Claims:1. A process for the preparation of a substituted phenothiazine of general formula V

comprises the steps of
(i) Step-I: heating a mixture of substituted phenol (I) and substituted aniline (II) in the presence of an acid (para-toluene sulfonic acid) and a solvent, with the removal of water to obtain diphenyl aminophenol (III);
(ii) Step-II: methylating diphenyl aminophenol (III) using dimethyl sulfate in alkaline condition to obtain methoxy diphenylamine (IV); and
(iii) Step-III: reacting methoxy diphenylamine (IV) at high temperature with sulphur and iodine to obtain substituted phenothiazine (V).

2. The process according to claim 1, wherein R1 and R2 are each independently selected from the group consisting of but not limited to H, alkyl, aryl, hydroxyl, methoxy, acetoxy, and halide.

3. The process according to claim 1, wherein the condensation reaction of the substituted phenol and the substituted aniline involves adjustment of pH by acid base treatment.

4. The process according to claim 1, wherein the solvent in the condensation reaction is xylene.

5. The process according to claim 1, wherein the solvent used in the methylation reaction is chlorobenzene.

6. The process according to claim 1, wherein the methylation can be carried out in the presence of a phase transfer catalyst such as benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, methyl tributyl ammonium chloride, methyl tricapryl ammonium chloride, methyl trioctyl ammonium chloride, benzyl tributyl ammonium bromide, ethyl trimethyl ammonium iodide, tetrabutyl ammonium acetate, cetyl trimethyl ammonium hydrogen sulfate, and the like.
7. The process according to claim 1, wherein the methylation further comprises recrystallization from a mixture of methanol and water.

8. The process according to claim 1, wherein the crude substituted phenothiazine can be recrystallized from chlorobenzene and methanol to obtain the pure product.

9. A highly pure substituted phenothiazine prepared with a purity of 98-99.8% by a process comprising:
(i) Step-I: heating a mixture of substituted phenol (I) and substituted aniline (II) in the presence of an acid (para-toluene sulfonic acid) and a solvent, with the removal of water to obtain diphenyl aminophenol (III);
(ii) Step-II: methylating diphenyl aminophenol (III) using dimethyl sulfate in alkaline condition to obtain methoxy diphenylamine (IV);
(iii) Step-III: reacting methoxy diphenylamine (IV) at high temperature with sulphur and iodine to obtain substituted phenothiazine (V).

10. A substituted phenothiazine prepared with an yield ranging from 65-70%, by a process comprising:
(i) Step-I: heating a mixture of substituted phenol (I) and substituted aniline (II) in the presence of an acid (para-toluene sulfonic acid) and a solvent, with the removal of water to obtain diphenyl aminophenol (III);
(ii) Step-II: methylating diphenyl aminophenol (III) using dimethyl sulfate in alkaline condition to obtain methoxy diphenylamine (IV); and
(iii) Step-III: reacting methoxy diphenylamine (IV) at high temperature with sulphur and iodine to obtain substituted phenothiazine (V).
, Description:FIELD OF THE INVENTION

The present invention relates to a process for the preparation of a substituted phenothiazine of the general formula V. In particular, the present invention relates to a process for the preparation of a substituted phenothiazine by the condensation of substituted phenol and substituted aniline followed by methylation and cyclization.

BACKGROUND OF THE INVENTION

2-methoxyphenothiazine is an important organic intermediate of anti-psychotic drugs such as methotrimeprazine, methoxypromazine etc. methoxyphenothiazine can be used widely in the preparation of various antioxidants, polymerization inhibitors in agrochemical, pharmaceutical, dyestuff fields. It also exhibits tuberculostatic activity.

US 3,450,764 discloses a method for the preparation of hydroxy substituted diarylamine. The prior-art processes such as the processes disclosed in US 2,360,295 and US 2,433,658 deal with the production of phenothiazine by reacting sulphur with diphenylamine in the presence of a condensing catalyst.

However, the typical processes for the synthesis of substituted phenothiazine in the prior-art are associated with low yields and undefined purity of material. The prior-art processes are also not viable for commercial production.

The present invention addresses the drawbacks in prior-art processes and provides a commercially suitable process for the preparation of a substituted phenothiazine from substituted phenol and substituted aniline with enhanced yield and purity.

OBJECTIVE OF THE PRESENT INVENTION

The principal objective of the present invention is to provide a process for the preparation of a substituted phenothiazine.

Another objective of the present invention is to provide a highly pure substituted phenothiazine with enhanced yield.

SUMMARY OF THE PRESENT INVENTION

The present invention relates to a process for the preparation of a substituted phenothiazine of formula V by the condensation reaction of a substituted phenol and substituted aniline followed by methylation and cyclization.

The process for the preparation of a substituted phenothiazine of the general formula V,

wherein R1 and R2 are each independently selected from the group consisting of, but not limited to H, alkyl, aryl, hydroxyl, methoxy, acetoxy, halide;
comprises the steps of
(i) Step-I: heating a mixture of substituted phenol (I) and substituted aniline (II) in the presence of an acid (para-toluene sulfonic acid) and a solvent, with removal of water to obtain diphenylaminophenol (III);
(ii) Step-II: methylating diphenylaminophenol (III) using dimethylsulfate in alkaline conditions to obtain methoxydiphenylamine (IV); and
(iii) Step-III: reacting methoxydiphenylamine (IV) at high temperature with sulphur and iodine to obtain substituted phenothiazine (V).
The following experimental studies are provided for illustrative purposes only and are not limiting to this disclosure in any way. Various modifications of the invention, in addition to those shown and described herein, will become apparent to those skilled in the art from the following examples and the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.

