CA1057740A - 3-heterothio (alkoxycarbonyl and alkoxythiocarbonyl)-thioacetyl) cephalosporin derivatives - Google Patents
3-heterothio (alkoxycarbonyl and alkoxythiocarbonyl)-thioacetyl) cephalosporin derivativesInfo
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- CA1057740A CA1057740A CA229,638A CA229638A CA1057740A CA 1057740 A CA1057740 A CA 1057740A CA 229638 A CA229638 A CA 229638A CA 1057740 A CA1057740 A CA 1057740A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Abstract
ABSTRACT
3-Heterothio[alkoxycarbonyl and alkoxythiocarbonyl)-thioacetyl]cephalosporin derivatives which have the formula wherein R1 is hydrogen, lower alkyl, phenyl, furyl or thienyl; R2 is lower alkyl or phenyl-lower alkyl; R3 is hydrogen, lower alkyl, phenyl-lower alkyl, tri(lower alkyl)silyl, tri(lower alkyl)stannyl, a salt forming ion, or -CH2-O-?-R; R is lower alkyl, phenyl or phenyl-lower alkyl; Z is O or S; R4 is a nitrogen and/or sulfur or oxygen containing heterocyclic ring system selected from the group consisting of oxadiazole, thiazole, tetrazole and thiadiazole and in addition, when Z is O, isoxazole, isothiazole and 1-oxopyridine and when Z is S, triazole and thiatriazole, and lower alkyl substituted analogs of said heterocyclic rings;
are useful as antibacterial agents.
3-Heterothio[alkoxycarbonyl and alkoxythiocarbonyl)-thioacetyl]cephalosporin derivatives which have the formula wherein R1 is hydrogen, lower alkyl, phenyl, furyl or thienyl; R2 is lower alkyl or phenyl-lower alkyl; R3 is hydrogen, lower alkyl, phenyl-lower alkyl, tri(lower alkyl)silyl, tri(lower alkyl)stannyl, a salt forming ion, or -CH2-O-?-R; R is lower alkyl, phenyl or phenyl-lower alkyl; Z is O or S; R4 is a nitrogen and/or sulfur or oxygen containing heterocyclic ring system selected from the group consisting of oxadiazole, thiazole, tetrazole and thiadiazole and in addition, when Z is O, isoxazole, isothiazole and 1-oxopyridine and when Z is S, triazole and thiatriazole, and lower alkyl substituted analogs of said heterocyclic rings;
are useful as antibacterial agents.
Description
10577~0 This invention relates to new 3-heterothio[alkoxycarbonyl and alkoxythiocarbonyl)thioacetyl]cephalosporin derivatives which have the formula (I) IRl S
R2-O-C-S-CH - CO - NH ~ ( Z ~ CH 2 - S - R4 Rl is hydrogen, lower alkyl, phenyl, thienyl or furyl.
R2 is lower alkyl or phenyl-lower alkyl.
R3 is hydrogen, lower alkyl, tri(lower alkyl)silyl, tri(lower alkyl)stannyl, phenyl-lower alkyl, a salt forming ion, or -CH2-O-C-R wherein R is lower alkyl, phenyl, or phenyl-lower alkyl.
Z is O or S.
R4 is a nitrogen and/or sulfur or oxvaen-containing heterocyclic rin~ system selected from the arou~ consistinq of oxadiazole, thiazole, tetrazole and thiadiazole and in addition, when Z is O, i~oxazole, isothiazole and l-oxo-pyridine and wnen Z i8 S, triazole and thiatriazole, and lower alkyl substituted analogs of said heterocyclic rings;
are useful as antibacterial agents.
'q~
The various groups represented by the symbols have the meanings defined below and these definitions are retained throughout this specification.
The lower alkyl groups are straight or branched chain hydrocarbon groups containing 1 to 8 carbon atoms, preferably 1 to 4 carbons. Examples of the type of these groups are methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, isopentyl, etc. The phenyl-lower alkyl groups include one or two phenyl radicals attached to such lower alkyl groups, e.g., benzyl, phenethyl, benzhydryl, etc.
The salt forming ions represented by R3 are metal ions, e.g., alkali metal ions such as sodium or potassium;
alkaline earth metal ions such as calcium or magnesium, or an amine salt ion, of which a number are known for this purpose, for example, especially lower alkylamines like methylamine or triethylamine, and phenyl-lower alkylamines like dibenzylamine.
The nitrogen containing heterocyclics are particularly 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,3,4-oxadiazole, tetrazole, 1,2,3-triazole, 1,2,3,4-thiatriazole and their lower alkyl derivatives, especially the radicals 3-lower alkyl-1,2,4-thiadiazol-5-yl, 5-lower alkyl-1,3,4-thiadiazole-2-yl,
R2-O-C-S-CH - CO - NH ~ ( Z ~ CH 2 - S - R4 Rl is hydrogen, lower alkyl, phenyl, thienyl or furyl.
R2 is lower alkyl or phenyl-lower alkyl.
R3 is hydrogen, lower alkyl, tri(lower alkyl)silyl, tri(lower alkyl)stannyl, phenyl-lower alkyl, a salt forming ion, or -CH2-O-C-R wherein R is lower alkyl, phenyl, or phenyl-lower alkyl.
Z is O or S.
R4 is a nitrogen and/or sulfur or oxvaen-containing heterocyclic rin~ system selected from the arou~ consistinq of oxadiazole, thiazole, tetrazole and thiadiazole and in addition, when Z is O, i~oxazole, isothiazole and l-oxo-pyridine and wnen Z i8 S, triazole and thiatriazole, and lower alkyl substituted analogs of said heterocyclic rings;
are useful as antibacterial agents.
'q~
The various groups represented by the symbols have the meanings defined below and these definitions are retained throughout this specification.
The lower alkyl groups are straight or branched chain hydrocarbon groups containing 1 to 8 carbon atoms, preferably 1 to 4 carbons. Examples of the type of these groups are methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, isopentyl, etc. The phenyl-lower alkyl groups include one or two phenyl radicals attached to such lower alkyl groups, e.g., benzyl, phenethyl, benzhydryl, etc.
The salt forming ions represented by R3 are metal ions, e.g., alkali metal ions such as sodium or potassium;
alkaline earth metal ions such as calcium or magnesium, or an amine salt ion, of which a number are known for this purpose, for example, especially lower alkylamines like methylamine or triethylamine, and phenyl-lower alkylamines like dibenzylamine.
The nitrogen containing heterocyclics are particularly 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,3,4-oxadiazole, tetrazole, 1,2,3-triazole, 1,2,3,4-thiatriazole and their lower alkyl derivatives, especially the radicals 3-lower alkyl-1,2,4-thiadiazol-5-yl, 5-lower alkyl-1,3,4-thiadiazole-2-yl,
2-lower alkyl-1,3,4-oxadiazole-5-yl and l-lower alkyl-1,2,3,4-tetrazol-5-yl. The preferred lower alkyl group is methyl.
Preferred embodiments of this invention are as follows:
R1 is hydrogen, lower alkyl of 1 to 4 carbons, phenyl, furyl, thienyl, especially hydrogen,phenyl or thienyl.
GG21yl94 ~05'7740 R2 is lower alkyl of 1 to 4 carbons, especially methyl or ethyl.
oR3 is hydrogen, alkali metal, diphenylmethyl or -CH2-O-C-R, especially hydrogen, pivaloyloxymethyl, sodium or potassium. R is lower alkyl, especially t-butyl.
R4 is thiadiazole, tetrazole and their methyl substituted analogs, especially, 1,3,4-thiadiazole, 5-methyl-1,3,4-thiadiazole, tetrazole and most especially l-methyl-lH-tetrazole.
The new derivatives of alkoxycarbonyl and alkoxvthio-carbonyl)thioacetyl]cephalosporins of this invention are produced by reacting 7-aminocephalosporanic acid (7-ACA) (or derivative wherein R3 is other than hydrogen) with a mercaptan HS-R4 at a pH of about 8-8.5 to obtain the derivative of the formula (II) S
2 ~
~ I CH 2 - S- R4 The product of formula II is then acylated on the amino group with a thioacetic acid of the formula (III) IRl z or activated derivatives thereof. The symbols have the meanings already defined.
The activated derivatives referred to include, for example, the reaction product with an anhydride forming reagent ~uch as ethylchloroformate, benzoyl chloride, 1~57 74~ GG211/194 pivaloyl chloride, etc., or with bisimidazolecarbonyl, dicyclo-hexylcarbodiimide, p-nitrophenol or the like.
According to a preferred modification, the 7-amino-cephalosporanic acid derivative of formula II, preferably in the form of its diphenylmethyl ester, in an organic solvent like tetrahydrofuran is added to a mixture containing the acid of formula III and dicyclohexylcarbodiimide in an organic solvent like the one mentioned above at a reduced temperature of about 0 C. The dicyclohexylurea formed during the reaction is removed and the product is recovered from the filtrate. When the preferred diphenylmethyl ester is used, the ester group is removed by treatment with trifluoroacetic acid and anisole.
The acids of formula III wherein Z is O are formed by reacting a mercaptoacetic acid of the formula -(IV) Rl-CH-COOH
SFi with a chloroformic acid ester of the formula (V) Cl--C-O-R2 in the presence of an inorganic or organic base, e.g., an alkali metal hydroxide such as potassium hydroxide or triethylamine or dimethylaniline.
~0S~'~40 The acids of formula III wherein Z is S are produced by the method of Bonner, J. Org. Chem. 33, 1831(1968) as described in U.S. 3,880,845 issued April 29, 1975.
