulfinyl-4-oxo-3-
benzyloxycarbonylamino-l-azetidinyl)-3-butenoate, derived
from benzyl 6-benzyloxycarbonylamino penicillanate sul-
foxide, is cyclized to benzyl 7-benzyloxycarbonylamino-3-
methylenecepham-4-carboxylate sulfoxide;
4'-Methoxybenzyl-3-methyl-2-(2-sulfino-4-oxo-3-
phenoxyacetamido-l-azetidinyl)-3-butenoate, derived from
4'-methoxybenzyl 6-phenoxyacetamidopenicillanate sulfoxide,
is cyclized to 7-phenoxyacetamido-3-methylenecepham-4-car-
boxylic acid sulfoxide;
X-4372A -38-
1C~S63~Z
2',2',2'-Trichloroethyl 3-methyl-2-(2-chloro-
sulfinyl)-4-oxo-3-phenylacetamido-1-azetidinyl)-3-butenoate,
derived from 2',2',2'-trichloroethyl 6-phenylacetamidopeni- .
cillanate sulfoxide, is cyclized to 2',2',2'-trichloroethyl
7-phenylacetamido-3-methylenecepham-4-carboxylate sulfoxide;
4'-Nitrobenzyl 3-methyl-2-[2-(N,N'-di(carbomethoxy)-
hydrazosulfinyl)-4-oxo-3-(2-thienylacetamido)-1-azetidinyl]-
3-butenoate, derived from 4'-nitrobenzyl 6-(2-thienylacet-
amido)penicillanate sulfoxide, is cyclized to 4'-nitrobenzyl
7-(2-thienylacetamido)-3-methylenecephem-4-carboxylate
sulfoxide;
Benzhydryl 3-methyl-2-[2-chlorosulfinyl-4-oxo-
3-(2,2-dimethyl-3-nitroso-5-oxo-4-phenyl-1-imidazolidinyl)-
l-azetidinyl]-3-butenoate, derived from benzhydryl 6-(2,2-
dimethyl-3-nitroso-5-oxo-4-phenyl-1-imidazolidinyl)penicil-
lanate sulfoxide [hetacillin benzhydryl ester], is cyclized
to 7-(2,2-dimethyl-3-nitroso-5-oxo-4-phenyl-1-i.midazolidinyl)-
3-methylenecepham-4-carboxylic acid sulfoxide;
2'-Iodoethyl 3-methyl-2-(2-sulfino-4-oxo-3-chloro-
20 acetamido-1-azetidinyl)-3-butenoate, derived from 2'-iodo- :
ethyl 6-chloroacetamidopenicillanate sulfoxide, is cyclized
to 2'-iodoethyl 7-chloroacetamido-3-methylenecepham-4- ~:
carboxylate sulfoxide; :~
Dimethylallyl 3-methyl-2-(2-chlorosulfinyl-4- .
oxo-3-maleimido-1-azetidinyl)-3-butenoate, derived from
dimethylallyl 6-maleimidopenicillanate sulfoxide, is cy-
clized to dimethylallyl 7-maleimido-3-methylenecepham-
4-carboxylate sulfoxide;
Succinimidomethyl 3-methyl-2-(2-chlorosulfinyl-
4-oxo-3-cyanoacetamido-1-azetidinyl)-3-butenoate, derived
X-4372A -39-
``` 10563~Z
from succinimidomethyl 6-cyanoacetamidopenicillanate sul-
foxide, is cyclized to succinimidomethyl 7-cyanoacetamido-
3-methylenecephem-4-carboxylate sulfoxide;
4'-Nitrobenzyl 3-methyl-2-[2-sulfino-4-oxo-3-
(4-nitrobenzyloxycarbonylamino)-1-azetidinyl]-3-butenoate,
derived from 4'-nitrobenzyl 6-(4-nitrobenzyloxycarbonyl-
amino)penicillanate sulfoxide, is cyclized by 4'-nitrobenzyl
7-(4-nitrobenzyloxycarbonylamino)-3-methylenecepham-4-
carboxylate sulfoxide; :
4'-Nitrobenzyl 3-methyl-2-[2-chlorosulfinyl-
4-oxo-3-(4-chlorobenzamido)-1-azetidinyl]-3-butenoate,
derived from 4'-nitrobenzyl 7-(4-chlorobenzamido)penicil-
lanate sulfoxide, is cyclized to 4'-nitrobenzyl 7-(4-chloro-
benzamido)-3-methylenecephem-4-carboxylate sulfoxide;
Benzhydryl 3-methyl-2-[2-chlorosulfinyl-4-oxo- :
3-(2-tert-butoxycarbonylamino-2-phenylacetamido)-1-azeti-
dinyl]-3-butenoate, derived from benzhydryl 6-(2-tert-
butoxycarbonylamino-2-phenylacetamido ? penicillanate sul-
foxide, is cyclized to 7-(2-amino-2-phenylacetamido)-3-
methylenecepham-4-carboxylic acid sulfoxide;
4'-Methoxybenzyl 3-methyl-2-[2-chlorosulfinyl-4-
oxo-3-(2-benzyloxy-2-phenylacetamido)-1-azetidinyl]-3-
butenoate, deriv~d from 4'-methoxybenzyl 6-(2-benzyloxy-2-
phenylacetamido)penicillanate sulfoxide, is cyclized to
7-(2-benzyloxy-2-phenylacetamido)-3-methylenecepham-4-car-
boxylic acid sulfoxide;
2',2',2'-Trichloroethyl 3-methyl-2-[2-chloro-
sulfinyl-4-oxo-3-(2-benzyloxy-2-phenylacetamido)-1-azeti-
dinyl]-3-butenoate, derived from 2',2',2'-trichloroethyl
X-4372A -40_
I, :
105637Z
6-(2-benzyloxy-2 phenylacetamido)penicillanate sulfoxide, is
cyclized to 2',2',2'-trichloroethyl 7-(2-benzyloxy-2-
phenylacetamido)-3-methylenecephem-4-carboxylate sulfoxide;
4'-Nitrobenzyl 3-methyl-2-(2-isoproxysulfinyl-
4-oxo-3-benzamido-1-azetidinyl)-3-butenoate, derived from
4'-nitrobenzyl 6-benzamidopenicillanate sulfoxide, is
cyclized to 4'-nitrobenzyl 7-benzamido-3-methylenecepham-
4-carboxylate sulfoxide;
2'-Iodoethyl 3-methyl-2-(2-cyclohexyloxysulfinyl-
4-oxo-3-chloroacetamido-1-azetidinyl)-3-butenoate, derived
from 2'-iodoethyl 6-chloroacetamidopenicillanate sulfoxide,
is cyclized to 2'-iodoethyl 7-chloroacetamido-3-methylene-
cepham-4-carboxylate sulfoxide;
2',2',2'-Trichloroethyl 3-methyl-2-[2-N,N'-di(car-
boethoxy)hydrazosulfinyl-4-oxo-3-(2-thienylacetamido)-1- ~-
azetidinyl]-3-butenoate, derived from 2',2',2'-trichloro- ~ ;
ethyl 6-(2-thienylacetamido)penicillanate sulfoxide, is
cyclized to 2',2',2'-trichloroethyl 7-(2-thienylacetamido)-
3-methylenecepham-4-carboxylate sulfoxide;
Methyl 3-methyl-2-[2-carbamylhydrazosulfinyl-4- ... .
oxo-3-(3-nitrophenoxyacetamido)-1-azetidinyl]-3-butenoate,
derived from methyl 6-(3-nitrophenoxyacetamido)penicillanate
sulfoxide, is cyclized to methyl 7-(3-nitrophenoxyacetamido)-
3-methylenecepham-4-carboxylate sulfoxide;
Benzhydryl 3-methyl-2-[2-(4-chloroanilinosulfinyl)-
4-oxo-3-(4-nitrobenzyloxycarbonylamino)-1-azetidinyl]-3-
butenoate, derived from benzhydryl 6-(4-nitrobenzyloxycarbonyl-
amino)penicillanate sulfoxide is cyclized to 7-(4-nitrobenzyl-
oxycarbonylamino)-3-methylenecepham-4-carboxylic acid sulfoxide;
X-4372A -41-
1~5637Z
4'-Nitrobenzyl 3-methyl-2-(2-phthalimidosulfinyl-
4-oxo-3-phenylacetamido-1-azetidinyl)-3-butenoate derived
from 4'-nitrobenzyl 6-phenylacetamidopenicillanate sulfoxide,
is cyclized to 4'-nitrobenzyl 7-phenylacetamido-3-methylene-
cepham-4-carboxylate sulfoxide;
2'-Iodoethyl 3-methyl-2-(2-bromosulfinyl-4-oxo-
3-phthalimido-1-azetidinyl)-3-butenoate, derived from 2'-
iodoethyl 6-phthalimidopenicillanate sulfoxide, is cyclized
to 2'-iodoethyl 7-phthalimido-3-methylenecepham-4-carboxylate :~
sulfoxide;
4'-Nitrobenzyl 3-methyl-2-(2-phenylthiosulfinyl-
4-oxo-3-phenoxyacetamido-1-azetidinyl)-3-butenoate, derived
from 4'-nitrobenzyl 6-phenoxyacetamidopenicillanate sulfoxide,
is cyclized to 4'-nitrobenzyl 7-phenoxyacetamido-3-methylene-
cepham-4-carboxylate sulfoxide;
Phenacyl 3-methyl-2-[2-(2-phenylethylthiosulfinyl)-
4-oxo-3-(2-benzyloxy-2-phenylacetamido)-1-azetidinyl]-3-
butenoate derived from phenacyl 6~(2-benzyloxy-2-phenyl-
acetamido)penicillanate sulfoxide, is cyclized to phenacyl
20 7-(2-benzyloxy-2-phenylacetamido)-3-methylenecepham-4-car-
boxylate sulfoxide;
tert-Butyl 3-methyl-2-[2-methylcarbamylhydrazo-
sulfinyl-4-oxo-3-(4-methoxyphenylacetamido)-1-azetidinyl]-3-
butenoate, derived from tert-butyl 6-(4-methoxyphenylacet-
amido)penicillanate sulfoxide, is cyclized to 7-(4-methoxy-
phenylacetamido)-3-methylenecepham-4-carboxylic acid sulfoxide;
Trimethylsilyl 3-methyl-2-(2-carbomethoxyhydrazo-
sulfinyl-4-oxo-3-phenylacetamido-1-azetidinyl)-3-butenoate, : :
derived from trimethylsilyl 6-phenylacetamidopenicillanate ::
;:
X-4372A -42-
.
