Patent GB-1199192-A (GB)
Title: A Process for the Preparation of Substituted Isothiazoles
Inventor: CRENSHAW RONNIE RAY
IPC: C07D295/18
Filed: 1967-07-24
Abstract: 1,199,192. Isothiazole - 4 - carboxylic acids; penicillins; cephalosporins. BRISTOL MYERS CO. 24 July, 1967 [25 July, 1966], No. 33885/67. Headings C2A and C2C. Isothiazole-4-carboxylic acids of the formula where R and R<SP>2</SP> are the same or different and represent C 1-6  alkyl groups or the group where A, B and C are hydrogen, fluorine, chlorine, bromine or iodine or -CF 3 , methylsulphonyl, nitro, C 1-6  alkyl or C 1-6  alkoxy groups, are prepared by (a) reacting at 50- 300‹ C. an imino compound of the formula with a dithio compound of the formula where R<SP>1</SP> represents -COOH, -COOR<SP>4</SP>, -CN, -CONH 2 , -CONHR<SP>4</SP> or -CONR<SP>4</SP>R<SP>5</SP> (where R<SP>4</SP> and R<SP>5</SP> are as R and R<SP>2</SP> above) and R<SP>3</SP> represents a C 1-6  alkyl group or a radical -C n H 2n CH 2 COOH, -C n H 2n CH 2 CO.OC m H 2m - CH 3  or -C n H 2n CH 2 CN where n and m are 0 or 1-6; (b) oxidizing the resultant product with an agent selected from 2,3-dichloro-5,6- diazano-1,4-benzoquinone, O 2 , air, halogen in the presence of an acid scavenger, I 2 , Br 2 , Cl 2 , H 2 O 2 , sulphur, FeCl 3 , Na 2 S 2 O 8  and chloranil, and when R<SP>1</SP> is other than -COOH; (c) hydrolysing the oxidation product with an acid or base. The imino compound and dithio compound are preferably reacted in equimolar proportions in the presence of a solvent and yield an intermediate which exists, is six tautomeric forms having the general formula three of said forms being isothiazolines and three being acylic imines or amines. When R<SP>1</SP> is other than -COOH, the imino reactant may be used in the form of an alkali metal salt. The oxidation step is preferably effected in a solvent at 0-100‹ C. using iodine in the presence of an acid-acceptor as the oxidizing agent. Acids prepared in the examples include the 3-phenyl derivatives in which the phenyl group is substituted by Cl, F, -CF 3 , -NO 2 , -CH 3  and methoxy groups. The acid chloride of the isothiazole-4-carboxylic acids may be prepared by reacting the free acid with thionyl chloride. The imino compounds (which can exist in the tautomeric unsaturated amino form) may be prepared (1) where R<SP>1</SP> is -COOR<SP>4</SP>, from a Grignard reagent RMgX and a cyano-acetate CN-CH 2 COOC 2 H 5 , or (2) where R<SP>1</SP> is -CN, by reacting an aldoxime R-CH = N-OH with acetic anhydride to give a nitrile R-CN which yields the imino-nitrile on reaction with acetonitrile in the presence of Na metal. The dithio compounds can be prepared by reacting (1) a thiol R<SP>3</SP>SH with a nitrile R<SP>2</SP>CN in the presence of dry HCl to give the thioimidocarboxylate R<SP>2</SP>C( = NH)-S-R<SP>3</SP> which on treatment with H 2 S and pyridine yields a dithiocarboxylate, or (2) by reacting a N-acyl piperidine with P 2 S 5  to yield the N-thioacyl piperidine which is condensed with bromoacetic acid to give the salt which on treatment with H 2 S yields R<SP>2</SP>CS 2 CH 2 - COOH. Isothiazole penicillins and cephalosporins are obtained by acylation of 6-aminopenicillanic or 7-aminocephalosporanic acid with isothiazole- 4-carboxylic acids prepared by the above process, or acylating derivatives thereof. Examples 1 and 7 describe the preparation of sodium 6- (5 - methyl - 3 - phenylisothiazole - 4 - carboxamido) - penicillanate and sodium 6 - [3 - (2- chlorophenyl) - 5 - methylisothiazole - 4 - carboxamido] penicillanate, the latter being obtained in two crystalline forms.