When R3 is the acyloxymethyl group -CH2-O-CO-R, this group can be introduced onto the 7-ACA moiety prior to the reaction with the acid of formula III by treatment with one to two moles of a halomethyl ester of the formula (VI) hal -CH2OCOR
wherein hal is halogen, preferably chlorine or bromine, in an inert organic solvent such as dimethylformamide, acetone, dioxane, benzene or the like at about ambient temperature or below.
Further process details are also provided in the illustrative examples.
Certain of the compounds of this invention may exist in different optically active forms. The various stereo-isomeric forms as well as racemic mixtures are within the scope of the invention.
The compounds of this invention have antibacterial activity against both gram positive and gram negative organisms such as Staphylococcus aureus, Proteus rettgeri, and E. hafniae. They may be used as antibacterial agents in a prophylactic manner or to combat infections caused by organisms such as those named above, and in general can be utilized in a manner similar to cephradine and other cephalo-sporins. For example, a compound of formula I or a physiologically acceptable salt thereof can be used in various animal species in an amount of about 1 to 50 mg/kg daily, orally or parenterally, in single or two to four lOS7740 GG211/194 divided doses to treat infections of bacterial origin, e.g., 5.0 mg/kg has been found useful in mice.
Up to about 600 mg. of a compound of formula I
or a physiologically acceptable salt thereof can be incorporated in an oral dosage form such as tablets, capsules or elixirs or in an injectable form in a sterile aqueous vehicle compounded according to conventional pharmaceutical practice.
The following examples are preferred embodiments which are illustrative of the invention and serve a models for the preparation of other compounds of this invention.
Additional variations are produced in the same manner by appropriate substitution in the starting materiaI. All temperatures are in degrees celsius.
Example 1 DL-2[[(EthoxYcarbonyl)thio]phenyl]acetic acid
Preferred embodiments of this invention are as follows:
R1 is hydrogen, lower alkyl of 1 to 4 carbons, phenyl, furyl, thienyl, especially hydrogen,phenyl or thienyl.
GG21yl94 ~05'7740 R2 is lower alkyl of 1 to 4 carbons, especially methyl or ethyl.
oR3 is hydrogen, alkali metal, diphenylmethyl or -CH2-O-C-R, especially hydrogen, pivaloyloxymethyl, sodium or potassium. R is lower alkyl, especially t-butyl.
R4 is thiadiazole, tetrazole and their methyl substituted analogs, especially, 1,3,4-thiadiazole, 5-methyl-1,3,4-thiadiazole, tetrazole and most especially l-methyl-lH-tetrazole.
The new derivatives of alkoxycarbonyl and alkoxvthio-carbonyl)thioacetyl]cephalosporins of this invention are produced by reacting 7-aminocephalosporanic acid (7-ACA) (or derivative wherein R3 is other than hydrogen) with a mercaptan HS-R4 at a pH of about 8-8.5 to obtain the derivative of the formula (II) S
2 ~
~ I CH 2 - S- R4 The product of formula II is then acylated on the amino group with a thioacetic acid of the formula (III) IRl z or activated derivatives thereof. The symbols have the meanings already defined.
The activated derivatives referred to include, for example, the reaction product with an anhydride forming reagent ~uch as ethylchloroformate, benzoyl chloride, 1~57 74~ GG211/194 pivaloyl chloride, etc., or with bisimidazolecarbonyl, dicyclo-hexylcarbodiimide, p-nitrophenol or the like.
According to a preferred modification, the 7-amino-cephalosporanic acid derivative of formula II, preferably in the form of its diphenylmethyl ester, in an organic solvent like tetrahydrofuran is added to a mixture containing the acid of formula III and dicyclohexylcarbodiimide in an organic solvent like the one mentioned above at a reduced temperature of about 0 C. The dicyclohexylurea formed during the reaction is removed and the product is recovered from the filtrate. When the preferred diphenylmethyl ester is used, the ester group is removed by treatment with trifluoroacetic acid and anisole.
The acids of formula III wherein Z is O are formed by reacting a mercaptoacetic acid of the formula -(IV) Rl-CH-COOH
SFi with a chloroformic acid ester of the formula (V) Cl--C-O-R2 in the presence of an inorganic or organic base, e.g., an alkali metal hydroxide such as potassium hydroxide or triethylamine or dimethylaniline.
~0S~'~40 The acids of formula III wherein Z is S are produced by the method of Bonner, J. Org. Chem. 33, 1831(1968) as described in U.S. 3,880,845 issued April 29, 1975.
When R3 is the acyloxymethyl group -CH2-O-CO-R, this group can be introduced onto the 7-ACA moiety prior to the reaction with the acid of formula III by treatment with one to two moles of a halomethyl ester of the formula (VI) hal -CH2OCOR
wherein hal is halogen, preferably chlorine or bromine, in an inert organic solvent such as dimethylformamide, acetone, dioxane, benzene or the like at about ambient temperature or below.
Further process details are also provided in the illustrative examples.
Certain of the compounds of this invention may exist in different optically active forms. The various stereo-isomeric forms as well as racemic mixtures are within the scope of the invention.
The compounds of this invention have antibacterial activity against both gram positive and gram negative organisms such as Staphylococcus aureus, Proteus rettgeri, and E. hafniae. They may be used as antibacterial agents in a prophylactic manner or to combat infections caused by organisms such as those named above, and in general can be utilized in a manner similar to cephradine and other cephalo-sporins. For example, a compound of formula I or a physiologically acceptable salt thereof can be used in various animal species in an amount of about 1 to 50 mg/kg daily, orally or parenterally, in single or two to four lOS7740 GG211/194 divided doses to treat infections of bacterial origin, e.g., 5.0 mg/kg has been found useful in mice.
Up to about 600 mg. of a compound of formula I
or a physiologically acceptable salt thereof can be incorporated in an oral dosage form such as tablets, capsules or elixirs or in an injectable form in a sterile aqueous vehicle compounded according to conventional pharmaceutical practice.
The following examples are preferred embodiments which are illustrative of the invention and serve a models for the preparation of other compounds of this invention.
Additional variations are produced in the same manner by appropriate substitution in the starting materiaI. All temperatures are in degrees celsius.
Example 1 DL-2[[(EthoxYcarbonyl)thio]phenyl]acetic acid
3.4 gms. (20 mM) of a-mercaptophenylacetic acid are dissolved with 2.2 gms. (40 mM) of potassium hydroxide in 50 ml. of water. 25 ml. of chloroform are added and, at a temperature of 5, 2.2 gms. (25 mM) of ethyl chloro-20 formate are added dropwise with intensive stirring. After14 hours, the chloroform phase is separated, the water phase is acidified with 2N hydrochloric acid and extracted with ether. After drying and evaporating the solvent, 2.6 gms. of white crystalline DL-2-[[(ethoxycarbonyl)thio]-phenyl]acetic acid are obtained, m.p. 108-110.
iO5'7'740 Example 2 DL-2-[[(Methoxycarbonyl)thioJphenyl]acetic acid By substituting methyl chloroformate for the ethyl chloroformate in the procedure of Example 1, white crystalline DL-2-[(methoxycarbonyl)thio~phenylacetic acid is obtained, m.p. 58.
Example 3 DL-2-[(Methoxycarbonyl)thio]-2-phenylacetic acid chloride 2.8 gms. (15 mM) of the acid obtained in Example 2 are heated with 15 ml. of thionyl chloride and 15 ml. of absolute ether for 24 hours under reflux with the exclusion of water vapor. After evaporating the solvent and excess thionyl chloride, crude DL-2-[(methoxycarbonyl)thio~-2-phenylacetic acid chloride is obtained which is used in the next step without further purification.
ExamPle 4 7-[[DL-2-[(Methoxycarbonyl)thio]-2-phenylacetyl]amino~-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0~oct-2-ene-carboxylic acid, 3-acetate A solution of 1.9 gms. (10 mM) of the product of Example 3 in a little chloroform is added dropwise at a temperature of -20 to a solution of 2.7 gms. (10 mM) of 7-ACA and 2 gms. of triethylamine in chloroform, with stirring. The mixture is stirred for 20 minutes at -20 and 18 hours at room temperature. The solution cools to 0, 30 ml. of 2N hydrochloric acid are added and the solution shaken well. The chloroform is separated and washed twice each with 50 ml. of water. It is then dried over sodium sulfate and after evaporating the solvent, the 7-[[DL-2-[(methoxycarbonyl)thio~-2-phenylacetyl~amino]-3-(hydroxy-~o57740 GG211/194 methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylic acid, 3-acetate is obtained in the form of a sticky mass which, after the addition of chloroform, solidifies. After recrystallization from methylene chloride/carbon tetrachloride, the pure product forms as light beige crystals, m.p.
74-75 (dec.).
The potassium salt is obtained by the freeze drying of a solution containing one equivalent each of the acid and potassium bicarbonate, m.p. 175 (dec.).
Example 5 7-1[DL-2-[(Ethoxycarbonyl)thio]-2-Phenylacetyl]amino]-3-(hydroxYmethY1)-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 3-acetate By substituting DL-2-[[(ethoxycarbonyl)thio]phenyl]-acetic acid for the DL-2-[[(methoxycarbonyl)thio]phenyl]acetic acid in the procedure of Bxample 3 and then following the procedure of Example 4 with the product, 7-[[DL-2-[(ethoxy-carbonyl)thio]-2-phenylacetyl]amino]-3-(hydroxymethyl)-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 3-acetate is obtained m.p. 112.
The potassium salt is obtained by the procedure of Example 4, m.p. 167.
