Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
10406Z0
1 BACKGRO~ND OF THE INVENTION
This invention relates to a process for the preparation
of 6-alkoxy-6-acylamidopenicillins and to the novel acids obtained.
In particular it relates to a process for the conversion of 6-
acylamidopenicillin sulfoxides to 6-alkoxy-6-acylamidopenicillins,
or to 7-alkoxy-7-acylamidodeacetoxycephalosporins and to the novel
compounds obtained.
Since the discovery of the penicillin antibiotîcs and
more recently the cephalosporin antibiotics a vast amount of
r~search effort has been expanded by organic chemists, micro- -~
biologists, and biochemists in the synthesis of new penicillin and
cephalosporin antibiotics having enhanced microbiological activity.
- In the penicillin antibiotics the structural variations which
have led to greater microbiological activity have been concerned
with the 6-acylamido side chain. In the cephalosporin antibiotics ~ ;
likewise considerable structural variation has been accomplished
in the 7-acylamido side chain. Recently, however, R. Nagarajan
et al., ~mer. Chem. Soc., 93, 2308 tl971), have described the
.
isolation of two new cephalosporin type antibiotics which bear a
methoxyl substituent on the carbon atom in the 7-position of the
B-lactam ring. Earlier, J.~. Strominger and D.J. Tipper~ Amer.
J. Med., _, 708 (1965), had proposed 6-methylpenicillanic acid.
SUMMARY OF THE INVENTION
In the process of this invention, 6-alkoxyl penicillins
and anhydropenicillins are formed by reacting a 6-acylamino
penicillin sulfoxide, or 6-acylamino anhydropenicillins with a
positive halogen compound in the presence of a weak base or buffer
to replace a hydrogen atom with a halogen atom. The halogenated
penicillin is then reacted with Cl to C4 alkanol to replace the
:
104V620
1 halogen atom with an alkoxyl group. The reaction proceeds as
illus~rated by Equation I.
(O)m 0 12 (O)m
R ~ \Y
wherein R, Rl, R2, Yl, m and Z are described more particularly below.
10 Prior to halogenation, any groups on the penicillin reactant ~ : .
which would be halogenated in preference to a hydrogen atom are
blocked with a protective radical in a manner well known in the
art and are removed after adding the alkoxyl radical. The penicillin -~
sulfoxide, is reduced to form a penicillin after adding the alkoxyl :~
group and the anhydropenicillin is rearranged after such change.
The cephalosporins are formed from the alkoxylated penicillins by
ring expansion under mildly acidic conditions. :~
. .
DETAILED DESCRIPTION
The compounds of this invention include the alkoxylated
penicillin sulfoxide intermediates, the alkoxylated penicillins
and the alkoxylated cephalosporins which are microbiologically -
active or convertable to microbiologically active penicillins or :
cephalosporins and are represented by the following formu~ae I and ;
II. The alkoxylated penicillin sulfoxides and alkoxylated peni~
cillins are represented by formula I ~
R ~
~ N__----~~~Yl .
Formula I ~ .
wherein Yl, is:
-- 2 --
104~6Z0
\ /CH2Z
I C~ Formula Ia
- f H 3
~OORl ~ ~
\C= O ~ ~ '
..
CH3 CH3 Formula Ib
R is Cl - C7 alkyl, phenyl, halophenyl, lower alkylphenyl
lower alkoxyphenyl,hydroxyphenyl, alkylthiomethyl, 5'-protected
amino-5'-carboxyvaleramido, 5' amino-5'-carboxyvaleramido; or
a group of the formula
Ia
P (O)m. ~CH2)n C -
wherein P is phenyl, halophenyl, lower alkylphenyl, lower alkoxy-
20 phenyl, nitrophenyl, hydroxyphenyl, cyanophenyl, carboxyphenyl, ~ ~ :
lower alkoxycarbonylphenyl, carboxamidophenyl, protected amino-
phenyl, aminophenyl, 2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl
. ~ or 3-furylmethyl;
m is 0 or 1;
. n is 0, 1 or 2;
a is hydrogen or Cl-C3 lower alkyl;
b is hydrogen, Cl-C3 lower alkyl hydroxy amino or
protected amino;
Rl can be a carboxyl protective group such as Cl-C4 alkyl,
benzyl, diphenylmethyl, 4-methoxy-diphenylmethyl, 3,5-dimethoxy-
: benzyl, 4-methoxybenzyl, 4-nitrobenzyl or with the active penicillin,
:~ ~
: ;
, . , . , . , . . , . . : . ' ! . . ,~ .
