Several synthetic processes have been reported for the preparation of 2- [phenothiazin-10-yl] ethanol of the formula (4), which is an important intermediate in the preparation of 2- [phenothiazin-10-yl] ethylmethane sulphonate of formula (1).

In our international publication No. WO 98/52946, we have disclosed the compound of formula (I) and its preparation from 2- [phenothiazin-10- yl] ethanol of the formula (4).

B. Dahlbom [Swed. 129,842 (1950), Acta. Chem. Scand. 6,310 (1952)], described the preparation of 2- [phenothiazin-10-yl] ethanol of the formula (4) by reaction of 10H-phenothiazine of the formula (2) with ethylene oxide in presence of condensing agent such as alkali amides, PhONa, or EtCO2Li in toluene. The reaction is shown in scheme-1 below:

Scheme-1 This process has the following drawbacks: * Ethyleneoxide used for N-alkylation of lOH-phenothiazine of the formula (2) is a low boiling solvent and will polymerise easily into polyethylene oxide, which poses handling problem in bulk quantities.

The reaction is carried out using moisture sensitive pyrophoric reagents such as NaNH2, which needs careful handling.

M.G. Canquil, A. Casadorall and M.E. Casadovall (Bull. Soc. Chim., France, 1566 (1960)] described the process for preparation of 2-[phenothiazin-10- yl] ethanol of the formula (4) by initial fusion reaction of 10-H-phenothiazine of the formula (2) with Lithium metal, followed by reaction of 10-lithiophenic thiazine with ethyleneoxide. The reaction is shown in scheme-2 below: Scheme-2 K. Hiroyoshi [Japan, 73,33,755 (1974), CA. 81: 261835] described the process for the preparation of 2-[phenothiazin-10-yl] ethanol by fusion reaction of 10H-phenothiazine of the formula (2) with ethylene carbonate at 200 °C.

The reaction is shown in scheme-3 below:

Scheme-3 O. Saburo, U. Koji [Japan Kokai, 74,40,675 (1974), CA 82 : 170988p (1975)] described the process for the preparation of 2- [phenothiazin-10- yl] ethanol of the formula (4) by initial fusion reaction of lOH-phenothiazine of the formula (2) with KOH at 30 °C, followed by reaction of potassium salt of phenothiazine with ethylene oxide in xylene medium. The reaction is shown in scheme-4 below: Scheme-4 The processes described in the above schemes have the following drawbacks.

'The reactions are carried out at very high temperatures ranging from 200-300 °C, which is very difficult for scale-up operations and also from safety point of view.

At very high temperature charring of the RM was observed, affecting the yield.

Ethylene oxide or ethylene carbonate used for N-alkylation of phenothiazine of the formula (2) can lead to radical polymerization, which poses handling problem in bulk quantities.

In view of the importance of the compound of formula (1), it is essential to have a commercially viable, cost effective, high yielding process for preparing the compound of formula (1).

Objective of the invention The main objective of the present invention is therefore to provide an improved process for the preparation of. 2- [phenothiazin-10-yl] ethylmethane sulphonate of the formula (1).

Another objective of the present invention is to provide an improved process for the preparation of 2-[phenothiazin-10-yl] ethylmethane sulphonate of the formula (1), avoiding pyrophoric reagents, thereby making the process easy to operate in commercial scales.

The objective of the present invention has been achieved by employing polar aprotic solvents such as DMF, DMSO, DMAc and the like and avoiding column chromatography.

Detailed description of the Invention Accordingly, the present invention provides a process for the preparation of 2- [phenothiazin-10-yl] ethylmethane sulphonate of the formula (1), which comprises: i). N-alkylating the lOH-phenothiazine of the formula (2) with 2- haloethanol of the formula (8) where X represents halogen atom such as fluorine, chlorine, bromine or iodine in the presence of a polar aprotic solvent and a nucleophilic organic or inorganic base to get 2- [phenothiazin-10- yl] ethanol of the formula (4), ii). mesylating the 2-[phenothiazin-10-yl] ethanol of the formula (4) obtained in step (i) to yield compound of formula (1) by treating with methane sulphonyl chloride in the presence of an organic base and an organic solvent and iii). isolating the compound of formula (1) by conventional methods.

