Note: Descriptions are shown in the official language in which they were submitted.
1~E;78~
; PRIOR ART
Known commerical cephalosporins such as cephalexin,
cephaloglycin, cephaloridine, cephalothin, cefazolin, and
cephapirin are obtained by a number of dif-ferent processes,
which also involve preparing a variety of intermediates for
the respective cephalosporins.
Cephalosporin C and desacetoxycephalosporin C can
be obtained by fermentation processes. The aminoadipyl moiety
in these compounds is removed by various chemical processess
to give 7-aminocephalosporanic acid (7-ACA) and 7-aminodes-
acetoxycephalosporanic acid (7-ACDA) respectively. These
basic compounds are then reacylated to introduce the appro-
priate group. In most instances, further chemical modification
of the molecule is necessary to provide the desired antibiotic.
The disadvantage of this route is t;he realtive difficulty and
consequent high cost of preparing and isolating cephalosporin
C and desacetoxycephalosporin C. As a result, alternate
methods have been investigated~
Another approach makes use of the readily available,
low cost, commerical penicillins G and V as starting materials.
Cephalexin, a commercially important cephalosporin, is manu~
factured by a multi-stage process starting from penicillin V,
the process employed being illustrative of this method.
Penicillin V is converted to its sulfoxide which is rearranged
under appropriate conditions to the cephalosporin. The
cephalosporin is then deacylated to 7-ADCA or its ester, and
reacylated by a variety of described processes to cephalexin.
The necessity to protect and later deprotect the amine and/or
acid functions during some of these operations adds to the
number of stages and hence to the cost of this process.
~.
9'~
A useful alternate approach is to react the
penicillin sulfoxide with a mercaptan when an azetidinone-
disulfide is obtained. Analagous sulfenamides are obtained by
heating the sulfoxide in the presence o~ a silylated amide, or
by treating the uns~m-azetidinonedisulfide with a suitable
amine. These compounds on chlorination or bromination by
various reagents produce the 2~chloro- (or bromo~ methylpenam
or the 3-chloro- (or bromo-~cephams the compounds being inter-
convertible. These 3-chloro- (or bromo-)cephams are also
prepared ei$her by heating a penicillin sul~oxide in the
presence of a chloride or bromide salt, or ~rom the 3-hydroxy~
cepham. The chloro- or bromo- cephams can be dehydrohalogen-
ated to the respective cephems by methods described in the
literature, and these cephems in turn deacylated by known
~ processes to 7-~DCA and its derivatives, which are the
; startiLg materials for certain commercial cephalosporins.
Un~ortunately, when proceeding to the dehydrohalogen-
ation oi' the known 3-chloro- or 3 bromo- cephams, the biologi-
cally inactive ~ -cephems are also ~ormed and this will involve
either conversion o~ the ~2-cephem to the active ~3-cephem by
a series o~ reactions, thereby increasing the cost o~ the
desirable ~3-cephems or separation o~ the Q2_ and ~3 mixture
has to be carried out which will also cause a decrease in
yield.
Accordingly it would be highly desirable to produce
a halogenated cepham derivative which would overcome the
drawbacks oi the prlor art 3~chloro- or 3-bromo- cephams.
'?~
THE INVENTION
:
In accordance with the present invention, there is
now provided the novel compounds, the 3-iodocephams or 2-iodo-
methylpenams which have been d~r.i~ed from the 1,2,4-dithiaz-3-
eneazetidinones 2, the thiazol-2-eneazetidinones 3, the ~y~-
azetidinone disulfides 4, the unsym-azetidinone disulfides or
azetidinone sul~onamides 5, by a novel process.
The novel compounds of the present invention are
the 3-iodocephams or 2-iodomethylpenams corresponding to the
general formula:
R H R2 H
RCON ~ I . ~ < CH2I
~' 13 'COOR
: H COOR
1 lA
wherein R stands for benzyl, phenoxymethyl, 4-amino-4-carboxy-
l-butyl and suitably protected drivatives thereof, a-amino-
benzyl and protected de.~ivatives thereof, lower alkyl, aryl,
heteroaryl, and R30-, R3S-, R3R4N- wherein R3 is lower alkyl,
aryl, or arylloweralkyl and R4 is hydrogen or R3; R2 is hydro-
gen or methoxy; and Rl is hydrogen or a cleavable radical such
as -CH20CH3, lower alkyl, 2,2,2-trichloroethyl, benzyl, p~
nitrobenzyl, benzhydryl, phenacyl or trimethylsilyl.
Due to the fact that it is known that certain 3-
halocephams are readily converted to the 2-halomethylpenams,
it is intended herein that the novel 3-iodocephams 1 disclosed
and claimed herein also include their isomeric ~orms which are
the 2-iodomethylpenams lA obtained in accordance with the
above illustration.
'7892
It is immaterial whether the cephams 1 or penams lA
are used as the starting materials. Further, it is difficult
to distinguish between the structures and stereochemistries of
the isomeric penams and cephams~ The structural assignment of
the 3-iodocephams, 1 herein is made mainly from the close
ressemblance of the nmr spectra of these compounds ~obtained
under identical conditions) with the corresponding spectra of
the respective 3-chlorocepham and 3-bromocepham, and the
difference from that of the spectra of the 2~chloromethYlPenam
and the 2-bromomethylpenam. It should, however, be noted
that the 3-iodocephams and the 2-iodomethylpenams are to be
considered as synonymous.
Generally, the novel 3-iodocephams 1 of the present
invention are prepared by iodinating either the 1,2,4-dithiaz-
3-eneazetidinones 2, the thiazol-2-eneazetidinones 3, the sym-
azetidinone disulfides 4 or the unsym-azetidinone disulfides
or azetidinone sulfenamides 5 in a suitable inert solvent and
preferably in the presence of moisture~ These various
reactions are schematically illustrated in Flowsheet I:
~67~
U~
8 ^ ~ 'D o el
~ C~ ~
' ~ \ ~
X
~1 \ . /
o~
0~1 1 ~
~ ~ / 8 a~
V ~ O
~ z
o
- 5 --
3L~678~'~
In Flowsheet I the values of R, Rl, and R , are as
defined previously, while X stands for S, R5 stands for lower
alkyl; -(CH2)nCOO-lower alkyl where n is an integer of from
1 to 3, phenyl, heteroaryl and the group -C~7 where R6
stands for lower alkyl, phenyl, heteroaryl, -O-lower alkyl,
-O-phenyl, -S-lower alkyl, -S-phenyl, or NHR8, and R and R
may be the same or different and each taken from the group H,
lower alkyl, phenyl or heteroaryl.
As iodinating agent there may be used iodine, an
iodinating agent such as N-iodosuccinimide or sulfenyl
iodides, or mixture thereof. Depending on the starting
compound, the amount of iodine is at least one mole equivalent
or at least one atomic equivalent. When starting with the
unsym-azetidinones 5, iodine is the preferred iodinating agent.
As iodine generating compounds there is preferably
used sulfenyl iodides and iodine whereby near quantitive
yields of 3-iodocephams 1 or 2-iodomethylpenams lA are obtain-
ed. In certain cases optimum yields are obtained in presence
of moisture. The sulfenyl iodide is best prepared in situ by
the action of iodine on a mercaptan such as for example a
lower alkyl mercaptan, an aryl mercaptan such as phenyl
mercaptan, a heteroaryl mercaptan such as 2-mercaptobenzo-
thiazole, an arylloweralkyl mercaptan such as benzyl mercaptan
or a disulfide such as ~ 2-benzothiazole disulfide or benzyl,
disulfide, a thioamide such as thioacetamide or thiobenzamide
thiourea or a thioacid such as thioacetic acid or thiobenzoic
acid, in a suitable inert solvent such as carbon tetrachloride,
methylene chloride or chloroform. The sulfur compound-iodine-
water system is thus preferred when having the azetidinones
2, 3 or 4 as starting compounds, since under these conditions
near quantitative yields are obtained. Nevertheless it should
-- 6 --
~06~8~2
also be appreciated that the nature o~ the substituent R
group and the nature of the sulfenyl compound will effect
the yield. Thus, for example, when R is phenoxymethyl in
azetidinone 2 or 3, near quantitative yields result when using
certain sulfenyl iodides such as benzothiazole-2-sulfenyl
iodide in the presence of moisture, while when R is phenoxy,
low yields ~f the order of 5 to 30% are obtained with these
same sulfenyl iodides and otherwise identical conditions.
The stoichiometry is again of importance when better
yields are desired, Thus, compounds 2 or 3 with a mercaptan,
thioamide or acid (1.5 mole equivalent) or a disulfide (Q~8
mole equivalent) and iodine (3 mole equivalent) give near
quantitative yields of compound 1, while with compound 4, 3
mole equivalent of the mercaptan and 6 mole equivalent o~
iodine are preferable.
Also when using the unsym--compounds 5 as starting
compounds the reaction proceeds smoothly and in excellent
yields at ambient temperature and the stoichiometry does not
appear to be important. Thus, reactions using an atomic
equivalent or a molar equivalent of iodine gave essentially
the same yields of over 90% and thus are preferred.
The iodination reaction is preferably carried out at
room temperature and the reaction time is from 5 to 30 hours~
The moisture necessary in certain cases is preferably intro-
duced by bubbling moist air through the reaction mi~ture
while stirring, or by stirring the reaction mixture with
water.
As suitable solvents, there may be used dioxane,
tetrahydrofuran, ethyl acetate, methylene chloride, aceto-
nitrile, and similar solvents.
- 7 -
10~7~9;Z
The preparation o~ the 1,2,4-dithiaz-3-eneazetidi-
nones 2 is described in Can~ Appl. Ser. No. 208,248, filed Aug.
30, 1974. The preparation of thiazol-2-eneazetidinones 3 is
described in U.S.P~ 3,594,389, July 10, 1971 while the sym-
azetldinone disulfides 4 are obtained ~rom azetidinone di-
sulfide as described in Tetra.Letters, 3001(1973) T. Kamiya ~t
; al.
The unsym-azetidinone disulfides 5 are obtained by
heating a penicillin sulfoxide (either the ~- or ~sulfoxides
or a mixture thereof) of the formula:
R2 H O
RCON ~ S
N
EI
with a mercaptan (Tetra.Letters, 3001(1~73~ T~ Kamiya et al)
or with a thioamide of the formula:
R6-~-NHR7
; where R6 and R7 are as previously defined. The reaction is
carried out in the presence o~ a suitable solvent such as for
example dioxane or toluene. As an example of suitable thio-
amides, there may be mentioned thioacetamide,thiourea, thio-
semicarbazide, thiocarbamate and dithiocarbamate~
In the case o~ the 1,2,4-dithiaz-3-eneazetidinones
3, it is not necessary to isolate the compounds 3, so that a
simpli~ication o~ the process is possible, starting from the
penicillin sul~oxide thioamide.
With an atomic equivalent o~ iodine and otherwise
identical conditions, the 1,2,4-dithiaz-3-eneazetidinones 2,
or the thiazol-2-eneazetidinone 3, are converted in high
- 8 --
789Z
yields to the ~ azetidinone disulfides 4. This procedure
constitutes a new process i'or the preparation o~ compounds 4.
The 3-iodocephams were ~ound to b~ stable and besides
the obvious advantages o~ high yields (usually over 90%3 and
simple reaction conditions, were found to be particularly
suitable in certain reactions. Thus, ~or example, an attempt
to prepare the bromo-compound by reacting the disulfide 5,
(Flowsheet II) with bromine under controlled conditions was
unsuccessful. The reaction with iodine, on the other hand,
gave good yields o~ the 3-iodocepham, 1, (Flowsheet II~.
Another advantage in the use o~ the 3-iodocephams is
their rapid and facile dehydroiodination in the presence of a
base such as pyridine, to the 3-cephem. As a result, the
yields in this stage are also high, and complications such as
the possible co-i'ormation o~ the bioinactive 2-cephem are
minimized and almost non~existent.