. t . :- '~ '', ', ' . . ' ' . ' ' ~ ' :
104~6Z0
1 hydrogen or a pharmaceutically acceptable cation;
Z is hydrogen, C2-C4 alkoxy or Cl-C4 alkyl and,
P is 0 or 1.
X2 ls Cl-C4 alkyl,
The alkoxylated cephalosporins are represented by ':
Formula II.~ ~2
R - C - N ~ \
~ N Y2 Formula II
O
1 0 ' ' ' ' ' ' " ' '
1 2
C/Z
- ICH / ~ H3 Formula IIa
COORl
Formula IIb
CH3
T
COOR
. ............................ .............. ................ ...,- . .
ClH
/ C - CH3 Formula IIc
- --ICH :
CH2 Rl .,,
CIH2
~C -- CH2 ( O ) q-R3
_ f Formula IId
COOR
_ 4 -
..
. ~ , . ., . ~ " . .
1(~4~620
- 1 R3 is pyridinyl, lower alkyl or lower alkanoyl such as acetyl,
q is 0, 1 or 2 and wherein R, Rl, R2 and Z are as described above.
As is evident from the above, applicants' invention not only
includes the microbiologically active alkoxylated penicillins and
cephalosporins bu~ the alkoxylated precursors which are convertable
easily to the alkoxylated penicillins and cephalosporins by
reduction of the sulfoxide radical and/or by the removal of carboxyl
and/or amino protective radicals.
In accordance with this invention, halogenation followed
by alkoxylation of the penicillin is conducted only after the
sulfur atom of the thiazolidine ring of the penicillin is converted
to the sulfoxide to prevent halogenation of the ring sulfur atom in
preferenceto replacing the hydrogen atom with halogen. A conven-
tional means for converting this sulfur atom to the sulfoxide
can be employed. In contrast, when an anhydro-pennicillin is to
be halogenated, the sulfur atom of the thiolactone ring need not
be converted to the sulfoxide since it is not halogenated. With
either starting material, any carboxyl or amino radicals are
s~bstituted with protective radicals in any conventional manner.
The penicillin reactant is reacted with an oxidizing agent, for
example, sodium metaperiodate, hydrogen peroxide, or an organic
peracid such as peracetic acid, perbenzoic acid and preferably
m-chloro perbenzoic acid to obtain the corresponding sulfoxide.
The penicillin sulfoxide is reacted at a temperature
between about 0C. and about 45C. with a positive halogen compound
for example, N-chlorosuccinimide, N-bromosuccinimide, cyanuric
chloride, or t-butyl hypochlorite in the presence of a weak in-
organic base. At temperatures below about 0C, reaction is un-
desirably slow or does not occur at all. At temperatures above
about 45C, undesirable ester interchange occurs between the
:
. . -
: . .
104~)620
1 protective group on the carboxyl group and the alkoxy group being
added to the molecule. The halogenated penicillin can be recovered
and subsequently reacted with an alkanol. However, it is preferred
that halogenation and alkoxylation be conducted sequentially in
the same reaction step by admixing the penicillin with the halo-
genation reactant and the alkanol under the pH and temperature
conditions set forth above.
Weak inorganic bases which can be employed in the present
process are those which act as buffers in the present process so -
as to maintain the pH of $he reaction mixture at between about pH
6.0 and 7.5. Illustrative of such bases which can be employed are
sodium bicarbonate, sodium borate, sodium phosphate, and the like. -
preferred weak inorganic base is sodium borate.
The positive halc,gen compound is employed in an amount
corresponding to from about 2 equivalents to 3 equivalents of ~`
the starting penicillin sulfoxide ester. The weak inorganic base,
for example sodium borate, is employed in an amount equivalent to
the amount of positive halogen compound.
When conducting the process to effect contemporaneous
halogenation and alkoxylation, it is carried out in the following
manner. The penicillin sulfoxide or anhydropenicillin is dissolved
in a small volume of an inert solvent, for example a chlorinated
hydrocarbon solvent such as dichloromethane or chloroform and the
solution cooled to the reaction temperature. To the cooled solution
is added a solution of one equivalent of sodium borate or other
weak inorganic base in an excess amount of the alcohol. The
reaction mixture is stirred and thereafter one equivalent of the
positive halogen compound, for example t-butyl hypochlorite, is
added. The reaction mixture is agitated for a short while and
generally for about ten to 15 minutes before an additional equivalent
,
11~144:~6ZO
1 of sodium borate is added followed immediately thereafter by the
addition of a further equivalent of the positive halogen compound.
