Patent GB-1426717-A (GB)
Title: Penicillins
IPC: C07D499/72
Filed: 1972-03-13
Abstract: 1426717 Carbonic esters of penicillins ASTRA LAKEMEDEL AB 12 March 1973 [13 March 1972] 11692/72 Heading C2C [Also in Division A5] Novel penicillins comprise compounds of formula or pharmaceutically acceptable salts thereof, wherein R is phenyl, thienyl or furyl; R<SP>1</SP> is H or R<SP>2</SP> is as for R<SP>1</SP> or C 1 -C 8  alkyl, aryl or aralkyl; R<SP>3</SP> is H or CH 3 ; R<SP>4</SP> is a C 1 -C 8  alkyl, alkenyl or alkynyl, C 3 -C 7  cycloalkyl, phenyl, benzyl, indanyl, thienyl, furyl, furfuryl, pyridyl, pyridylmethyl or 2-methyl-1,3-dioxanyl group, these groups being optionally substituted with one or more amino, substituted amino or nitro groups or halogen; provided that R<SP>2</SP> is where R<SP>1</SP> is H. The compounds are prepared (a) by reacting 6-aminopenicillanic acid with a compound R<SP>7</SP>'Y, wherein R<SP>7</SP>' is R<SP>7</SP>, wherein R<SP>7</SP> is wherein R<SP>3</SP> and R<SP>4</SP> are as defined above or R<SP>7</SP>' is a protected R<SP>7</SP> group and Y is halogen or a functionally equivalent group, to provide esters of Formula IV wherein R<SP>7</SP>' is as defined above, which are reacted with a compound of formula wherein R is as defined above, R<SP>2</SP>' is R<SP>2</SP> or a protected R<SP>2</SP> group and -COZ is an amideforming group and, if necessary, removing protecting groups, or (b) by reacting an ester of formula  wherein RCO is the acyl group of a natural or biosynthetic penicillin, and R<SP>7</SP> is as defined above with a phosphorus halide to form an imino halide, reacting this with a lower alcohol and reacting the imino ether produced with a compound of Formula III as above or (c) by esterifying a compound of formula wherein R and R<SP>2</SP> are as defined above with a compound R<SP>7</SP>'Y, wherein Y is an esterifying group or halogen and R<SP>7</SP>' is as defined above, or (d) by reacting a compound of formula wherein R and R<SP>2</SP>' are as defined above, with a compound of Formula IV as above, or (e) by esterifying a compound of formula wherein R is as defined above, Q is H or a cation and R<SP>8</SP>' is an R<SP>1</SP> or protected R<SP>1</SP> group, with a compound R<SP>6</SP>'Y, R<SP>6</SP>' being an R<SP>2</SP> or protected R<SP>2</SP> group, neither R<SP>1</SP> nor R<SP>2</SP> being H, or (f) by reacting a compound of formula wherein R is as defined above with a compound wherein R<SP>4</SP> is R<SP>4</SP>' as defined above or a protected R<SP>4</SP> group, and R<SP>3</SP> is as defined above or (g) by reacting a suitable activated malonic acid ester with 6-APA or (h) by reacting an α-carboxy, 3-protected carboxy penicillin with a compound of formula wherein Y, R<SP>3</SP> and R<SP>4</SP>' are as defined above or (i) by reacting a 6-N-acylated natural or biosynthetic penicillin having a protected carboxy group with a phosphorus halide to give an imino halide which is treated with a lower alcohol to give an imino ether, which is reacted with a suitable malonic acid ester derivative or (j) by reacting a compound of formula wherein R, R<SP>4</SP>' and R<SP>3</SP> have the above-defined meanings with 6-APA having the carboxy group protected or (k) by reacting an acid α-carboxy 6-acylated penicillanic with a compound of formula wherein Y, R<SP>3</SP>, X and R<SP>4</SP>' have the meanings defined above to yield a mixture of compounds of formulae wherein R, R<SP>3</SP> and R<SP>4</SP> have the above meanings. Chloromethylethyl carbonate is prepared by reacting chloromethyl chloroformate with ethanol and is then reacted with potassium phenylacetate to form ethoxycarbonyloxymethylphenyacetate, from which phenylmalonic acid ethoxycarbonyloxymethyl monoester is prepared by reaction with dry ice (CO 2 ) in the presence of n-butyllithium. The acid chloride of the monoester is prepared by reaction with thionyl chloride. Ethoxycarbonyloxymethyl - (3 - thienyl) - acetate, 3- thienylmalonic acid ethoxycarbonyloxymethyl monoester, its acid chloride, chloromethylphenyl carbonate, phenylacetic acid phenoxycarbonyloxymethyl ester, its acid chloride, phenylmalonic acid phenoxycarbonyloxymethyl monoester, its acid chloride, chloromethyl-2-N- benzyloxycarbonylmethylamino ethyl carbonate, and α - chloroethylcyclopentyl carbonate are produced by similar methods 3-thienylacetic acid acid chloride is produced by reacting 3-thienylacetic acid with thionyl chloride and the product is esterified to yield benzyl-(3-thienyl) acetate. N-benzyloxycarbonyl methylamino ethanol is prepared by reacting chloroformic acid with 2 - methyamino ethanol. Phenylmalonic acid (1<SP>1</SP> - ethoxycarbonyloxyethyl)monoester is produced from the diester by hydrogenation, the diester being produced by methods similar to those above. Pharmaceutical compositions comprise a compound of the invention and a pharmaceutically acceptable carrier. Other antibiotics may be present (see Division A5).