Illustrative of the advantages o~ the use of the
3-iodocephams, are the processes summarized in Flowsheets II
and III in which the readily available, comparatively cheap,
commercial ampicillin and penicillin V are conveniently con-
verted to cephalexin and 7-phenoxyacetamido-3-methylceph-3-
em-4-carboxylic acid respectively,
As illustrated by Flowsheet II, ampicillin 6 was
converted to ampicillin sul~oxide 7~ This compound when
treated with chloromethylmethylether and triethylamine in the
presence o~ carbon dioxide, gave the diprotected ampicillin
sulfoxide 8, in one step. Heating compound 8 with a mercaptaa
such as benzothiazole-2-thiol in dioxane for 16 hours gave a
near quantitative yield of the unsym-azetidinone disulfide 5,
30 which on iodination with iodine ln methylene chloride gave the
-
6789Z
3-iodocepham 1. Dehydro-iodination of 1 with pyridine,
followed by deprotection by acid (trifluoroacetic acid) gave
cephalexin 9, isolated as its trifluoroacetate salt. Free
cephalexin could be obtained from the salt by neutralization
or by the use of an ion-exchange resin.
~ lowsheet III illustrates a similar conversion of
penicillin V, lO, to 7-phenoxyacetamido-3-methylceph-3-em-4-
carbo~ylic acid, 12. Penicillin V, lO, was converted to
penicillin V sulfoxide, 11, which could be used as such, or
optionally converted to an ester such as the methoxymethyl-
ester. Compound 11 on heating with a suitable mercaptan, such
as benzothiazole-2-thiol, was converted to the unsym-azeti-
dinone disulfides, 5, in excellent yeilds. Iodination gave
the 3-iodocephams, 1. In the case of the free acid, silyation
was desirable for the iodination reaction, for reasons of
solubility, the silyl group being removed during the work-up
process. Dehydroiodination of 1 provides compound 12.
The processes can be further simplified by super-
imposing the reactions in the same pot. It will be obvious to
one skilled in the art that various other modifications o~
this process are possible for the conversion, for example of
ampicillin to cephalexin; 6-APA to 6-ADCA;carbenicillin, ~-
sulfobenzylpenicillin and 6-mandelamidopenicillin to the
respective cephalosporins;and the 6-methoxypenicillins to the
7-methoxycephalosporins. Another advantage is that the novel
3-iodocephams and 2-iodomethylpenams can be converted to
various 3-substituted cephams and 2-substituted methylpenams
with side chains ~such as D-phenylglycyl) which are known to
confer enhanced activities; compounds which otherwise are
difficult to prepare.
- 10 -
-
9z
The 3-iodocephams show antibiotic activity~ Thus,
7-phenoxyacetamido-3-methyl_3-iodocepham-4-carboxylic acid, 1
(R = 0OCH2, R1 = H, R2 = H) is active against Bacillus subtilis
NCIB 8057. This acid also shows the following activity
compared to 7-phenoxyacetamido-3-methylceph-3-em-4-carboxylic
acid.
(MIC in ~g/lm)
Staph.aureus S. lutea
7-phenoxyacetamido-3-methyl
ceph-3-em-4-carboxylic acid 0.254 1.01
Iodocepham acid 0.254 0.507
It should also be appreciated that the 3-iodocephams,
1, are useful intermediates for the preparation of cephalo-
sporins. For example, on treatment with bases such as pyridine
and collidine, they undergo a facile dehydroiodination to
provide the cephems. The cephems thus obtained can be
deacylated by known procedures to the 7-ADCA deri~atives and
; these compounds may in turn be converted by processes described
in the literature to the commercially important cephalexin.
FLOWSH~~ET II -~ ~ m
Conversion of Am~c;Lllin to Cephaloxin
CHCONH
~:~ NH ~ S ~ Amplcilli~
COOH
CHCON ~ S
NH2~ -Ampic~ n Sulfoxide `~
CO H
/C2/clcH2clcH3
CHCONH ~ S ~ "Protected"
N V ~ Ampicillin Sulfoxide
CoocH2ocH3 COocH20cH3 `~
CHCO~H ~ S- S - R ~ Azetidlnone D1sulfide
H o~ N ~
~` COOCH20CH3 CoOcH20cH3
CHCONH~. ~ S -~
- - I ~ 3-Iodocepham : :
:~ NH ~ N ~
COOCH2C 3 ~ h
3 COOCH20CH3
-HY
. ~ICHCONH ~ S . :~
NH2 ~ N ~ ~ ~ephalexin
: COOH
,
l Z ~
,
- :~0~ii789Z - - ~
~ FLOWSHEET II.I
. . - , . . , . - :
, . . . i , : . - .
.~: Conversion of Penicillin V to Desacetosycephalosporin V~
. ~OCH2CONH ,fS
. ~ ~ : : Penicillin V
COOH
OCH CON~ S
2 ~ : ~ : ~ Penicillin Sulfoxlde
COOCH20CH
OCH2CONII S_S~
Unsym-Azetidinone Disulfide
COOH (COOCH20CH3)
- l. Silylation
; : - . ~ :2.: I2
:- - : - 3, Desilylation
OCH2CONH ~ ~ , S~
I i I : . 3-Iodocepham - ~::
~- O - N ~ 3
COOH (COOCH20CH3)
, , ~
l. Silyla*ion ~ : -
. 2, -HI
3. Desilylation
.
~OCH CON ~ S ~
2 ~ Desacetoxycephalosporin V
CH3 l2
COOH
.
- 13 -
,
- '-'''' '", '''''~'
67~9~
.- ~ : -- EXAMPLES .
~- The present invention will be more readily understood~
.-~ by referring to the following Examples which are given only to
: ~ illustrate the invention rather than limit its scope.
EXA~PLE 1 ~
- ~- Methyl 7-Phenoxyacetamido-3-Methyl-3-Iodocepham-4-Carbo~ylate-
~ 1 (R =;~OCH2-, R2 - H, R~ CH3) from ~lethyl 6-Phenoxythloacet-:
.~` - ;. - amidopenicillanate Sulfoxide with Isolation of 2 (R~= ~OCH2-~
R2 - H, Rl = CU3 ~
. 10:.~ . A solution of pure methyl 6-phenoxythioacet-amidopeni- .
~ ` cillanate sulfoxide (503 mg, 1.3 mmoles) in toluene (~125 ml)
`~ ~ was heated ~in an o11 bath:at 12() C) with stirring under re-
- flux, under n:itrogen, in a.~lask fitted with a Dean-Stark trap~
. for 3~ hours. The toluene was removed in vacuo. An nmr s.pec-;
--trum (CDC13) of the waxy~residue:shoued complete reaction aDd:.
. -:
. -. formation of methyl 3-phenoxymathyl-4,5-dithia-2,7-di~abicy-~
: clo~4,2,0]oct-2-ene-8-one-7-isopropenylacetate, 2 (R = ~OCH2,~ :
R = ~ R = CH3) ~7.5 to 6.9(m,~ SH, C~5), 5.72(d with wings,
: 2H, ~-lactam protons), 5.19 an.d~.O8(ds, 2H, ~ ), 4.95(s,`.
~.
20 : lH, CHCOOCH3), 4.87~s, 2H, -oc~ - ? 3.8(~, 3HI COOCH3), l.90(s~
~: CX3 ~ -
The total residue was dissolved in purified dloxane and~
iodine (365 mg, 1.43 mmoles3 added~, the.mixtur.e was stirred and
moist air obtained by bubbllng air throu~h water then passed
through the solution A~ter lB ~ours the reaction mixture was
concentrated to dryness and an nmr spectrum obtained on the
residue. The dark bro-~m residue c~uld .he partially purified
by taking up in ethyl acetat~ or~met;h~lene chloride or chloro-
.
`- ~O~i7~39~2
form, washing with aqueous sodium thiosulfate and watsr, dry-
ing over magnesium sulfate with added decolorising charcoai,
and concentrating, when a pale yellow thick oil resulted. The
nmr spectra of the crude material and the partially purified
product showed the formation of about 35~ iodocepham, 1, which
could be distinguished by the -CH2-S quartet at about ~3 and
the=~cH singlet at about ~2.2. The presence of the iodo-
cepham, 1, was confirmed by a thin layer chromatogram run with
an authentic sample of 1 as reference.
EXAMPLE ~
Methyl 7-Phenoxyacetamido-3-Methyl-3-Iodocepham-4-Carboxylate,
1, (R = ~OCH2-, R = H, Rl = CH3) from Methyl 6-Phenoxythio-
acetamidopenicillanate Sul~oxide without Isolation of 2 (R 8
~OCH2, R2 = H, Rl ~ CH3~
A solution of pure methyl 6-phenoxythioace$amidopeni-
cillanate sulfoxide (2 g., 5.2 mmoles) ln dioxane (500 ml)
was heated with stirring under reflux in a nitrogen atmosphere,
in an oil bath at 120 C for ~ hours. (Prior experiments had
shown that these conditions gave a quantitative yield of the
methyl 3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo[4,2,0]oct-
2-ene-8-one-7-isopropenylacetate, 2.) The reaction mixture
was cooled to ambient temperature, iodine (1.52 g., 6 mmoles)
was added and moist air bubbled through the stirred solution
at ambient temperature for 16 hours. The reaction mixture was
then taken to dryness, the residue taken up in methylene chlor-
ide, washed with aqueous sodium thiosulfate and water and dried
over magnesium sul~ate with decolorising charcoai. The nmr
spectrum oi thi~ Yoam indicated the presence oi ~bout 20~ oi
the 3-iodocepham, 1
~ 15 -
67893;~
The crude product (1 g.) was purified by gradient elu-
tion chromatography on silica (Mallinckrodt Silicar CC-7) using
ether:hexane = 3:1 ~ ether as the eluants. The pure 3-iodo-
cepham (100 mg.) was thus obtained as an amorphous faint yel-
low solid and was identical (ir and nmr spectra and tlc) to an
authentic sample prepared by the alternate route (see Example
17). The nmr spectrum (CDC13) ~7.85 to 6.92( m, 6H, C5H5 and
NH), 5.88 and 5.7(dd, lH, J = 4c/s, C7-H), 5.42(d, lH, J =
4c/s, C6-H), ~.95(s, lH, C4-H), 4.7(s, 2H, -O-CH2-), 3-85(s,
3H, COOCH3), 2.98(ABq, 2H, J = 15c/s, C2-CH2), 2.22(s, 3H,
C3-CH3) is quite charactsristic of these co~pounds.
In a similar manner using trimethylsilyl 3-phenoxymethyl~
4,5-dithia-2,7-diazabicyclo[4,2,0]oct-2-ene-8-one-7-isopropen-
ylacetate,
methoxymethyl 3-phenoxymethyl-4,5-dithia-2,7-biazabicyclol4,2,
O]oct-2-ene-8-one-7-isopropenylacetate,
trichloroethyl 3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo~4,2,
O~oct-2-ene-B-one-7-isopropenyl acetate,
trimethylsilyl 3-phenoxy-4,5-dithia-2,7-diazabicyclo~4,2,0~oct-
2-ene-8-one-7-isopropenyl acetate,
methoxymethyl 3-phenoxy-4,5-dithia-2,7-diazabicyclo[4,2,0]oct-
2-ene-8-one-7-isopropenyl acetate,
methyl 3-methylthio-4,5-dithia-2,7-diazabicyclo[4,2,0~oct-2-
ene-8-one-7-isopropenyl acetate,
methoxymethyl 3-methylthio-4~5-dithia-2~7-diazabicyclo[4~2
oct-2-ene-8-one-7-isopropenyl acetate,
trimethylsilyl 3-methylthio-4~5-dithia-2~7-diazabicyclo~4l2~oJ
oct-2-ene-8-one-7-isopropenyl acetate,
benzyhydryl 3-phenylthio-4,5-dithia-2,7-diazabicyclo[4,2,01-
oct-2-ene-8-one-7-isopropenyl acetate,
methyl 3-phenylthio-4,5-dithia-2,7-diazabicyclol4,2,01oct-2-
ene-8-one-7-isopropenyl acetate,
- : :
r ~ 7 89;~ ~
- .
.; ~ methoxymethyl 3-phenylthio-4,5-dithia-2,7-diazabicyclo[4,2,0oct-2-ene-8-one-7-isopropenyl acetate,~
trimethylsilyl 3-phenylthio-4,5-dithia-2,7-diazablcyclo[4,2,0
oct-2-ene-8-one-7-isopropenyl acetate~
:: - . - - ~ ~ :
--~ : trichloroethyl 3-benzyl-4,5-d.ithia-2,7-diazabicyclo~4,2,0~-
::. oct-2-ene-8-one-7-isopropenyl acetate, it is possible to obtain`
the followlne compounds~
7-phenoxyacetamido-3-methy1-3-iodocepham-4-carboxylic acid, ~.
.methoxymethyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-car-
10~ boxylate,
1 ~ : trichloroethyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-car- ::-
. boxylate,
.:7-phenoxyamido-3-methyl-3-iodocepham-4-carboxylic acid, . .
,: . :. . . . . ................................................. .
methoxymethyl 7-phenoxyamido-3-methyl-3-iodocepham-4-carboxy-
- late 1: '
. methyl 7-methyIthiolcarbamido-3-methyl-3-iodoceph~m~4-carboxy-
.-methoxymethyl 7-methyl~hiolcarbamido-3-methyl-3-iodocepham-4-
carboxylate,
7-methylthiolcarbamido-3-methyl-3-iodocepham-4-carboxylic àcld,~
benzhydryl 7-phenylthiolcarbamido-3-methyl-3-iodocepham-4-car-
- : . . . . . .
. - -`. boxylate,
,
methyl 7-phenylthiolcarbamido-3-methyl-3-iodocepham-4-carboxy-
late,
metho.Yymethyl 7-phenylthiolcarbamido-3-methyl-3-iodocepham-4-
carboxylate,
7-phenylthiolcarbamido-3-methyl-3-iodocepham-4-carboxylic, and
trichloroethyl 7-phenylacetamido-3-methyl-3-iodocepham-4-car- .
boxylate. ~ . ~
,
'
- 17 -
- - r~.
89Z
EXA~IPLE 3 - - -
Preparation o~ 3-Phenoxy-4,5-Dithia-2, 7-Diazabicvclo 14 . 2, 01 Oct-
2-Ene-8-One-7-Isopropenylacetic Acid, 2 (R = ~0, R2 = H, Rl =H~
solution of~ 6-phenoxythlocarbamidopenicillanic acid:
sulfoxide'(15 g., O.04 mole) in purified dioxane (300 mls) was~
heated with stirring under re~'lux in a dry nitrogen atmosphere~
' ;in an oil bath maintained at 130 ,~for 4 hours. The,reaction ' ~'
mixture was concentrated in vacuo and dried under hi-vac. The '~
yellowish brown solid thus obt~alned was dlssolved in the mini-
~mum amount of warm acetone, the solution treated with charcoa?,'~ -
and filtered. The filtrate was concentrated to about 1/3 its
volume and just sufficient hexane added to induce crystallisa~
tion. The mixture was'cooled overnight~ at about -10 and the~-
resulting pale yellow crystals isolated by filtration and dry- `
ing, when 10.5 g (75%) of 3-phenoxy-4,5-dithia-2,7-diazabicy-
clot4,2,0]oct-2-ene-8-onc-7-isopropenylacetic acid was obtained.
;The compound could be purified by recrystalllsation from ace-
tone-hexane. It was obtained as white crystals,m.p. 146-148
dec.~ A high resolution mass spectral analysis gave a mass of ;-
~350.0404 for the parent ion, that calculated for C15H14N2S
being 850.0396. The nmr (D~SOd6)spectrum ~7.~8 to 7.15(m, 6H,~
C6H5 and COOH), 5.87 and 5.53(A q,~2H, J = Sc/s, B-lactam pro-
~tons'cis fused), 5.2(s, 2H, ~ ),- 4.85(s, lH, -CHCOOH),
1.89(s, 3H, ~ CH ) is'in agreement with the assignment.
.
- - . :
EXA~.IPLE 4
:: :
' Preparation of ~Icthvl 8-Phenoxy-4,5-~ithia-2,7-Diazabicyclo~4,`~
2,0]0ct-2-Ene-8-One-7-Isopropenyl Acetate,2,(R=~O,R2=H,Rl=CI~3)
J. . ~:
' ' 3-Phenoxy-4,5-dithia-2,7-diazabicyclo~4,2,0]oct-2-ene-
8-one-7-isopropenyl~cetic acid (10.0 g., 28.5 mmole) was dis- ~'
- t8 -
- :'''~
678~Z
- solved in tetrahydrofuran (~50 ml~ and the solution cooled la
an ice-bath. Diazomethane in ether~'(100 ml-excess) was added'
and the solution stirred ln the ice-bnth for 0.5 hours and .then
. ~ . -
~ : concentrated in vacuo. The residue was taken up in the minimum
-
o~ ether and cooled in a dry ice-ace~one bath while adding an
-. . ~ equal volume of hexane. The resulting white precipitate was -
: ~ ~' filtered off and dried to give ~.0 g~of the product, m~.'p. 79-
. - O ~ -
' 82 C. A further 1.5 g was obtained from the mother liquor
after concentratlon and repeating.the ether-he~ane precipita-
~- 10 tion. The two crops were combined (~.5 g, 81~o) since.:they were
~ ~ identical (nmr spectra and tlc). 'The nmr(CDCl ) spectrum: ~7.6'
. : . 3 . ... .
to 7.1(m, 5H, C6H5), 5.7 and 5.48(ABq, ~H, J=4c/s, ~-lactam ~ ~'
' '' protons cis-fused), 5.22 and 5.12(d, s, 2H,-~CH2), 5.0(s, lH,
~' . ' '~CHCOOCX3), 3.8(s, 3H, COOCH3~ and 1.97(s, 3H ~ ) was in
' CH3
. ' agreement with the assigned structure. A.high resolution mass
spectral analysls gave a mass of 364.0565 for the parent ion',
tha~ calculated for C16H16N ~2 4 being 3~4.0552. ~ ~'
- . EXA~IPLE 5 '~ ....~ . - - .
- ' :Methyl 7-Phenoxyamido-3-~lethyl-3-Iodocepham-4-Carhoxylate, 1,
: 20 (R = ~0, R2 = H, Rl = CH3) Using ~5ethylene Chloridè~
~ethyl 3-phenoxy-4,5-dithia-2,7-diazabicyclo[4,2,0]oct-
2-ene-8-one-7-isopropenyl acetate (2.0 g, 0.005 mole) was dis-
.
solved in purified methylene chloride (50 ml) and iodine(l.4 g,.
0.0055 mole) added. The reaction mixture was stirred at room
temperature for 20 hours, concentrated, the residue taken up-in
dioxane and reacted with moist air for 16 hours, then concen-
trated and redissolved in methylene chloride.' The resultin~
solution was extracted with aqueous sodium thiosulfate (t~vice)
, and then water (twice). The organic phase was dried with mag-
ncsium suifate and charcoal, filt~red and concentrated to ~iYe
- 19 -.
. .
' '` - - ~01~789Z~
.
9 g of a yellow foam whose nmr spectrum indicated the~pres-
. ence c~ about 22% of the 3-iodocepham, 1. This was confirmed
.. ~ . . ,
: by a tlc using an authentic sample of 1 prepared by the altèr--
nate route (see Example 34).-
ethyl 7-Phenoxyamido-3-Methyl-3-Iodocepham-4-Carboxylate, 1
- : . . . . . . .
(R = ~O-, R2 = H, Rl - CH3) Using Ethyl Acetate - . :
When purified ethyl acetate was used as solvent under
the same conditions as in~Example 5, a 30% yie1d of the 3-1odo-
cepham as estimated from the nmr spectrum was realised.
EXAMPLE 7
:Methyl 7-Phenoxyamido-3-Methyl-3-Iodocepham-4-Carbo~ylate, 1,
~(R~= ~O-, R2 = H, R3 = CH3) Using Dioxane
When purified dioxane was used as solvent:under
: ~ the same conditions as in Example~5:, a: 257c yield of the 3-
iodocepham as estimated from the nmr spectrum was:realised.
~ : : . EXAMPLE 8 - -~
- : Methyl 7-Phenoxyamido 3-Methyl-3-Iodocepham-4 Carboxylate, 1, - ~
(R = ~O-, R2 = H, R3 = CH3) Using Tetrahydrofuran
: 20 When purified tetrahydrofuran was used.as solvent under
the same conditions as in Example 5, a 12.5~o yleld 0~ the
3-iodocepham as estlmated from the nmr spectrum was reallsed.
- '' ' '' ~ '':
': :
. - 20 ~ :
- ~ ~
671~92 : - -
- - - . . :
- ~ EXA~IPLE 9 ;
~ (Methyl 3-Phenoxyacetamidoazetidinone-l-Isopropenyl Acetate~ :~
.
-4-Disulfide,4, (R = ~OCH2-, R2~- H, Rl = CH3) from ~ethyl 3-
, . ~
Phenoxymethvl-4,5-Dithia-2,7-Diaæabicyclo[4 2,0]0ct-2-Ene-3-One-
~~ 7-Isopropenylacetate, 2 (R = ~OCH2-, R2 = H, Rl-= CH3)
- ~ llethyl 6-phenoxythioacetamidopenicillanate sulfoxide
- -: ~ : . :: .
(1.0 g, 2.6~mmoles) was converted to methyl 3-phenoxymethyl-4,5-
- dithià-2,7-diazabicyclo[4,2,0]oct-2-ene-8-one-7-isopropenyl-
- acetate, 2 (R = ~OCH2-, R = U, Rl = CH3) as~descrlbed in Ex-~
` 10 ample 1. The total residue from the thermol~sis in toluene was-
dissolved in purified dioxane (500 mls), iodine~(330 mg.,
: . - --- :
1.3~mmoles) added and moist air bubbled through the stirred
- solution at ambient temperature for 20 hours. The-solution
- was concentrated, *he residùe dissolved in methylene chloride
~ `
- - a~d the resulting solution washed with aqueous sodium thio-
sulfate (twlce) and water (tulce), drled over magnès1um sul-
fate and charcoal, and concentrated. The resuIting yellow ~
foam ~eighed O.9 g (94~0) and was the ~ azetidinone, 4 (R =
- . ~ .
~ OCH2-, R = H, R = CH3). The nmr (CDC13) spectrum ~7.8(d, lH,
; 20 ( . , C6H5), 5.52 to 5.37(m, 2H,~ ~-lactam
protons), 5.22 and 5.1(brs, s, 2H, -~ 2), 4.9(s, lH,CHCOOCH3),
4.6(s, 2H, -O-CH2), 3.75(s, 3H, COOCH3), i.91(s, 3H, ~ CH ) was
consistent with the assigned structure.
,
- EXA~.IPLE 10
lethyl 3-Phenoxyacetamidoazetidinone~l-Isopropenyl Acetate)
-4-Disulfide, 4 (R = ~OCH~-, R = H, Rl = CH3) from ~lethyl
3-Phenoxvmethvl-4-Thia-2,G-Diazabicyclo[3 2,0]Hept-2-Ene-~-
One-6-Isopropenylacetate, 3 ~R = ~OCH2-, R2 = H, Rl = CH3)
.
- 21 - ~ `
~_ ~INg¦~
6789Z - -- :
.
When methyl 3-phenoxymethyl-~-thia-2,6-diazabicyclo[3,2,
; :.- OJhept-2-ene-7-one-6-isopropenylacetate, 3, (R =~OCH2-;, B2~=H,
l = CH3) (100 mg, 0.29 mmoles) was treated with an atomic
~:. equival-ent (40 mg, 0.15 mmoles) of iodine in dioxane (100 mls) .
in the same way as described in Example 9, the same:product 4
(R = ~OCH2-, R2 = H, Rl = CH3) was obtalned. The~nmr spectrum~
~:: . was identical to that o~ the product in E~ample 9.
EXA~IPLE ll~
ethyl 7-Phenoxyacetamido-3-Methyl-3-Iodocepham-4-Carboxylate,l
-.10 (R = ~OCH2-, R2= H, Rl= CH3) from Methyl 3-Phenoxymethyl-4-~
:Thia-2,6-Diazabicyclo[3,2,0~ ept-2-Ene-7-One-6-Is~opropenylace-
: .; . ~ tate, 3, (R - ~OCH2-,~R2 = H, Rl = CH3)~
~ ;hen methyl 3-phenoxyme~thyl-4-thia-2,6-diazabicyclo[3,2:,
: : - 2
. ..O]hept-2-ene-7-one-6-isopropenylacetate, 3 (R - ~OCH2-, R. = H.,
l = CH3) was treated with at least one molnr equivalent of
- , . .