The reaction is shown in scheme-5 below:

Scheme-5 The N-alkylation lOH-phenothiazine of the formula (2) with 2-haloethanol of formula (8) wherein X represents halogen atom such as chlorine, fluorine, bromine or iodine in step (i) may be carried out in the presence of polar aprotic solvents such as DMF, DMSO, DMAc and the like in the presence of nucleophilic organic or inorganic bases such as sodium hydride, t-BuOH, and sodium methoxide. The yield of the resultant, 2- [phenothiazin-10-yl] ethanol of the formula (4) is in the order of 57-66 % and purity of 99 %. This compound can be used directly for the next step without purification involving column chromatography, thereby saving the time and cost. The reaction of 2- [phenothiazin-10-yl] ethanol of the formula (4) with methane sulfonyl chloride may be carried out in the presence of solvent such as DCM, DCE, toluene and the like and a base such as triethylamine, tributylamine and the like. The final compound namely 2- [phenothiazin-10-yl] ethylmethane sulfonate of the formula (1) is obtained in quantitative yield and purity of 99 %.

The invention is described in the example given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Example-1 Step (1) 2-[Phenothiazin-lO-yllethanol ofthe formula (4) Sodium hydride (54.6 g) (60 % dispersion in oil) was taken in 2 L four necked round bottom flask and thoroughly washed with toluene (2 x 20 ml) under N2 atmosphere with stirring. DMF (200 ml) was added to the washed sodium hydride, freed from oil and toluene. lOH-phenothiazine (100 g) in DMF (100 ml) was added dropwise to the mixture in about 30 min. 2-Chloroethanol (87.3 g) in DMF (50 ml) was added at 50-60 °C in about 1 h. After addition, the reaction mass was maintained at room temperature for 1 h, monitoring the reaction by TLC. Methanol (100 ml) was added slowly to quench the unreacted hydride followed by toluene (2 L). The toluene layer was washed with water (3 x 1 L), decolorized with activated charcoal and concentrated on rotavapor at 50-90 °C/150 mm till no more drops of toluene were observed.

The residue was distilled in high vacuum to afford 2-phenothiazin-10- yl] ethanol of the formula (4) as light brown oil, b. p. 210 °C, (weighs about 72- 85 g, yield: 58-64%, purity 99% by HPLC). The IR,'H-NMR data are consistent with assigned structure.

Step (ii) 2-fPhenothiazin-lO-yllethylmethane sulfbnate of the formula (I) In a 2 L four necked round bottom flask fitted with a mechanical stirrer and condenser, 2-lphenothiazin-10-yl] ethanol of the formula (4) (170 g) obtained as described in step (i) above and dichloromethane (850 ml) were added under N2 atmosphere with stirring. Triethylamine (1. 13. 4 g, 157 ml) was added portion wise under N2 atmosphere in about 10 min. at room temperature under stirring. Methane sulfonyl chloride (107 g,-73 ml) was added to the reaction

mixture at 5-10 °C under stirring in about 30 min. The reaction mass was maintained at 25-35 °C for 3 h, monitoring the reaction by TLC.

Demineralised water was added, followed by fresh dichloromethane and stirred for 30 min. The organic layer was separated, washed with DM water (3 x 300 ml), dried over Na2S04 and was concentrated under reduced pressure in a rotavapor to a volume of-600 ml. Petroleum ether (-600 ml) was added to a conc. solution of organic layer at 10-15 °C under stirring. The precipitated solid was filtered, dried in hot air oven at 45 °C to yield 2- [phenothiazin-10- yl) ethyl methane sulfonate of the formula (1), m. p. 113-115°C (weighs about 222 g, Yield: 95%, Purity 99% by HPLC). The IR, 1H NMR data are consistent with assigned structure.

Example 2 Step (i): 2-UPhenothiazin-10-yllethanol of the formula (4) Sodium hydride (54.6 g) (60 % dispersion in oil) was taken in 2 L four necked round bottom flask and thoroughly washed with toluene (2 x 20 ml) under N2 atmosphere with stirring. DMF (200 ml) was added to the washed sodium hydride, freed from oil and toluene. lOH-phenothiazine (100 g) in DMF (100 ml) was added dropwise to the mixture in about 30 min. at room temperature.

2-Bromoethanol (137 g) in DMF (50 ml) was added dropwise at room temperature in about 4 h under N2 atmosphere with stirring. After addition, the reaction mass was maintained at room temperature for 1 h, monitoring the reaction by TLC. Methanol (100 ml) was added slowly to quench the unreacted hydride followed by toluene (2 L). The toluene layer was washed with water (3 x 1 L), decolorized with activated charcoal and concentrated on rotavapor at 50-90 °C/150 mm till no more drops of toluene were observed.

The residue was distilled in high vacuum to afford 2-phenothiazin-10- yl] ethanol of the formula (4) as light brown oil, b. p. 210 °C (weighs about 75

g, yield 60%, purity 99% by HPLC). The IR, IH NMR data are consistent with the assigned structure.

