Patent GB-1435801-A (GB)
Title: Beta-lactam antibiotics and the production thereof
IPC: C07D205/085
Filed: 1973-04-06
Abstract: 1435801 1-Oxapenicillins and processes for their preparation QUEENS UNIVERSITY OF TORONTO 6 April 1973 [10 April 1972] 16642/73 Heading C2C The invention comprises (a) compounds of Formula I wherein R<SP>1</SP> is a benzyl or phenoxymethyl group which may be prepared by reacting a compound of Formula II wherein R<SP>1</SP> is as defined above or R is a C 1 -C 10  alkyl, 2,2,2-trichloroethyl, benzhydryl or benzyl group with a compound of formula where R<SP>2</SP> is a C 1 -C 10  alkyl group in a molar ratio of about 1 : 1 in solution in the compound of formula (b) a compound of Formula III which may be prepared by reacting a compound of Formula I with a deacylating agent, e.g. S. lavendulae or E. coli and (c) a compound of Formula I (above) in which or a group having one of the Formulae IVa- IVe wherein R<SP>4</SP> represents a hydrogen, fluorine, chlorine bromine or iodine atom, an amino, carbobenzyloxyamins, phenyl, hydroxy, (C 1 - C 10  alkan) oyloxy or C 1 -C 10  alkoxy group; R<SP>5</SP> and R<SP>6</SP> each represent a hydrogen atom, a phenyl, benzyl, phenethyl or C 1 -C 10  alkyl group; R<SP>7</SP> represents a C 1 -C 10  alkyl group; R<SP>8</SP> and R<SP>9</SP> each represent a C 1 -C 10  alkyl, C 1 -C 10  alkythio, benzylthio, cyclohexyl, cyclopentyl, cycloheptyl, benzyl, phenethyl, phenylpropyl, furyl, thienyl, napththyl or Ar group; R<SP>10</SP> represents a C 1 -C 10  alkylamino, di-C 1 -C 10  alkylamino, C 3 -C 7  cycloalkylamino, allylamino, diallylamino, phenyl-C 1 -C 10  alkylamino, morpholino, C 1 -C 10  alkylmorpholino, di C 1 -C 10  alkylmorpholino, morpholino-C 1 -C 10  alkylamino, pyrrolidino, C 1 -C 10  alkylpyrrolidino, di-C 1 -C 10  alkylpyrrolidino, N,N-hexamethyleneimino, piperidino, C 1 -C 10  alkylpiperidino, di C 1-10  alkylpiperidino, 1,2,5,6-tetrahydropyridino, N-C 1 -C 10  alkylpiperazino, N-phenyl piperazino, N-C 1 -C 10  alkyl-C-C 1 -C 10  alkyl piperazino, N-C 1 -C 10  alkyl-di-C-C 1 -C 10  alkyl piperazino, furfurylamino, tetrahydrofurfurylamino, N-C 1 -C 10  alkyl-N-furfurylamino, N- alkyl-N-amilino or C 1 -C 10  alkoxyanilino group; R<SP>11</SP> represents a C 1 -C 10  alkyl, C 1-10  cycloalkyl, naphthyl, benzyl, phenethyl or group; R<SP>12</SP> represents a benzyl or 2,2,2-trichloroethyl group, Z<SP>1</SP>, Z<SP>2</SP> and Z<SP>3</SP> each represent a C 1 -C 10  alkyl or Ar group and Ar represents a monovalent radical having one of the Formulµ Va-Vc wherein R<SP>13</SP>, R<SP>14</SP> and R<SP>15</SP> are each H, Cl, Br, or I atoms, a CF 3 , phenyl, C 1 -C 10  alkyl or C 1 -C 10  alkoxy group provided that only one of R<SP>13</SP>, R<SP>14</SP> or R<SP>15</SP> is a phenyl group which may be prepared by acylating a compound of Formula III with a carboxylic acid of formula R<SP>1</SP>CO 2 H in which R<SP>1</SP>CO is as defined above. An hydro-6-phthalimidopenicillin is chlorinated in methylene choride to obtain a mixture of 2 (2R<SP>1</SP> - chloro - 3<SP>1</SP>5 - phthalimido - 4<SP>1</SP> - oxo)- azetidinyl - 3 - methyl - 2 - butenoic acid chloride and its 2<SP>1</SP>5 epimer having the Formulµ 4a and 4b In like manner the p-toluenesulphonic acid salt of anhydro-6-aminopenicillin is