Zambon S.p.a.

Zambon Group

Mariano Meneghin

Claudio Giordano

Francesco Minisci

Piero Piccinelli

Giulio Perdoncin

A process for the direct and regioselective functionalization of phenothiazine which allows one to introduce an SH group in position 2 is described. The thus-obtained 2-mercapto-phenothiazine is easily transformed into 2-methylthio-phenothiazine, an important intermediate for the preparation of pharmacological active compounds. One of the reaction routes (described in detail in the specification) involves the production of an N-aryl-phenothiazine-2-sulfinic acid [compound (III)] which can be isolated as a salt (e.g., an alkaline salt) by treatment with an aqueous alkaline solution. Thus compound (III-A) is produced.

Process for the direct and regioselective functionalization in position

A process for the direct and regioselective functionalization of phenothiazine which allows to introduce an SH group in position 2 by reaction with sulfur dioxide (SO.sub.2) and aluminum trichloride (AlCl.sub.3) with subsequent reduction is described.

Preparation of 2-alkylthio-phenothiazines by direct functionalization of phenothiazine by reaction of the phenothiazine, N-protected by an acryl group, with a sulfonating agent such as sulfuric acid, sulfuric anhydride, chlorosulfonic acid, or oleum, in order to obtain, after work-up of the reaction mixture, phenothiazine-2-sulfonic acid, followed by the reduction of this or, optionally, of its acyl chloride derivative, to obtain 2-mercapto-phenothiazine which subsequently is subjected to S-alkylation to thereby obtain the desired target compound.

A process is described for the preparation of cis-5-fluoro-2-methyl-1-(4-methylthiobenzylidene)-indene-3-acetic acid that consists in reacting a lower alkyl ester of 5-fluoro-2-methylindene-3-acetic acid with a substantially equimolecular amount of 4-methylthio-benzaldehyde in a solid-liquid two-phase system in which the solid phase is a potassium alcoholate or hydroxide and the liquid phase is a solution of the reagents in an organic solvent inert in the reaction conditions, in the presence of a phase transfer catalyst and at a temperature comprised between -20.degree. and +20.degree. C.

Process for the preparation of

Process for the preparation of pharmacologically active compounds containing a sulfoxide group by oxidation of a thioether with hypochlorite in an alkaline medium at a pH higher than 10 and at a temperature comprised between 0.degree. and 40.degree. C.

Process for the preparation of pharmacologically active compounds

Process to reduce stereoselectively 3alpha-hydroxy-7-keto-5beta-cholanic acid to 3alpha,7beta-dihydroxy-5beta-cholanic acid in ter.alcohols by using, as reducing agent, sodium metal in the presence of other metal salts. Examples of metal salts particularly useful are: potassium, cesium and rhubidium organic salts and, more particularly, potassium acetate or potassium ter.butylate.

Process for preparing 3alpha, 7beta-dihydroxy-5beta-cholanic acid

Process for carboxylating 2',4'-difluoro-4-hydroxy-1,1'-diphenyl or a derivative thereof with an alkaline alkylcarbonate at atmospheric pressure to afford 2',4'-difluoro-4-hydroxy-(1,1'-diphenyl)-3-carboxylic acid.

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Revine-Lago, Italy

Mariano Meneghin