.iodine in dioxane by the same process as described in Example~-l
-the nmr spectrum of the~product~:showed the presence of about~
.25~o 0f: the 3-iodocepham,~
EXAMPLE l~
Methyl 7-Phenoxyacetamido-3 Methyl-3-Iodocepham-4-Carboxylate,l
-
: _ (R = ~OCH2-, R2 = H, Rl = CH3) from ~ ethyl 3-Phenoxyacet-
-amidoazetidinone-l-Isopropenylacetate)-~-Disulfide, 4 ~R = :.
~OCH2-, R = H, R1 = CH3j ..
.
. When sym(methyl 3-phenoxyacetamidoazetidinone-1-isopro- .
penylacetate)-4-disulfide, ~, (R = ~OCH2-, R2 = H, Rl z Cl13?
: , was treated with one molar equivalent of iodine in dioxane by
the same process as described in Example 1, the nmr spectrum-
- 22 - .
- - .
L0678gZ - ~
- ~ of the product showed the presence of about-20%.of the 3-iodo-
:, . . - - ,; ~ ',
- cepham, 1.
.
- .
EXA~PLE 13
~- Methy1 7 Phenoxvacetamido-3-~ethvlce~h-3-em-4-CarboxYlate from
:. - . :
Methyl 7-Phenoxyacetamido-3-~lethyl-3-Iodocepham-4-Carboxylate,l
(R = ~OCH2-, R2 = H, R1 - CH3)
A so~ution of methyl 7-phenoxyacetamido-3-methyl-3-
iodocepham-4-carboxylate (250 mg,~ 0.5 mmole) in benzene (3 mls)
~ containing~pyridine(100 mg, 1.25~mmoles) was~heated under reflux
t ~ 10 ~or l hr. Filtration and concentration gave~a quantitative
yield of methyl`7-phenoxyacetamido-3-methy1-3-em-4-carboxy-
late and the starting compound in a ratio of 3~:~ 1 respec~ively,
.
~ as estimated from the nmr spectrum. The cephem producèd has a
., ~ , - ~
characteristic nmr spectrom with~signals àt ~7.8 to 6.9(C6H6);
- 5.97 and 5.8(dd, C7-H); 5.08(d, C6-H); 4.61(s~, O-CH2-)`; 3.88(s,
COOCH3~); 3.4(d, C2-CH2) and 2.2(s, C3-CH3).~ Although most~of
` ~ these signals overlap with those of the 3-iodocepham, the ~-
- - - ~ ~ ~
- cephem is easily identified by the doublet at 3. and the dis:lp-
- - ~ pearance of the C4H singlet at 4.~5(present in the 3-iodocepham).
~ ~ ~ EXAMPLE 14
Methyl 7-Phenoxyacetamido-3-Methyl-3-Iodocepham-4-Carboxylate,l
(R=~OCH2-, R2=H, Rl=CH3) from Methyl-3-Phenoxymethyl-4,5-Dithia~
- 2,7-Diazabicyclo[4,2,0]0ct-2-Ene-8-One-7-Isopropenylacetate, 2
(R= ~OCH2-, R2 =H, Rl =CH3) using Sulfenyl Iodides-Iodine-Water
.
: - - , ~ .
- A mixture of methyl 3-phenoxymethyl-4,5-dithia-2,~
diazabicyclot4,2,0]oct-2-ene-8-one-7-isopropenylacetate(150 mg,
0.38 mmoles), thiourea(44 m~, 0.57 mmoles), and iodine(290 m~,
- 23 - ~
.
-F
67~39Z
- ' : - ' - .. - :
1.14mmoles) in methylene chloride (10 ml) was stirred with water
(I0 ml) at ambient temperature for 12~hrs. The or~anic laye~ -
.~ - . . .
~ was dried over magnesium sulfate, ~iltered and concentrated.
- .
The nmr spectrum (CDC13) o~ the product indicated over 85~o of
. . -. . :
the 3-iodocepham to be present.
- Exactly similar reactions were rùn using the following
mercaptans in place of thlourea with the~results-indicated:
Sulfenyl Iodide Precursor ~-Yield of 3-iodocepham (~j
~ 2-~Sercaptobenzothiazole ~ 8S~
- 10 2-Mercaptobenzimidazole ~ 30
; Triphenylmethylmercaptan ~ 30
p-Chlorothiophenol - - -~ 60
-~ Ethyl 2-mercaptoacetate ~ 30
~ - 2-~lercaptothiazolene ~ 75
;~ ~ Thioacetamide ~-50
- t-Butylmercaptan ~ 70
Besides the above, other mercaptans such as methyl,
ethyl, isopropyl, phenyl and benzyl mercaptans; thioamides such
~: - , . . .
as benzamide, N,N'-dimethylthiourea and N,N'-diphenylthiourea;
- 20~ and thioacids such as thloacetlc~acid and thiobenzolc acid and
disulfides such as methyl, benzyl, t-butyl and p-tolyl can also
- be~used.
In a similar manner, using the thlo compounds such as
those described above and
.
methoxymethyl 3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo[4,2,
Oloct-2-ene-8-one-7-isopropenylacetate,
~ trichloroethyl 3-phenox~methyl 4,5-dithia-2,7-diazabicyclo[4,2,
:
O]oct-2-ene-8-one-7-isopropenylacetate,
- benzyl 3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo[4,2,0]oct-
2-ene-8-one-7-isopropenylacetate,
p-nitrobenzyl 3-phenoxymethyl-4,5-dithia-2,7-diazabicyclo[4,2,
O]oct-2-ene-8-one-7-isopropenylacetate,
methoxymethyl 3-benzyl-4,5-dithia-2,7-diazabicyclo[4,2,0]oct-2-
ene-8-one-7-isopropenylacetate,
- 24 -
... . . . , .. ._, .. .,, ,,~
- - - :1~67892
--- ~ . ' ., . - . . - .
- - trichloroethyl 3-benzyl-4,5-dithia-~,7-diazabicyclo~4,2,01oct-
2-ene-8-vne-7-isopropenylacetate,
~. benzyl.3-benzyl-4,.5-dithia-2,7-diazabicyclo[4,~,0]oct-2-ene-8-
.: one-7~isopropenylacetate
-:. ben2hydryl 3-benzyl-4,5-dithia-2,7-diazabicyclo[4,2,0~oct-2-ene-
-:. .8-one-7-isopropenylacetate, and
trichloroethyl l-methoxy-3-phenoxymethyl-4,5-dithia-2,7-diaza-
bicy.clo[4,2,0]oct-~-ene-8-one-7-isopropenylacetate,.it is
; - ~ possible to prepare the~followlng compounds
methoxymethyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carbox-
.ylate.~
:. - trichloroethyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-car-
~ boxylate,
: . ~ benzyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate, .
. ~ : . - :
nitrobenzyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-car- .
. ; boxylate,
methoxymethy-l 7-phenylacetamldo-3-methyl-3-1odocepham-4-car--
-boxylate, .~
- . . : - , .
"~ : . trichloroethyl 7-phenylacetamido-3-methyl-3-iodocepham-4-car- :
~ boxylate,
- - benzyl 7-phenylacetamido-3-methyl-3-iodocepham-4-carboxylate~
, . . - ~ .
-~ . : benzhydryl 7-phenylacetamido-3-methyl-3-iodocepham-4-carboxylat~,
-
:and
trichloroethyl 7-methoxy-7-phenoxyacetamido-3-methyl-3-iodoceph-
am-4-carboxylate.
~ 25 ~
~ ~ ,
.~J - ~ ~6789
-. ~ E~AMPLE 15
. . . ; . . . ~,,
Methyl 7-Phenoxyacetamido-3-Methyl-3-Iodocepham-~-Carboxylate,l
2 1 -
(R = ~OCH2, R = H, R - CH3) from Methyl 3-Phenoxymethyl-4- ~
Thia-2,6-Diazablcyclot3,2,0]Hept-2-Ene-7-One-6-Isopropenylace- ~`
~` ~ tate, 3 (R = ~OCH2, R = H, Rl~=CH3) using Sulfenyl Iodides- `-
, ~
- Iodine-~'Jater
2-~lercaptobenzothiazole (70.2 mg., O.42 mmoles)~and
iodine (213 mg., 0.84 mmoles~ were added to a stirred solution
of methyl 3-phenoxymethyl-4-thia-2,6-diazabicyclo[3,2,0~ hépt-
2-ene~7-one-6-isopropenylacetate (lOO m~s.,0.28~mmoles) in~ --
methylene chloride (15 ml), and the`mixture stlrred at ambient -~
temperature for 15 mins. Water (15 mls3 u~as then added and the ~-
` ~ ~ mixture stirred-overnight at room temperature. ~The- organic
layer was separated, dried over magnesium sulfate, filtered and
~concentrated. The nmr spectrum of the residue showed the pre-
sence of about 80/~o of the 3-iodocepham.
- In a similar manner using the thio-compounds such as
thioacetamide, thioacetanillde, thiourea, N,N'-dlmethylthiourea,
N,N~-diphenylthiourea, t-butyl mercaptan, isopropylmercaptan, ~-
- ~ 20 thiophenolj p-chlorothiophenol, ethyl 2-mercaptoacetate, 2-mer-~
- . . . -:j
~- captobenzooxazole, 2-mercaptobenzimidazole, 2-mercaptothiazol-
ene, triphenylmethylmercaptan, benzylmercaptan, dimethyl disul-~
~ide, dibenzyldisulfide, di-t-butyldisulfide, di-~-tolyldisul-
. . . .
~ide, thioacetic acid and thiobenzoic acid and the followin~
compounds;
trichloroethyl 3-phenoxymethyl-4-thia-2,6-diazabicyclot3,2,01-
. .
hept-2-ene-7-one-6-isopropenylacetate,
~-nitrobenzyl 3-phenoxymethyl-4-thia-2,6-diæzabicyclo[3,2,0]-
hept-2-ene-7-one-6-isopropenylacetate,
~30 trichloroethyl 3-benzyl-4-thia-2,6-diazabicyclol3,2,0~hept-2-
~ne-7-one-6-isopropenylacetate,
- 26 -
.,, , ' . ' ~
- 1~)678~
~-nitrobenzyl 3-benzyl-4-thia-2,6-diazabicyclo[3,2,0]hept-2- - '
: , " ~ ~
- -ene-7-one-6-isopropenylacetate, and
trichloroethyl l-methoxy-3-phenoxymethyl-4-~hia-2,6-diazabicyclo-'
~; , . . ~ ,, .:
' ' t3,2,0]hept-2-ene-7-one-6-isopropenylacetàte,'
,,
it is possIble to obtain;
- trichloroethyl 7-phenoxyacetamido-3-me*hyl-3-iodocepham-4-car-
. : - - . . , - :
boxylate,
p-nitrobenzyl 7-phenoxyàcetamido-3-methyl-3-iodocepham-4-car-
boxylate,
trichloroethyl ~-phenylacetamido-3-methyI-3-iodocepham-4-car- ;~
boxylate,
~-nitrobenzyl 7-phenylacetamido-3-methyl-3-iodocepham-4-car~
boxylate, and
trichloroethyl 7-methoxy-7-phenoxyacetamido-3-methyl-3-iodo-
cepham-4-carboxylatè
EXAMPLE 16
Methyl 7-Phenoxyacetamido-3-Methyl-3-Iodocepham-4-Car~oxylate,l'
:
(R = ~OCH2, R2 = H, Rl = CH3) from ~ ethyl 3-Phenoxyacetami-
' doazetidinone-l-Isopropenyl Acetate~-4-Disu1fidej 4-(R = ~OCH
R = H, Rl = C~3), using Sulfenyl'Iodides-Iodine-~!ater -
'~ 2-Mercaptobenzothiazole (138 mg., 0.83 mmoles) and~io-
dine (4Z7 mg., 1.68 mmoles) were added to a stirred solution of
-sym-(methyl 3-phenoxyacetamidoaæetidinone-1-isopropenyl acetate)~
4-disulfide (200 mg., 0.28 mmoles) in methylene chloride (15 ml)
and the mixture stirred at room temperature for 15 mins. Water
(15 ml) was then added and the reaction mixture stlrred over-
night at room temperature. The organic layer was separated,
dried over magnesium sulfate, filtered and concentrated. The
, nmr spectrum of the residue showed the presence of about 80% of
the 3-iodocepham.