The reaction mixture is then agitated for about 15 minutes at the
reaction temperature and is then poured into a cold dilute solution
of sodium thiosulfate to neutralize free halogen. The alkoxylated
penicillin sulfoxide is recovered from the dilute mixture by
extraction with a suitable solvent such as ethyl acetate.
As previously mentioned the alkoxylation process of this
invention can be carried out at a temperature between about 0C.
and 45C., however, the preferred temperature range appears to be
between about 5C. and 15C.
In the foregoing formulae the term, "Cl-C7 alkyl" refers
to the straight and branched chained hydrocarbon groups such as
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl,
n-amyl, sec-amyl, n-hexyl, n-heptyl, and the like. "Cl-C4 lower
alkyl" refers to the hydrocarbon groups mentioned above and con-
taining from one to four carbon atoms. "Halophenyl" is defined
herein as a mono or dihalo substituted phenyl group as exemplified
by 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,4-dichloro-
phenyl, 4-bromophenyl, 4-iodophenyl, 4-fluorophenyl, 3-fluorophenyl,
3,4-dichlorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl and the
like. "Lower alkylphenyl" refers to a mono or di-Cl-C4 lower alkyl -~
substituted phenyl group, for example 4-methylphenyl, 4-iso-propyl
phenyl, 2,4-dimethylphenyl, 3-_-propylphenyl, 4-n-butylphenyl, 4-
t-butylphenyl, 2,6-dimethylphenyl, and the like. "Cl-C4 lower
alkoxyphenyl" refers to the mono and di-Cl-C4 lower alkyl phenyl
ether groups such as 4-methoxyphenyl, 4-isopropoxyphenyl, 2,6-
dimethoxyphenyl, 3-ethoxy-4-methoxyphenyl, 3,4-dimethoxyphenyl,
4-n-butyoxyphenyl, and the like. "Nitrophenyl" refers to the
mono nitro substituted phenyl groups such as 4-nitrophenyl.
-- 7 --
' ' : . . ' ' ~
1~)4(~620
1 nHydroxyphenyl" refers to 4-hydroxyphenyl, 2,4-dihydroxyphenyl, 3-
hydroxyphenyl and the like.- "Cyanophenyl" has reference to the
mono cyano substituted phenyl groups, for example, 4-carboxyphenyl,
3-carboxyphenyl and the like. The term "lower alkoxycarbonylphenyl"
refers to the Cl-C4 lower alkyl esters of the "carboxyphenyl" group
such as 4-methoxycarbonylphenyl, 4-ethoxycarbonylphenyl, 3-iso-
propoxycarbonylphenyl and the like. "Carboxamidophenyl" refers
to the amides formed with the carboxyphenyl group such as 4-
carboxyamidophenyl.
10The term "protected amino", as used herein, for example
"protected amino phenyl", refers to a substituted amino function -
wherein the substituting group is one of a number of such groups
~enerally employed as amino protecting groups as for example,
chloroacetyl, phthaloyl, _-butyloxycarbonyl, 2,2,2-trichlorocar-
boethoxy and the like.
Illustrative of the acylamido groups represented by the
above formulae are acetamido, propionamido, phenylacetamido,
phenoxyacetamido, 2-thienylacetamido, 2-furylacetamido, 2,6-di-
methoxybenzamido, 3-thienylacetamido, 3-hydroxybenzamido, 4-
nitrophenylacetamido, 4-chlorophenylacetamido, 3,4-dichlorobenz-
amido, phenylglycylamido, mandelamido, 4-methylphenoxyacetamido,
and the likeO
Representative of the alcohols which can be employed as
the alkoxylation agent in the present invention are methanol,
ethanol, n-propanol, iso-propanol, and the like. As was previously
mentioned the alcohol is employed in excess. The amount of excess
used is not critical and commonly sufficient alcohol is employed
to enhance the mobility of the reaction mixture particularly at
the lower temperatures. Generally, between 20 and 50 parts of
alcohol per 1 part of penicillin sulfoxide or anhydropenicillin are
suitable.