.
10~6372
sulfoxide, is cyclized to 7-phenylacetamido-3-methylenecepham-
4-carboxylic acid sulfoxide; and
4'-chlorophenacyl 3-methyl-2-[2-(2-chloroethoxy-
sulfinyl)-4-oxo-3-formamido-1-azetidinyl]-3-butenoate,
derived from 4'-chlorophenacyl 6-formamidopenicillanate
sulfoxide, is cyclized to 4'-chlorophenacyl 7-formamido-3-
methylenecepham-4-carboxylate sulfoxide.
The yield of the products will vary depending upon
the particular reactants which are employed, the relative
quantities of reagents and the other aforementioned con-
ditions of reaction.
The products produced in accordance with the
process of this invention can be isolated and purified by
employing conventional experimental techniques. These -~
include chromatographic separation, filtration, crystal-
lization, or recrystallization.
The most preferred side chains, Rl in the above
formulae, for the process of the present invention are those
' side chains found on penicillins produced directly by
fermentation, primarily the phenylacetamido and phenoxy-
acetamido side chains. Such penicillins can be esterified
and oxidized (not necessarily in that order) to the respec-
tive penicillin sulfoxide esters from which the sulfinyl
chloride intermediates, and other starting materials for the
process of the present invention, are derived. It should be
noted that the aforementioned preferred side chains are so
~ preferred primarily for economic reasons. Penicillin pre-
j cursors having such side chains are readily available and
relatively inexpensive; the advantage of performing the
X-4372A -43-
.`.
lOS63'~Z
process of this invention with the aforedescribed sulfinyl
intermediates derived therefrom is readily discernible. of
course, penicillin sulfoxides bearing other known side
chains may easily be prepared (by acylation of 6-APA or
6-APA esters and subsequent oxidation) and employed in the
process of the present invention.
The product 3-methylenecepham sulfoxides of the
process of this invention are useful as intermediates in the
preparation of antibiotic compounds. The sulfoxides can be
reduced by known procedures, typically with phosphorus tri-
chloride or phosphorus tribromide in dimethylformamide, to
provide the correspondlng 3-methylenecephams which are pre-
dictably converted in high yield to desacetoxycephalosporins
of the formula
R1\ /S
I--CH3
~ OOR
upon treatment with triethylamine in dimethylacetamide.
[Robert R. Chauvette and Pamela A. Pennington, J. Org.
Chem., 38, 2994 tl973).]. The desacetoxycephalosporin
esters are converted to active antibiotics by cleavage of
the ester function. Deesterification can be achieved,
depending on the nature of the protecting group, by any one
of several recognized procedures, including (1) treatment
with an acid such as trifluoroacetic acid, formic acid,
or hydrochloric acid; (2) treatment with zinc and an acid --
such as formic acid, acetic acid or hydrochloric acid; or
(3) hydrogenation i~ the presence of palladium, platinum,
X-4372A -44-
~. - .,. ,. .: - ., . . : , . ............................ ~
- . . -:. . ~ ,, .: . : . . ... -
10563~2
rhodium or a compound thereof, in suspension, or on a
carrier such as barium sulfate, carbon, or alumina.
Alternatively the exomethylenecephams can be em-
ployed in the preparation of novel cephem antibiotics of the
formula
\~---t \t
OOH
wherein Y is, for example, chloro, bromo or methoxy. Such
chemical conversions of 3-exomethylenecepham compounds have
been disclosed in the chemical literature ~Robert R. Chauvette
and Pamela A. Pennington, Journal of the American Chemical
Society, 96, 4986 tl974)].
In general, the exomethylenecepham compounds are
converted by low temperature ozonolysis to 3-hydroxycephems
which are in turn treated with diazomethane in methylene
chloride/ether at room temperature to afford the 3-methoxy-
cephem derivatives. The 3-halocephems are derived from the
3-hydroxycephem esters by treatment with a halogenating
reagent such as thionyl chloride or phosphorus tribromide
in dimethylformamide. The corresponding cephem acids
exhibit potent antibacterial activity.
The following examples are provided to further
illustrate the present invention. It is not intended that
this invention be limited in scope by reason of any of these
examples. In the following examples and prepara~ions nuclear
magnetic resonance spectra are abbreviated nmr. The nuclear -
magnetic resonance spectra were obtained on a Varian Associates
:
X-4372A -45_
-
105637Z
T-60 Spectrometer using tetramethylsilane as the reference
standard. The chemical shifts are expressed in ~ values in
parts per million (ppm) and coupling constants (J) are ex-
pressed as Hz in cycles per second.
Example 1
Methyl 7-Phthalimido-3-methylenecepham-4-carboxylate-1-
. . .
A. Stannic Chloride
A mixture of 18.8 g. (50 mmol.) of methyl 6-
phthalimidopenicillanate sulfoxide and 6.7 g. (50 mmol.) of
N-chlorosuccinimide in 1 1. of dry carbon tetrachloride was
refluxed for 70 min. The crude product was cooled to room
temperature, filtered, washed with water (1 x 500 ml.), and
dried (MgSO4). The solvent was then evaporated ln vacuo to
dryness. The nmr spectrum indicated a complete conversion
to the sulfinyl chloride; nmr (CDC13) ~1.97 (broad s, 3), -
3.86 (s, 3), 5.05 (br. s, 2), 5.2 (d, 1, J=2 Hz), 5.77 (d,
1, J=4 Hz), 5.9 (d, 1, J=4 Hz), and 7.83 (m, 4). The product
sulfinyl chloride was then dissolved in 1 1. of dry CH2C12
and 6 ml. (50 mmol.) of anhydrous stannic chloride was
added. The resulting solution was stirred for 45 min.,
washed with lN. hydrochloric acid (2 x 200 ml.), and dried
(MgSO4). Evaporation in vacuo gave 18.4 g. (98.4%) of a
mixture of R- and S-sulfoxides (ca. 3:2 by nmr) as a light
yellow foam. A portion of this mixture (1.26 g.) was
separated by chromatography over silica gel using chloro-
form/ethyl acetate as a so`lvent. Fractions 6-10 contained
pure R-sulfoxide (340 mg.) which was recrystallized from
methylene chloride/cyclohexane (m.p. 201-202);
nmr (CDC13) ~3.62 and 4.12 (ABq, 2, J=14 Hz), 3.85 (s, 3),
X-4372A -46-
..
.
105637Z
4.88 (d, 1, J=4.5 Hz), 5.25 (br. 5, 1), 5.58 (m, 2), 5.97
(d, 1, J=4.5 Hz), and 7.84 (m, 4); mass spectrum m/e 374, ~ --
358, 346,- 298, 287, 239, 220; ir (KBr): 1780, 1745, and
1390 cm 1.
Anal. Calcd. for C17H14N2O6S (374.37):
C, 54.54; H, 3.77; N, 7.48; O, 25.64; S, 8.56.
Found: C, 54.41; H, 4.06; N, 7.26; O, 25.59; and S, 8.41.
Fractions 11-18 contained a mixture of the R- and
S-sulfoxides and fractions 19-35 gave 210 mg. of the S-
sulfoxide, which was recrystallized from methylene chlo-
ride/cyclohexane; nmr (CDC13j ~3.63 (s, 2), 3.82 (s, 3),
4.90 (d, 1, J=4.5 Hz), 5.32 (s, 1), 5.46 (br. s, 1), 5.64
(d, 1, J= 4.5 Hz), 5.77 (s, 1), and 7.84 (m, 4); mass
spectrum m/e 374, 358, 346, 298, 287, 239, 200; ir (KBr)
1775, 1745, 1725, 1390, 1205, 1111, 1051, /30, and 715
cm- l ,
Anal. Calcd. for C17Hl~N2O6S:
C, 54.54; H, 3.77; N, 7.48.
Found: C, 54.33; H, 3.76; N, 7.36.
B. Titanium tetrachloride
A solution of 0.41 g. of methyl 3-methyl-2-(2-
chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl)-3-butenoate
and 0.12 ml. of titanium tetrachloride in 30 ml. of dry
1,2-dichloroethane was refluxed for 30 minutes. The mixture
was then cooled to room temperature, washed with lN.HCl and
brine and dried (MgSO4). Evaporation in vacuo to dryness
provided 0.34 g. of methyl 7-phthalimido-3-methylenecepham-
4-carboxylate l-oxide.
X-4372A _47_
~: ~ .. .
lOS637Z
C. Aluminum Chloride.
A mixture of 0.41 g. of methyl 3-methyl-2-(2-
chlorosulfinyl-4-oxo-3-phthalimido-l-azetidinyl)-3-butenoate
and 0.13 g. of aluminum chloride was refluxed in 30 ml. of
dry 1,2-dichloroethane. The mixture was then cooled to room
temperature, washed with lN.HCl and brine and dried (MgSO4).
Evaporation in vacuo to dryness provided 0.35 g. of the 3-
methylene cepham sulfoxide as a yellow foam.
D. Zinc bromide.
A mixture of 0.41 g. of methyl 3-methyl-2-(2-
chlorosulfinyl-4-oxo-3-phthalimido-l-azetidinyl)-3-butenoate -
and 0.27 g. of zinc bromide in 30 ml. of dry methylene
chloride was refluxed for l hour. The mixture was cooled to
room temperature, washed with lN.HCl and dried (MgSO4).
Evaporation in vacuo to dryness provided a mixture of the
R- and S-3-methylenecepham sulfoxide as a yellow foam.
E. Antimony pentachloride.
A solution of 0.41 g. of methyl 3-methyl-2-(2-
chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl)-3-butenoate
and 0.12 ml. of antimony pentachloride was stirred at room
temperature for 60 minutes. The reaction mixture was
washed with lN.HCl and brine, dried (MgSO4~ and evaporated
in vacuo to dryness to provide the desired 3-methylenecepham
sulfoxide as a yellow foam. The nmr spectrum of the product
sulfoxide mixture was poor. To confirm the presence of the
cepham sulfoxide, the reaction product was dissolved in 3
ml. of dimethylformamide and reacted with 0.09 ml. of
phosphorous trichloride. After the mixture was stirred at
0 for 30 minutes, it was poured over cracked ice/water.