' - - 27 -
- - 9L0~i789~
- In a similar manner using any of the thio-compounds
such as thioacetamide, thioacetanilide, thiourea, N,N'-dimethyl-
thiourea, N,N'-diphenylthiourea, t-butylmercaptan, isopropyl~
mercaptan, thiophenol, ~-chlorothiophenol, ethyl 2-mercaptoace-
~tate, 2-mercaptobenzoxazole, 2-mercaptobenzimidazole, 2-mercap-
tothiazolene, triphenylmcthylmercaptan, benzylmercaptan, di-
methyl disulfide, dibenzyl disulfide, di-t-butyl disulfid~, di- ;
-tolyldisulfide, thioacetlc acld and~thiobenzoic acld, and the
foll o W i D g compounds;
10~ (benzhydryl 3-phenoxyacetamidoazetidinone-i-~isopropenyl-
acetate)-4-disulfide,
sym-(methoxymethyl 3-phenoxyacetamidoazetldinone-1-isopropcnyl-
acetate)-4-disulfide, and
-(benzyl 3-phenylacetamidoazetidinone-1-isopropenylacetate)-~
- . ...
" ~ 4-disulfide, it is possible to obtain;
` benzhydryl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxy-
late,
methoxymethyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-car- -
~ ~ boxylate, and
'~ 20 benzyl ~-phenylacetamido-3-methyl-3-iodocepham-4-carboxylate.
- EXAMPLE 17 ` -~
:. - .: , ~
~qethyl 7-Phenoxyacetamido-3-Methyl-3-Iodocepham-4-Carboxylate,l
::
(R - ~OCH2, Rl = CH3, R - H ) from Methyl 2-O.Yo-3-(2-Phenoxy~
acetamido)-4-(Benzothiazol-2-yl)Dithio-a-Isopro~enylaæetldin-
l-Acetate, 5 (R = ~OCH2, Rl = CH3, R?a ~, X-R3 = S ~ ~
A mixture of methyl 2-o~o-3-(2-phenoxyacetamido)-4-
(benzothiazol-2-yl)dithio-a-isopropenylazetidin-1-acetate ` -
(5.2 g., 0.01 mole) and iodine~3.0 g., 0.012 mole) in methy-
lene chloride (200 ml) was stirred overnight~16 hrs) at
- 28 -
~ ~7~39Z
ambie~t temperature. The dark red reactio~ mixture was washed
with aq~eous sodium thiosul~ate (twice), then water (twice),
and dried over magnesium sul~ate with decolorising charcoal.
The light yellow Yiltrate was concentrated to a foam which was
extracted with ether. The ~iltered ether solution on concen-
tration gave 4.8 g.(97%) o~ the methyl 7-phenoxyacetamido-3-
methyl-3-iodocepham-4-carboxylate as an almost white foam. The
compound (2.8 g) was purified by gradient elution chromato-
graphy on sili~a gel (Mallinkrodt CC-7, 150 g) using hexane:
ether (2:1) ~ ether as the eluants. Tbe compound was isolated
(2 g~ as a pale amorphous yellow solid, m.p. 73-76~ (becomes a
glass) and melts at 116-120. An accurate high resolution mass
spectral analysis gave a measured parent peak of 490.0069,
while that calculated for C17HlgN205I127S32 is 490.0060.
The nmr (CDC13) spectrum: ~7;82 to 6.92(m, aryl pro-
tons and NH); 5.8(~, C7-H); 5.42(d, J = 4~z, C6-H); 4.95(s,
; C4-H); 4.70(s, - OCH2); 3.87(s, -COOCH3); 2.98(q, J = 15Hz,
C2-CH2~; 2.22(s, C3-CH3) are consistent with the assigned
; structure.
,~
EXAMPLE 18
Methyl 7-Phenoxyacetamido-3-Methyl~3-Iodocepham 4-Carboxylate,l
~ =~OCH2, Rl =CH3, R2 =H) using Iodine (one atomic equivalent)
-
When methyl 2-oxo-3-(2-phenoxyacetamido)-4-(benzothia-
zol-2-yl)dithio-a-isopropenylazetidin-1-acetate (0.53 g, 0.001
moles) was reacted with iodine (0.13 g, 0.0005 moles or 0.001 g
atom) in methylene chloride (25 ml) and the product worked up
as described in Example 17,essentially the same results were
obtained. The products ~rom Examples 17 and 18 were identical
(nmr and ir spectra and tlc).
- 29 -
'~ a~7ssz -.
- - - -
~ ~ : EXA~IPLF. 19
- ~
~~- Methyl 7-Phenoxyacetamido-3-~Iethyl-3-Iodocepham-4-Carbo~ylate,l
R - ~OCH2-, R =CH3, R2 =H) using N-Iodosuccln1mlde
Methyl 2-oxo-3-(2-phenoxyacetamido)-4-(benzothia- . :
zol-2-yl)dithio-~-isopropenylazetid1n-l-acetate (203 mg,
0.38 mmoles) was reacted with N-lodosucclnimlde (94 mg
0.416 mmoles) in methylene chloride at ambient temperature.~
; After 4 hrs, an nmr spectrum~of the residue from an aliquot
o~ the reaction mlxture showed essentlally startln~ materials.;
- 10 After 3 days, however, the nmr spectrum of the residue in- ~:
dicated the presence of about 28% of the 3-iodocepham.
EXA~PLE 20
:7-Phenoxyacetamido-3-Methyl-3-Iodocepham-4-Carboxylic Acid, 1
_
(R -~OCH2, R = H,~R = ~) from 2-Oxo-3-(2-Pheno~acetnmido)~
(Benzothiazol-2-yl)Dithio-~-Isopropenylazetidin-l-Acetic Acid,5
(R = ~OCH2, Rl= H, R2= H, X-R3= S~
~ ~ S
.
~. A slurry of 2-oxo-3-(2-phenoxyacetamido)-4 (benzothia-
zol-2-yl)thio--isopropenylazetidin-1-acetic acid (5.15
10 mmoles) in methylene chloride (200 mls) and bis-trimethyl-
silyltrifluoroacet~mide (2.5 6, 10 mmoles) w~s stlrred until
.
,
- - 3~ - .
'
,
.
~ J - - 106~892 -~
- ~
' solution was complete (about 10 mins) then lodine (1.5 g, ~ ''~` -
' 11.8 mmoles) was added and the mixture stirred overnight at
~- ambient temperature. The reaction mixture was concentrated and~
- . -
the residue treated with ethyl acetate (50 mls). The resulting~
- slurry was filtered to separate the~bis-benzothiazoledisulfide,
1.4 g (85ao). The filtrate was treated~with methanol ~3.0 g,
100 mmoles) for 0.5 hrs and then extracted successively with 5~--
` aqueous sodium Ithiosulfate (2~x 30'mls),-water~(3 x 30 mls),
and saturated brine, dried over magnesium sulfate, and~the fil-`
0 trate concentrated. The-residue (4.~7~g,-99%)-had ir~spectrum
(CHC13): I770, 1740-and 1690 cm l;~-~ nmr~spectrum ~DC13): ' '
2.27(s, 3H); 2.65 and 3.13(ABd, 2~, J - 15Hz); 4.65(s, 2H);
4.90(s, lH); 5.38~d, J = 4Hz, lH); 5.70(q,~J = 4 and lOHz,
~' lHj; 7.3 to 8.3(m.), 7.92(d, J - lOHz, lH); and 10.2(s, lH);~ -
- - ~ in agreement wlth the assigned structure.
~ In a similar manner using~
~' 2-oxo-3-(2-phenylacetamido)-4-(benzothiazo:l-2-yl)dithio-~-iso-
propenylazetidin-l-acetic acid, and ' ~
2-oxo-3-(2-phenoxyamido)-4-(benzothlazol-2-yl)dithio--isopro-
penylazetidin~l-acetic acid, lt is~posslble ~to obtain~
' 7-phenylacetamido-3-methyl-3-iodocepham-4-carboxylic
~ acid and
- 7-phenoxyamido-3-methy'l-~-iodocep'ham-4-carboxylic
acid. - ''
~XA~PL~
' . ~ -
7-Phenoxyacetamido-3-~.~ethyl-3-Cephem-4-Carboxylic Acid,12, and
. . ~ . , . .-
?~Phenoxyacetam _ o-3-~eth~1-3 Cephem
7-Phenoxyacetamido-3~methyl-3-1o~ocepham-~-carboxylic
acid (0.9 g, 1.9 mmoles) and bls-trimcthylsilyltrifluoroacet-
amide (0.9 g, 3.5 mmo~es) in bcn7,cnc.S10 mls) wore stirred
- 31 -
,
' ' '"''' '-~
~ ~6,q~9z
.
- until solution was complete. Pyridine (0.5 g, 6,3 mmoles) was-
added and the resulting mixture heated under reflu~ for. l hr -
,
- and then filtered. The filtrate was treated with methanol
~- (o.3 g, 10 mmoles) for 0.5 hrs, and the reaction mixture extrac-
ted successively with water (4 x 5 mls) and~saturated brine and
- dried over magneslum sulfate, and concentràted. The~lnfrare~
- and nmr spectra of the resulting resldue (250 mg, 40%) was con-
- ~ slstent ~or 7-phenoxyacetamido-3-methyl-3-cephem.
- The combined aqueous extracts were layered wlth ethyl -
acetate (30 mls), stirred and acld1fled to pH l with conc.
hydrochloric acid. Thè ethyl acetate layer was extracted with
saturated brine, dried over magnesium sulfate and concentrated
:~. - . . :
to give 400 mg, 60%, of 7-phenoxyacetamido-3-methyl-3-cephem
4-carboxylic acid.
- ~
- - - EXA~IPLE 22
Methoxymethyl 6-Phenoxyacetamidopenicillinate Sulfoxide, 11
Penicillin V sulfoxide (19.2 g, 0.05 moles) and tri-
ethylamine (5.2 g, 0.052 moles~ were stirred in methylene
- chloride (50 mls~ until~ a pale yellow solution resulted. This~
solution was stirred in an ice bath while chloromethyl methyl
ether (4.5 g, 0.055 moles) was added slowly, maintaining the
temperature below 8C. There ~as an exo~hermic re~ction, the
. ~ :
- ~ _colour of the reaction mixture changed from pale yellow to al-
most colourless, and a white sslid (triethylamine hydrochloride)
- separated from solution. After stirri~g ~or about 2 hrs, the
reaction mixture was extracted with coI~ water (2 x 25 mls), and
the pale yellow organic layer dried ov~r ma~nesium sulfate, fil-
téred and concentrated to ~ive a thick p~le yellow oil. Cold
methanol (50 mls) was added and the mixture stirred in an ice
bath ~or 1 hr, by which time a white solid had formed. Filtra-
i789Z - -
.
tion and drying gave 16.5 g (80%) of the desired ester, m.p.
107-109 C, [~ + 192 (c, 1 1n CHC13?. A second crop of 2.2 g
was obtained from the mother liquorj making a total of 18.7 g
(91%) of methoxymethyl 6-phcnoxyacetamidopenicillinate sulfoxide.
The ir spectrum tNUjol); 1790,1760,1700,1600 and 1590(sh)cm 1
and nmr spectrum (CDC13); ~8.28(d, lH, J = 10.5Hz, -NH); 7.42
to 6.83(m, 5H, C6H5); 6.2 and 6.3(dd, lH, J - 4.5Hz,C~-H); 5.47
and 5.28(ABq, 2H, J = 6Hz, COOCH2O-, restricted rotation); 5~.1
(d, lH, J = 4.5Hz, C5-H); 4.71(s,~ 1H, C3-H); 4 SS(~s, 2H, ~ ~
-O-CH2-CO-); 3.52(s, 3H, -OCH3);~ 1.75 and 1.27(ss, 6H, em-CH3)
are in agreement with the assigned structure.
EXA~IPLE 23
Methoxymethvl 2-Oxo-3-(2-Phenoxvacetamido)-4-(Benzothiazol-2-yl)-
Dithio-~-Isopropenylazetidin-l-Acetate, 5 (R = ~OCH2, Rl=CH3OCH2,
--
R2 H X R3 S ~
-A mixture of 2-mercaptobenzothiazole (3.68 g, 0.022
~, . .