BRIEF DESCRIPTION OF THE PRESENT INVENTION

Fig. 1 shows the schematic representation of the process for the preparation of a substituted phenothiazine of the present invention.

DESCRIPTION OF THE PRESENT INVENTION

The present invention relates to the process for the preparation of a substituted phenothiazine of formula V by the condensation reaction of substituted phenol and substituted aniline followed by methylation and cyclization.

A process for the preparation of a substituted phenothiazine comprises the steps of
(i) Step-I: heating a mixture of substituted phenol (I) and substituted aniline (II) in the presence of an acid (para-toluene sulfonic acid) and a solvent, with the removal of water to obtain diphenyl aminophenol (III);
(ii) Step-II: methylating diphenyl aminophenol (III) using dimethyl sulfate in alkaline condition to obtain methoxy diphenylamine (IV); and
(iii) Step-III: reacting methoxy diphenylamine (IV) at high temperature with sulphur and iodine to obtain substituted phenothiazine (V).

According to the present invention, the crude substituted phenothiazine is recrystallized from chlorobenzene and methanol to obtain the high purity substituted phenothiazine.

According to the present invention, the reaction of resorcinol and aniline involves an acid base treatment wherein the pH is initially adjusted to 12.5 and then to 2.5.

According to the present invention, the reaction of the substituted phenol and the substituted aniline further comprises the step of hyflo bed filtration to remove the impurities.

According to the present invention, the solvents used in Step-I and in Step-II can be selected from the group consisting of, but not limited to, xylene, chlorobenzene, cyclohexane, heptane, dichloromethane, toluene, ortho-dichlorobenzene, anisole, and diphenyl ether. However, except xylene and chlorobenzene, the remaining solvents are expensive, the recovery is in small quantities after completion of the reaction, require comparatively more time for the completion of the reaction, and have scarce commercial availability.

The advantages of xylene and chlorobenzene include cheap and easy availability on commercial scale, minimal loss of material during the process leading to high recovery, and recyclability due to their unreactive nature.

According to the present invention, methylation can be carried out in the presence of a phase transfer catalyst such as benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, methyl tributyl ammonium chloride, methyl tricapryl ammonium chloride, methyl trioctyl ammonium chloride, benzyl tributyl ammonium bromide, ethyl trimethyl ammonium iodide, tetrabutyl ammonium acetate, cetyl trimethyl ammonium hydrogen sulfate, and the like.

According to the present invention, the step of methylation further comprises recrystallization from a mixture of methanol and water.

According to the present invention, the crude 2-methoxyphenothiazine can be recrystallized from chlorobenzene and methanol to obtain 98.5 - 99.8% purity.

The present invention is further illustrated by considering 2-methoxyphenothiazine as an example in the following experimental details. However, it is to be understood that it has been considered only as an exemplary case and not to be considered as limiting the scope of the invention.

EXPERIMENTAL SECTION

Step-I: Preparation of 3-anilinophenol
Resorcinol (1M), aniline (2M), para-toluenesulfonic acid (10% by weight) and xylene (200% volume) were heated under reflux for 12-16 hrs with separation of water in Dean-Stark apparatus. After the collection of 1 mole of water, toluene (15 volumes) was added and washed with 10% sodium bicarbonate solution. It was then distilled under vacuum (550-650 mm of Hg) to recover xylene, toluene and aniline. The reaction mass was diluted with water (2 volume), made pH alkaline using caustic lye and filtered through a hyflo bed. The pH was readjusted to less than 2 using hydrochloric acid, filtered, washed with water, and dried at 55-60 °C to obtain stage-1 material as a brown solid with 98% of HPLC purity, 90-92% of yield and a melting point of 76-78 °C.

Step-II: Preparation of 3-methoxy-N-phenylaniline
Step-I material (1M), chlorobenzene (15 volume), dimethyl sulphate (1.5M), caustic lye (5.7 volume), and triethyl benzyl ammonium chloride (5% by weight) were stirred at room temperature (25-30 °C) for 13 hr. Water (3.5 volume) was added to it and stirred followed by separation of the chlorobenzene layer and distillation under vacuum to obtain the residue. The residue was dissolved in methanol (23 volume) under reflux, and the clear solution was allowed to cool to room temperature and water (1.2 volume) was added. It was filtered, washed with water (1 volume), and dried below 50 °C to obtain stage-2 material as an off-white solid with 98% HPLC purity, 93-95% of yield and melting point in the range of 70-75 °C.

Step-III: Preparation of 2-Methoxyphenothiazine
Step-II material (1M), sulphur (3.2M) and iodine (1% by weight) were heated at 160-165 °C under nitrogen atmosphere for 8-10 hr. Chlorobenzene (10 volume) was added, allowed to cool to room temperature, filtered and washed with methanol (1 volume) to obtain the crude 2-methoxyphenothiazine [HPLC purity 97-98%, yield 70-75%]. The crude 2-methoxyphenothiazine was dissolved in chlorobenzene (15 volumes) at 130 °C, allowed to stir at room temperature for 3 hr, filtered and washed with methanol (1 volume). It was then dried at 70-80 °C under vacuum to obtain 2-methoxyphenothiazine with 98-99.8% of HPLC purity, 65-70% of yield and a melting point in the range of 180-185°C.

The above results demonstrate that the compound of the present invention, 2-methoxyphenothiazine was prepared with enhanced yield and purity.

While this invention has been described with reference to illustrative embodiments, this description is not intended to be construed in a limiting sense. Various modifications of the illustrative embodiments, as well as other embodiments of the invention, will be apparent to persons skilled in the art upon reference to this description. It is therefore contemplated that the appended claims will cover any such modifications or embodiments as fall within the true scope of the invention.