X-4372A -48-
,
1~56;~72
The yellow precipitate which then formed was collected by
filtration and dried under vacuum. An nmr spectrum of the
product (0.15 g.) showed it to be methyl 7-phthalimido-
3-methylenecepham-4-carboxylate: (CDC13) ~3.47, 3.96 (ABq,
2, J=17 Hz, C2-H), 3.87 (s, 3, C4-H), 5.20 (d, 1, J=4.5 Hz),
5.80 (d, 1, J=4.5 Hz), and 7.83 (m, 4).
F. Mercuric chloride.
A mixture of 0.20 g. of methyl 3-methyl-2-(2-
chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl)-3-butenoate
and 0.14 g. of mercuric chloride in 10 ml. of dry 1,2-
dichloroethane was refluxed for 1 hour. The mixture was
cooled to room temperature, washed with lN . HCl, dried
(MgSO4) and evaporated in vacuo to dryness to provide 0.14
g. of the 3-methylenecepham sulfoxide as a mixture of R- ;~
and S-sulfoxide isomers.,
G. Ferric chloride. ~, '
The same procedure was followed as in (F) above
with the exception that 0.08 g. of ferric chloride was
employed as the catalyst instead of mercuric chloride.
20 Comparative thin-layer chromatography confirmed the sulfinyl ~'
chloride to 3-methylenecepham sulfoxide conversion.
H. Zirconium tetrachloride.
The same procedure was followed as in (F) above
with the exception that 0.12,g. of zirconium tetrachloride
was employed as the catalyst instead of mercuric chloride.
Comparative thin-layer chroma~ography confirmed a clean
conversion of the sulfinyl chloride to the 3-methylenecepham
sulfoxide. The nmr spectrum of the product was identical to
that of the product in (A) above.
X-437~A , -49-
105637Z
I. Polyphosphoric acid.
Methyl 3-methyl-2-(2-chlorosulfinyl-4-oxo-3-
phthalimido-l-azetidinyl)-3-butenoate (0.20 g.) was stirred
in about 27 g. of polyphosphoric acid for 20 minutes. Ice
water and ethyl acetate (25 ml.) was added to the reaction
mixture. The organic layer was separated and washed suc-
cessively with water, aqueous sodium bicarbonate, and brine,
dried (MgSO4), and evaporated in vacuo to dryness to give
methyl 7-phthalimido-3-methylenecepham-4-carboxylate 1-
oxide (0.05 g.) as a white foam.
J. Sulfuric acid.
A solution of 0.20 g. of methyl 3-methyl-2-~2-
chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl)-3-butenoate
and 2 drops of concentrated sulfuric acid in 10 ml. of dry
1,2-dichloroethane was refluxed for 1 hour. The reaction
mixture was cooled, washed with brine, dried (MgSO4) and
evaporated in vacuo to dryness to provide 0.09 g. of a
colorless foam, the nmr spectrum of which shows it to be
primarily the desired 3-methylenecepham sulfoxide.
K. Methanesulfonic acid.
The same procedure was followed as in (I) above
with the exception that 0.03 ml. of methanesulfonic acid was
employed as the catalyst instead of sulfuric acid. The
product, as identified by nmr spectroscopy, was the desired
3-methylenecepham sulfoxide.
L. Trifluoroacetic acid.
A solution of 0.29 g. of methyl 3-methyl-2-(2-
chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl)-3-butenoate
in 10 ml. of trifluoroacetic acid was refluxed for 30 min-
X-4372A -50-
1056372
utes and then was evaporated ln vacuo to dryness. The
product was dissolved in 20 ml. of ethyl acetate. The
resulting solution was washed successively with aqueous
sodium bicarbonate (3X), water, and brine, dried (MgSO4),
and evaporated in vacuo to dryness to provide methyl 7-
phthalimido-3-methylenecepham-4-carboxylate l-oxide.
M. Silver _-toluenesulfonate.
. . .
Silver p-toluenesulfonate (0.80 g.) was added to a
solution of 1.0 g. of methyl 3-methyl-2-(2-chlorosulfinyl-
4-oxo-3-phthalimido-1-azetidinyl)-3-butenoate in 75 ml. of
dry toluene. The reaction mixture was stirred at room
temperature for 2.5 hours and then filtered. The filtrate
was evaporated in vacuo to dryness, and the residue thereby
obtained was dissolved in 50 ml. ethyl acetate. The solu-
tion was washed in vacuo to dryness. The product was
identified by nmr spectroscopy as methyl 7-phthalimido-3
methylenecepham-4-carboxylate l-oxide.
Example 2
Methyl 7-phthalimido-2,2-dideuterio-3-methylenecepham-4-
carboxylate.
A mixture of 3.76 g. (10 mmol) of methyl 6~-
phthalimidopenicillanate sulfoxide, 5 ml. deuterium oxide,
and 500 ml. dry carbon tetrachloride was refluxed for 3 hr.
The layers were then separated and organic layer dried
(MgSO4). Evaporation in vacuo gave 3.59 g. of a white
amorphous foam. The nmr spectrum showed deuterium (H2)
incorporation into the 2a-methyl group only and the residual
hydrogen (Hl) in that group of less than 29% (by integration).
Mass spectral analysis gave the following deuterium dis-
tribution in the 2a-methyl group: do~ 5.8%; dl, 20.5%; d2,
X-4372A -51-
.
1056372 `
41.3%; d3, 32.4% + 2~. Recrystallization from acetone/di-
ethyl ether gave colorless prisms, mp 148-151; mass
spectrum, m/e 379, 378, 377, 376, 361, 360, 359, 358,
302,/301, 300, 299; ir (KBr) 1800, 1775, and 1725 cm 1;
nmr (CDC13) ~1.83 (s, 3); 3.85 (s, 3); 4.62 (s, 1); 4.85 (d,
1, J=4.5 Hz), 5.86 (d, 1, J=4.5 Hz); 7.83 (m, 4).
Anal- Calcd- for C17H16N26S (376-387)
C, 54.25; H, 4.2~; N, 7.44; o, 25.50; S, 8.52.
Found: C, 54.05; H, 4.28; N, 7.26; O, 25.61; S, 8.53.
A solution of 0.57 g. (1.5 mmol.) of the methyl
2!3-methyl-2a-trideuteriomethyl-6~-phthalimidopenicillanate- :.
l-oxide and 0.20 g. (1.5 mmol) N-chlorosuccinimide was re-
fluxed for 30 min. in 25 ml. of dry 1,1,2-trichloroethane,
cooled, washed with water (1 x 50 ml), brine (1 x 50 ml),
and dried (MgSO4). The solvent was then evaporated in vacuo
to provide 0.69 g. of a mixture of R- and S-sulfinyl chlorides
as a light yellow amorphous foam. This mixture was then
dissolved in 25 ml. of dry methylene chloride and 0.20 (1.7
mmol) of anhydrous stannic chloride was added. The re-
sulting mixture was stirred for 50 min., washed with lN.
hydrochloric acid, dried (MgSO4), and evaporated in vacuo
yielding 0.57 g. of a mixture of R- and S-sulfoxides as a
yellow foam. The material so obtained was dissolved in 4
ml. of dry N,N-dimethylformamide, cooled in an ice bath and
0.14 ml. (1.6 mmol) of phosphorus trichloride was then
added. After 35 min. the crude mixture was poured onto
water-cracked ice and stirred. The resulting precipitate
was collected by filtration and dried under vacuum. Yield
was 0.38 g. The nmr spectrum exhibited only a very small
X-4372A -52-
1056372
signal for the C2 position (~10% of theory by nmr inte-
gration) while the signal for the exomethylene C'3 position
was normal indicating selective incorporation of the
deuterium into the C2 position. Mass spectral analysis gave
the following deuterium (H2) distribution in the C2 position:
do~ 2.2~; dl 25.5%; d2, 72.3~ + 2~. Recrystallization from
methylene chloride/cyclohexane gave colorless crystals, mp
198-201 (dec); mass spectrum m/e 360, 273, 174; ir (KBr)
1770, 1740, and 1710 cm 1; nmr (CDC13) ~3.80 (s, 3), 5.32
(m, 3), 5.46 (d, 1, J=4.5 Hz), 5.67 (d, 1, J=4.5 Hz), 7.83
(m, 4).
Anal. Calcd. for C17H14N2O5S (358.372):
C, 56.98; H, 3.94; N, 7.82; O, 22.32; S, 8.95.
Found: C, 56.96; H, 3.85; N, 7.94.
Example 3
4'-Nitrobenzyl 7-phenoxyacetamldo-3-methylenecepham-4-
carboxylate-l-oxide.
A. Stannic chloride.
A mixture of 6.0 g. (12 mmol) of 4'-nitrobenzyl-
6-phenoxyacetamidopenicillanate l-oxide and 500 ml. of dry
toluene was refluxed for 10 minutes by using a Dean-Stark
trap to remove a trace amount of water. Then 1.8 g. of
N-chlorosuccinimide was added and the mixture was refluxed
for 90 minutes and cooled to ca. 50. To the resulting
solution of sulfinyl chloride 1.8 ml. of anhydrous stannic
chloride was added. The mixture was stirred at room tem-
perature for 90 minutes. Then 100 ml. of water and 100 ml.
` of ethyl acetate was added. The organic layer was separated
and washed (lN.HCl, aqueous NaHCO3, brine), and dried
(MgSO4). Evaporation ln vacuo to dryness provided a product
X-4372A _53_ ;
. - , .
.
`` 105637Z
which crystallized from ethyl acetate to give 2.16 g. (36%)
of the title product. A sample was recrystallized from
ethyl acetate/acetone to give large prisms (m.p. 200-201):
nmr (CDC13) ~3.5 and 3.75 (ABq, 2, J=14 Hz), 4.55 (s, 2),
4.83 (d, 1, J=4.5 Hz), 5.3 (s, 2), 5.33 (s, 1), 5.5 (s, 1),
5.78 (s, 1), 5.94 and 6.1 (q, 1, J=4.5 Hz and 8.0 Hz),
6.9-8.3 (m, 9).
Anal. Calcd. for C23H2lN3O8S (499.5)
C, 55.31; H, 4.24; N, 8.41; O, 25.62; S, 6.42.
Found: C, 55.06; H, 4.14; N, 8.30; O, 25.62; S, 6.26.
