CA1040620A - 6-alkoxy-6-acylamidopenicillins 7-alkoxy-7-acylamido acetoxycephalosporins and process - Google Patents
6-alkoxy-6-acylamidopenicillins 7-alkoxy-7-acylamido acetoxycephalosporins and processInfo
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- CA1040620A CA1040620A CA183,763A CA183763A CA1040620A CA 1040620 A CA1040620 A CA 1040620A CA 183763 A CA183763 A CA 183763A CA 1040620 A CA1040620 A CA 1040620A
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- Prior art keywords
- penicillin
- formula
- microbiologically active
- cephalosporin
- hydrogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
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- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
This invention provides 6-acylamino penicillins having a 6-C1 to C4 alkoxy group and 7-acylamino cephalosporins having a 7-C1 to C4 alkoxy group. They are prepared by reacting a 6-acylamino penicillin sulfoxide or 6-acylamino anhydropenicillin with a halogenating agent in the presence of weak base and reacting the halogenated penicillin with a C1 to C4 alkanol. The alkoxylated penicillin sulfoxide or anhydropenicillin then is reduced or re-arranged to the corresponding penicillin or alkoxylated anhydro-penicillin. The cephalosporins are formed from the alkoxylated penicillin sulfoxide by ring expansion.
This invention provides 6-acylamino penicillins having a 6-C1 to C4 alkoxy group and 7-acylamino cephalosporins having a 7-C1 to C4 alkoxy group. They are prepared by reacting a 6-acylamino penicillin sulfoxide or 6-acylamino anhydropenicillin with a halogenating agent in the presence of weak base and reacting the halogenated penicillin with a C1 to C4 alkanol. The alkoxylated penicillin sulfoxide or anhydropenicillin then is reduced or re-arranged to the corresponding penicillin or alkoxylated anhydro-penicillin. The cephalosporins are formed from the alkoxylated penicillin sulfoxide by ring expansion.
Description
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 :
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:
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 ' ' ' ' ' ' " ' ' C/Z
- ICH / ~ H3 Formula IIa COORl Formula IIb T
COOR
. ............................ .............. ................ ...,- . .
ClH
/ C - CH3 Formula IIc - --ICH :
CH2 Rl .,, ~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.
' ' : . . ' ' ~
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.
~`~ . ;
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, 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.
~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~
PhocH2coN~
' S~XCH '~ . ~
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),
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 :
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:
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 ' ' ' ' ' ' " ' ' C/Z
- ICH / ~ H3 Formula IIa COORl Formula IIb T
COOR
. ............................ .............. ................ ...,- . .
ClH
/ C - CH3 Formula IIc - --ICH :
CH2 Rl .,, ~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.
' ' : . . ' ' ~
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.
~`~ . ;
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, 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.
~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~
PhocH2coN~
' S~XCH '~ . ~
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
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 ' .. . ~ ~ ....... . . ....... .
. -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, ' .. . .. .. . . .
.' :, . ,;, .
.
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.
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- ~-.~
~ .
~, ',~ ~
:~ . ,~, . . ~ .
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.
::
.
.
.
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 ' .. . ~ ~ ....... . . ....... .
. -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, ' .. . .. .. . . .
.' :, . ,;, .
.
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.
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- ~-.~
~ .
~, ',~ ~
:~ . ,~, . . ~ .
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.
::
.
.
.
Claims (13)
- Claim 1 continued:
Formula III B
wherein R is defined hereinbefore, R1 is defined hereinbefore, m is defined hereinbefore, n is defined hereinbefore, a is defined hereinbefore, b is defined hereinbefore, R2 is defined hereinbefore; which comprises the process of part (a) further including the step of rearranging the compound of formula I to form a cephalosporin. - 2. A microbiologically active penicillin, a precursor to a microbiologically active penicillin, a microbiologically active cephalosporin, a precursor to a microbiologically active cephalosporin selected from the group of compounds consisting of the compounds of formula I of claim 1 and the compounds of formula III of claim 1 whenever prepared by the process as claimed in claim 1.
- 3. The process as claimed in claim 1(b) wherein said rearrangement comprises the steps of heating the alkoxy penicillin sulfoxide in an inert solvent in the presence of dipyridine phosphate at a temperature between about 75°C and 135°C.
- 4. The microbiologically active cephalosporin or precursor to a microbiologically active cephalosporin of the Formula III
of claim 1 whenever prepared by the process as claimed in claim 3. - 5. The process as claimed in claim 1(a) wherein R2 is hydrogen or a pharmaceutically acceptable cation.