Step (ii) 2-fPhenothiazin-lO-yllethyl methane sulfonate of formula (1) In a 2 L four necked round bottom flask fitted with a mechanical stirrer and condenser, 2-[phenothiazin-10-yl] ethanol of the formula (4) (170 g) obtained as described in step (i) above and dichloromethane (850 ml) were added under N2 atmosphere with stirring. Triethylamine (113.4 g, 157 ml) was added portion wise under N2 atmosphere in about 10 min. at room temperature under stirring. Methane sulfonyl chloride (107 g,-73 ml) was added to the reaction mixture at 5-10 °C under stirring in about 30 min. The reaction mass was maintained at 25-35 °C for 3 h, monitoring the reaction by TLC.

Demineralised water was added, followed by fresh dichloromethane and stirred for 30 min. The organic layer was separated, washed with DM water (3 x 300 ml), dried over Na2S04 and was concentrated under reduced pressure in a rotavapor to a volume of-600 ml. Petroleum ether (-600 ml) was added to a conc. solution of organic layer at 10-15 °C under stirring. The precipitated solid was filtered, dried in hot air oven at 45 °C to yield 2-[phenothiazin-10- yl) ethyl methane sulfonate of the formula (1), m. p. 113-115°C (weighs about 222 g, Yield: 95%, Purity 99% by HPLC). The IR, 1H NMR data are consistent with assigned structure.

Example 3 Step (i) 2-UPhenothiazin-10-yllethanol ofthe formula (4) Sodium hydride (54.6 g) (60 % dispersion in oil) was taken in 2 L four necked round bottom flask and thoroughly washed with toluene (2 x 20 ml) under N2 atmosphere with stirring. DMF (200 ml) was added to the washed sodium hydride, freed from oil and toluene. lOH-phenothiazine (100 g) in DMF (100 ml) was added dropwise to the mixture in about 30 min. at room temperature.

2-Iodoethanol (171 g,-78 ml) in DMF (50 ml) was added dropwise at room temperature in about 15 h under stirring N2 atmosphere. After addition, the reaction mass was maintained at room temperature for 1 h, monitoring the reaction by TLC. Methanol (100 ml) was added slowly to quench the unreacted hydride followed by toluene (2 L). The toluene layer was washed with water (3 x 1 L), decolorized with activated charcoal and concentrated on rotavapor at 50-90 °C/150 mm till no more drops of toluene were observed.

The residue was distilled in high vacuum to afford the 2- [phenothiazin-10- yl] ethanol of the formula (4) as light brown oil, b. p. 210 °C, (weighs about 70 g, yield 56 %, purity 99 % by HPLC). The IR, IH NMR data are consistent with the assigned structure.

Step (ii) 2-UPhenothiazin-10-yllethylmethane sulfonate of the formula (1) In a 2 L four necked round bottom flask fitted with a mechanical stirrer and condenser, 2- [phenothiazin-10-yl] ethanol of the formula (4) (170 g) obtained as described in step (i) above and dichloromethane (850 ml) were added under N2 atmosphere with stirring. Triethylamine (113.4 g, 157 ml) was added portion wise under N2 atmosphere in about 10 min. at room temperature under stirring. Methane sulfonyl chloride (107 g,-73 ml) was added to the reaction mixture at 5-10 °C under stirring in about 30 min. The reaction mass was maintained at 25-35 °C for 3 h, monitoring the reaction by TLC.

Demineralised water was added, followed by fresh dichloromethane and stirred for 30 min. The organic layer was separated, washed with DM water (3 x 300 ml), dried over Na2S04 and was concentrated under reduced pressure in a rotavapor to a volume of-600 ml. Petroleum ether (-600 ml) was added to a cone. solution of organic layer at 10-15 °C under stirring. The precipitated solid was filtered, dried in hot air oven at 45 °C to yield 2- [phenothiazin-10- yl) ethyl methane sulfonate of the formula (1), m. p. ll3-115°C (weighs about

222 g, Yield: 95%, Purity 99% by HPLC). The IR, IH NMR data are consistent with assigned structure.

Advantages of the Invention . The process does not require the use of expensive reagents and dry solvents, thereby making the process safe and economical.

The purification by column chromatography is totally avoided resulting in further economy of the process.

'The time required for the completion of the reaction is reduced drastically, the overall yield and purity of the product is enhanced thereby making the process commercially economical.

The process is commercially viable and can be employed for the easy and quick preparation of the compounds of formula (1).