B. Zinc chloride.
4'-Nitrobenzyl 3-methyl-2-(2-chlorosulfinyl-4-
oxo-3-phenoxyacetamido-1-azetidinyl)-3-butenoate was pre-
pared by refluxing a solution of 1 g. of 4'-nitrobenzyl 6-
phenoxyacetamidopenicillanate sulfoxide and 0.27 g. of
N-chlorosuccinimide in 40 ml. of 1,1,2-trichloroethane for
30 minutes. Then 0.27 g. of zinc chloride was added to the
reaction mixture. The mixture was then refluxed for an
additional 45 minutes. After cooling the mixture to room
temperature, it was washed with lN.HCl (2X), dried (MgSO4),
and evaporated in vacuo to dryness. An nmr spectrum of the
product showed it to be the desired 4'-nitrobenzyl 7-phenoxy-
acetamido-3-methylenecepham-4-carboxylate l-oxide.
C. Silver p-toluenesulfonate.
A solution of 1 g. of 4'-nitrobenzyl 6-phenoxy-
acetamidopenicillinate l-oxide and 0.27 g. of N-chloro-
succinimide in 10 ml. of dry toluene was refluxed for 1
hour. Silver p-toluenesulfonate (0.61 g.) was added to the
hot solution. The mixture was stirred for 45 minutes (while
cooling to room temperature). The reaction mixture was
X-4312A -54-
..
!
10563~2
filtered, washed with water (2X) and brine, dried (MgSO4),and evaporated ln vacuo to dryness to provide 0.43 g.
4'-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-
carboxylate l-oxide (with some impurities) as a yellow foam.
Example 4
4'-Nitrobenzyl 7-phthalimido-3-methylenecepham-4-carboxylate
l-oxide .
To a solution of 23.1 g. of 4'-nitrobenzyl 3-
methyl-2-(2-chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl)-
3-butenoate in 400 ml. of dichloromethane at room temperature
was added 6.1 ml. of anhydrous stannic chloride. An in-
creasing amount of precipitate was noted as the reaction
progressed. After 45 minutes the reaction mixture was
washed with lN. sulfuric acid, water, sodium bicarbonate
solution, and brine. The organic layer was dried and
evaporated in vacuo to dryness to provide 16.72 g. (78%) of
; the title product. The R- and _-sulfoxide isomers were ~-
separated by fractional recrystallization from acetone and
dichloromethane.
The R-sulfoxide is obtained as colorless prisms
20 which softened at 155 and melted completely at 213: ir
(CHC13) 1790, 1780, 1738 and 1723 cm 1; mass spectrum m/e
495, 479, 367, 343; nmr (CDC13) ~3.58 and 4.10 (ABq, 2, J=13
Hz), 4.87 (d, 1, J=4.5 Hz), 5.33 (s), 5.57 (m, 2), 5.95 (d,
1, J=4.5 Hz), 7.4-8.4 (m, 8, ArH).
Anal- Calcd- for C23H17N38S (495-5)
C, 55.76; H, 3.46; N, 8.48; O, 25.83; S, 6.47.
, Found: C, 55.50; H, 3.45; N, 8.65; O, 25.17; S, 6.32.
The S-sulfoxide was isolated as colorless prisms
! (mp 190-192): ir (mull) 1780, 1775, 1741 and 1728 cm 1;
30 nmr (CDC13) ~3.5 and 3.7 (ABq, 2, J=15 Hz), 4.9 (d, 1,
X-4372A -55-
.
:
~OS637Z
J=4.5 Hz), 5.34 (s, 2), 5.46 (m, 2), 5.6 (d, 1, J=4.5 Hz),
5.8 (s, 1), 7.4-8.4 (m, 8).
Anal. Calcd. for C23H17N3O8S
C, 55.76; H, 3.46; N, 8.48; O, 25.83; S, 6.47.
Found: C, 55.58; H, 3.62; N, 8.25; O, 25.19; S, 6.18.
Example 5
2',2',2'-Trichloroethyl 7-phenylacetamido-3-methylenecepham-
4-carboxylate l-oxide
.
A mixture of 1.0 g. of 2',2',2'-trichloroethyl
7-phenylacetamidopenicillanate l-oxide, 0.5 g. of N-
chlorosuccinimide and 80 ml. of dry toluene was refluxed for
90 minutes, then cooled, and washed (water and brine). To
the resulting solution of sulfinyl chloride was added 0.28 ~-
ml. of anhydrous stannic chloride. The resulting mixture
was stirred for 90 minutes. After washing (water and brine)
the solvent was evaporated in vacuo to dryness. The product
was crystallized from ethyl acetate-ether to provide the
title product as colorless prisms: m.p. 187-189; nmr
(CDC13) ~3.5 and 3.81 (ABq, 2, J=14 Hz); 3.63 (s, 2), 4.8
(m, 2), 4.9 (d, 1, J=4.5 Hz), 5.37 (s, 1), 5.5 (s, 1), 5.82
(s, 1), 5.9 and 6.07 (q, 1, J=4.5 Hz and 10.0 Hz), 7.0 (d,
NH, J=10 Hz), 7.33 (s, 5).
Example 6
Methyl 7-(2,2-dimethyl-3-nitroso-5-oxo-4-phenvlimidazolidin-
l-yl)-3-methylenecepham-4-carboxylate l-oxide.
A mixture of 0.896 g. of N-nitrosohetacillin sul-
foxide methyl ester and 0.536 g. of N-chlorosuccinimide in
55 ml. of dry benzene was refluxed under nitrogen for about
1 hour. The reaction mixture was cooled and a 5 ml. aliquot
of the mixture was evaporated in vacuo to dryness. The nmr
spectrum of the residue thereby obtained was consistent with
X-4372A -56-
-~: ~ ,,.
:1 .
.... . .
~OS637Z
the structure of the desired intermediate sulfinyl chloride.
The remainder of the reaction mixture was cooled under
nitrogen in an ice bath, and 0.33 ml. of stannic chloride
was added. A light orange precipitate formed immediately.
After stirring the mixture for 2 hours and 15 minutes at
room temperature, 5.5 ml. of dimethylacetamide and 55 ml. of
ethyl acetate was added. The resulting solution was washed
with water and brine, dried over CaSO4, and evaporated ln
vacuo to dryness to provide 1.3 g. of a yellow oil. The
product was dissolved in methylene chloride and applied to 4
preparative thin-layer chromatography plates. The plates
were developed with a 1:1 mixture of benzene and ethyl
acetate. Two prlmary bands were noted, the one having the
lower rf value representing the title compound. The 3-
methylenecepham sulfoxide (a mixture of R- and S-sulfoxides)
was isolated by extracting the identified band with acetoni-
trile: nmr (CDC13) ~2.07 (s, 6, gem-dimethyl), 3.73 (s, 3,
COOCH3), 4.7-5.6 (m), and 7.3 ~s, ArH).
Example 7
4'-NitrobenzYl 3-methyl-2-(2-sulfino-4-oxo-3-~hthalimido-1
azetidinyl)-3-butenoate.
.
A solution of 49.7 g. (0.1 mol) 4'-nitrobenzyl 6-
phthalimidopenicillanate l-oxide and 13.4 g. of (0.1 mol) of
N-chlorosuccinimide in 1.5 1. of 1,2-dichloroethane was re-
fluxed for 70 minutes. After cooling the reaction mixture
was washed with water and brine, dried (MgSO4). The solvent
was evaporated ln vacuo to dryness to provide 52.0 g. of the
azetidinone sulfinyl chloride product: nmr (CDC13) ~1.97
(s, 3), 5.05 (s, 1), 5.4 (s, 2), 5.76 (d, 1, J=5 Hz), 5.91
(d, 1, J=5 Hz), 7.83 (m, 8, ArH).
X-4372A -57-
- ,
- 105637Z
The sulfinyl chloride was converted to the sul-
finic acid by slurrying an ethyl acetate solution thereof
with a 5~ solution of sodium bicarbonate at room temperature
for 2 hours. Acidification of the aqueous layer with
hydrochloric acid in the presence of ethyl acetate provided, ~ -
after separation, drying (MgSO4), and evaporation in vacuo -~
of the organic layer, the desired sulfinic acid as a col-
orless foam: nmr (CDC13) ~1.92 (s, 3), 4.88 (s, 1, J=4.5
Hz), 5.00 (s, 2), 5.18 (broad s, 1), 5.38 (s, 2), 5.67 (d,
10 1, J=4.5 Hz), and 7.5-8.3 (m, 9, ArH).
Example 8
2',2',2'-Trlchloroethyl 7-phenoxyacetamido-3-methylenecepham-
4-carboxylate-1-oxide.
A mixture of 4.82 g. (10 mmol) of 2',2',2'-tri-
chloroethyl 6-phenoxyacetamidopenicillanate l-oxide, 150 ml.
of dry toluene, and 2.0 (11 mmol) of N-chlorophthalimide
was refluxed for 60 minutes using a Dean-Stark adapter. A
5 ml. aliquot of the mixture was evaporated; the nmr spectrum
thereof showed a complete conversion to the expected sul-
finyl chloride.
The solution of the sulfinyl chloride in toluene ;~
was cooled to ca. 40, and 1.4 ml. of stannic chloride was
added. The mixture was stirred for 60 minutes and then was
`, washed successively with lN.HCl, aqueous NaHCO3, and brine
I and dried (MgSO4). After evaporation of the solvent, 30 ml.
l of chloroform was added to the residue, and the insoluble
~ phthalimide was filtered. The filtrate was evaporated to --
,~ .
dryness and the yellow amorphous product was dried in vacuo.
Yield: 3.4 g. (70 percent) of the title compound; nmr
(CDC13) 3.56 and 3.80 (ABq, 2, J=14 Hz), 4.48 (s, 2), 4.75
(m, 2, C_2CC13), 4.89 (d, 1, J=4.5 Hz), 5.33 (s, 1), 5.48
~! X-4372A -58- -
: -
1056372
(s, 1), 5.78 (s, 1), 5.9 and 6.07 (q, 1, J=4.5 Hz), 6.8-7.4
(m, 5, ArH), and 8.1 (d, NH, J=10 Hz).
Example 9
Methyl 3-methyl-2-(2-sulfino-4-oxo-3-phthalimiao-l-azetidinyl)
3-butenoate.
. _
A mixture of 3.76 g. of methyl 6-phthalimido-
penicillinate sulfoxide and 1.4 g. of N-chlorosuccinimide in ~-
250 ml. of dry ~CaC12) carbon tetrachloride was refluxed for
70 minutes. The mixture was cooled to room temperature,
filtered, washed with water and brine and dried (MgSO4).
Evaporation in vacuo to dryness provided methyl 3-methyl-
2-t2-chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl)-3-
butenoate as a white foam (See Example lA).