The following additional products are similarly obtained:
7-[[DL-2-(ethoxycarbonyl)thio]acetyl]amino]-3-(hydroxymethyl3-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene carboxylic acid 3-acetate 7-l[DL-2-[(n-butoxycarbonyl)thio]acetyl]amino-3-(hydroxymethyl)-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene carboxylic acid-3-acetate 7-[[DL-2-[(benzyloxycarbonyl)thio]-2-phenyl-acetyl]amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid-3-acetate 7-[[DL-2-[(Benzyloxycarbonyl)thio]acetyl]amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid-3-acetate.
Example 6 3-[[(5-Methyl-1,3,4-thiadiazol-2-Yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carbox lic acid y A mixture of 13.6 g. (0.5 M) of 7-aminocephalo-sFor~nic acid (7-ACA) in 100 ml. of water and 50 ml. of acetone are brought to pH 8 with sodium hydroxide while stirring. 9.8 g. (0.57 M) of 2-methyl-1,3,4-thiadiazole-5-thiol are added and the mixture is heated at 80 for four hours. After cooling to 5, this is acidified to pH 3.5 with dilute hydrochloric acid and stirred for 15 minutes.
The precipitated solid is filtered under suction and washed with acetone. This 3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio~-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is purified by dissolving in sodium bicarbonate solution and reprecipitating with 2N hydrochloric acid; yield 12.7 g., m.p. 206.
Example 7 3-[[(3-MethYl-1,2,4-thiadiazol-5-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.01oct-2-ene-2-carboxylic acid By substituting 3-methyl-1,2,4-thiadiazole-5-thiol for the 2-methyl-1,3,4-thiadiazole-5-thiol in the procedure of Example 6, 11.6-g. of 3-[[(3-methyl-1,2,4-thiadiazol-5-yl)thiolmethyl]-7-amino-8-oxo-5-thia-1-azabicyclol4.2.01oct-2-ene-2-carboxylic acid, m.p. 186 _g_ (dec.) are obtained.
Example 8 3-[[(1-Methyl-lH-tetrazol-5-yl)thio]methYl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid By substituting 0.57 M of l-methyl-lH-tetrazol-5-thiol for the 2-methyl-1,3,4-thiadiazol 5-thiol in the pro-cedure of Example 7, 3-[[(1-methyl-lH-tetrazol-5-yl)thio]-methyl]-7-amino-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is obtained.
Example 9 3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclol4.2.0]oct-2~ene-2-carboxylic acid, diphenylmethyl ester 18 g. of 7-amino-3-[[(5-methyl-1,3,4-thiadiazol-S-yl)thio]methyl]-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid are suspended in 350 ml. of tetrahydrofuran.
iO5'7'740 Example 2 DL-2-[[(Methoxycarbonyl)thioJphenyl]acetic acid By substituting methyl chloroformate for the ethyl chloroformate in the procedure of Example 1, white crystalline DL-2-[(methoxycarbonyl)thio~phenylacetic acid is obtained, m.p. 58.
Example 3 DL-2-[(Methoxycarbonyl)thio]-2-phenylacetic acid chloride 2.8 gms. (15 mM) of the acid obtained in Example 2 are heated with 15 ml. of thionyl chloride and 15 ml. of absolute ether for 24 hours under reflux with the exclusion of water vapor. After evaporating the solvent and excess thionyl chloride, crude DL-2-[(methoxycarbonyl)thio~-2-phenylacetic acid chloride is obtained which is used in the next step without further purification.
ExamPle 4 7-[[DL-2-[(Methoxycarbonyl)thio]-2-phenylacetyl]amino~-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0~oct-2-ene-carboxylic acid, 3-acetate A solution of 1.9 gms. (10 mM) of the product of Example 3 in a little chloroform is added dropwise at a temperature of -20 to a solution of 2.7 gms. (10 mM) of 7-ACA and 2 gms. of triethylamine in chloroform, with stirring. The mixture is stirred for 20 minutes at -20 and 18 hours at room temperature. The solution cools to 0, 30 ml. of 2N hydrochloric acid are added and the solution shaken well. The chloroform is separated and washed twice each with 50 ml. of water. It is then dried over sodium sulfate and after evaporating the solvent, the 7-[[DL-2-[(methoxycarbonyl)thio~-2-phenylacetyl~amino]-3-(hydroxy-~o57740 GG211/194 methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylic acid, 3-acetate is obtained in the form of a sticky mass which, after the addition of chloroform, solidifies. After recrystallization from methylene chloride/carbon tetrachloride, the pure product forms as light beige crystals, m.p.
74-75 (dec.).
The potassium salt is obtained by the freeze drying of a solution containing one equivalent each of the acid and potassium bicarbonate, m.p. 175 (dec.).
Example 5 7-1[DL-2-[(Ethoxycarbonyl)thio]-2-Phenylacetyl]amino]-3-(hydroxYmethY1)-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 3-acetate By substituting DL-2-[[(ethoxycarbonyl)thio]phenyl]-acetic acid for the DL-2-[[(methoxycarbonyl)thio]phenyl]acetic acid in the procedure of Bxample 3 and then following the procedure of Example 4 with the product, 7-[[DL-2-[(ethoxy-carbonyl)thio]-2-phenylacetyl]amino]-3-(hydroxymethyl)-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 3-acetate is obtained m.p. 112.
The potassium salt is obtained by the procedure of Example 4, m.p. 167.
The following additional products are similarly obtained:
7-[[DL-2-(ethoxycarbonyl)thio]acetyl]amino]-3-(hydroxymethyl3-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene carboxylic acid 3-acetate 7-l[DL-2-[(n-butoxycarbonyl)thio]acetyl]amino-3-(hydroxymethyl)-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene carboxylic acid-3-acetate 7-[[DL-2-[(benzyloxycarbonyl)thio]-2-phenyl-acetyl]amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid-3-acetate 7-[[DL-2-[(Benzyloxycarbonyl)thio]acetyl]amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid-3-acetate.
Example 6 3-[[(5-Methyl-1,3,4-thiadiazol-2-Yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carbox lic acid y A mixture of 13.6 g. (0.5 M) of 7-aminocephalo-sFor~nic acid (7-ACA) in 100 ml. of water and 50 ml. of acetone are brought to pH 8 with sodium hydroxide while stirring. 9.8 g. (0.57 M) of 2-methyl-1,3,4-thiadiazole-5-thiol are added and the mixture is heated at 80 for four hours. After cooling to 5, this is acidified to pH 3.5 with dilute hydrochloric acid and stirred for 15 minutes.
The precipitated solid is filtered under suction and washed with acetone. This 3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio~-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is purified by dissolving in sodium bicarbonate solution and reprecipitating with 2N hydrochloric acid; yield 12.7 g., m.p. 206.
Example 7 3-[[(3-MethYl-1,2,4-thiadiazol-5-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.01oct-2-ene-2-carboxylic acid By substituting 3-methyl-1,2,4-thiadiazole-5-thiol for the 2-methyl-1,3,4-thiadiazole-5-thiol in the procedure of Example 6, 11.6-g. of 3-[[(3-methyl-1,2,4-thiadiazol-5-yl)thiolmethyl]-7-amino-8-oxo-5-thia-1-azabicyclol4.2.01oct-2-ene-2-carboxylic acid, m.p. 186 _g_ (dec.) are obtained.
Example 8 3-[[(1-Methyl-lH-tetrazol-5-yl)thio]methYl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid By substituting 0.57 M of l-methyl-lH-tetrazol-5-thiol for the 2-methyl-1,3,4-thiadiazol 5-thiol in the pro-cedure of Example 7, 3-[[(1-methyl-lH-tetrazol-5-yl)thio]-methyl]-7-amino-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is obtained.
Example 9 3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclol4.2.0]oct-2~ene-2-carboxylic acid, diphenylmethyl ester 18 g. of 7-amino-3-[[(5-methyl-1,3,4-thiadiazol-S-yl)thio]methyl]-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid are suspended in 350 ml. of tetrahydrofuran.
4.1 ml. of 70% perchloric acid are added dropwise. After 30 minutes, a slightly turbid solution forms. This solution is filtered and to the filtrate is added dropwise with stirring 12 g. of diphenyldiazomethane and 20 ml. of tetrahydrofuran.
After 3 hours, the reaction mixture is poured into 2 liters of absolute ether. The solid, light brown precipitate, which is the perchloric acid salt of the desired product, is dried over Kieselgel in a dessiccator. To obtain the base, the perchloric acid salt is dissolved in water and treated with the calculated equivalent of potassium bicarbonate.
The aqueous solution obtained is extracted with chloroform.
The chloroform phase i5 treated with activated carbon and sodium sulfate to obtain the 10 g. of the product, 7-amino-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, as a light brown powder, m.p. 157-159. The product is recrystallized from tetrahydrofuran/petroleum ether. The isomeric thiadiazolyl derivative is similarly obtained from the product of Example 7.
Example 10 3-[[(1-Methyl-lH-tetrazol-5-Yl)thio]methyl]-7-amino-8-oxo-5-thia-l-azabicvclo[4.2.0]oct-2-ene-carboxylic acid, diPhenYl-methyl ester The product, 7-amino-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylic acid, diphenylmethyl ester, m.p. 168-169 (dec.), is obtained by the procedure of Example 9 utilizing as starting material 7-amino-3-[[(1-methyl-lH-tetrazol-5-yl)-thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Example 11 3-[[(1-Methyl-lH-tetrazol-5-yl)thio]methyl]-7~-[[[(methoxy-carbonYl)thio]phenylacetyl]amino]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester 1.1 g. (5 mM) of the product of Example 2 is dissolved in 25 ml. of tetrahydrofuran and added at 0 to 1.0 g. of dicyclohexylcarbodiimide in 5 ml. of tetrahydrofuran.