~:~ moles) and metho~ymethyl 6-phenoxyacetamidopenicillinate sul-
~- foxide (8.4S g, 0.02 moles) in pu~rified dioxane (100 mls) was
- . O
heated under reflux for 6 hrs in an oil bath maintained at 120 .
~ - .
- 20 The reaction mixture was taken to dryness, the residue taken
up in chloroform, treated with decolorising charcoal, filtered
and concentrated. The residue was triturated with methanol-
~ether, filtered and dried when 4.0 g of an electrostatic white
posder, m.p. 121-123 was obtained. The ir spectrum (Nujol);
3400,1780,1750,1680,1520cm 1 and nmr spectrum (CDC13): ~8.0 to
6.85(m, 9 aryl protons and -~H); 5.70 to 5.15(m, ~-lactam pro-
~ CH2
tons, CH and -COOCH2O-); 5.0(s, CHCOO); 4.55(s, OCH2CO);
3.43(s,-CH2OCH3) and 2.0(s, ~ ) were consistent wlth the
assigned structure.
- 33 -
~7~92
..
~ - EXAMPLE 24
Methoxymethyl 7-Phenoxyacetamido-3-Methyl-3-Iodocepham-4
-;~
~ Carboxylate, 1 (R = ~OCH2, Rl= CH3OCH2 , R2 = H) from ~lethoxy-
:
~- methyl 2-Oxo-3-~2-Phenoxyacetamido)-4-(Benzothiazol-2-yl)Di-
thio-~-Isopropenylazetidin-l-Acetate, 5 (R= ~OCH2, Rl=CH3OCH2
R~HL~X-~3- S ~
A mixture of methoxymethyl 2-oxo-3-(2-phenoxyacetami-
do)-4-(benzothiazol-2-yl)dithio-~- isopropenylazetidin-l-ace-
tate (0.4 g, 0.0007 moles) and lodine (0.18 g, 0.0007 moles~ ln
methylene chloride was stirred~at ambient temperature for 3.5
-~ hrs (by which time the reaction was found to be complete). The
: , ' ` . - :
reaction mixture was washed with~aqueous sodium thiosulfnte
~2 x lO mls), then water (2 x 10 mls) and dried over m~gnesium
. .. , .. .. . . - . ................................................ . .
sul~ate. The filtered solution was concentrated and th~ resi~
due extracted with ether (to remove most o~ the lnsoluble ben- -
zothiazole component). The ether on concentration gave the
desired compoùnd, 0.34 g, (96%). The nmr spectrum (CDCl );
~- - - 3
~7.92 to 6.92(m, aryl protons and -~H); 5.80 and 5.61(dd, C7-H);
:
- 5.45 to 5.32(m, C6-H, and COOCH~O); 4.89(s, C4-H)-;
4.62(s, -O-CH2-CO); 3.52(s, CH2OCH3~; 2.92(ABq, J = 15~Iær
C2-CH2); 2.22(s, C3-CH3) is consistent with the assigned
. . .
- structure.
, ~ .
XAMPLE 25
Methoxymethyl 7-Phenoxyacetamido-3-Meth~1-3-Cephem-~-Carboxv-
late by the Dehydroiodination of ~ethoxymethyl 7-Phenoxyace-
~
tamido-3-Methyl-3-Iodoce~ham-~-C~rboxylate, 1 (R = ~OClI2, -
1 2
R = CH3OClI2, ~ = H
~ . . .
- 34 -
- ~ Y
~0678~Z
When methoxymethyl 7-phenoxyacetamido-3-methyl-3-iodo-
; cepham-4-carboxylate was dehydroiodinated by the process des-
cribed in Example 13, an about 70~ yield o~ the 3-cephem was
obtained as estimat~d from the nmr spectrum.
.
EXAMPLE 26
Methoxymethyl N-Methoxymethyloxycarbonylampicillin Sulfoxide,8
from Ampicillin Sulfoxide, 7
.
A mixture o~ ampicillin sulfoxlde (14.6 g, 0,004 moles)
and triethylamine (9.7 g, 0.096 moles) in methylene chloride
(125 mls) was stirred until solutlon was complete (approximate-
ly 1 hr). This solution was then stirred in an ice bath while
chloromethyl methyl ether (7,1 g, 0,088 moles~ w~s added slowly
in the presence o~ a slow stream O:e carbon dioxide~ The reac-
tion mixture tContaining solids) was stirred an additional ~ hr
in the ice-bath and a further 1 hr at room temperature in the
continued presence o~ the carbon dioxide stream. The reaction
mixture was then cooled well and filtered. The resulting solid
was washed with water (2 x 50 mls) and then with ether and
dried, giving 8.7 g (43.7%) of the methoxymethyl N-methoxy-
- 20 methylcarbamoylampicillin sulfoxide, m.p. 178-180 . Recrystal-
lisation ~rom methylene chloride-ether raised the m,p, to 186-
O
Analysis: C H N S
Calc'd ~or C21H27N3SO9 50.69 5.47 8.44 6.45
Found " " 50.73 5.40 8.17 6.50
The ir spectrum (Nujol~; 3350,1780,1740,1710,1700(sh)
1675(sh), 1660,1520cm and nmr sp~ctrum (DMSOd6); ~8.22(d,
2H,two -NH-), 7.45(brs, 5H, C6 ~ ); 6.0 and 5.85(dd, J ~ 4Hz,
C6-H); 5.55 to 5.17(m, 6H, C5-H, -CHC0, and two -OC 20-)
4.52(8, lH, C3-H); 3.42 and 3.35(~6, 6H, two -OCH~); 1.5
35 -
067~9Z
.
and 1.17(ss, 6H, gem dimethyl) are in a~reement with the assig~
.
ned structure.
From the combined organic filtrates o~ this reaction,
: 6. 5 g, (33~o) of a solid was isolated. The ir and nmr spectra
.. ..
of this material were consistent with it being methoxymethyl
~` ~ ampicillin sulfoxide. ; ~ - -
EXA~PLE 27 ~ - ~
.
. ~ . - - . . . . : . -
Methox~methyl 2-Oxo-3~ lethoxymethyloxycarbonylamino Phenyl-
acetamido)-4-(Benz.othiazol-2-yljDithio-~-Isopropenylazetidin-l-
, , - , . . -. ~ ................. . . ..
;10 ~Acetate,S ~R-~CHtN'HCOOCH20CH3), Rl=CH3OCH2,R2=H,XR3=-S 4 ~ ]
- A mixture of 2-mercaptobenzothiazole (0.22 g, 0.00125
moles) and methoxymethyl ~-methoxymethyloxycarbonylampicillin
sulfoxide (0.6 g, 0.00125 moles) in purified dioxane (65 mls)
was heated under reflux for 16 hrs in an oil bath maintained
O
- at 130 C. The reaction mixture was then taken to dryness. The
product (0.7 g, 93%) was separated from unreacted material by
- - eXtraction with an excess of ethér-the product being soluble.
,
The product forms a glass at 60 65 and melts at about 120 C. -
The ir spectrum (Nujol): 3350 a~nd 1790 to 1660(multlplets~cm 1
and nmr spectrum (CDC13): ~7.93 to 7.20(br multiplets, aryl
- protons); 6.52(d, NH); 5.6 to 4.9(m, 10H); 3.39(s, two
C~
_-O-CH3); 1.90(5, ~cH2) are consistent with the assigned
structure. -
. . :
;: . ' -
)
--
- ~6 -
.. . .. ... ... .
~06789Z
~ EXA~PL~ 28 ~ ~ ,
- : -
~' ethoxymethyl 7~ ethox~methyloxycarbonylamino)Phenylaceta-
amido-3-1Iethyl-3-Iodocepham-4-Carboxylate,l !R=~CH(NHCOOCH20CH3')
. . ~
~ , ,, Rl = CH30CH2~,R2 = H] '~
- . . . . .
:-. ~ : :
~ A mixture of methoxymethyl 2-oxo-3-t~-methoxymethyl-
.
~ oxycarbonylamino phenylacetamido)-4-(benzothiazol-2-yl)dithio-'
- . , ~.
isopropenylazetidin-1-acetate;~700 mg,;l.12 mmQles) and io-
dine (302 mg, 10.4 mmoles) in methylene chloride (70 mls) was
~ . ~ . : . . . ~
~ , stirred at ambient temperature. The reaction was found to be
`~ ~10 complete after about 3 hrs. The reaction mixture,v:as washed
. .
; 'with aqueous sodium thiosulfate (twice), then water (twice) and
the organic layer dried over magnesium. Concentration of the
iltrate gave 700 mg o~ a light~brown foa-m whose nmr-spectrum '~
showed the presence of about 6070 of the 3-iodocepham, charac-
.: . . . .
terised by the C3-CH3 singlet at ~2.2 and the C2-CH2 A~quartet
" ' ~ at about ~2.85.
. ~ . . . . .
' EXA~IPLE 2g
Iethoxymethyl 7-a-(~lethoxymethyloxycarbon~lamino)Phenylaceta-
amido-3-Methyl-3-Cephem-4-Carboxylate and Cephalexin 9
~ hen methoxymethyl 7-~-(methoxymethyloxycarbonylami-
~no)phenylacetamido-3-methyl-3-iodocepham~4-carboxylate was
- ~ heated with pyridine in benzene for l hr and the reaction work-
,
ed up as described in Example 13, metho~ymethyl 7-~-(methoxy-
methyloxycarbonylamino)phenylacetamido-3-methyl-3-cephem-~-car-
boxylate was the product as shown from the nmr spectrum and a
thin layer chromato~ram usin~ a~reference sample made from
.cephalexin by the method described in Example 26.
The compound was readily converted to cephalexin by
' treatment with aqueous acids such as hydrochloric acid, sul- -
;: - 37 -
789Z ~ -
.
furic acid, ~ormic acid, methanesulfo~ic acid and tri~luoro_
acetic acid, followed by adJustment of the pH to about 4.5,
to precipitate the cephalexln. A convenient purification step
is to isolate the salt such~as, for example, cephalexin tri-
~luoroacetate, by addition of solvents such as ether to a solu-
- .
- ~ tion oi the title compound in the minimum amount o~ trifluorD-
~ ~ acetic acid after solution is~complete. ~ ~
- , .
6-Phenoxyamidopenicillanlc Acld Sulfoxide
;`~ 10 - A slurry o~ 6-aminopenicillanic acid sulfoxide (23.3 g
0.1 mole~ in water (250 mls) was cooled to 0 to 5 C and then
- treated with aqueous potassium hydroxide (2N) until a clear
. .
~- solution was obtained and the pH of the solution reached 8. -
The resulting solution was diluted with tetrahydrofuran(250 ml).
.
A solution of phenyl chloroformate (23.5 g, 0.15 mole) in
tetrahydrofuran (100 mls), and an aqueous solution o-f potas-
sium hydroxide (2N) were added separately at such a rate as to
maintain the pH of the reaction mixture at between 7.5 and 8.5.
After completion of the addition and when thepH had stabilized
~ 20 at 8 for lS mins, the reaction mixture was concentrated to
; o~e-halP its volume. The aqueous concentrate (pH 8.7) was ex-
tracted with ethyl acetate (discarded), then layered with ethyl
--- acetate (500 mls) and the pH of-the mixture lowered to 2 with-~
aqueous hydrochloric aGid (611). The aqueous laycr was furthor
extracted with ethyl acetate (200 mls) and thc combincd ethyl
acetate extracts dried over magnesium sulfate, filtered and
concentrated. The residue (23.6S g, 67~o) had m.p. 158-167
(decomp.); ir spectrum (Nujol): 3400,1800,1750,1720 and
- , 1530cm ; nmr spectrum (D~ISOd6): ~1.30(s, 3H); 1.67(s, 3H)
4,48(s, lH); 5.53(d, J = 4.5~ l); 5.80(q, J - 4.5 and 9HY"
, _ 3~ .
~6~6789Z - -
,
- lH); 7.0 to 8.3(m, ~X); and 8.1(br, s, lH). - A sample recrysta-
llised from methanol had m.p~ 175~1?7(decomp.).