- 8 -
~`~ . ;
1040620
1 As indicated by the above description the present
alkoxylation process proceeds rapidly. When the present process'is
carried out at temperatures much above the preferred temperature
range the alkoxylation reaction is accompanied by ester interchange
involving the exchange of the ester function, Rl, of the peni-
cillanic acid sulfoxide with the alcohol employed as the alkoxy-
lation agent. The ester interchange occurs more rapidly at
elevated temperatures than at the preferred temperatures. Ester
interchange will also occur when the reaction mixture is allowed
to stand for an appreciable time prior to work up. It is therefore
desirable in the present process to recover the alkoxylated-product
from the reaction mixture as soon as possible after the reaction
is completed.
The alkoxylated penicilli~ sulfoxides are recovered for
example from the reaction medium in the following manner. The
reaction mixture is poured into a dilute solution of sodium thio-
sulfate with stirring,,and the reaction product is extracted from
the dilute mixture with a suitable organic solvent such as ethyl
acetate.
The preferred process conditions of the present invention
are as follows. The preferred inorganic base, used as a buffer in
the present process, is sodium borate, the preferred halogenating
agent is t-butyl hypochlorite. ~'~
The reaction product, a 6-alkoxylated penicillin sulfoxide
is converted to a 6-alkoxypenicillin preferably by reduction with
phosporous tribromide in dimethylformamide at a temperature
between about -78C. and -10C. according to the conditions des-
cribed in U.S. Patent No. 3,641,014. Accordingly the reduction '
is carried out by first dissolving the alkoxylated sulEoxide in
dimethylformamide (DMF) and then cooling the solution in a dry
_ g _
104~1620 :~
1 ice-acetone mixture. To the cold mi~ture is added a solution of
phosporous tribromide in benzene. After approximately 5 to 10
minutes the cold reaction mixture is warmed to a temperature of
about -1~C. After approximately 5 to 10 minutes at this tem-
perature the reac'ion mixture is worked up to provide the 6-
alkoxy-6-acylamidopenicillin. Reduction of the penicillin sulfoxides
can be conducted either prior to or subsequent to the removal of
the amine or carboxyl protective groups.
The ester moiety, Rl in the above formulae, can be removed
by known procedures to provide the 6-alkoxylated-penicillanic acid
antibiotic. When Rl represents the p-nitro-benzyl group, benzyl,
diphenylmethyl, or a methoxylated ben2yl group the ester function
can be removed by catalytic hydrogenolysis. When the group ~1
is t-butyl the ester can be removed by mild base hydrolysis.
- According to a further aspect of the present invention
the 6-alkoxypenicillin sulfoxide or 6-alkoxyanhydropenicillin
obtained by the process described above can be rearranged under
certain reaction conditions to provide a 7-alkoxy-7-acylamidode- ; -
acetoxycephalosporin as shown in Formula II above. According to
20 ~this aspect of the invention the alkoxy penicillin sulfoxide or
anhydropenicillin is heated in an inert solvent in the presence of
dipyridine phosphate at a temperature between about 75C. and 135C. ~
Inert solvents which can be employed are those which are unreactive ~ -
with the starting materials and products of the rearrangement
temperature. Inert solvents which can be employed are, for example,
dioxane, n-butyl ether, iso-butyl ether, and other unreactive
solvents.
The conversion reaction is carried out for example by
heating a solution ofthe sulfoxide in an inert solvent and pre-
3~ ferably dioxane containing between 0~5 and 2.5 equivalents of
~ 10 -
16~4(~6ZO
l dipyridine phosphate. The preferred temperature of the present
rearrangement is between about 90 and 100C. For example, 6-
methoxy-6-phenylacetamido-penicillanic acid p-nitrobenzyl ester of
7-methoxy-7-phenylacetamidodeacetoxycephalosporanic acid. Removal
of the ester group according to the procedures described above for
the penicillanic acid esters provides the deacetoxycephalosporanic
acid antibiotic.
When in the foregoing process the starting material has
a protected amino group, for example, when the 6-acyl-amido side
chain, R-~-, is a 5'-protected-amino-5'-carboxyvaleramido group,
the protecting groups are removed according to procedures known in
the art.
