Improved synthesis of 2‐methoxyphenothiazine

Abstract

A procedure for synthesis of 2‐methoxyphenothiazine (1) has been developed, starting from resorcinol and aniline by condensation, following methylation and cyclization. p‐Toluenesulfonic acid and polysubstituted aromatics were employed as the catalyst of condensation and the solvent of cyclization, respectively, to improve the yield. The use of parallel experiments, statistical experimental design, and multivariate modeling made the total yield of the procedure as high as 74.2%. J. Heterocyclic Chem., (2012).

Points of Interest in the Chemistry of the Levomepromazine Drug Substance: Recycling of Undesired Enantiomer, Identification of New Phenothiazine Dimers, Synthesis of a Pharmacopeial Impurity, and an Unexpected Rearrangement

“…First, we planned to synthesize compound 13, a possible intermediate of target compound 12, by treating 4,4′-sulfanediyldianiline (14) with resorcinol in the presence of p-toluenesulfonic acid. 36 Surprisingly, instead of the expected product (13), the formation of a multicomponent mixture was observed with dimer 15 as the main product, which could be isolated by flash chromatography in 19% yield as a compound unknown in the literature. The main feature of this unexpected result is that the sulfur and the nitrogen atoms, which were in para position in the starting material 14, have ended up in ortho position to each other in product 15, unknown in the literature.…”

“…The formation of the 2-hydroxyphenothiazine moiety of compound 15 requires the incorporation of resorcinol into the molecule. As the reaction of aniline with resorcinol resulting in 3-(phenylamino)phenol is known, 36 it can be assumed that the analogous reaction of compound 20 with resorcinol gives product 21 (Scheme 11). The next step is the elimination of aniline, which is followed by cyclization to give the phenothiazine core.…”

“…D, it is not described in the literature. First, we planned to synthesize compound 13 , a possible intermediate of target compound 12 , by treating 4,4′-sulfanediyldianiline ( 14 ) with resorcinol in the presence of p -toluenesulfonic acid . Surprisingly, instead of the expected product ( 13 ), the formation of a multicomponent mixture was observed with dimer 15 as the main product, which could be isolated by flash chromatography in 19% yield as a compound unknown in the literature.…”