- 6. The penicillin of Formula I of claim 1 wherein R2 is a hydrogen or a pharmaceutically acceptable cation whenever prepared by the process as claimed in claim 5.
- 7. The process as claimed in claim 1(a) wherein R1 is methyl.
- 8. The penicillin of the Formula I of claim 1 wherein R1 is methyl whenever prepared by the process as claimed in claim 7.
- 9. The process as claimed in claim 1(b) wherein R2 is hydrogen or a pharmaceutically acceptable cation.
- 10. The cephalosporin of the Formula III of claim 1 wherein R2 is hydrogen or a pharmaceutically acceptable cation whenever prepared by the process as claimed in claim 9.
- 11. The process as claimed in claim 1(b) wherein R1 is methyl.
- 12. The cephalosporin of the Formula III of claim 1 wherein R1 is methyl whenever prepared by the process as claimed in claim 11.
- 13. The process as claimed in claim 1 wherein said alcohol is methanol.
1. A process for the production of a microbiologically active penicillin, a precursor to a microbiologically active penicillin, a microbiologically active cephalosporin or a precursor to a microbiologically active cephalosporin, said process selected from the group of processes:
(a) for the production of a microbiologically active penicillin or precursor to a microbiologically active penicillin of the formula I
Formula I
wherein Y is Formula I A
wherein R is C1-C7 alkyl, phenyl, halophenyl, lower alkylphenyl, lower alkoxyphenyl, hydroxyphenyl, alkylthiomethyl, 5'-protected-amino-5'-carboxy valveramido, 5'-amino-5'-carboxy valveramido;
or a group of the formula Claim 1 continued:
wherein X is phenyl, halophenyl, lower alkylphenyl, lower alkoxy-phenyl, nitrophenyl, hydroxyphenyl, cyanophenyl, carboxyphenyl, lower alkoxycarbonylphenyl, carboxamidophenyl, protected amino-phenyl aminophenyl, 2-thienylmethyl, 3-thienylmethyl, 2-furyl-methyl or 3-furylmethyl;
m is 0 or 1;
n is 0, 1 or 2;
a is hydrogen or C1-C3 alkyl;
b is hydrogen, C1-C3 alkylhydroxyamino or protected amino;
R2 is a carboxyl protective group, hydrogen or a pharmaceutically acceptable cation;
R1 is C1-C4 alkyl;
Z is hydrogen;
p is 1;
which comprises reacting a compound of the general formula II
Formula II
with a positive halogenating agent to replace a hydrogen atom with a halogen atom thereby forming a halogenated penicillin and reacting said penicillin with a C1-C4 alcohol;
(b) for the production of a microbiologically active cephalos-porin or precursor to a microbiologically active cephalosporin of the formula III
Formula III
wherein Y1 is:
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US30642872A | 1972-11-14 | 1972-11-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1040620A true CA1040620A (en) | 1978-10-17 |
Family
ID=23185242
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA183,763A Expired CA1040620A (en) | 1972-11-14 | 1973-10-18 | 6-alkoxy-6-acylamidopenicillins 7-alkoxy-7-acylamido acetoxycephalosporins and process |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JPS49133390A (en) |
| CA (1) | CA1040620A (en) |
| FR (1) | FR2207695A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5750684A (en) * | 1982-12-14 | 1998-05-12 | Beecham Group Plc. | Process for the preparatin of β-lactam compounds |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3311638A (en) * | 1961-08-16 | 1967-03-28 | Bristol Myers Co | Anhydropenicillins |
| IL36281A (en) * | 1970-03-13 | 1977-04-29 | Merck & Co Inc | Cephalosporin derivatives antibiotic mixtures containing them and process for their preparation |
| AR205683A1 (en) * | 1970-06-16 | 1976-05-31 | Merck & Co Inc | PROCEDURE FOR THE PREPARATION OF BENZYL ESTER OF 6-METHOXY-6-PENICILANIC ACID |
| BE794554A (en) * | 1972-01-31 | 1973-07-26 | Lilly Co Eli | NEW DERIVATIVES OF PENICILLIN AND CEPHALUSPORIN |
-
1973
- 1973-10-18 CA CA183,763A patent/CA1040620A/en not_active Expired
- 1973-11-08 JP JP12617373A patent/JPS49133390A/ja active Pending
- 1973-11-13 FR FR7340343A patent/FR2207695A1/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5750684A (en) * | 1982-12-14 | 1998-05-12 | Beecham Group Plc. | Process for the preparatin of β-lactam compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2207695A1 (en) | 1974-06-21 |
| JPS49133390A (en) | 1974-12-21 |
| FR2207695B1 (en) | 1977-04-22 |
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