As previously mentioned,the products of the present
process, the 6-alkoxy-6-acylamidopenicillanic acid ester sulfoxides -
are reduced by the known method to the ester sulfides followed by
removal of the ester group to provide the 6-alkoxy-6-acylamido-
penicillanic acid antibiotics.
Illustrative of the 6-alkoxypenicillanic acids obtained
by the process of this invention are
6-methoxy-6-phenylacetamidopenicillanic acid,
6-methoxy-6-phenoxyacetamidopenicillanic acid,
6-acetamido-6-methoxypenicillanic acid,
6-mandelamido-6-methoxypenicillanic acid,
6-methoxy-6-(D-a-phenylglycylamido)penicillanic acid,
6-ethoxyphenylacetamidopenicillanic acid,
6-~2-(2'-thienyl) acetamido]-6-methoxypenicillanic acid,
6-~2-(2'-furyl) acetamido]-6-methoxypenicillanic acid,
6-propionamido-6-isopropoxypenicillanic acid,
6-(2,6-dimethoxybenzamido)-6-methoxypenicillanic acid,
6-(p-chlorophenylacetamido)-6-methoxypenicillanic acid,
-- 11 --
104~ Z0
1 6-(a-phenoxy-a,-dimethylacetamido)-6-methoxypenicillanic acid,
6-(p-hydroxyphenylacetamido)-6-methoxypenicillanic acid, and the
esters thereof and the pharmaceutically acceptable salts thereof.
The 6-alkoxy-6-acylamidopenicillin sulfoxides can also
be converted by the known penicillin sulfoxide rearrangement to
7-alkoxy-7-acylamidodeace~oxycephalosporanic acids. Illustrative
of the deacetoxycephalosporanic acids which can be prepared with
the products of the present process are
7-acetamido-7-methoxydeacetoxycephalosporanic acid,
7-phenoxyacetamido-7-methoxydeacetoxycephalosporanic acid,
7-phenylacetamido-7-methoxydeacetoxycephalosporanic acid,
7-mandelamido-7-methoxydeacetoxycephalosporanic acid,
7-(D-a-phenylglycylamido)-7-methoxydeacetoxycephalosporanic acid, ,
7-(2,6-dimethoxybenzamido~-7-methoxydeacetoxycephalosporanic acid,
7-propionamido-7-methoxydeacetoxycephalosporanic acid,
7-~2-(2-thienyl) acetamido]-7-ethoxydeacetoxycephalosporanic acid,
7-~2-(2-thienyl) acetamido]-7-methoxydeacetoxycephalosporanic acid,
7-phenylacetamido-7-isopropoxydeacetoxycephalosporanic acid,
7-(4-chlorophenoxyacetamido)-7-methoxydeacetoxycephalosporanic
~ acid, the esters thereof and the pharmaceutically acceptable salts
thereof.
~ he penicillins and cephalosporins of this invention are
useful to destroy or inhibit the growth of many micro organisms
such as the Staphylococci, the Streptococci, and the Bacilli and
can be administered in any convenient form as for example in
topical sterilants. Suitable dosages are from 5 and 500 mg. per
killogram of body weight.
The following examples illustrate the present invention
and are not intended to limit the same.
- 12 -
~4~6ZO
EXAMPLE I
To a solution of 0.2 gm of 6-(phenoxyacetamido)-anhydro-
pencillin in 100 ml. of ether was added with stirring, a solution
of 0.34 gm. of sodium borate in 40 ml. of methanol and thereafter,
with continued stirring, 1/2 ml. of t-butylhypochlorite was added.
The reaction mixture was maintained at 0C for about one hour
while stirring was continued. The reaction product comprising 6-
methoxy-6(phenoxyacetamido) anhydropenicillin was recovered in
nearly quantitative crude yield by recovering the ether layer.
The product was purified by washing with water and drying with
sodium sulfate.
The structure of the 6-methoxy-6(phenoxyacetamido)
anhydropenicillin has been identified as follows~
CH3
PhocH2coN~
' S~XCH '~ . ~
CH3 3
Infrared exhibits an N-H (3400 cm 1)
a ~-lactam (1785 cm 1,
an amide
and an a,~-unsaturated thiolactone (1700 cm 1)
The NMR spectrum was as follows: ~7.9 (s,l, N-H), 7.5 (m,5,
aromatic H), 5.65 (s,l,C-5-H), 4.56 (s,2,-CH2-), 3.54 (s,3,-OCH3),
2.17 (s,3, gem-methyl), 2.09 (s,3, gem-methyl). Analysis for
C17H18N2O5S requires: C, 56.35; H, 5.01; N, 7.73; Found: C, 56.38;
H, 5.42; N, 7.60.