To a solution of 0.20 g. of the sulfinyl chloride
in 25 ml. of chloroform was added 2 drops of water. The
mixture was refluxed for 30 minutes, cooled, dried (MgSO4)
and evaporated ln vacuo to dryness to provide the title
product as a colorless foam: nmr (CDC13) ~1.93 ~s, 3, -CH3),
3.80 (s, 3, -COOCH3), 4.88-5.15 tm, 4, C3-H, =CH2, q-lactam
H), 5.70 (d, 1, J=5.0 Hz, ~-lactam H), 7.80 (m, 4, ArH).
The sulfinyl chloride is also converted to the title sul-
finic acid upon standing at room temperature open to the air
for 2 days.
Example 10
Methyl_7-phthalimido-3-methylenecepham-4-carboxylate-l-oxide
rom azetldinone sul ln1c acid .
-
- A. Phosphorus Pentoxide.
A solution of 0.10 g. of methyl 3-methyl-2-(2-
~ulfino-4-oxo-3-phthalimido-1-azetidinyl)-3-butenoate and
0.04 g. of phosphorus pentoxide in 20 ml. of 1,2-dichloro-
ethane was stirred at room temperature for 1 hour. A tlc of
X-4372A -59-
.~
. .
~ ., . -
l~)S637Z : ~
the reaction mixture indicated only trace amounts of the
methylenecepham sulfoxide. The mixture was then refluxed
for 30 minutes, cooled to room temperature, and combined
with 25 ml. of ethyl acetate and 50 ml. of brine. The
organic layer was separated, washed with aqueous sodium
bicarbonate and brine and dried (MgSO4). Evaporation ln
vacuo to dryness provided 0.04 g. of the title product as a
white froth.
s. Sulfuric acid.
The same procedure was followed as that described
in Example 1 (J) above except 0.20 g. of methyl 3-methyl-
2-(2-sulfino-4-oxo-3-phthalimido-1-azetidinyl)-3-butenoate
was employed as the starting material instead of the sul-
finyl chloride. The procedure provided 0.03 g. of the title
compound.
C. Polyphosphoric acid.
The same procedure was followed as in Example 1
(I) above except 0.20 g. of methyl 3-methyl-2-(2-sulfino-
4-oxo-3-phthalimido-1-azetidinyl)-3-butenoate was employed
as the starting material instead of the sulfinyl chloride.
The reaction provided 0.10 g. of the title compound. -
D. Trifluoroacetic acid.
.
The same procedure was followed as described in
Example 1 (L) above except 0.20 g. of methyl 3-methyl-2-(2-
sulfino-4-oxo-3-phthalimido-1-azetidinyl)-3-butenoate was
employed as the starting material instead of the corresponding
sulfinyl chloride. An nmr spectrum of the product showed
the title compound to be the major constituent.
X-4372A -60-
.:
.. ~ .......... . ,... .,,....... .,.. .. . . .. - -, -
~.: . ,. . : .. :. . - ~, - . -
lOS637Z
Example 11
4'-Nitrobenzyl 3-methyl-2-[2-chlorosulfinvl-4-oxo-3-(N-
phenoxyacetyl-N-(2,2,2-trichloroethoxycarbonyl)amino)-1-
azetidinyl]-3-butenoate.
A. A mixture of 4.855 g. (10 mmol) of 4'-nitrobenzyl
6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate, 16.94 g.
(80 mmol) of 2,2,2-trichloroethyl chloroformate, 18 ml. of
N,O-(bis-trimethylsilyl)trifluoromethylacetamide, and 20 ml.
of methylene chloride was prepared. The mixture was per-
mitted to stand at room temperature overnight. The mixture
then was heated at reflux for 7 hours after which it was
again permitted to stand at room temperature overnight.
Heating then was continued for an additional 6 hours. The
mixture then was evaporated to a residue; the residue
was dissolved in benzene, and the resulting solution then was
added to a large excess of heptane. The resulting insoluble
material was filtered off, dissolved in benzene, and chroma-
tographed over silica gel using a benzene-ethyI acetate
elution gradient. 4'-Nitrobenzyl 6-[N-phenoxyacetyl-N-
(2,2,2-trichloroethoxycarbonyl)amino]-2,2-dimethylpenam-3-
20 carboxylate (4.76 g.; 72 percent) was obtained as product:
nmr (CDC13) ~1.41 (s, 3), 1.62 (s, 3), 4.61 (s, 1), 4.84 (d,
1, J=12 Hz), 4.99 (d, 1, J=12 Hz), 5.20 (s, 2), 5.30 (s, 2),
5.56 (s, 2), 6.8-7.4 (m, 5), 7.53 (d, 2, J=9 H2), and 8.22
(d, 2, J=9 Hz).
B. Sulfoxide preparation.
To about 75 ml. of acetone were added 2.54 g.
(3.84 mmol) of the above product. The mixture was cooled
to -70C., and an excess of ozone was admitted to the reaction
mixture at approximately 1.17 mmol per minute for nine
minutes during which time the reaction mixture turned blue.
X-4372A -61-
lOS637Z
The mixture was maintained at -70C. for about 35 minutes
after which it was warmed to room temperature. The solvent
was removed in vacuo to obtain 2.76 g. of 4'-nitrobenzyl
6-[N-phenoxyacetyl-N-(2,2,2-trichloroethoxycarbonyl)amino]-
2,2-dimethylpenam-3-carboxylate-1-oxide. nmr (CDC13) ~1.22
(s, 3), 162 (s, 3), 4.60 (s, 1), 4.78 (d, 1, J=5 Hz), 4.93 (s,
2), 5.26 (s, 2), 5.30 (s, 2), 5.93 (d, 1, J=5Hz), 6.8-7.4
(m, 5), 7.51 (d, 2, J=9 Hz) and 8.20 (d, 2, J=9 Hz).
C. Sulfinyl chloride preparation.
To 40 ml. of dry benzene were added 792 mg. (about
one mmol) of the above product and 155 mg. (about 1.2 mmol)
of N-chlorosuccinimide. The resulting mixture was heated at
reflux for one hour. An nmr of the reaction mixture indi-
cated the presence of the title compound: nmr (CDC13) ~1.92
(s, 3), 4.89 (s, 1), 4.96 (s, 2), 5.05 (s, 2), 5.23 (s, 2),
5.26 (s, 1), 5.34 (s, 2), 5.64 (d, 1, J=5 Hz), 5.95 (d, 1,
J=5 Hz), 6.10 (d, 1, J=5 Hz), 6.8-7.5 (m, 5), 7.56 (d, 2,
J=9 Hz), and 8.23 (d, 2, J=9 Hz).
D. Conversion to 4'-Nitrobenzy1_7-[N-~henoxyacetyl-N-
(2,2,2-tri_hloroethoxycarbonyl)amino]-3-methylënecepham-
4-carboxylate-1-oxide.
To the reaction mixture from (C) above, cooled to
room temperature, were added 390 mg. (1.5 mmol) of stannic
chloride. The mixture was maintained at room temperature
for 75 minutes, and 5 ml. of methanol then were added.
Additional benzene was added, and the resulting mixture was
washed three times with a mixture of HCl and aqueous sodium
chloride. The benzene layer was separated, dried over ~ -
sodium sulfate, and evaporated ln vacuo to dryness. The
residue was chromatographed over silica gel (15% water) with
a benzene-ethyl acetate gradient to obtain 246 mg. of the
X-4372A -62-
,
``` 1~563'7Z
exomethylenecepham sulfoxide: nmr (CDC13) ~3.42 (d, 1, J=13
Hz), 3.98 (d, 1, J=13 Hz), 4.64 (d, 1, J=5 Hz), 4.94 (s, 2),
5.25 (s, 2), 5.30 (s, 2), 5.34 (s, 1), 5.47 (s, 1), 6.04 (d,
1, J=5 Hz), 6.8-7.4 (m, 5), 7.55 (d, 2, J=9 Hz), and 8.23
(d, 2, J=9 Hz).
Example 12
4'-Bromophenacyl 7-Phenoxyacetamido-3-methylenecepham-4-
carboxyl`ate-l-oxide.
To 200 ml. of dried toluene were added 5.6 g.
(10 mmol) of 4'-bromophenacyl 6-phenoxyacetamido-2,2-
dimethylpenam-3-carboxylate-1-oxide and 5.2 g. (50 mmol) of
sodium bisulfite. The mixture was heated at reflux, and 1.5
g. (11 mmol) of N-chlorosuccinimide were added. The
resulting mixture was stirred and refluxed for one hour,
cooled in an ice bath, and 1.3 g. (11 mmol) of stannic
chloride then were added. The resulting mixture was stirred
at room temperature for about two hours and then was poured
into a mixture of ethyl acetate and water. The organic
layer was separated and washed successively with 5 percent
hydrochloric acid, 5 percent sodium bicarbonate solution,
and brine. The mixture then was dried over magnesium
sulfate. Upon evaporation to near dryness ln vacuo, 1.75 g.
(31 percent) of the title compound crystallized and was
collected. An nmr analysis of the product was consistent
with the structure of the title compound.
Anal. Calcd. for C24H21N2O7SBr:
C, 51,35; H, 3.77; N, 4.99; Br, 14.23.
Found: C, 51.03; H, 3.91; N, 5.10; Br, 14.46.
X-4372A -63-
.
~056372
Example 13
7-Phenoxyacetamido-3-methylenecepham-4-carboxylic acid-
l-oxide.
To 200 ml. of dried toluene were added 4.95 g. (10
mmol) of 4'-methoxybenzyl 6-phenoxyacetamido-2,2-dimethyl-
penam-3-carboxylate-1-oxide and 5.2 g. (50 mmol) of sodium
bisulfite. The mixture was heated at reflux, and 1.5 g. (11
mmol) of N-chlorosuccinimide were added. The mixture then
was stirred and refluxed for one hour after which it was
cooled in an ice bath, and 1.3 gms. (11 mmol) of stannic
chloride were added. The mixture then was stirred at room
temperature for about 2 hours after which it was poured into
a mixture of ethyl acetate and water. The organic layer was
separated and washed successively with 5 percent hydro-
chloric acid and brine. The organic layer then was ex-
tracted with 5 percent sodium bicarbonate solution. The
extract was slurried with ethyl acetate, and acidified to pH
2.5. The ethyl acetate layer was separated, washed with
water, dried over magnesium sulfate, and concentrated ln
vacuo to a small volume from which 1.3 gms. (35 percent) of
the title compound were obtained as crystals. Analysis of
the product by nmr was consistent with the structure of the
title compound.
Anal. Calcd. for C16H16N2O6S:
C, 52.74; H, 4.43; N, 7.69.
