Patent GB-1435802-A (GB)
Title: Azetidinones and the production thereof
IPC: C07D205/085
Filed: 1973-04-06
Abstract: 1435802 Azetidinones and processes for their preparation QUEENS UNIVERSITY OF TORONTO 6 April 1973 [10 April 1972] 50923/75 Divided out of 1435801 Heading C2C The invention comprises compounds of the Formula I wherein R<SP>1</SP> is a benzyl or phenoxymethyl group and R is a hydrogen atom or a C 1 -C 10  alkyl, 2,2,2-trichloroethyl, benzhydryl or benzyl group which may be prepared (a) by mixing a compound of Formula II in which R<SP>1</SP> is as defined above and R is a C 1 -C 10  alkyl, 2,2,2-trichloroethyl, benzhydryl or benzyl group with alumina or silica gel or (b), to obtain a compound of Formula I as defined above in which R is hydrogen, reacting a compound of Formula I as above in which R is other than hydrogen with a compound of formula where R<SP>2</SP> is a C 1 -C 10  alkyl group in solution in a compound of formula in which process a compound of Formula III is also obtained. 2 - (2<SP>1</SP>R - Chloro - 3<SP>1</SP>S - phthalimido - 4<SP>1</SP> - oxo)- azetidinyl - 3 - methyl - 2 - butenoic acid chloride and its 2<SP>1</SP>S epimer are prepared by chlorination of anhydro-6-phthalimido penicilin and separated by fractional crystallization, these isomers of Formulµ 4a and 4b are reacted with a pH 7À95 buffer, methanol or t-butanol to obtain the corresponding acid, and esters respectively, the methyl ester also being obtained by reaction of the free acid with diazomethane. Chlorination of anhydro-6-phthalimidopenicillin for 10 seconds followed by immediate evaporation to dryness gives rise to a compound of Formula IV The p-toluenesulphonic acid salts 2-(2<SP>1</SP>R- chloro - 2<SP>1</SP>S - amino - 4<SP>1</SP> oxo) - azetidinyl - 3- methyl - 2 - butenoic acid chloride or the 2<SP>1</SP>S epimer are obtained by chlorination of the p-toluenesulphonic acid salt of anhydro-6-amino-penicillin and are reacted with methanol to obtain the corresponding methyl ester which is neutralized with bicarbonate to obtain the corresponding free amino compound of Formula 6a and 6b Hydrolysis of the p-toluene sulphonic acid salts of the above 3<SP>1</SP>S amino-2-butenoic acid chloride with D 2 O in deuteroacetase gives rise to the deuterated salts of Formulµ Va and Vb Methyl - 2 - [2<SP>1</SP>R - chloro - 3<SP>1</SP>S - phenylacetamido - 4<SP>1</SP>oxo] - azetidinyl - 3 - methyl - 2 - butenoate and its 2<SP>1</SP>S epimer of Formulae 7a and 7b are prepared by reaction of the free amino compound of Formulµ 6a and 6b (above) with phenyl acetic acid and dicyclohexylcarbodiimide, the corresponding free acid of Formula VI being obtained both by phenyl acetylation of the corresponding free acid free amino compound and by chlorination and hydrolyses of anhydropenicillin C 1 . The p-toluenesulphonic acid salt of methyl-2- (2<SP>1</SP>R - chloro - 3<SP>1</SP>S - amino - 4<SP>1</SP> - oxo)azetidinyl- 3-methyl-2-butenoate is reacted with tetramethyl guanidinium chloride and then with carbobenzyloxy chloride and the products separated by chromatography to obtain a compound of Formula VII and a compound of Formula VIII Oxapenicillin G (2,2 - dimethyl - 3R - carboxy- 7S - phenylacetamido - 1 - oxa - 4 - aza - SR- bicyclo[3,2,0]heptan - 7 - one of Forumula IX is prepared by reaction of 2-benzyl-6-(1<SP>1</SP>- methoxycarbonyl-2<SP>1</SP>-methyl prep-1<SP>1</SP>-enyl)-1-oxa 3,6 - diaza - 4S,5R - bicyclo[3,2,0]hept-2-en-7- one of Formula 2 with one mole of t-BuSLi or n-C 3 H 7 SLi in hexamethylphosphoric triamide. In addition to the above specified preparations of intermediates disclosure is also made of some associated and similar reactions and interconversions between compounds such as are described above. The compounds of the invention function as inhibitors of the enzyme #-lactamase.