This example illustrates that when employing an anhydro-
penicillin as a starting material, it need not be converted to a
sulfoxide prior to halogenation.
EXAMPLE II
To a solution of 485 mg. of p-nitrobenzyl-6-(phenyl-
`b~ `!
'': '' ~ , , ' . . :
' ' ' :` ' '
1~4~6ZO
1 acetamidopenicillanate) sulfoxide in 5 ml. of dichloromethane wasadded with stirring a solution of 380 mg. of sodium borate in 30
ml. of methanol and thereafter,with continued stirring, one ml. of
t-butylhydrochlorite was added. The reaction mixture was stirred
for one hour and an additional 380 mg. of sodium borate and 1 ml.
of t-butylhypochlorite were adaed. After another hour of continued
stirring an additional 380 mg. of sodium borate and 1 ml. of t-
butylhypochlorite was added to the reaction mixture. The reaction
mixture was stirred for another hour and then was poured into a
lO cold diluted solution of sodium thiosulfate. The reaction product ,
was extracted from the cold mixture with ethyl acetate and the
extract was washed with an aqueous sodium chloride solution and
with water before drying. The dried extract was evaporated in the
- 13a -
104~620
1 vacuum to yield 306 mg. of p-nitroben~yl-6-methoxy-6-(phenylacet-
amidopenicillanate) sulfoxide as a solid residue in a 60 percent
yield. -
EXAMPLE III
The p-nitrobenzyl-6-methoxy-6-(phenylacetamidopenicillanate) ~ -
sulfoxide prepared and described in Example II was dissolved in a
solid mixtureof 25 ml. of dichloromethane and 25 ml. of dimethyl-
formamide and the solution was cooled in a dry ice-acetone bath.
To the cold solution was added a solution of 270 mg. of phosphorus
tribromide in benzene and after 5 minutes the solution temperature
increased to about -10C. Analysis of the reaction mixture
showed that the sulfoxide had been converted to the corresponding
penicillin. The penicillin product was recovered by adding to
the mixture 20 ml.of ethyl acetate and 10 ml. of sodium bicarbonate,
shaking the resultant mixture and thereafter separating the ethyl
acetate layer. The ethyl acetate was washed with saturated sodium
chloride solution and then water and then was dried and evaporated
in vacuo. 180 mg. of p-nitrobenzyl-6-methoxy-6-phenylacetamido
penicillin was obtained.
EX~PLE IV
The p-nitrobenzyl ester, prepared as described by Example
3, is dissolved in 20 ml. of tetrahydrofuran and 50 ml of methanol
containing 3 drops of lN hydrochloric acid. To this solution is
added 250 mg. of 5% palladium on carbon and the mixture is hydro-
genated for 2.5 hours at room temperature under 50 p.s.i. hydrogen
pressure. The catalyst is filtered and washed with tetrahydrofuran.
The filtrate and wash are combined and concentrated in vacuo to
remove volatile solvents. The aqueous residue is slurried with -~ ~ -
ethyl acetate and the pH of the mixture is momentarily adjusted to
- 14 -
'
.. . ~ ~ ....... . . ....... .
. -
1~)4~6ZO
1 pH 10 with lN sodium hydroxide. Immediately the aqueous phase is
then extracted wit~ ethyl acetate and the extract is washed with ~ -
water and then driedc~er magnesium sulfate. The dried extract is
then evaporated to dryness to afford 6-methoxy-6-phenylacetamido-
penicillanic acid.
EXA~IPLE V
The compound obtained by the procedure of Example IV was ;~
converted to the corresponding cephalosporin by the following
procedure.
395 mg. of methyl 6-methoxy-6-(phenylacetamido) penicil-
lanate sulfoxide was refluxed with 100 mg. of monopyridium
phosphate and 35 ml. dioxane for 24 hours. The reaction mixture
then was evaporated in vacuo and the sticky residue obtained was
dissolved in ethyl acetate and washed repeatedly with water. The
product then was dried and evapo~atéd in vacuo to recover 313 mg.
of methyl-7-methoxy-7-(phenylacetamido) 3-methyl-3-cephem-4-
carboxylate.