Found: C, 52.99; H, 4.64; N, 7.51.
Example 14
Benzhydry1 3-methy1-2-(2-chlorosulfiny1-4-oxo-3-phenoxy-
acetamido-l-azetidinyl)-3-butenoate.
A. To 800 ml. of dried toluene were added 20 g. of
benzhydryl 6-phenoxyacetamido-2,2-dimethylpenam-3-carboxyl-
X-4372A -64- -
. ., . . ~ . :
.
~, ~ . . . . . . . .
1056372
ate-l-oxide. The mixture was refluxed in a system having a
Dean-Stark water trap to azeotropically remove any moisture.
To the mixture then were added 12.2 g. of N-chlorosuccin-
imide. Refluxing was continued for 1.5 hours. The product
was analyzed by nmr analysis which was consistent with the
structure of the title compound: nmr (CDC13) ~1.88 (s, 3),
4.53 (s, 2), 4.90 (s, 1), 5.14 (s, 2), 5.54 (d, 1, J=4 Hz),
6.24 (q, 1, J=4 Hz and 8 Hz), 6.95 (s, 1), 7.15-7.4 (m, 15),
and 8.0 (d, 1, J=8 Hz).
B. Conversion to exomethylene sulfoxide.
In accordance with the procedure described in
Example 13 hereinabove, the azetidinone sulfinyl chloride
from (A) was cyclized with stannic chloride to 7-phenoxy-
- acetamido-3-methylenecepham-4-carboxylic acid-l-oxide.
- Example 15
2',2',2'-Trichloroethvl 3-methyl-2-[2-chlorosulfinYl-4-oxo-
- 3-(4-nitrobenzyloxycarbamido?-l azetidinyl]-3-butenoate.
A. A mixture of 300 ml. of 1,1,2-trichloroethane
and 10.26 g. of 2',2',2'-trichloroethyl 6-(4-nitrobenzyloxy-
carbamido)-2,2-dimethylpenam-3-carboxylate-1-oxide was
prepared. The mixture was refluxed with removal of about
75 ml. of the solvent to promote drying of the reaction
medium. The mixture then was cooled, and propylene oxide
was added followed by 4 g. of N-chlorosuccinimide. The
temperature of the mixture was raised to 102C., and the
mixture was refluxed for 2.5 hours. A sample of the reaction
mixture was removed; the solvent was evaporated. An nmr
analysis of the residue was consistent with the structure of
the title compound: nmr (CDC13) ~1.94 (bs, 3), 4.83 (s, ~ -
2~, 5.25 (s, 2), 5.0-5.4 (m, 3), 6.2 (d, 1, J=4 Hz), 7.55
(d, 2, J=8 Hz), and 8.24 (d, 2, J=8 Hz).
X-4372A -65-
- - .
105637Z
B. Conversion to 2',2',2'-trichloroethyl 7-(4- _trobenzyl- -
oxycarbamido)-3-methylenecepham-4-carboxylate-1-oxide.
A portion represen'ing about one-third of the
reaction mixture from (A) above was evaporated, and the
residue was dissolved in 100 ml. of dried methylene chloride.
To the resulting mixture were added 5 ml. of stannic
chloride. The mixture was treated in accordance with the
method of Example 12 to obtain 700 mg. of the 3-methylene-
cepham sulfoxide: nmr (CDC13) ~3.60, 3.88 (ABq, 2, J=15 Hz),
4.82 (s, 2), 4.94 (d, 1, J=4.5 Hz), 5.23 (s, 2), 5.40
(s, 1), 5.56 (s, 1), 5.83 (s, 1), 6.37 (d, 1, J=10 Hz),
7.46 (d, 2, J=9 Hz), and 8.20 (d, 2, J=9 Hz).
Example 16
4'-Nitrobenzyl 3-methyl-2-(2-chlorosulfinyl-4-oxo-3-acetamido-
l-azetidinyl)-3-butenoate. -
A. Toluene (500 ml.) was heated in equipment having
a Dean-Stark water trap to azeotropically remove any moisture.
To the resulting dried toluene was added 1.0 g. (2.4 mmol)
of 4'-nitrobenzyl 6-acetamido-2,2-dimethylpenam-3-carboxylate-
l-oxide. The resulting mixture was refluxed again using a
Dean-Stark water trap to remove any additional amounts of
water. The mixture then was cooled, and 400 mg. (2.9 mmol)
of N-chlorosuccinimide were added. The mixture then was
refluxed for 1 hour. A sample of the reaction mixture was
withdrawn, and the solvent was removed. The product which
was obtained was consistent by nmr analysis with the structure
of the title compound: nmr (CDC13) ~1.86 (bs, 3), 2.04,
2.09 (2s, 3), 4.80 (m, 1), 5.2 (m, 2), 5.28 (s, 2), 5.63
(m, 1), 6.05 (d, 1, J=4 Hz), and 7.4-8.4 (q, 4, ArH).
.,,
-~
X-4372A -66-
. : .
- . - . . ~ .
.. - , .
- 1056372 -:
B. Conversion to 4'-Nitrobenzyl 7-acetamido-3-methylene-
cepham-4-carboxyla-te 1-oxide.
The reaction mixture from (A) above was cooled in
an ice bath, and 1 ml. of stannic chloride was added. The
mixture was maintained for two hours at room temperature
after which it was evaporated in vacuo to dryness. The
resulting residue was dissolved in ethyl acetate, and the
ethyl acetate mixture was washed once with a mixture of HCl
and aqueous sodium chloride and twice with aqueous sodium
chloride, dried over magnesium sulfate, and evaporated ln
vacuo to dryness. The residue was dissolved in a minimum of
ethyl acetate, and, after standing overnight, crystals of
the 3-methylenecepham sulfoxide formed and were collected:
nmr (CDC13) ~1.92 (s, 3), 3.80 (bs, 2), 5.00 (d, 1, J-4
Hz), 5.32 (s, 2), 5.45-5.80 (m, 5), 7.60 (d, 2, J=8 Hz),
7.86 (d, 1, J=9 Hz), and 8.20 (d, 2, J=8 Hz).
Example 17
4'-Nitrobenzyl 7-phenoxyacetamido-3-methylenecep-am-4
carboxylate-l-oxide. (Complex isolation)
Toluene (750 ml.) was refluxed for 15 minutes using
a Dean-Stark trap. To the dried toluene were added 35 ml.
of propylene oxide, 25 g. of 4'-nitrobenzyl 6-phenoxyacet-
amidopenicillanate-l-oxide and 7.37 g. of N-chlorosuccin-
imide. The reaction mixture was refluxed at 100C. for 2
hours after which time 120 ml. of toluene was-distilled from
the mixture. After cooling, 7.3 ml. of stannic chloride was
added. Filtration of the reaction mixture provided 17.1 g.
of an orange complex which was dissolved in ethyl acetate
and washed with aqueous HCl and brine. The ethyl acetate
solution was dried and evaporated in vacuo to dryness to
provide 6.9 g. of the title product.
X-4372A -67-
1056372
Example 18
Methxl 3-methyl-2-(2-bromosulfinyl-4-oxo-3-phthalimido-1-
azetidinyl)-3-butenoate.
A. A mixture of 1.88 g. of methyl 6-phthalimido-
penicillanate-l-oxide and 890 mg. of N-bromosuccinimide in
150 ml. of carbon tetrachloride was refluxed for 80 minutes.
The reaction mixture was cooled, washed with water and
brine, dried over anhydrous MgSO4, and evaporated in vacuo
to dryness to provide 1.82 g. of the title product: nmr
(CDC13) ~1.98 (bs, 3~, 3.82 (s, 3, COOC_3), 5.0-5.35 (m, 3),
5.8-6.2 (m, 2, ~-lactam H), and 7.80 (bs, 4, ArH).
. Conversion to exomethylenecepham sulfoxide.
The azetidinone sulfinyl bromide from above was
dissolved in 20 ml. of methylene chloride; 0.6 ml. of
stannic chloride was added to the solution. After 45
minutes at room temperature the reaction mixture was washed
with water and brine, dried over anhydrous MgSO4, and
evaporated in vacuo to dryness to provide 1.15 g. of methyl
7-phthalimido-3-methylenecepham-4-carboxylate-1-oxide (a
mixture of R- and S-sulfoxide isomers). For the predominant
isomer: nmr (CDC13) ~3.64, 4.20 (ABq, 2, J=13.0 Hz, C2-H),
3.84 (s, 3, COOC_3), 4.90 (d, 1, J=4.0 Hz, ~-lactam H),
5.3-5.7 (m, 3), 5.97 (d, 1, J=4.0 Hz, ~-lactam H), and 7.84
(bs, 4, ArH).
Example 19
4'-Nitrobenzyl 3-methyl-2-(2-isopropylthiosulfinyl-4-oxo-
3-l~henc,xYacetamldo-l-azetidinvl)-3-butenoateO :-
A. To a solution of 10 g. of 4'-nitrobenzyl 3-
methyl-2-(2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-
azetidinyl)-3-butenoate in 450 ml. of toluene was added 1.9
ml. of isopropyl mercaptan and 3.5 ml. of propylene oxide.
X-4372A - -68-
" 1056372
The mixture was allowed to stand for several days at room
temperature and then was evaporated ln vacuo to dryness to
provide an oil which was chromatographed on a silica gel
column using a toluene-ethylacetate gradient. A total of
6.62 g. of the title product was isolated: nmr (CDC13)
~1.40 (d, 6, J=6.0 Hz, SCH(CH3)2), 2.01 (s, 3), 3.55 (m, 1,
SCH(CH3)2), 4.60 (s, 2, side chain CH2), 5.1-5.4 (m, 3),
5.33 (s, 2, ester CH2), 6.20 (dd, 1, J=4.5 and 10.0 Hz, ~-
lactam H), 6.9-8.3 (m, 9, ArH) and 8.6 (d, 2, J=10.0 Hz,
N_).
B. Conversion to exomethylenecepham sulfoxide.
The title product (682 mg.) was dissolved in 3.4
ml. of methane sulfonic acid. After 30 minutes the solution
was poured into a separatory funnel containing ethyl acetate
and saturated aqueous sodium bicarbonate solution. The
organic layer was separated, washed successively with
aqueous sodium bicarbonate, water and brine (2X), and dried
over anhydrous MgSO4. The product crystallized from ethyl
acetate upon standing overnight. A total of 60 mg. of
4'-nitrobenzyl 7-phenoxyacetamido-3-methylenecephem-4-
carboxylate-l-oxide was isolated.