'~ . . ' ' . . ' ' ' :
EXA~SPLE 31 ~~
Methyl 6-Phenoxvamidopenicillanate Sulfoxide
~-~ - A solution of 6-phenoxyamidopenicillanic acid sulf-
0
oxide (13.5 g)lin tetrahydrofuran (200 mls) at O to 5 C was
- treated with a solution of diazomethane in ether until evolu-
tlon of nltrogen ceased and the yellow colour pe~rsisted for
0.5 hr. Concentration gave the title compound`(14.0 g, .~lOO~o)~
~10 m.p. 50-70 ; ir spectrum (CHCl~); 3400jl800,I750,1500 and
~ . .
~ 1480cm 1; nmr spectrum (CDC13): ~1.20(s, 3H~ 1.73(s, 3H);
.
- 3.37(s, 3H); 4.72(s, lH); 5.13(d, J~= 4.5Hz, lH); 5.83(q, ~- -
J = 4.5 and llHz, lH); 6.80(d, J = llHz, lH)~, and 7.1 to
; 7.7(m, 5H3~
EXAMPLE 32
Methyl Z-Oxo-3-(Phenoxyamido)-4-(Benzothiazol-2-yl)Dithio-~-Iso-
- . ~ . .
propenylazetidin-l-Acetate,5~(R = ~O,Rl = CH3, X-d3 = -S
A solution of methyl 6-phenoxyamidopenicillanate sul~-
oxide (11.0 g, 30 mmoles) and 2-mercaptobenzothiazole (5.5 g, -~
.. . .
20 ~ 33 mmoles) in dioxane ~180 mls) was heated under reflux for 6hr.
Concentration gave a residue ~(16.1 g), a portion (13.6 g) of
which was chromatographed on ~allinckrodt Silicar CC-7 (300 g,
200-325 mesh) using benzene-ethyl~acetate mlxtures. Elutlon ;-
with a:l and 3:2 benzene-ethyl acetate mixtures gave the title
compound(g g) of sufficient purity for further transformations.
The compound had an ir spectrum (CNCl~): 1780 and 1750cm 1;
- ' nmr spéctrum (CDC13): ~l.90(s, 3H); 3.73(s, 3H); 4.93(s, lH);
.
11. ~67892
- - -
5.07(brs, 1~); 5.20(brs, lH), -5.40(q, J = 5 and 8Hz, lH),
,''S.58(d, J = 5Hz, lH) and 6.9 to 8.1(m). ,
- . . .
~ -' `- EXAMPLE 33
- - - .
- : :
2-Oxo-3-(Phenoxyamido)-~-(Ben7,othia~ol-2-yl)Dithio--Isopro-
penylazetidin-l-Acetic Acid, 5( r= ~0, Rl- H, X-R3 = -S~3
This compound is obtained by he'ating 2-mercaptobenzo- ~
., . . ~:
thiazole with ~-phenoxyamidopenicillanic acid sulfoxide in -
dioxane for 6-~rs. -'~
, EXAMPLE 34
Methyl 7 Phenox,~amido-3-~.Iethyl-3-Iodocepham-4-Carb~xylate, 1
O, ~ = CH3,'R = H)
.. . : - . - . .
.
~ , ' - A mixture of methyl 2-oxo-~-(phenoxyamido)-4-(benzo-
. . - . ~ -. :
"~ thiazol-2-yl)dithio-~-isopropenylazetidin-l--acetate (0.52 g, -~
,
0.00l mole) and iodine (0.25 g, 0.00l mole) in methylene chlor-~'
ide (25 mls) was stirred at,àmbient temper,ature for i2 hrs.
~- The reaction mixture was,then washed with aqueous sodium thio~
sulfate (twice) and water (twice~ and'dried over magnesium sul-
~fate and decolorising charcoal. The filtrate was concentrated
to a yellow foam~(O.7 g)~. The '~oam~was e~tracted with ether
20 (three times) and the ether solution conce,ntrated to give 0.4 g
(85~) of the title compound as a pale yeIlow foam_ The com-
pound was further purified by gra~lent eLution column chroma~
tography using Mallinckrodt Silic~ CC-7 and hexane:ether (2:1)~
~ ether. It was obtained as a,pale yel'l-~ foam, nmr spectrum`
(CDCl3): ~7.35(br d, SH, C6H5), 6.48~d,, lH, -NH-, exchanged
with D20); 5.62 and 5.4(dd with a superlmposed s at ~5.43, 2H,~
~-lactam protons ~the pattern c~anges to a quartet on D2O ex-
' ;'
~ 789~
.
.
. change~); 4.95(s, lH, C4-H); 3.83(s, 3H, COOCH3)'; 3.02(AB~
- J = 15Hz, 2H, C2-CH2); ~.22(s, 3H, C3-CH3)'.
. ~-~ . - ..
' .In a similar manner using~
trichloroethyl 2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-
yl)dithio-~-isopropenylazetidin-l-acetate,'
~ ~:
~ trichloroethyl 2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2- :
- ~ , . , "
yl)dithio-~-isopropenylazetidin-l-acetate, '~
methoxymethyl 2-oxo-3-(2-phenoxyamido)-4-(benzothiazol-2-yl)-
;~ dithlo~ sopropenylazetidln-l-acetate,
~: '10. benzyl 2-oxo-3-.~2-benzyloxyamido)-~-(benzothiazol-2-yl)dithio-
a-isopropenylazetidin-l-acetate,
:...... ~trichloroethyl 2-oxo-3-(7~-tFichloroethoxyamido)-4-(benzothla- ':
- ~ zol-2-yljdithio-~-isopropenylazetidln-1-acetate,~
methyl 2-oxo-3-2-phenoxyacetamido)-4-acetimidoyldithio-~-iso-
- propenylazetidin-`l-acetate, ~
~ methyl 2-oxo-3-(:2--phenoxyacetamido~-4-N-phenylacetimldoyldi-
~ thio-a-isopropenylazetidin-l-acetat;e~.and,
~.' methy]. ~-oxo-3-C2-phenoxyacetamido~-4-anili.nothio-~-isopro~
~,
penylazetidin-l-~acetate
2Q it is possible to obtain the following compounds~
.-,.,v, .r
.: ~ trichloroethyl'7-phenoxyacetamido-3-methyl-~-iodocepham-~-car~
boxylate~
trichloroethyl 7-phenylacetamido-3-methyl-3-iodocepham-4-car-
.'~ boxylate,
methoxymethyl 7-phenoxyamido-3-methyl-3-io.d~cepham-4-carboxy- :
: late,
- :
: ~ benzyl 7-benzyloxyamido-3-methyl-'3-io.doc~pham-4-carboxylate, .~'
trichloroethyl'7-trichloroethoxyamido-3-met-hyl-~-iodocepham-4-
. . carboxylate, and ' ' ': ~
methyl 7-phenoxyacetamido-3-methyl~-1odocepham-4-carboxylate. -~'
. :
- '
- ~ r~
`` : IL~671~39z
: . ..... .
: EXAMPLE 35.
'' ' :' -
- ~Iethyl 7-Phenoxyacetamido-3-~lethyl-3-Iodocepham-4-Carboxylate,.
1, (R = ~OCH2-, R.- H, R = CH3) from ~lethyl 3-Phenoxymethyl-4,
: .
.~ 5~Dithia-2,7-Diazabicyclo[~,2,010ct-2-Ene-8-One-7-Isopro~enyl
- acetate, 2 (R = ~OCH2-, R2= H, Rl= CH3) using Disulfides-
-- . .
. Iodine-Water
A mixture of methyl 3-phenoxymethyl-4,5-dith1a-2,7-
dia7.abicyclo[4,2,0]oct-2-ene-8-one-7-isopropenylacetate .~
100 mg., 0.253 mmoles), dibenzyl disulfide (47 mg.,O.2 mmoles)
and iodine (193 mg., 0.76 mmoles~ in methylene chloride (lO ml):
.
was stirred with water ~10 ml) at amblent temperature~for
16 hrs. The organic layer was dried over magnesium sulfate,
~ : . . . . . .
- . i'iltered and concentrated. The nmr spectrum (CDC13) of the ~.
~ : . product indicated over 85% of the 3-iodocepham to be present.
: Exactly similar reactions werè run using the-following
~ disulfides in place of dibenæyl disulfide, The yield of the
~ . - ~ .
. 3-iodo~epham in ~ach case was estimated as better than SOZ.
: . Dimethyl dis-llfide
- ~:
: 2,2'-Dithiobis~benzothiazolé)
.
. EXAMPLE 36
Methyl 7-Phenoxyacetamido-3-,'~.1ethyl 3-Iodocepham-4-Carboxylate,
1, (R = ~OCH2-, R = H, R = CH3) ~rom ,~lethyl 3-Phenoxymethyl-4,~
5-Dithia-2,7-Diazabicyclo~4 9 2,0]0ct-2-~ne-~-One-7-Isopro~enyl-
.
acetate, 2 (R = ~OCH2-, R2= H, Rl=CH3) using Thioacids-Iodine-
Water
__..
' A mixture o~ methyl 3-phenoxymethyl-4,5-dithia-2,7- .
diazabicyclo[4,2,0]oct-2-ene-8-one-7-isopropenylacetate(100 mg.,
- 42 -
:
3~ 39Z - - ;
o.253 mmoles), thiobenzoic acid (53 mg., 0.38 mmoles) and ~ ~
. .
; iodine (193 mg., 0.76 mmoles) in met-hylens chloride (lO ml)
..
was stirrsd with water (10 ml) at ambient temperature for 16hrs.
The organic layer was dried over magnesium sulfate~ filtered,
and concentrated. The nmr spectrum (CDC13) of the product in-
dicated over 85% o~ the 3-iodocepham to be present.
When the reaction was repeated as above, using thio-
acetic acid in place of thiobenzoic acid, low ylelds (about ~ -
~20~) of the 3-iodocepham were obtained.
~ ~-A~PI~ ~7
ethyl 7-Phenoxyacetam1do-3-Methylceph-3-em-~-Carboxylate from
Methyl 7-Phenoxyacetamido-3-Methyl-3-lodocepham-4-Carboxylate.
-: :
1, (R = ~OCH2-, ~2= H, R = ~H3), using Pyridine in Benzene ~ --
- A solution of methyl 7-phenoxyacetamido-3-methyl-3-
iodocepham-4-carboxylate and pyridine in bsn~ene was heated
O ' :
~; under reflux, in an oil-bath maintained at 90 .- Periodically
- aliquots of the reaction mixturs were removed and the progress~
: . . . -.~
of the reaction followed by analysing the nmr~spectrum~of the ,
-residue.- The 3~iodocepham:in the mixturs is characterisèd by ;
the C4-H singlet-at ~4.9, the C6-H doublet at ~5.38 and the
C2-CH2 quartet at ~2095; the ceph-3-em is characterised by
its C6-H doublet at ~5.05 and its C2-CH2 doublet at ~3.35. ;~
Any ceph-2-em produced is easily detected by its C3-CH3 sing-
.:
let at ~1.92 and its C2-H signal at 66.1. In all our ex-
periments using pyridine as the base there were no detectable
amounts of the ceph-2-em isomer produced. The following table~
summarizes the results of experiments in which the relative
amount of pyridine was varied.
- 43 -
'''''' '~
~6789~
.
- . -
~ ~ TAELE 1
:
Dehydroiodination of 3-Iodocepham~uslng P~ridine in Benzene
No Mole Ratio of Pyridine Time of Reflux Yield of Ceph-3-em(~
1. 2.S equivalents 0.5 hr 4
2. 2.5 " 1.0 hr 60
3. 2.5 " ;~l.S hr ~ 67
4. ~ ~5 equivalents 0.5 hr ; ; 50
5. 5 ~ " 1.0 hr ~ 66
6. 5 ~ 1.5 hr ~ 80
7. 5 ~ 3.0 hr ~100
8. 10 equivalents ~ ` ~.5 hr ~60
9. lQ ~" - 1.0 hr ~100 `
10. 10 " 1.5 hr 100
* There was no detectable trace of any ceph-2-em isomer in
. ~
any of these experiments. ~ -
EXAMPL~ 38
Methyl 7-Phenoxyacetamido-3-3fethylceph-3-em-4=Carbo ylate from
Me~l 7-Phenoxyacetamido-3-~lethyl-3-Iodocepham-4-Carbox~ate,`
; 1 (R = ~OCH2-, R2= H, Rl= CH3) using Pyridine alone
- 20 -- Methyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-car~
- boxylate (100 mg) was dissolved in pyridine d5 (O.S ml)~and
the reaction monitored by running an nmr spectrum on the sample
" ,. . .
periodically. After about 15 mins at ambient temperature there~
was about 50S conversion to the ceph-3-em, and after 2 hrs the
reaction was complete. ~he nmr spectrum did not chan~e after
a 24-hour period and again no detectable amount of the
ceph-2-em isomer was obscrved.