chlorinated to obtain the p-toluenesulphonic acid salts of the epimeric 2 - (2<SP>1</SP> - chloro - 3<SP>1</SP>5 - amino - 4<SP>1</SP>- oxo)- azetidinyl - 3 - methylbut - 2 - enoic acid chlorides of Formulµ 5a and 5b Starting from the compounds thus prepared many other intermediates are obtained by known means. Thus, the 3<SP>1</SP>-chlorine atom is replaced by and groups the acid choride group is converted into free acid, methyl t-butyl and benzhydryl esters, isocyanate and groups, and the 3<SP>1</SP> amino group is deacylated or its toluenesulphonic acid salt neutralized and the free amino group further substituted by phenyl acetyl, benzyloxycarbonyl, α-chlorophenoxyethylcarbonyl and 2,2,2 - trichloroethoxycarbonyl groups. Chlorination of anhydro-6-phthalimidopenicillin for 10 sees. followed by immediate evaporation to dryness gives a compound of Formula VI Compounds of the Formulµ VIIa and VIIb are obtained by hydrolysis of the compounds of Formulµ 5a and 5b with D 2 O-CD 3 COCD 3 . 2 - Benzyl - 6 - (11 - methoxycarbonyl - 2- methylprop - 1 - enyl) - 1 - oxa - 3,6 - diaza- 4S,5R - bicyclo[3,2,0]hept - 2 - en - 7 - one having the Formula 2 is obtained by reaction of methyl 2-(2<SP>1</SP>R-chloro- 3<SP>1</SP>5 - amino - 41 - oxo)azetidinyl - 3 - methyl- 2-butenoate with phenylacetic acid and dicyclohexylcarbodiimide or by chromatography of the cis - 2<SP>1</SP>R - chloro - 3<SP>1</SP>5 - phenylacetamido methyl ester or alumina or silica gel. Methyl 1 - bromo - 2 - (2<SP>1</SP>R - chloro - 3<SP>1</SP>5- phthalimido - 4<SP>1</SP>- oxo)azetidinyl - 3 - bromomethyl - 2 - butenoate and its 2<SP>1</SP>5- epimer of Formulµ 8a and 8b are prepared by allylic bromination with N- bromosuccinimide of the epimers of methyl-2- (2<SP>1</SP>5 - chloro - 3<SP>1</SP>5 - phthalimido - 4<SP>1 </SP>- oxo)- azetidinyl - 3 - methyl - 2 - butenoate in a molar ratio of 2 : 1 whilst the use of a 1 : 1 molar ratio of reactants gives rise to a mixture of 1-bromo-3-methyl and 3-bromomethyl compounds of Formulae VIIIa and VIIIb Reaction of the p-toluene sulphonic acid salt of the epimeric methyl-2-(2<SP>1</SP>-chloro-3<SP>1</SP>5-amino- 41 - oxo)azetidinyl - 3 - methyl - 2 - butenoates with benzylchloroformate gives a compound of Formula IX Anhydrocarbobenzyloxypenicillin and anhydro- 2,2,2 - trichloroethoxypenicillin are prepared by reaction of the p-toluenesulphonic acid salt of anhydro-6-aminopenicillin with carbobenzyloxy chloride and 2,2,2-trichloroethylchloroformate respectively and have the Formulµ X and Xa 2 - Trichloroethoxy - 6 - (11 - benzhydryloxycarbonyl - 2<SP>1</SP>- methyl - prep - 1 - enyl) - 1- oxa - 3,6 - diaza - 4S,5R - bicyclo[3,2,0]hept - 2- en-7-one of Formula XI is prepared by reaction of 2-(2<SP>1</SP>-chloro-3<SP>1</SP>5 -trichloroethoxycarbonylamino - 4<SP>1 </SP>- axo)azetidinyl - 3 - methyl - 2 - butenoate with tetramethylguanidinium formate. An epimeric mixture of 1-(2<SP>1</SP>-chloro-3<SP>1</SP>5- phenylacetylamino - 4<SP>1</SP>- oxo)azetidinyl isopropyl ketones of Formula XI above is prepared by reacting the compound of Formula XII with HCl in anhydrous THF Pharmaceutical compositions comprise a compound of Formula I together with a suitable physiologically acceptable carrier or excipient and have antibiotic activity for oral and parenteral dosage.