After 30 minutes, 2.48 gm. of 3-[[(1-methyl-lH-tetrazol-5-yl]thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester dissol~ed in 15 ml. of tetrahydrofuran is added. After stirring for 12 hours, the dicyclohexylurea which has formed is filtered ~ff. The filtrate is treated with activated carbon and the solvent is drawn off leaving 3-[[(1-methyl-lH-tetrazol-5---11-- , yl)thio]methyl]-7~-[[[(methoxycarbonyl)thio]phenylacetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester as a light brown powder, yield 2.7 g., m.p. 92-94 (dec.).
Example 12 3-[[(1-Methyl-lH-tetrazol-5-yl)thio]methyl]-7~-[[[(methyl-carbonyl)thio]phenylacetyl]amino]-8-oxo-5-thia-1-azabi-cyclo[4.2.0]oct-2-ene-2-carboxylic acid 2 g. of the product of Example 11 is stirred in a mixture of 15 ml. of trifluoroacetic acid and 3 ml.
of anisole at 0 for 15 minutes. After the solvent is drawn off and the residue is treated with ether/petroleum ether (1:1), the solid brown residue is taken up in sodium bicarbonate solution, filtered and the filtrate is extracted with ethyl acetate and then acidified to pH 2.5 with 2N
hydrochloric acid while cooling with ice. This is extracted with ethyl acetate. The organic phase is treated with activated carbon and the solvent is drawn off to obtain the product 3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-7~-[[[(methoxycarbonyl)thio]phenylacetyl]amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. The product is recrystallized from tetrahydrofuran/petroleum ether as a light brown powder, yield 0.5 g., m.p. 128 (dec.).
Example 13 3-1[(1-MethYl-lH-tetrazol-5-yl)thio]methyl]-7~-[[[(methoxy-carbonYl)thio]phenylacetyl]amino-8-oxo-5-thia-l-azabi [4.2.0]oct-2-ene-2-carboxylic acid! potassium salt The potassium salt of the product of Example 12 is obtained by freeze drying an equimolar aqueous solution of the acid of that example and potassium bicarbonate, 105~40 GG 211/194 m.p. 153-154 (dec.).
Examples 14 - 44 The products below are obtained by reacting the acid ll O
with the diphenylmethyl ester of one of the following according to the procedure of Example 11 and then following with the procedure of Example 12. Salts are produced by continuing with the procedure of Example 14.
3-[[(5-methyl-1,3,4-thiadiazolyl-2-yl)thio]-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid 3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-3-[[(3-isothiazolyl)thio]methyl]-7-ACA
3-[[(1,3,4-oxadiazol-2-yl)thio]methyl]-7-ACA
3-[[(5-ethyl-1,3,4-oxadiazol-2-yl)thio]methyl]-3-[[(1,2,3,4-tetrazol-5-yl)thio]methyl]-7-ACA
3-[[(1-ethyl-lH-tetrazol-5-yl)thio]methyl]-7-ACA
3-[[(3-methyl-5-isothiazolyl)thio]methyl]-7-ACA
3-[[(3-isothiazolyl)thio]methyl]-7-ACA
3-[[(3-isoxazolyl)thio]methyl]-7-ACA
3-[[(5-methyl-3-isoxazolyl)thio]methyl]-7-ACA
3-[[(1,2,4-thiadiazol-3-yl)thio]methyl]-7-ACA
3-[[(5-butyl-1,2,4-thiadiazol-3-yl)thio]methyl]-3-[[(5-ethyl-3-isoxazolyl)thio]methyl]-7-ACA
3-[[(3-methyl-4-i~oxazolyl)thio]methyll-7-ACA
3-[[(3-methyl-1,2,4-oxadiazol-5-yl)thio]methyl]-3-[[(5-ethyl-3-isothiazolyl)thio]methyl]-7-ACA
3-[[(2-methyl-1,3,4-thiadiazol-5-yl)thio]methyl]-3-[[(1,2,4-thiadiazol-5-yl)thio]methyl]-7-ACA
3-1[(2-pyridinyl-N-oxide)thio]methyl]-7-ACA
Example 14 7~-[[[[2-(methoxycarbonyl]thio]-2-(2-pyridyl)-acetyl]amino]-3-[[(1,3,4-thiazol-2-yl)thio]methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 7~-[[[[2-(n-butoxy)carbonyl]thio]-2-phenylacetyl]-amino]-3-[[(1,3,4-oxadiazol-2-yl)thio]methyll-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 16 7~-1[[[2-ethoxy)carbonyl]thio]-2-(2-pyridyl)acetyl]-amino]-3-[[(5-ethyl-1,3,4-oxadiazol-2-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2- ene-2-carboxylic acid 17 7~-[[[[2-(methoxy)carbonyl]thio]acetyl]amino]-3-[[(3-methyl-5-isothiazolyl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 18 7~-[[[[(2-ethoxy)carbonyl]thio]-2-(2-thienyl)ace.tyl]-amino]-3-[[(3-isothiazolyl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 19 7~-[[[[2-(benzyloxy)carbonyl]thio]-2-phenylacetyl]-amino]-3-[[(3-isoxazolyl)thio]methyl]-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 105 ~74~ GG211/194 Example 7~-[[[[2-(methoxy)carbonyl]thio]-2-phenylacetyl]-amino]-3-[[(5-methyl-3-isoxazolyl)thio]methyl]-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 21 7~-[[[[2-(propoxy)carbonyl]thio]-2-phenylacetyl]-amino]-3-[[(1,2,4-thiadiazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 22 7~-[[[[2-(phenethoxy)carbonyl]thio]acetyl]amino]-3-[[(1,2,4-thiadiazol-3-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 23 7~-[[[[2-(methoxy)carbonyl]thio]-2-phenylacetyl]-amino]-3-[[(5-butyl-1,2,4-thiadiazol-3-yl)thio-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 24 7~-[[[2-(methoxy)carbonyl]thio]butyramido]-3-[[(1,2,3,4-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 7~-[[[(2-benzyloxy)carbonyl]thio]propionamido]-3-[[(S-methyl-3-isothiazolyl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 26 7~-[[[[2-(methoxy)carbonyl]thio]-2-phenylacetyl]amino]-3-[[3-isoxazolyl)thio]methyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid 27 7B-[[[[2-(butoxy)carbonyl]thio]-2-phenylacetyl]-amino]-3-[[(3-methyl-4-isoxazolyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid lOS7740 GG 211/194 Example 28 7~-[[[[2-(methoxy)carbonyl]thio]-2-phenylacetyl]-amino]-3-[[(3-methyl-1,2,4-oxadiazol-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 29 7~-[[[[2-(methoxy)carbonyl]thio]acetyl]amino]-3-[[l-ethyl-lH-tetrazol-5-yl)thio]methyl]-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid 7~-[[[[2-(methoxy)carbonyl]thio]-2-phenylacetyl]-amino]-3-[[(1-ethyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.01oct-2-ene-carboxylic acid 31 7~-[[[[2-(ethoxy)carbonyl]thio]-2-phenylacetyl]amino]-3-[[3-thiazolyl]thio]methyll-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid 32 7~-[[[[2-(methoxy)carbonyl]thio]-2-phenylacetyl]-amino]-3-[[(2-methyl-1,3,4-thiadiazol-5-yl]thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 33 7~-[[[[2-(ethoxy)carbonyl]thio]-2-(2-furyl)acetyl]-amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio)-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and potassium salt 34 7B-[[[[2-(propoxy)carbonyl]thio]-2-(2-thienyl)acetyl]-amino]-3-[[(1,3,4-oxadiazol-2-yl)thio]methyl]-8-oxo-
After 3 hours, the reaction mixture is poured into 2 liters of absolute ether. The solid, light brown precipitate, which is the perchloric acid salt of the desired product, is dried over Kieselgel in a dessiccator. To obtain the base, the perchloric acid salt is dissolved in water and treated with the calculated equivalent of potassium bicarbonate.
The aqueous solution obtained is extracted with chloroform.
The chloroform phase i5 treated with activated carbon and sodium sulfate to obtain the 10 g. of the product, 7-amino-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, as a light brown powder, m.p. 157-159. The product is recrystallized from tetrahydrofuran/petroleum ether. The isomeric thiadiazolyl derivative is similarly obtained from the product of Example 7.
Example 10 3-[[(1-Methyl-lH-tetrazol-5-Yl)thio]methyl]-7-amino-8-oxo-5-thia-l-azabicvclo[4.2.0]oct-2-ene-carboxylic acid, diPhenYl-methyl ester The product, 7-amino-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylic acid, diphenylmethyl ester, m.p. 168-169 (dec.), is obtained by the procedure of Example 9 utilizing as starting material 7-amino-3-[[(1-methyl-lH-tetrazol-5-yl)-thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Example 11 3-[[(1-Methyl-lH-tetrazol-5-yl)thio]methyl]-7~-[[[(methoxy-carbonYl)thio]phenylacetyl]amino]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester 1.1 g. (5 mM) of the product of Example 2 is dissolved in 25 ml. of tetrahydrofuran and added at 0 to 1.0 g. of dicyclohexylcarbodiimide in 5 ml. of tetrahydrofuran.
After 30 minutes, 2.48 gm. of 3-[[(1-methyl-lH-tetrazol-5-yl]thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester dissol~ed in 15 ml. of tetrahydrofuran is added. After stirring for 12 hours, the dicyclohexylurea which has formed is filtered ~ff. The filtrate is treated with activated carbon and the solvent is drawn off leaving 3-[[(1-methyl-lH-tetrazol-5---11-- , yl)thio]methyl]-7~-[[[(methoxycarbonyl)thio]phenylacetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester as a light brown powder, yield 2.7 g., m.p. 92-94 (dec.).