.
- 44 -
:106'7~92
- . . ` ~ ~
.
EXAMPLE 39
~fethyl 7-Phenoxyacetamido-3-~Iethylceph-3-(and -2-)em-9-Carbox~
late from Methyl 7-Phenoxyacetamido-3-~lethyi-3-Iodocepham-~-
Carboxylate, 1 (R = ~OCH2-, R2= X, Rl- CH3~ using Hunig's Base
A mixture o$ methyl 7-phenoxyacetamido-3~methyl-3~iodo-
- cepham-4-carboxylate (200 mg.~ 0.395 mmoles) and diisopropyl--
-ethylamine ~510 mg., 3.95 mmoles) ln benzene~d6 (1 ml) was
heated under reflux for 1 hr. The reaction mixture was washed
with hydrochloric acid (2N solution), then water, and dricd.
~The nmr spectrum showed complete reaction but a mixture of
about 40% of the ceph-2-em and 60% of the-ceph-3-em compounds.
EXAMPLE 40 ;~
Methyl 7-Phenoxyacetamido-3-Methylceph-3-(and -2-)em-4-Carboxy-
late from Methyl 7-Phenoxyacetamido-3-.llethyl-3-Iodocepham-4-
Carboxylate, 1 (R = ~OCH2-, R2= H, RL=~CH3)~using DBU~and DBN
. _ _
,~ . .
~-A mixture of methyl 7-phenoxyacetàmido-3~methyl-3-iodo-
cepham-4-carboxylate (100 mg. 7 0.2 mmoles) and 1,5-diazsbicy-
:clo[5,4,0]undec-5-ene (DBU, 300 mg., 2.0 mmoles) in benzene d6
~ (1 ml) was left at ambient temperature ior l.S hrs. The reac- -
tion mixture was washed with hydrochloric acid (2N solution),
: .
then water, and dried. The nmr-spectrum showed about 75%
reaction with a mixture of ceph 2-em and ceph-3-em being
formed. ~ ~
When l~5-diazabicyclo[~3~olnon-5-ene (DB~) was substi-
tuted ~or DBU in the ahove reaction, and with a re~ction time
of 2 hrs at ambi~nt temperature, the reaction was essentially
complete, the product consistin~ o~ a mixture oi the ceph-2-em
and ceph-3-em isomers in the ratio oi about 3:7.
- 45 -
.. .
,.
~)6~89Z
EXAMPLE 41
- . ~ '
. ~
ethyl 6-Phenoxyacetamido-2-~ethyi-2-Iodomethylpenam-3-Carbo~y-
lats, lA ~R = ~OCH2-, R = CH3, R = H) and'Methyl 7-Phenoxyacet-
' amido-3-~Iethyl-3-Iod'ocepham-4-Carboxylate, 1 (R = ~OCH2-, Rl=
, CH3, R = H) from Methyl 2-Oxo-3 (2-Phenoxyacetamido)-4-~Benzo-~
_. -
thiazol-2-yl)Dithio-a-Isopropenylazetidin-l-Acetate, 5 (R=~'OCH2,
Rls CH3, R2= H , X-R3= -S-< ~
~ A mixture of methyl 2-oxo-3-(2-phenoxyacetamido)-4-
benzoth1azol-2-yl)dithio-~-isopropenylazetidln-l-acetate (5.0 g.,
9.5 mmoles) and iodi,ne (1.~ g., 14.2 mmol,es) in methylene ~
.
, chloride (100 ml) was stirred at amhient temperature for 16 hrs.
, ~ , . . .
The reaction mixture was then washed quickly with an aqueous ,
- soidum thiosulfate (5%) solution (twice), and the methylene,
~; chloride layer dried over magnesium sulfate and taken to drynéss ~
, ~ to give 5.2 g of a yellow foam. ~ ~
- 'The material was chromatographcd on a ~allinkrodt
SiliCar CC-7 (350 g.) column u~ing ether as-the eluant, and
,
collecting fraction of about 5 mls. The appropriate fractions
~ were combined according to their thln layer chromatograms. ~;
`~ 20 Fractlons 5 to 22 were combined and concentrated to~
~give 1.3 g. o~ a yellow foam, whose nmr spectrum indicated a '
mixture of the ben~othiazole disu'lfide, the 3-iodocepham and the
2-iodomethylpenam, characterised by its ~-lactam multlplet at~
about ~5.9 to 5.65,C3-H singlet at ~4.9, -OCH2CO- sin,glet at
~4.6, -CH2I at ~4.45, -COOC~I2 singlet at ~3.8, and -CH3- singlet
at ~l.fi.
i Fractions 23 to 34 wcre combined and concentrated to
give 1.2 'g. o~ a yel1ow ~oam consistin~ o~ the 3-lodocepham ~nd
,,
, - 46 -
,. . . .
!
.
- ~067892 -
the 2-iodomethylpenam, in the ratio o~ about 7 3~
Fractions 35 to 65 were combined and concentr~ted to
.~
giYe 2.4 g. of a p~le yellow ~oam, consisting o~ the 3-iodo-~
~: cepham, with traces (about 5%~ of the 2-iodomethylpenam.
::
EXAMPLE 42 - --
Me~hyl 2-Oxo-3-Phenoxyacetamido-4-Acetimidoyldithio-a-
Isopropenylazetidin-l-Acetate, 5 (R = ~OCH2CONH9 Rl = CH3,
R2 _ H, R3 = CH3, R4 _ H) and Methyl Penicillin V~
A mixture of methyl penicillin V sulfoxide (0.38 9.,
0.001 mole) and thioacetamide (0.08 9., 0.001 mole)~in purified
-dioxane (25 ml) was heated und r reflux wi~th stirring for S ~hrs,
in an oil-bath maintained at 120C. The clear reaction mixture
was concentrated under vacuum to a brown foam. The ir spectrum
(CHC13) showed s-trong sharp singlets at 1780, 1745, and -1700
; ~ cm 1 with weaker absorptions at 1600 and 3400 cm l~. The nmr
spectrum (CDC13) indicated a mixture containing methyl 2-oxo-3-
phenoxyacetamido-4-acetimidoyldithio-~-isopropenylaz~etidin-1-
~: - . , , , - . . .
acetate, 5, as the main product characterized by signals at
65.22 and 5.1 ( ~H2), 2.55 ( ~ CH3), and 1.92 ( ~ cH2)~
CH3 ~ NH ~ CH3
-~ 20 among others9 and methyl penicill~n V (estimated at 20% and ~ ~
confirmed by thin layer chromatogra-phy characterized by its ~-
-dimethyl signals at ~1.65 and 1.~. In addition, there were
trace amounts of methyl 4-phenoxyacetamidoisothiazol-3-one-1-a-
isopropenylacetate, characterized by its signals at~ca. ~9.2
and 8~.83.
EXAMPLE 43
Methyl 2-Oxo-3-Phenoxyacetamido-4-(N-Phenylacetimidoyl)Dithio-
~-Isopropenylazetidin-l-Acetate, 5 (R - ~OCH2CONH, Rl - CH3,
R ~ H, R _ CH3, R
.
A mixture of methyl penicillin V sulfoxide (0.38 9.,
O.OOl mole) and thioacetanilide (0.15 g., 0.001 mole) in puri-
. .. ... ~ -
- 47 ~
.
, .. . . . .: .. . .. . ~ .. ... ~.
- ~L067~9Z
fied dioxane (25 ml) was heated under reflux with stirring ~Qr :`~`
5 hrs in an oi1-bath kept at 120C. The clear reac~ion mixtur~
~ on concentration under vacuum gave a brown foam. The n~r
~ spectrum (CDC13) indicated that the reaction was incomplete7
- ~ about 20% of methyl penicillin V sulfoxide being present, alo~g-
; with methyl 2-oxo-3-phenoxyacetamido-4-(N-phenylacetimidoyl)-
dithio--isopropenylazetidin-l-acetate characterized by ~5.7
to 5.3 (m, ~-lactam protons),~ 5.2 and~.05 ( ~CH2), 4.92
3 ( CH2 ?. 2.72 ( ~ ~ ) and 1.92 ( ~ CH2)
10~ In a similar manner using solvents such as toiuene,
. ~,,~.
dichloroethane, mesitylene, and thioamides such as thiobenz- ~
amide, N-methylthioa~etamide, N-methylthiobenzamide, N-phenyl--~-
thiobenzamide, thionicotinamide, thioisonicotinamide, 2-thi-
azolethioacetamide and 2-thiazolethiobenzamide~ and penicillin
sulfoxides such as trichloroethyl penicillin V sulfoxide,
.
- methoxymethyl penicillin V sulfoxide, p-nitrobenzyl penicillin
Y sulfoxide, penicillin G sulfoxide9 methoxymPthyl penicillin G
sulfoxide, trichloroethyl pe~nicillin G~sulfoxlde, 6-phenoxy-
amidopeniciliin sulfoxide, methoxymethyl N-(methoxymethyloxy-
carbonyl)ampicillin sulfoxide, di(methoxymethyl)carbenicillinsulfoxide, and 6-thien-2-ylacetamido-6-methoxypenicillin
sulfoxide: various azetidinone disulfides of formula 5 are
obtained.
EXAMP~E 44
Methyl 7-Phenoxyacetamido-3-Methyl-3-Iodocepham-4-Carboxylate
- from Methyl 2-Oxo-3-Phenoxyacetamido-4-(Aminoimldoyl~Dithio-~-
Isopropenylazetidin-l-Acetate, 5 (R - ~OCH2CONH, R = CH3,~
~2 = H R3 ~ NH2. R4 - H) - ~ -
The total crude product obtained in Example 43 was
dissolved in methylene chloride (5 ml) and stirred with iodine(0.13 ~., 0.00052 moles) at ambient temperature for 16 hrs.
- 48 -
.
1 , ~', ,~.
- 1 ~6 ~ ~ 9 Z . -
The reaction mixture was then concentrated to give a b~rown
.
foamO The formation of methyl 7-phenoxyacetamido;3-methyl-3
:iodocepham-4-carboxyla~e in this reaction was shown by~com-
paring the nmr spectrum of~the crude product with that of
~ authenti~c sample. A thin~iayer chromatogram usin~ an authen~e~
- - sample of-the 3-iodocepham confirmed its presence in the ~::
reaotion~mixture. ~`
~~ ~ EXAMPLE 45
Dehydroiodination of Methyl 7-Phenoxyacetamldo-3-Methyl-3
lO :~ Iodocepham-4-Carboxylate Using Pyridine in ûenzene -~
:~ ~ ; A solution of methyl 7-phenoxyacetamido-3-methyl-3- ~
~ iodocepham-4-carboxylate and pyridine in benzene was heated -'' !
under refluxl in an oil-bath maintained at 90. Perlodically ~ -
aliquots of the reaction mixture were removed and the progress :~
. ~ of the reaction followed by analysing the nmr spectrum of~the
. ~ ~
: residue. The 3-iodocepham ir. the mixture is char~cterized by
the C4-H singlet at ~4.9, the C6-H doublet at ~5.38 and the
C2-CH~ quartet at ~2.95i the ceph-3-em is characterized by its~
G6-H doublet at ~5.05 and its C2-CH2~doublet at 63.35. Any
20~ ceph-2-em produced is easily detected by its C3-CH3 singlet at
l.92 and its ~2-H signal at:~6.1. In a-ll our experiments :~
: using pyridine as the base there were no detectable amounts of `
the ceph-2-em isomer produced. The following table summarizes~
~ the results of experiments in which~the relative amount of
H pyridine was varied.
.
.
.' ~
_ ~9 _