EXAMPLE VI
In accordance with the procedure of Example II, methyl-
6(phenoxyacetamido) penicillanate sulfone was reacted in methanolic
sodium borate solution (1.5 equivalents) and t-butylhypochlorite
(1.5 equivalents) at o& for about two hours. The reaction mixture
was purified on silica gel by elution with 5% ethyl acetate in
ether to obtain a 56% yield of methyl-6-methoxy-6 (phenoxyacetamido)
penicillanate sulfone.
EXAMPLE VII
Benzyl 6-(phenoxyacetamido) penicillanate was treated
with m-chloroperbenzoic acid (one equivalent) in chloroform at
0C for one hour. The chloroform solution was washed with water,
- 15 -
'
.. . .. .. . . .
.' :, . ,;, .
.
1'04~6ZO
1 5% aqueous sodium bicarbonate and finally with water and then dried.
The product was crystallized from ether and comprised benzyl 6-
(phenoxyacetamido) penicillanate s~lfoxide.
The sulfoxide (0.3 grams, 0.66 mole) in methanol (50 ml.) -
with sodium borate (0.328 gm, 0.86 mm mole) was treated with t-
butylhypochlorite (0.12 ml. ) for two hours at room temperature.
Ethyl acetate (200 ml.) was added to the solution and the resultant
solution was washed four times with water and dried. Evaporation
of the solvent afforded an oil which was purified on silica gel
10 with 3% ethyl acetate in ether to give 124 ml. of benzyl-6-methoxy-
6-~phenoxyacetamido) penicillanate sulfoxide.
EXAM2LE VIII
In accordance with the procedure of Example II,~he
compound, benzyl-6-methoxy-6-(phenoxyacetamido) penicillanate
sulfoxide was produced from benzyl-6-(phenoxyacetamido) penicil- ;
lanate sulfoxide.
EXAMPLE IX
6-Aminopenicillanic acid (2.5 gm., 0.0116 mole) was
suspended in water ~100 ml) and acetone ~100 ml) with sodium
bicarbonate (3.1 gm, 0.037 mole) at 0C while 2,2,2-trichloroethyl-
chloroformate ~2.5 gm, 0.0116 mole) in acetone (40 ml) was added.
After stirring for three hours at 0, the acetone was removed in
vacuo and the solution was extracted twice with ethyl acetate.
The aqueous solution was cooled to 0C and acidified to pH of 2
with lN HCl and was extracted with ethyl acetate three times. The
- ethyl acetate solutions were washed with water and were dried
(Na2SO4). Evaporation afforded the compound 6-(2,2,2-trichloro-
carboethoxyamido) penicillanic acid as an oil, 4 gm. 89% yield.
The acid was dissolved in ether and treated with dia- ~-
- 16 -
.~
~ .
~, ',~ ~
:~ . ,~,
. . ~ .
104~620
1 zomethane excess in ether to obtain methyl-6-(2,2,2-trichloro-
carboxyamido) penicillanate, 95% yield.
The penicillin ester in chloroform was treated with m-
chloroperbenzoic acid at 0 for one hour. The solution was washed
with sodium bicarbonate and was dried (Na2SO4). Evaporation
afforded the compound, methyl-6-(2,2,2-trichlorocarboethoxyamido)
penicillanate sulfoxide as a glossy solid, 90~ yield.
The sulfoxide (0.3 gm, 0.71 m mole) in methanol (50 ml)
with sodium borate (0.352 gm, 0.923 m mole) was treated with t-
butylhypochlorite (0.104 ml, 0.923 m mole) for two hours at roomtemperature. The reaction was worked up as above and the mixture
purified by TLC on silica gel with ether to give, 90 mg 31% yield
of methyl-6-methoxy-6-(2~2~2-trichlorocarboethoxyamido)penicilla
nate sulfoxide.
While this invention is described above with reference to
the use of a penicillin sulfoxide or anhydropenicillin as the
starting material in the halogenation and alkoxylation reaction it
is to be understood that a penicillin sulfone can be employed as
a starting material with the same results, i.e. effecting
alkoxylation while protecting the sulfur atom of the thiolactam
ring. However, sulfone starting materials are not desirable since
their reduction to the corresponding penicillin or cephalosporin
has not been successful. The sulfones starting material can be
produced kyreacting the penicillin with a strong oxidizing agent
such as potassium permanganate.
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