GB1455016A - Dethiacephalosporanic acid derivatives and their preparation and use - Google Patents

Abstract

1455016 Dethiacephalosporin derivatives; their preparation and use MERCK & CO Inc 5 Nov 1973 [6 Nov 1972 18 Sept 1973] 51301/73 Headings C2C and C2P Compounds of the formulµ and isomers of the compounds of Formula I, wherein R is an acyl radical, B is H, OCH 3 , CH 3 or SR wherein R is C 1-6 alkyl or aryl R<SP>1</SP> is hydrogen or a protecting group, A<SP>1</SP> is hydrogen or an organic radical, X is -O-, -CH 2 - or -NY-, wherein Y is hydrogen, benzyl, formyl or C 1-6 alkyl, and R 6 is azido, amino, benzaldimino or substituted benzaldimino, or a non-toxic pharmacologically acceptable salt, ester or amide derivative of such a compound, may be prepared in a number of different ways. The 7- acylamino compounds (Formula I) may be prepared by treating a 7-amino or 7-substituted imino compound of the formula wherein R<SP>4</SP> is hydrogen or both R<SP>4</SP> groups taken together represent optionally substituted benzylidene, with a suitable acylating agent, generally at -20‹ C. to +100‹ C. and preferably in the presence of a solvent; when an imino compound is employed it is preferably first treated with a metal catalyst. The 7#-amino and 7#-substituted imino compounds may be prepared by various processes depending upon the nature of the X group. When X is methylene, the procedure shown in the following flow diagram (III) may be employed wherein R<SP>5</SP> is C 1-5 alkyl or an aryl radical. Compound B is suitably reacted with azidoacetyl chloride in the above flow diagram and the product, compound G, treated with an oxidizing agent; ring closure of compound D may be effected with a base and the product, compound E subsequently reduced, e.g. by treatment with hydrogen in the presence of a noble metal catalyst. Alternatively the oxoazetidinone (D) in the above flow diagram (III) may be obtained by utilizing a valeraldehyde, which contains a 4-carbonyl group precursor or a 4-masked carbonyl group, in place of the 4- methylene valeraldehyde of flow diagram (III), according to the following flow diagram wherein X and Y represent a carboxyl precursor grouping or a masked carboxyl group. Regeneration of the carboxyl group to form the oxoazetidinone (D) may be effected by treating the azetidinone (C<SP>1</SP>) with an oxidizing agent, in the case of a carboxyl precursor grouping, or employing acid hydrolysis where X and Y represent a masked carboxyl group. 7#-Amino compounds (IIa), wherein X is -O- or -NY-, may be obtained according to the following flow diagram wherein X<SP>1</SP> is a divalent radical selected from -O- and -NY-. The α-aminophosphousacetic ester (A) is reacted with a thionoformate ester to produce the corresponding thioformamido ester (J), which may then be alkylated and the product, (K), treated with azidoacetylchloride; the resultant H-methylthio compound (L) may be converted to the corresponding H-chloro compound (M) (a) by treatment with an oxidizing agent such as N-bromoacetamide and subsequent reaction of the 4-methylsulphonyl compound (L 1 ) with acetyl chloride, or (b) by treatment with a chlorinating agent. The H-propyloxy or propylamino compound (N) may be ring closed by reaction with a base, and the mixture of the 7α- and 7#-azidodethiacephalosporanates (O) converted to the correspondingly substituted 7-amino compound by treatment with hydrogen in the presence of a noble metal catalyst. The amino products are racemic mixtures and the optically active components may be separated by conventional methods. The 7#-amino-7α-methoxy derivatives may be obtained by treating the 7-amino compound with an appropriate aromatic aldehyde to form the corresponding imino compound, and the imino derivative may then be activated with a strong base, e.g. an alkali metal hydride or an organometallic compound, and the activated intermediate treated directly with a halogenating agent to afford the 7-amino-7- halo compound which is subsequently treated with methanol in the presence of a base; the 7#-imino-7α-methoxy compound can then be acylated or treated with an amine in the presence of an acid catalyst to give the product. 7-Substituted products wherein B is CH 3 , OCH 3 , or SR may be prepared by first preparing the imino derivative of the 7-amino compound, treating the said imino derivative with an activating agent, such as an organic or inorganic base and, without isolating the activated intermediate, treating if with a reagent which will introduce the described group B, such as an alkyl sulphate, halide peroxide, disulphide, sulphenyl halide or methanethiol sulphonate, phenyl sulphenyl halide or haloalkyl sulphenyl halide; the imino group can then be converted into an amino group by treatment with an amine in the presence of an acid catalyst. During the above reactions, functional groups which are present in the various compounds may be protected and subsequently cleared by known methods. In the products of the invention the acyl group B may be a substituted or unsubstituted aliphatic, aromatic, heterocyclic, araliphatic or heterocyclicaliphatic acyl radical, or a carbothioic acid radical, such as the acyl radicals of the known cephalosporins and penicillins, including sulphoxamido moieties. The organic radical A<SP>1</SP> may be, for example, hydrogen, hydroxy, amino, N-substituted amino, mercapto, C 1-6 alkylthio, carbamoyloxy, thiocarbamoyloxy, a quaternary ammonium group, N-(C 1-6 alkyl)carbamoyloxy, N,N-di(C 1-6 alkyl)- carbamoyloxy, N-(C 1-6 alkyl)thiocarbamoyloxy, or N,N-di(C 1-6 alkyl)thiocarbamoyloxy, azido, halogen, cyano, acyloxy or a heterocyclic thio group in which the heterocyclic ring is 5- membered and contains from 1 to 4 heteroatoms. The 7-acylamino products are antibiotics and may be employed as bactericides to inhibit the growth of harmful bacteria.