Example 12 3-[[(1-Methyl-lH-tetrazol-5-yl)thio]methyl]-7~-[[[(methyl-carbonyl)thio]phenylacetyl]amino]-8-oxo-5-thia-1-azabi-cyclo[4.2.0]oct-2-ene-2-carboxylic acid 2 g. of the product of Example 11 is stirred in a mixture of 15 ml. of trifluoroacetic acid and 3 ml.
of anisole at 0 for 15 minutes. After the solvent is drawn off and the residue is treated with ether/petroleum ether (1:1), the solid brown residue is taken up in sodium bicarbonate solution, filtered and the filtrate is extracted with ethyl acetate and then acidified to pH 2.5 with 2N
hydrochloric acid while cooling with ice. This is extracted with ethyl acetate. The organic phase is treated with activated carbon and the solvent is drawn off to obtain the product 3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-7~-[[[(methoxycarbonyl)thio]phenylacetyl]amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. The product is recrystallized from tetrahydrofuran/petroleum ether as a light brown powder, yield 0.5 g., m.p. 128 (dec.).
Example 13 3-1[(1-MethYl-lH-tetrazol-5-yl)thio]methyl]-7~-[[[(methoxy-carbonYl)thio]phenylacetyl]amino-8-oxo-5-thia-l-azabi [4.2.0]oct-2-ene-2-carboxylic acid! potassium salt The potassium salt of the product of Example 12 is obtained by freeze drying an equimolar aqueous solution of the acid of that example and potassium bicarbonate, 105~40 GG 211/194 m.p. 153-154 (dec.).
Examples 14 - 44 The products below are obtained by reacting the acid ll O
with the diphenylmethyl ester of one of the following according to the procedure of Example 11 and then following with the procedure of Example 12. Salts are produced by continuing with the procedure of Example 14.
3-[[(5-methyl-1,3,4-thiadiazolyl-2-yl)thio]-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid 3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-3-[[(3-isothiazolyl)thio]methyl]-7-ACA
3-[[(1,3,4-oxadiazol-2-yl)thio]methyl]-7-ACA
3-[[(5-ethyl-1,3,4-oxadiazol-2-yl)thio]methyl]-3-[[(1,2,3,4-tetrazol-5-yl)thio]methyl]-7-ACA
3-[[(1-ethyl-lH-tetrazol-5-yl)thio]methyl]-7-ACA
3-[[(3-methyl-5-isothiazolyl)thio]methyl]-7-ACA
3-[[(3-isothiazolyl)thio]methyl]-7-ACA
3-[[(3-isoxazolyl)thio]methyl]-7-ACA
3-[[(5-methyl-3-isoxazolyl)thio]methyl]-7-ACA
3-[[(1,2,4-thiadiazol-3-yl)thio]methyl]-7-ACA
3-[[(5-butyl-1,2,4-thiadiazol-3-yl)thio]methyl]-3-[[(5-ethyl-3-isoxazolyl)thio]methyl]-7-ACA
3-[[(3-methyl-4-i~oxazolyl)thio]methyll-7-ACA
3-[[(3-methyl-1,2,4-oxadiazol-5-yl)thio]methyl]-3-[[(5-ethyl-3-isothiazolyl)thio]methyl]-7-ACA
3-[[(2-methyl-1,3,4-thiadiazol-5-yl)thio]methyl]-3-[[(1,2,4-thiadiazol-5-yl)thio]methyl]-7-ACA
3-1[(2-pyridinyl-N-oxide)thio]methyl]-7-ACA
Example 14 7~-[[[[2-(methoxycarbonyl]thio]-2-(2-pyridyl)-acetyl]amino]-3-[[(1,3,4-thiazol-2-yl)thio]methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 7~-[[[[2-(n-butoxy)carbonyl]thio]-2-phenylacetyl]-amino]-3-[[(1,3,4-oxadiazol-2-yl)thio]methyll-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 16 7~-1[[[2-ethoxy)carbonyl]thio]-2-(2-pyridyl)acetyl]-amino]-3-[[(5-ethyl-1,3,4-oxadiazol-2-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2- ene-2-carboxylic acid 17 7~-[[[[2-(methoxy)carbonyl]thio]acetyl]amino]-3-[[(3-methyl-5-isothiazolyl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 18 7~-[[[[(2-ethoxy)carbonyl]thio]-2-(2-thienyl)ace.tyl]-amino]-3-[[(3-isothiazolyl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 19 7~-[[[[2-(benzyloxy)carbonyl]thio]-2-phenylacetyl]-amino]-3-[[(3-isoxazolyl)thio]methyl]-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 105 ~74~ GG211/194 Example 7~-[[[[2-(methoxy)carbonyl]thio]-2-phenylacetyl]-amino]-3-[[(5-methyl-3-isoxazolyl)thio]methyl]-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 21 7~-[[[[2-(propoxy)carbonyl]thio]-2-phenylacetyl]-amino]-3-[[(1,2,4-thiadiazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 22 7~-[[[[2-(phenethoxy)carbonyl]thio]acetyl]amino]-3-[[(1,2,4-thiadiazol-3-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 23 7~-[[[[2-(methoxy)carbonyl]thio]-2-phenylacetyl]-amino]-3-[[(5-butyl-1,2,4-thiadiazol-3-yl)thio-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 24 7~-[[[2-(methoxy)carbonyl]thio]butyramido]-3-[[(1,2,3,4-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 7~-[[[(2-benzyloxy)carbonyl]thio]propionamido]-3-[[(S-methyl-3-isothiazolyl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 26 7~-[[[[2-(methoxy)carbonyl]thio]-2-phenylacetyl]amino]-3-[[3-isoxazolyl)thio]methyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid 27 7B-[[[[2-(butoxy)carbonyl]thio]-2-phenylacetyl]-amino]-3-[[(3-methyl-4-isoxazolyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid lOS7740 GG 211/194 Example 28 7~-[[[[2-(methoxy)carbonyl]thio]-2-phenylacetyl]-amino]-3-[[(3-methyl-1,2,4-oxadiazol-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 29 7~-[[[[2-(methoxy)carbonyl]thio]acetyl]amino]-3-[[l-ethyl-lH-tetrazol-5-yl)thio]methyl]-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid 7~-[[[[2-(methoxy)carbonyl]thio]-2-phenylacetyl]-amino]-3-[[(1-ethyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.01oct-2-ene-carboxylic acid 31 7~-[[[[2-(ethoxy)carbonyl]thio]-2-phenylacetyl]amino]-3-[[3-thiazolyl]thio]methyll-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid 32 7~-[[[[2-(methoxy)carbonyl]thio]-2-phenylacetyl]-amino]-3-[[(2-methyl-1,3,4-thiadiazol-5-yl]thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 33 7~-[[[[2-(ethoxy)carbonyl]thio]-2-(2-furyl)acetyl]-amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio)-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and potassium salt 34 7B-[[[[2-(propoxy)carbonyl]thio]-2-(2-thienyl)acetyl]-amino]-3-[[(1,3,4-oxadiazol-2-yl)thio]methyl]-8-oxo-
5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and sodium salt 7~-[1[[(2-ethoxy)carbonyl]thio]acetyl]amino]-3-1[(5-ethyl-1,3,4-oxadiazol-2-yl)thiolmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0~oct-2-ene-2-carboxylic acid Example 36 7~-~[[[2-(n-butoxy)carbonyl]thio]acetyl]amino]-3-[[(1,2,3,4-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 37 7~-[[[[2-(methoxy)carbonyl]thio]-2-(2-thienyl)acetyl]-amino]-3-[[(2-methylthiazol-5-yl)thio]methyl-8~oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid triethylamine salt 38 7~-1[[[2-(benzyloxy)carbonyl]thio]-2-(3-furyl)acetyl]-amino]-3-[[(1,2,4-thiadiazol-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid pivaloyloxymethyl ester 39 7~-[[[[2-(methoxy)carbonyl]thio]-2-(3-pyridyl)]acetyl]-amino]-3-[[(3-isoxazolyl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid trimethylsilyl ester 7~-[[[[2-(methoxy)carbonyl]thio]-2-(2-thienyl)-acetyl]amino]-3-[[(1,3,4-oxadiazol-2-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid phenylmethyl ester 41 7~[[[[2-(ethoxy)carbonyl]thio]-2-phenylacetyl]-amino]-3-[[(2-pyridinyl-N-oxide)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4..2.0]oct-2-ene-2-carboxylic acid 42 7~-[[[[2-(benzyloxy)carbonyl]thio-2-phenylacetyl]-amino]-3-[[(2-pyridinyl-N-oxide)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid pivaloyloxymethyl ester G~ 211/194 10577~0 Example 43 7~-[[[[2-(methoxy)carbonyl]thio]acetyl]amino]-3-[[(2-pyridinyl-N-oxide)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and potassium salt.
44 7~-[[[[2-(methoxy)carbonyl]thio]-2-phenylacetyl]-amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and sodium salt.
Example 45 3-[[(5-Methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2 O]oct-2-ene-2-carboxylic acid A mixture of 13.6 g. (0.5 M) of 7-am~nocephalosporanic acid (7-ACA) in 100 ml. of water and 50 ml. of acetone are brought to pH 8 with sodium hydroxide while stirring.
9.8 g. (0.57 M) of 2-methyl-1,3,4-thiadiazole-5-thiol are added and the mixture is heated at 80 for four hours.