Example 20
4'-Nitrobenzyl 3-methyl-2-(2-tert-butylthiosulfinyl-4-oxo-
3-phenox~acetamido-1-azetidinyl)-3-butenoate.
A. The same procedure was followed as described in
Example 19 except 2.4 ml. of tert-butyl mercaptan was used
in place of isopropyl mercaptan. 4.69 g. of the title
product was isolated after chromatography: nmr (CDC13)
~1.43 (s, 9, tert-butyl), 2.01 (s, 3), 4.57 (s, 2, side ~ -
chain -CH2), 5.0-5.4 (m, 5~, 6.20 (dd, 1, J=4.0 and 11.0 Hz,
X-4372A -69-
: ~-
.,, : ..
lOS6372
~-lactam H), 6.8-8.2 (m, 9, ArH) and 8.64 (d, 1, J=11.0 Hz,
NH).
B. Conversi n to exometh~lenecepham sulfoxide.
The title product (700 mg.) was dissolved in 3.5
ml. of methanesulfonic acid. Following the same procedures
as described in the second paragraph of Example 19, 190 mg.
of 4'-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-
carboxylate-l-oxide was isolated.
Example 21
4'-Nitrobenzyl 3-methyl-2-(2-methoxysulfinyl-4-oxo-3-
PhenoxYacetamldo-l-azetidlnYl)-3-butenoate.
.
A. To a solution of 4'-nitrobenzyl 3-methyl-2-(2-
chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl)-3-
butenoate, derived from 10 g. of 4'-nitrobenzyl 6-phenoxy-
acetamidopenicillanate-l-oxide and 2.68 g. of N-chloro-
succinimide, in 400 ml. of toluene was added 25 ml. of dry
methanol. The reaction mixture was stirred at room tem-
perature overnight, and then was washed successively with
aqueous sodium bicarbonate (2X), water, and brine (2X).
Evaporation ln vacuo to dryness yielded 10 g. of the impure
title product which was purified by chromatography over
acid-washed silica gel using a toluene-ethyl acetate
gradient. The product was isolated as a mixture of isomers
(R- and S- sulfinates). For the predominant isomer: nmr
(CDC13) ~1.90 (s, 3), 3.74 (s, 3, -OCH3), 4.52 (s, 2, side
chain CH2), 4.8-5.3 (m, 5), 5.32 (s, 2, ester CH2), 5.76
(dd, 1, J=5.0 and 9.0 Hz, ~-lactam H), and 6.8-8.2 (m, 9,
ArH).
X-4372A -70-
,
1. . . - . .
~05637Z
B. Conversion to exomethylenecepham sulfoxide.
The title product (590 mg.) was dissolved in 2.0
ml. of methanesulfonic acid. After 30 minutes at room
temperature, the mixture was worked-up in accordance with
the procedures described in the second paragraph of Example
19 hereinabove to provide 0.13 g. (40%) of 4'-nitrobenzyl
7-phenoxyacetamido-3-methylenecepham-4-carboxylate-1-oxide.
Example 22
4'-Nitrobenzy1 3-methy1-2-(2-menthyloxysulfiny1-4-oxo-3-
phenoxyacetamido-l-azetidinyl)-3-butenoate.
A. The same procedure was followed as described in
Example 21 except 3.12 g. (20 mmol) of menthol was employed
instead of methanol. The product sulfinate ester was
isolated by chromatography on an acid-washed silica gel
column using a toluene-ethyl acetate gradient. The product
was isolated as a mixture of isomers (R- and S- sulfinates).
For the predominant isomer: nmr (CDC13) ~0.6-2.4 (m, 18,
menthyl H), 1.86 (s, 3), 3.98 (bs, 1), 4.52 (s, 2, side
chain CH2), 4~72 (d, 1, J=5.0 Hz, ~-lactam H), 4.8-5.2 (m,
3), 5.36 (s, 2, ester CH2), 5.72 (dd, 1, J=5.0 and 9.0 Hz,
~-lactam H), 6.8-8.2 (m, 9, ArH), and 7.85 (d, 1, J=9.0
Hz, -N_).
B. Conversion to exomethylenecepham sulfoxide.
The title product (906 mg.) was dissolved in 4.6
ml. of methanesulfonic acid. After 30 minutes at room
temperature, the reaction mixture was worked-up in accor-
dance with the procedure described in the second paragraph
of Example 19 hereinabove. Conversion to 4'-nitrobenzyl 7-
phenoxyacetamido-3-methylenecepham-4-carboxylate-1-oxide was
confirmed by comparative thin-layer chromatography and nmr
30 spectroscopy. -
X-4372A -71-
- - ..
1~S637Z
Example 23
4'-Nitrobenzy1 3-methy1-2-(2-anilinosulfiny1-4-oxo-3-
phenoxyacetamido-l-azet_ inyl)-3-butenoate.
A. To a solution of 4'-nitrobenzyl 3-methyl-2-(2-
chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl)-3-
butenoate, derived from 10 g. of 4'-nitrobenzyl 6-phenoxy-
acetamidopenicillanate-l-oxide and 2.68 g. of N-chloro-
succinimide, in 400 ml. of toluene were added 3.6 ml. of
aniline. After 5 minutes at room temperature the reaction
mixture was washed with water (2X) and brine, dried over
anhydrous MgSO4, and evaporated ln vacuo to dryness to
provide the title product: nmr (CDC13) ~1.96 (s, 3),
4.5 (s, 2, side chain CH2), 5.34 (s, 2, ester CH2), 5.0-5.3
(m, 3), 5.77 (dd, 1, J=4.5 and 10.0 Hz, ~-lactam H), and
6.8-8.4 (m, 14, ArH).
B. Conversion to exomethylenecepham sulfoxide.
The title product (2.07 g.) was dissolved in 10
ml. of methanesulfonic acid. After 30 minutes, the solution
was poured slowly into a cold mixture of saturated aqueous
sodium bicarbonate and ethyl acetate. The ethyl acetate
layer was separated, washed successively with aqueous sodium
bicarbonate (2X), water (2X), and brine (2X), dried over
anhydrous MgSO4 and evaporated ln vacuo to dryness. 4'-
Nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-car-
boxylate-l-oxide (373 mg., 21%) crystallized from an ethyl
acetate solution of the impure product.
Example 24
Methyl 3-methyl-2-(2-N~succinimidosulfinyl-4-oxo-3-phenvl-
acetamido-l-azetidinyl)-3-butenoate.
A. A solution of 2.55 g. (7 mmol) of 4'-nitrobenzyl
6-phenylacetamidopenicillanate-1-oxide, 5.6 ml. (34 mmol) of
X-4372A -72-
.
1056372
N-trimethylsilylsuccinimide and 0.18 ml. of acetic acid in
41 ml. of dimethylacetamide was stirred for 3.5 hours at
105~C. After cooling, the reaction mixture was poured into
a cold mixture of 50 ml. of ethyl acetate and 150 ml. of
water. The water layer was extracted twice with ethyl ;-
acetate. The ethyl acetate extracts were combined, washed
with water, dried over anhydrous MgSO4, and evaporated in
vacuo to dryness to provide 3.3 g. of methyl 3-methyl-2-
(2-N-succinimidothio-4-oxo-3-phenylacetamido-1-azetidinyl)- ;
10 3-butenoate: nmr (CDC13) ~1.84 (s, 3), 2.78 (s, 4, succin-
imido), 3.65 (s, 2, side chain CH2), 3.74 (s, 3, COOCH3),
4.66 (s, 1), 5.0-5.5 (m, 4, ~-lactam H + olefinic CH2),
7.26 (s, 5, ArH), and 7.58 (d, 1, J=8.0 Hz, -N_).
The sulfenimide from above was dissolved in 50 ml.
of methylene chloride at 0C. and oxidized with 1.48 g. of
m-chloroperbenzoic acid. After 1 hour at 0C. the reaction
mixture was washed successively with saturated aqueous
sodium bicarbonate, water, and brine, dried over anhydrous
MgSO4 and evaporated ln v cuo to dryness to provide the
20 title product: nmr (CDC13) ~1.86 (s, 3), 2.60 (s, 4,
succinimido H), 3.54 (s, 2, side chain CH2), 3.78 (s, 3,
COOCH3), 4.8-5.2 (m, 3), 5.6-5.9 (m, 1, ~-lactam H), 6.04
(d, 1, J=5.0 Hz, ~-lactam H), and 7.3 (s, 5, ArH).
B. Conversion to exomethylene e~ham sulfoxide.
The title product (469 mg., 1 mmol) was dissolved
in 2.3 ml. of methanesulfonic acid. After 30 minutes at
room temperature the solution was poured slowly into a
mixture of saturated aqueous sodium bicarbonate and ethyl
acetate. The ethyl acetate layer was separated, washed
successively with aqueous sodium bicarbonate, water and
X-4372A -73-
105637Z
brine, dried over anhydrous MgSO4, and evaporated in vacuo
to dryness. Conversion to methyl 7-phenylacetamido-3-
methylenecepham-4-carboxylate-1-oxide was confirmed by
comparative thin-layer chromatography and nmr spectroscopy.
Example 25
4'-Nitrobenzyl 3-methyl-2-[2-(N,N'-dicarboethoxyhydrazo-
sulfinyl)-4-oxo-3-phenoxyacetamido-1-azetidin~__-3-butenoate.
A. A solution of 10 g. of 4'-nitrobenzyl 6-phenoxy-
acetamidopenicillanate-l-oxide in 300 ml. of dry 1,1,2-tri-
chloroethane was refluxed and dried using a Dean-Stark trap.
After about 50 ml. of the solvent was distilled, the mixture
was cooled and 6 ml. of diethylazodicarboxylate was added.
The reaction mixture was refluxed for 45 minutes and there-
after was evaporated ln vacuo to dryness. The residue was
triturated with hexane to remove excess diethylazodicar-
boxylate. Further drying provided the title product as an
impure yellow gum which was not further purified before
conversion to the exomethylenecepham sulfoxide: nmr (CDC13)
~1.40 (t, 3, J=7 Hz, CH2C_3), 1.95 (bs, 3), 3.8-4.7 (m, 6),
5.0-5.6 (m, 5) and 6.7-8.4 (m, 9, ArH).
B. Conversion to exomethy~_ne sulfoxide.
One gram of the product from (A) above was
dissolved in 20 ml. of methanesulfonic acid. The mixture
was stirred at room temperature for 20 minutes and then
poured into aqueous sodium chloride solution. The aqueous
solution was then extracted with 200 ml. of ethyl acetate.
The ethyl acetate extract was washed with aqueous sodium
bicarbonate, dried (MgSO4) and evaporated in vacuo to
dryness. The residue was purified by preparative thin layer
chromatography using silica gel plates developed with 90
X-4372A -74_
1~5637Z
ethyl acetate-benzene. A total of 160 mg. of 4'-nitrobenzyl
7-phenoxyacetamido-3-methylenecepham-4-carboxylate-1-oxide
was isolated.
Example 26
4'-Nitrobenzyl 3-methyl-2-[2-(N,N'-dicarbo-tert-butoxyhydra-
zosulfinyl)-4-oxo-3-acetamido-1-azetidinyl]-3-butenoate.
A. In accordance with the procedures described in
Example 25 820 my. of 4'-nitrobenzyl 6-acetamidopenicil-
lanate-l-oxide was reacted with 465 mg. of di-tert-butyl
azodicarboxylate to provide the title product: nmr (CDC13)
~1.50 (s, 18, tert-butyl) 1.90 (bs, 3), 2.00 (s, 3, CH3CNH-),
5.40 (s, 2, ester CH2), 5.0-6.0 (m, 5) and 7.6-8.4 (m, 4,
ArH). -~
B. Conversion to exomethylene sulfox e. ~ -
The title product from (A) was dissolved in 15 ml.
of methanesulfonic acid and after 10 minutes at room tem-
perature was poured into saturated aqueous sodium chloride
solution. The aqueous solution was extracted with ethyl
acetate. The organic extract was washed with aqueous sodium
bicarbonate, dried (MgSO4), and evaporated in vacuo to
dryness. Chromatographic purification of the residue
provided 90 mg. (12%) of 4'-nitrobenzyl 7-acetamido-3-
methylenecepham-4-carboxylate-1-oxide: nmr (CDC13~ ~2.04
O,
(s, 3, C_3CNH-), 3.66 (bs, 2, C2-H), 4.90 (d, 1, J=4.0 Hz,
C6-H), 5.26 (s, 3, C4-H + ester CH2), 5.45, 5.74 (2s,
I 2,=CH2), 5.92 (dd, 1, J=4.0 and 8.0 Hz, C7-H), 6.97 (d, 1,
J=8.0 Hz, ~NH), and 7.4-8.4 (m, 4, ArH).
~, X-4372A ~75-
.~i . ~ '.
;~' '
~05637Z
Example 27
2',2',2'-Trichloroethyl 7-(2-thienylacetamido)-3-methylene-
cepham-4-carboxylate sulfoxide
A solution of 1 g. of 2',2',2'-trichloroethyl
6-(2-thienylacetamido)penicillanate-1-oxide and 525 mg. of
di-tert-butyl azodicarboxylate in 50 ml. of 1,1,2-trichloro-
ethane was refluxed for 45 minutes. The reaction mixture
was then cooled and evaporated in vacuo to dryness. The
residue thereby obtained was dissolved in methanesulfonic
acid and after 15 minutes at room temperature the acid solu-
10tion was poured into saturated aqueous sodium chloride. The
aqueous solution was extracted with ethyl acetate. The
organic extract was washed with sodium bicarbonate solution,
dried (MgSO4) and evaporated 1n vacuo to dryness to provide
72 mg. (7~) of the title product: nmr (CDC13) ~2.87 (bs, 2,
C2-H), 3.75 (s, 2, side chain CH2), 4.80 (s, 2, ester CH2),
5.28 (d, 1, J=4.0 Hz, C6-H), 5.46, 5.77 (2s, 2,=CH2), 5.90
(dd, 1, J=4.0 and 8.0 Hz, C7-H) and 6.8-7.3 (m, 3, ArH).
; Example 28
4'-Nitrobenzvl 3-methYl-2-[2-(N,N'-dibenzovlhvdrazosul-
finyl)-4-oxo-3-phenoxyacetamido-1-azetidin ~ 3-butenoate.
A. In accordance with the procedures described in
Example 25 10 g. of 4'-nitrobenzyl 6-phenoxyacetamidopeni-
cillanate-l-oxide was reacted with 7.8 g. of dibenzoyl-
diimide in dry 1,1,2-trichloroethane.
B. Conversion to exomethylene sulfoxide.
One gram of the unpurified product from (A) above
was dissolved in 20 ml. of methanesulfonic acid. After 20
minutes the mixture was poured into 300 ml. of saturated
aqueous sodium chloride. The aqueous solution was extracted
with 200 ml. of ethyl acetate, and the organic extract was ~-~
X-4372A -76-
.
-
lOS6372
washed with sodium bicarbonate solution, dried (MgSO4), and
evaporated ln vacuo to dryness. 4'-Nitrobenzyl 7-phenoxy-
acetamido-3-methylenecepham-4-carboxylate-1-oxide (90 mg.,
40~) was isolated by preparative thin-layer chromatogr~aphy.
Example 29
4'-Nitrobenzy1 3-methy1-2-(2-acetylhydrazosulfinyl-4-oxo-
3-phenoxyacetamido-1-azetidinyl)-3-butenoate.
A. To a solution of 4'-nitrobenzyl 3-methyl-2-(2-
chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl)-3-
butenoate (derived from 50 g. of 4'-nitrobenzyl 6-phenoxy-
acetamidopenicillanate-l-oxide and 15 g. N-chlorosuccinimide
in 1000 ml. of 1,1,2-trichloroethane) at room temperature
was added 14.8 g. of acetyl hydrazide. After stirring about ~ -
30 minutes at room temperature the reaction mixture was
washed 3 times with 500 ml. portions of saturated sodium
chloride solution, dried (MgSO4) and evaporated ln vacuo to -
dryness. The residue was dissolved in ethyl acetate. Upon
standing in the refrigerator 29.7 g. (52%) of the title
O
product crystallized: nmr (CDC13) ~1.94 (s, 6, CH3C- +
allylic C_3), 4.65 (s, 2, side chain CH2), 4.9-5.4 (m, 5),
5.55 (s, 2, ester CH2) and 6.8-8.4 (m, 9, ArH).
B. Conversion to exomethYlene sulfoxide.
Two grams of the title product were dissolved in
20 ml. of methanesulfonic acid. After 15 minutes at room
temperature the acid solution was poured into a separatory
funnel containing 200 ml. of ethyl acetate, 250 ml. satu-
rated sodium chloride and 250 ml. of saturated sodium
bicarbonate solution. The organic layer was separated,
! 30 washed with sodium bicarbonate solution, dried (MgSO4), and
X-4372A -77-
,
,
.
10563~Z
evaporated in vacuo to dryness. The residue was dissolved
in a minimum amount of ethyl acetate, and upon standing 879
mg. (51%) of 4'-nitrobenzyl 7-phenoxyacetamido-3-methylene-
cepham-4-carboxylate-l-oxide crystallized.
Example 30
4'-Nitrobenzyl 3-methyl-2-~2-carbomethoxyhydrazosulfinyl-4-
oxo-3-phenoxyacetamido-1-azetid nyl)-3-butenoate.
A. In accordance with the procedures described in
Example 29 carbomethoxyhydrazide (4.5 g.) was reacted with
the sulfiny] chloride derived from 15 g. of 4'-nitrobenzyl
6-phenoxyacetamidopenicillanate-l-oxide to provide the title
product as a yellow gum: nmr (CDC13) ~1.92 (bs, 3), 3.66
(s, 3, COOCH3), 4.56 (s, 2, side chain CH2), 4.8-5.6 (m, 7,
e~ter CH2, ~-lactam H, olefinic H) and 6.7-8.4 (m, 9, ArH).
B. Conversion to exomethylene sulfoxide.
In accordance with the procedure described in the
second paragraph of Example 29, the title product (640 mg.)
was cyclized in methanesulfonic acid (10 ml.) to provide 240
mg. (45%) of 4'-nitrobenzyl-7-phenoxyacetamido-3-methyl-
enecepham-4-carboxylate-l-oxide.
; Example 31
4'-Nitrobenzyl 3-methyl-2-(2-tolylsulfonylhvdrazosulfinvl-4-
oxo-3-phenoxyacetamido-l-azetidinyl)-3-butenoate.
A. In accordance with the general procedure described
in Example 29, tosyl hydrazide (18 g.) was reacted with the -sulfinyl chloride derived from 30 g. of 4'-nitrobenzyl 6-
phenoxyacetamidopenicillanate-l-oxide to provide the title
product as a yellow gum which did not crystallize.
B. In accordance with the procedure described in the
second paragraph of Example 29, the title product was
cyclized in methanesulfonic acid (150 ml.) to provide 7.0 g.
X-4372A -78-
lOS637Z
(23%) of 4'-nitrobenzyl 7-phenoxyacetamido-3-methylene-
cepham-4-carboxylate-1-oxide.
Example 32
4'-Nitrobenzyl 3-methyl-2-(2-aminosulfinyl-4-oxo-3~phenoxy-
acetamido-l-azetidinYl)-3-butenoate.
-
A. To a solution of 5 g. of 4'-nitrobenzyl 3-methyl-
2-(2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl)-
3-butenoate in toluene was added a solution of 5 g. of
sodium cyanate in 100 ml. of water. After 1 hour at room
temperature, the organic phase was separated, dried (MgSO4)
and evaporated ln vacuo to dryness to provide a mixture of
the title product and 4'-nitrobenzyl 6-phenoxyacetamido-
penicillanate sulfoxide. For the title product: nmr
O
(CDC13) ~1.96 ts, 3), 4.55 (s, 4, side chain CH2 + -SN_2),
4.88 (d, 1, J=4.5 Hz, ~-lactam H), 5.0-5.5 (m, 5), 5.72 (dd,
1, J=4.5 and 9.0 Hz, ~-lactam H), 7.74 (d, 1, J=9.0 Hz, -NH)
and 6.9-8.4 (m, 9, ArH).
Anal. Calcd. for C23H24N4O8S:
C, 53.48; H, 4.68; N, 10.85; O, 24.78; S, 6.21.
Found: C, 53.69; H, 4.77; N, 10.62; S, 5.90.
B. Conversion to the exomethylene sulfoxide.
In accordance with the procedure described in the -
second paragraph of Example 29, the title product was
cyclized in methane sulfonic acid to provide 4'-nitrobenzyl
7-phenoxyacetamido-3-methylenecepham-4-carboxylate-1-
oxide.
'~
X-4372A -79-
: , ~. - . . .. ..