After cooling to 5 , this is acidified to pH 3.5 with dilute hydrochloric acid and stirred for 15 minutes. The precipi-tated solid is filtered under suction and washed with acetone.
This 3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is purified by dissolving in sodium bicarbonate solution and reprecipitating with 2N hydrochloric acid; yield 12.7 g., m.p. 206.
Example 46 .
3-[[(3-Methyl-1,2,4-thiadiazol-5-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid By substituting 3-methyl-1,2,4-thiadiazole-5-thiol for the 2-methyl-1,3,4-thiadiazole-5-thiol in the procedure of Example 45,11.6 g. of 3-[.[t3-methyl-1,2,4-thiadiazol-5-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid, m.p. 186 (dec.), are obtained.
Example 47 3-[[~1-Methyl-lH-tetrazol-5-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid By substituting 0.57 M of l-methyl-lH-tetrazol-5-thiol for the 2-methyl-1,3,4-thiadiazol-5-thiol in the procedure of Example 45~3-[[(1-methyl-lH-tetrazol-5-yl)thiol-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is obtained.
Example 48 3-~[(5-methYl-1,3,4-thiadiazol-2-vl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicYclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester 18 g. of 7-amino-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid are suspended in 350 ml. of tetrahydrofuran.
4.1 ml. of 70% perchloric acid are added dropwise. After 30 minutes, a slightly turbid solution forms. This solution is filtered and to the filtrate is added dropwise with stirring lZ g. of diphenyldiazomethane and 20 ml. of tetrahydrofuran.
After 3 hours, the reaction mixture is poured into 2 liters of ahsolute ether. The solid, light brown precipitate, 1057740 GG21l/194 which is the perchloric acid salt of the desired product, is dried over Kieselgel in a dessiccator. To obtain the base, the perchloric acid salt is dissolved in water and treated with the calculated equivalent of potassium bicarbonate.
The aqueous solution obtained is extracted with chloroform.
The chloroform phase is treated with activated carbon and sodium sulfate to obtain 10 g. of the product, 7-amino-3-~[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0~oct-2-ene-2-carboxylic acid,diphenylmethyl ester, as a light brown powder, m.p. 157-159 . The product is recrystallized from tetrahydrofuran/petroleum ether. The isomeric thiadiazolyl derivative is similarly obtained from the product of Example 2.
Example4g 3-[[(1-Methyl-lH-tetrazol-5-yl)thio]methyl]-7-amino-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-carboxylic acid, diphenyl-methyl ester The product, 7-amino-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylic acid, diphenylmethyl ester, m.p. 168-169 (dec.), is obtained by the procedure of Example 48utilizing as starting material 7-amino-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Example 50 3-[l(l-Methvl-lH-tetrazol-5-yl?thio]methyl]-7~-[[[[(methoxy)-thiocarbonyl]thiolphenylacetyl]amino]-8-oxo-5-thia-l-aza-bic~clol4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester At a temperature of 0 , ].2 g. (5 mM) of DL-[(methoxy-thiocarbonyl)thio]phenylclcetic acid (produced by the method o~ J Org. ~hern , supra) toyether ~ith 1 g. (5 mM) of 1057740 GG2~ 94 dicyclohexylcarbodiimide in 50 ml. of tetrahydrofuran are stirred for 15 minutes. A solution of 2.5 g. (5 mM) of 3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-7-aminocephalosporanic acid, diphenylmethyl ester in 20 ml. of tetrahydrofuran is added dropwise. After 24 hours of stirring, the mixture is filtered from the dicyclohexylurea whi,ch forms. After drawing off the solvent, a solid residue is obtained from the filtrate which, after being treated with charcoal and recrystallized several times, produces 3.1 g. of 3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-7~-[[[[(methoxy)thio-carbonyl]thio]phenylacetyl]amino]-8-oxo-5-thia-1-azabicYClo-[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, in the form of a beige powder, m.p. 105 (dec.).
Example 51 3-[[(1-MethYl-lH-tetrazol-5-yl)thio]methyl]-7~-[[[[(methoxy)-thiocarbonyl]thio]phenylacetyl]amino]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid 3 g. of the product obtained in Example 6 are stirred for 15 minutes at 0 in 30 ml. of trifluoroacetic acid/anisole (4:1). After drawing off the trifluoroacetic acid/anisole mixture in vacuum, the oily residue is solidified with ether/petroleum ether. The solid brown mass is stirred for 5 minutes in 50 ml. of saturated sodium bicarbonate solution and after filtration, the filtrate is cooled to and acidified with 2N hydrochloric acid to pH 3. The precipitate which forms is collected and dissolved in tetrahydrofuran/ethyl acetate. The solution is then treated with charcoal. After ether is added to the filtrate, 3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyll-7B-[[[[(methoxy)-thiocarbonyllthio3phenylacetyllamino]-8-oxo-5-thia-1-~ azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in the form of lOS7 740 GG211/194 a beige powder. After recrystallization from ethyl acetate/petroleum ether, 1.2 g. are obtained, m.p. 115 (dec.).
Example 52 3-[[(1-Methyl-lH-tetrazol-5-yl)thio]methyl]-7~-[[[[(methoxy)thio-carbonyl]thio]phenylacetyl]amino]-8-oxo-5-thia-1-azabic~clo-[4.2.0]oct-2-ene-2-carboxylic acid, potassium salt, monohydrate 3-[[(1-Methyl-lH-tetrazol-5-yl)thio]methyl]-7~-[[[[(methoxy)thiocarbonyl]thio]phenylacetyl]amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-carboxylic acid, potassium salt, monohydrate is obtained by freeze drying an equimolar aqueous solution of the acid obtained in Example 51 and potassium bicarbonate. A yellow powder is obtained, m.p. 123 (dec.).
Examples 53-83 The additional products below are obtained by reacting the acid IRl R -O-C-S-CH-COOH
2 1l with the diphenylmethyl ester of one of the following according to the procedure of Example 50 and then following with the procedure of Example 51. Salts are produced by continuing with the procedure of Example 52.
3-[[(5-methyl-1,3,4-thiadiazolyl-2-yl)thio]-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid 3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-7-ACA
3-11(1,3,4-oxadiazol-2-yl)thio]methyl]-7-ACA
3-[[~5-ethyl-1,3,4-oxadiazol-2-yl)thio]methyl]-7-ACA
3-[[(1,2,3,4-tetrazol-5-yl)thio]methyl]-7-ACA
3~ 3-1[(l-ethyl~ tetrazol-5-yl)thio]methyl]-7-ACA
-22- i 105~40 GG21yl94 3-[[~1,2,4-thiadiazol-3-yl)thio]methyl]-7-ACA
3-[[(5-butyl-1,2,4-thiadiazol-3-yl)thio]methyl]-7-ACA
3-[[(1,2,3-triazol-5-yl)thio]methyl]-7-ACA
3-[[(1,2,3,4-thiatriazol-5-yl)thio]methyl]-7-ACA
3-[[(3-methyl-1,2,4-oxadiazol-5-yl)thio]methyl]-7-ACA
3-[[(2-methyl-1,3,4-thiadiazol-5-yl)thio]methyl]-7-ACA
3-[[(1,2,4-thiadiazol-S-yl)thio]methyl-7-ACA
Example 53 7B-[[[[2-(methoxy)thiocarbonyl]thio]-2-(2-furyl)-acetyl]amino]-3-[[(1,3,4-thiazol-2-yl)thio]methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
54 7B-[[[[2-(n-butoxy)thiocarbonyl]thio]-2-phenylacetyl]-amino]-3-[[(1,3,4-oxadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
7B-[[[[2-(ethoxy)thiocarbonyl]thio]-2-(2-furyl)-acetyl]amino]-3-[[(5-ethyl-1,3,4-oxadiazol-2-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
56 7B-[[[[2-(methoxy)thiocarbonyl]thio]acetyl]amino]-3-[[(1,2,3-triazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
57 7B-[[[[(2-ethoxy)thiocarbonyl]thio]-2-(2-thienyl)acetyl]
amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
58 7B-[[[[2-(benzyloxy)thiocarbonyl]thio]-2-phenylacetyl]
amino]-3-1[(1,2,3,4-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 59 7B-[11[2-(methoxy)thiocarbonyl]thio]-2-phenylacetyl]-Example amino]-3-[[(1,2,3,4-thiatriazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
7B-[[[[2-(propoxy)thiocarbonyl]thio]-2-phenylacetyl]-amino]-3-[[(1,2,4-thiadiazol-5-yl)thio]methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
61 7B-[[[[2-(phenethoxy)thiocarbonyl]thio]acetyl]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
62 7B-[[[[2-(methoxy)thiocarbonyl]thio]-2-phenylacetyl]-amino]-3-[[(5-butyl-1,2,4-thiadiazol-3-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
63 7B-[[[2-(methoxy)thiocarbonyl]thio]but~ramido]-3_ [[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
64 7B-[[[(2-benzyloxy)thiocarbonyl]thio]propionamido]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
7B-1[~[2-(methoxy)thiocarbonyl]thio]-(2-furyl)acetyl]-amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
66 7B-[[[[2-(butoxy)thiocarbonyl]thio]-2-phenylacetyl]-amino]-3-[[(1,2,3,4-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
67 7B-[[[[2-(methoxy)thiocarbonyl]thio]-2-phenylacetyl]-amino]-3-[[(3-methyl-1,2,4-oxadiazol-S-yl)thio]-methyl~-8-oxo-5-thia-1-azabicyclo~4.2.0]oct-2-ene-~057740 Example 2-carboxylic acid.
68 7~-[[1[2-(methoxy)thiocarbonyl]thio]acetyl]amino]-3-[[(l-ethyl-lH-tetrazol-5-yl)thio]methyl]-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid.
69 7B-[[[[2-(methoxy)thiocarbonyl,]thio]-2-phenylacetyl]-amino]-3-[[(1-ethyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
7B-[[[[2-(ethoxy)thiocarbonyl]thio]-2-phenylacetyl]aminol-3-[[(1,2,3-triazol-5-yl)thio]methyl -8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
71 7B-[[[[2-(methoxy)thiocarbonyl]thio]-2-phenylacetyl]
amino]-3-[[5-methyl-1,3,4-thiadiazol-2-yl]thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
72 7B-[[[[2-(ethoxy)thiocarbonyl]thio]-2-(2-furyl)acetyl]-amino]-3-[[(5-methyl-1,3,4-thiadiaaol-2-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2 carboxylic acid and potassium salt.
73 7B-[[[[2-(propoxy)thiocarbonyl]thio]-2-(2-thienyl)-acetyl]amino]-3-[[(1,3,4-oxadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
74 7B-[[[[(2-ethoxy)thiocarbonyl]thio]acetyl]amino]-3-[1(5-ethyl-1,3,4-oxadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
7B-[1[[2-(n-butoxyjthiocarbonyl]thio]acetyl]amino]-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
-Example 76 7~-[~[[2-(methoxy)thiocarbonyl]thio]-2-(2-thienyl)-acetyl]amino~-3-[[(5-ethyl-1,3,4-oxadiazol-5-yl)thiol-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
77 7~-[[[[2-(benzyloxy)thiocarbonyl]thio]-2-(3-furyl)-acetyl]amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid pivaloyloxymethyl ester.
78 7~-[[[[2-(methoxy)thiocarbonyl]thio]-2-(3-thienyl)]-acetyl]amino-3-[[(1-methyl-lH-tetrazol-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
79 7~-[[[[2-(methoxy)thiocarbonyl]thio]-2-~2-thienylj-acetyl]amino]-3-[[(1,3,4-oxadiazol-2-yl)thio~methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid phenylmethyl ester.
7~-[[[[2-(ethoxy)thiocarbonyl]thio]-2-phenylacetyl]-amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid triethylamine salt.
31 7~-[[[[2-(benzyloxy)thiocarbonyl]thio]-2-phenylacetyl]-amino]-3-[[(1,2,3-triazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid pivaloyloxymethyl ester.
~2 7~-[[[[2-(methoxy)thiocarbonyl]thio]acetyl]amino]-3-[[(1,2,3,4-thiatriazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and potassium salt.
3~
GG2~ 194 ~057740 Example 83 7~-[[[[2-(methoxy)thiocarbonyl]thio]-2-phenylacetyl]-amino]-3-~[(5-methyl-1,3,4-thiadiazol-2-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and sodium salt.
44 7~-[[[[2-(methoxy)carbonyl]thio]-2-phenylacetyl]-amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and sodium salt.
Example 45 3-[[(5-Methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2 O]oct-2-ene-2-carboxylic acid A mixture of 13.6 g. (0.5 M) of 7-am~nocephalosporanic acid (7-ACA) in 100 ml. of water and 50 ml. of acetone are brought to pH 8 with sodium hydroxide while stirring.
9.8 g. (0.57 M) of 2-methyl-1,3,4-thiadiazole-5-thiol are added and the mixture is heated at 80 for four hours.
After cooling to 5 , this is acidified to pH 3.5 with dilute hydrochloric acid and stirred for 15 minutes. The precipi-tated solid is filtered under suction and washed with acetone.
This 3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is purified by dissolving in sodium bicarbonate solution and reprecipitating with 2N hydrochloric acid; yield 12.7 g., m.p. 206.
Example 46 .
3-[[(3-Methyl-1,2,4-thiadiazol-5-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid By substituting 3-methyl-1,2,4-thiadiazole-5-thiol for the 2-methyl-1,3,4-thiadiazole-5-thiol in the procedure of Example 45,11.6 g. of 3-[.[t3-methyl-1,2,4-thiadiazol-5-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid, m.p. 186 (dec.), are obtained.
Example 47 3-[[~1-Methyl-lH-tetrazol-5-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid By substituting 0.57 M of l-methyl-lH-tetrazol-5-thiol for the 2-methyl-1,3,4-thiadiazol-5-thiol in the procedure of Example 45~3-[[(1-methyl-lH-tetrazol-5-yl)thiol-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is obtained.
Example 48 3-~[(5-methYl-1,3,4-thiadiazol-2-vl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicYclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester 18 g. of 7-amino-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid are suspended in 350 ml. of tetrahydrofuran.
4.1 ml. of 70% perchloric acid are added dropwise. After 30 minutes, a slightly turbid solution forms. This solution is filtered and to the filtrate is added dropwise with stirring lZ g. of diphenyldiazomethane and 20 ml. of tetrahydrofuran.
After 3 hours, the reaction mixture is poured into 2 liters of ahsolute ether. The solid, light brown precipitate, 1057740 GG21l/194 which is the perchloric acid salt of the desired product, is dried over Kieselgel in a dessiccator. To obtain the base, the perchloric acid salt is dissolved in water and treated with the calculated equivalent of potassium bicarbonate.
The aqueous solution obtained is extracted with chloroform.
The chloroform phase is treated with activated carbon and sodium sulfate to obtain 10 g. of the product, 7-amino-3-~[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0~oct-2-ene-2-carboxylic acid,diphenylmethyl ester, as a light brown powder, m.p. 157-159 . The product is recrystallized from tetrahydrofuran/petroleum ether. The isomeric thiadiazolyl derivative is similarly obtained from the product of Example 2.
Example4g 3-[[(1-Methyl-lH-tetrazol-5-yl)thio]methyl]-7-amino-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-carboxylic acid, diphenyl-methyl ester The product, 7-amino-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylic acid, diphenylmethyl ester, m.p. 168-169 (dec.), is obtained by the procedure of Example 48utilizing as starting material 7-amino-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Example 50 3-[l(l-Methvl-lH-tetrazol-5-yl?thio]methyl]-7~-[[[[(methoxy)-thiocarbonyl]thiolphenylacetyl]amino]-8-oxo-5-thia-l-aza-bic~clol4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester At a temperature of 0 , ].2 g. (5 mM) of DL-[(methoxy-thiocarbonyl)thio]phenylclcetic acid (produced by the method o~ J Org. ~hern , supra) toyether ~ith 1 g. (5 mM) of 1057740 GG2~ 94 dicyclohexylcarbodiimide in 50 ml. of tetrahydrofuran are stirred for 15 minutes. A solution of 2.5 g. (5 mM) of 3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-7-aminocephalosporanic acid, diphenylmethyl ester in 20 ml. of tetrahydrofuran is added dropwise. After 24 hours of stirring, the mixture is filtered from the dicyclohexylurea whi,ch forms. After drawing off the solvent, a solid residue is obtained from the filtrate which, after being treated with charcoal and recrystallized several times, produces 3.1 g. of 3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-7~-[[[[(methoxy)thio-carbonyl]thio]phenylacetyl]amino]-8-oxo-5-thia-1-azabicYClo-[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, in the form of a beige powder, m.p. 105 (dec.).
Example 51 3-[[(1-MethYl-lH-tetrazol-5-yl)thio]methyl]-7~-[[[[(methoxy)-thiocarbonyl]thio]phenylacetyl]amino]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid 3 g. of the product obtained in Example 6 are stirred for 15 minutes at 0 in 30 ml. of trifluoroacetic acid/anisole (4:1). After drawing off the trifluoroacetic acid/anisole mixture in vacuum, the oily residue is solidified with ether/petroleum ether. The solid brown mass is stirred for 5 minutes in 50 ml. of saturated sodium bicarbonate solution and after filtration, the filtrate is cooled to and acidified with 2N hydrochloric acid to pH 3. The precipitate which forms is collected and dissolved in tetrahydrofuran/ethyl acetate. The solution is then treated with charcoal. After ether is added to the filtrate, 3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyll-7B-[[[[(methoxy)-thiocarbonyllthio3phenylacetyllamino]-8-oxo-5-thia-1-~ azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in the form of lOS7 740 GG211/194 a beige powder. After recrystallization from ethyl acetate/petroleum ether, 1.2 g. are obtained, m.p. 115 (dec.).
Example 52 3-[[(1-Methyl-lH-tetrazol-5-yl)thio]methyl]-7~-[[[[(methoxy)thio-carbonyl]thio]phenylacetyl]amino]-8-oxo-5-thia-1-azabic~clo-[4.2.0]oct-2-ene-2-carboxylic acid, potassium salt, monohydrate 3-[[(1-Methyl-lH-tetrazol-5-yl)thio]methyl]-7~-[[[[(methoxy)thiocarbonyl]thio]phenylacetyl]amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-carboxylic acid, potassium salt, monohydrate is obtained by freeze drying an equimolar aqueous solution of the acid obtained in Example 51 and potassium bicarbonate. A yellow powder is obtained, m.p. 123 (dec.).
Examples 53-83 The additional products below are obtained by reacting the acid IRl R -O-C-S-CH-COOH
2 1l with the diphenylmethyl ester of one of the following according to the procedure of Example 50 and then following with the procedure of Example 51. Salts are produced by continuing with the procedure of Example 52.
3-[[(5-methyl-1,3,4-thiadiazolyl-2-yl)thio]-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid 3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-7-ACA
3-11(1,3,4-oxadiazol-2-yl)thio]methyl]-7-ACA
3-[[~5-ethyl-1,3,4-oxadiazol-2-yl)thio]methyl]-7-ACA
3-[[(1,2,3,4-tetrazol-5-yl)thio]methyl]-7-ACA
3~ 3-1[(l-ethyl~ tetrazol-5-yl)thio]methyl]-7-ACA
-22- i 105~40 GG21yl94 3-[[~1,2,4-thiadiazol-3-yl)thio]methyl]-7-ACA
3-[[(5-butyl-1,2,4-thiadiazol-3-yl)thio]methyl]-7-ACA
3-[[(1,2,3-triazol-5-yl)thio]methyl]-7-ACA
3-[[(1,2,3,4-thiatriazol-5-yl)thio]methyl]-7-ACA
3-[[(3-methyl-1,2,4-oxadiazol-5-yl)thio]methyl]-7-ACA
3-[[(2-methyl-1,3,4-thiadiazol-5-yl)thio]methyl]-7-ACA
3-[[(1,2,4-thiadiazol-S-yl)thio]methyl-7-ACA
Example 53 7B-[[[[2-(methoxy)thiocarbonyl]thio]-2-(2-furyl)-acetyl]amino]-3-[[(1,3,4-thiazol-2-yl)thio]methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
54 7B-[[[[2-(n-butoxy)thiocarbonyl]thio]-2-phenylacetyl]-amino]-3-[[(1,3,4-oxadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
7B-[[[[2-(ethoxy)thiocarbonyl]thio]-2-(2-furyl)-acetyl]amino]-3-[[(5-ethyl-1,3,4-oxadiazol-2-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
56 7B-[[[[2-(methoxy)thiocarbonyl]thio]acetyl]amino]-3-[[(1,2,3-triazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
57 7B-[[[[(2-ethoxy)thiocarbonyl]thio]-2-(2-thienyl)acetyl]
amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
58 7B-[[[[2-(benzyloxy)thiocarbonyl]thio]-2-phenylacetyl]
amino]-3-1[(1,2,3,4-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 59 7B-[11[2-(methoxy)thiocarbonyl]thio]-2-phenylacetyl]-Example amino]-3-[[(1,2,3,4-thiatriazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
7B-[[[[2-(propoxy)thiocarbonyl]thio]-2-phenylacetyl]-amino]-3-[[(1,2,4-thiadiazol-5-yl)thio]methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
61 7B-[[[[2-(phenethoxy)thiocarbonyl]thio]acetyl]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
62 7B-[[[[2-(methoxy)thiocarbonyl]thio]-2-phenylacetyl]-amino]-3-[[(5-butyl-1,2,4-thiadiazol-3-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
63 7B-[[[2-(methoxy)thiocarbonyl]thio]but~ramido]-3_ [[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
64 7B-[[[(2-benzyloxy)thiocarbonyl]thio]propionamido]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
7B-1[~[2-(methoxy)thiocarbonyl]thio]-(2-furyl)acetyl]-amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
66 7B-[[[[2-(butoxy)thiocarbonyl]thio]-2-phenylacetyl]-amino]-3-[[(1,2,3,4-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
67 7B-[[[[2-(methoxy)thiocarbonyl]thio]-2-phenylacetyl]-amino]-3-[[(3-methyl-1,2,4-oxadiazol-S-yl)thio]-methyl~-8-oxo-5-thia-1-azabicyclo~4.2.0]oct-2-ene-~057740 Example 2-carboxylic acid.
68 7~-[[1[2-(methoxy)thiocarbonyl]thio]acetyl]amino]-3-[[(l-ethyl-lH-tetrazol-5-yl)thio]methyl]-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid.
69 7B-[[[[2-(methoxy)thiocarbonyl,]thio]-2-phenylacetyl]-amino]-3-[[(1-ethyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
7B-[[[[2-(ethoxy)thiocarbonyl]thio]-2-phenylacetyl]aminol-3-[[(1,2,3-triazol-5-yl)thio]methyl -8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
71 7B-[[[[2-(methoxy)thiocarbonyl]thio]-2-phenylacetyl]
amino]-3-[[5-methyl-1,3,4-thiadiazol-2-yl]thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
72 7B-[[[[2-(ethoxy)thiocarbonyl]thio]-2-(2-furyl)acetyl]-amino]-3-[[(5-methyl-1,3,4-thiadiaaol-2-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2 carboxylic acid and potassium salt.
73 7B-[[[[2-(propoxy)thiocarbonyl]thio]-2-(2-thienyl)-acetyl]amino]-3-[[(1,3,4-oxadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
74 7B-[[[[(2-ethoxy)thiocarbonyl]thio]acetyl]amino]-3-[1(5-ethyl-1,3,4-oxadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
7B-[1[[2-(n-butoxyjthiocarbonyl]thio]acetyl]amino]-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
-Example 76 7~-[~[[2-(methoxy)thiocarbonyl]thio]-2-(2-thienyl)-acetyl]amino~-3-[[(5-ethyl-1,3,4-oxadiazol-5-yl)thiol-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
77 7~-[[[[2-(benzyloxy)thiocarbonyl]thio]-2-(3-furyl)-acetyl]amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid pivaloyloxymethyl ester.
78 7~-[[[[2-(methoxy)thiocarbonyl]thio]-2-(3-thienyl)]-acetyl]amino-3-[[(1-methyl-lH-tetrazol-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
79 7~-[[[[2-(methoxy)thiocarbonyl]thio]-2-~2-thienylj-acetyl]amino]-3-[[(1,3,4-oxadiazol-2-yl)thio~methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid phenylmethyl ester.
7~-[[[[2-(ethoxy)thiocarbonyl]thio]-2-phenylacetyl]-amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid triethylamine salt.
31 7~-[[[[2-(benzyloxy)thiocarbonyl]thio]-2-phenylacetyl]-amino]-3-[[(1,2,3-triazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid pivaloyloxymethyl ester.
~2 7~-[[[[2-(methoxy)thiocarbonyl]thio]acetyl]amino]-3-[[(1,2,3,4-thiatriazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and potassium salt.
3~
GG2~ 194 ~057740 Example 83 7~-[[[[2-(methoxy)thiocarbonyl]thio]-2-phenylacetyl]-amino]-3-~[(5-methyl-1,3,4-thiadiazol-2-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and sodium salt.
Claims (14)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the formula wherein R1 is phenyl; R2 is lower alkyl; R3 is hydrogen or a salt forming ion; Z is O or S; R4 is lower alkyl tetrazole, characterized by acylating a compound of the formula with a thioacetic acid of the formula
2. A process according to claim 1 wherein Z is O.
3. A process according to claim 1 wherein Z is S.
4. A process according to claim 1 wherein R2 is methyl.
5. A process according to claim 1 wherein R4 is 1-methyl-1H-tetrazol-5-yl.
6. A process according to claim 1 wherein R2 is methyl, Z is O and R4 is 1-methyl-1H-tetrazol-5-yl.
7. A process according to claim 1 wherein R2 is methyl, Z is S and R4 is 1-methyl-1H-tetrazol-5-yl.
8. A compound of the formula wherein R1 is phenyl; R2 is lower alkyl; R3 is hydrogen or a salt forming ion; Z is O or S; R4 is lower alkyl tetrazole, whenever prepared by the process of claim 1.
9. A compound according to claim 8 wherein Z is O, whenever prepared by the process of claim 2.
10. A compound according to claim 8 wherein Z is S, whenever prepared by the process of claim 3.
11. A compound according to claim 8 wherein R2 is methyl, whenever prepared by the process of claim 4.
12. A compound according to claim 8 wherein R4 is 1-methyl-1H-tetrazol-5-yl, whenever prepared by the process of claim 5.
13. A compound according to claim 8 wherein R2 is methyl, Z is O and R4 is 1-methyl-1H-tetrazol-5-yl, whenever prepared by the process of claim 6.
14. A compound according to claim 8 wherein R2 is methyl, Z is S and R4 is 1-methyl-1H-tetrazol-5-yl, whenever prepared by the process of claim 7.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US501905A US3926983A (en) | 1974-08-30 | 1974-08-30 | 3-Heterothio{8 (alkoxycarbonyl)thioacetyl{9 cephalosporanic derivatives |
| US54832475A | 1975-02-10 | 1975-02-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1057740A true CA1057740A (en) | 1979-07-03 |
Family
ID=27053960
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA229,638A Expired CA1057740A (en) | 1974-08-30 | 1975-06-18 | 3-heterothio (alkoxycarbonyl and alkoxythiocarbonyl)-thioacetyl) cephalosporin derivatives |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPS5152197A (en) |
| CA (1) | CA1057740A (en) |
| DE (1) | DE2537789A1 (en) |
| FR (1) | FR2282894A1 (en) |
| GB (1) | GB1506233A (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI42085B (en) * | 1968-05-20 | 1970-02-02 | Laeaeketehdas Orion Oy |
-
1975
- 1975-05-19 GB GB21240/75A patent/GB1506233A/en not_active Expired
- 1975-06-18 CA CA229,638A patent/CA1057740A/en not_active Expired
- 1975-08-25 DE DE19752537789 patent/DE2537789A1/en not_active Withdrawn
- 1975-08-27 FR FR7526385A patent/FR2282894A1/en active Granted
- 1975-08-30 JP JP50105555A patent/JPS5152197A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| FR2282894A1 (en) | 1976-03-26 |
| GB1506233A (en) | 1978-04-05 |
| FR2282894B1 (en) | 1979-08-24 |
| JPS5152197A (en) | 1976-05-08 |
| DE2537789A1 (en) | 1976-03-11 |
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