WO2002034733A1

WO2002034733A1 - An improved process for the preparation of 2-[phenoxazin-10-yl]ethylmethane sulphonate

Info

Publication number: WO2002034733A1
Application number: PCT/IB2000/001556
Authority: WO
Inventors: Chandrasekhar Batchu; Ramabhadra Sarma Mamillapalli; Om Reddy Gaddam
Original assignee: Dr. Reddy's Research Foundation
Priority date: 2000-10-26
Filing date: 2000-10-26
Publication date: 2002-05-02
Also published as: AU2000279388A1

Abstract

The present invention relates to an improved process for the preparation of 2-[phenoxazin-10-yl]ethylmethane sulphonate of formula (1) which comprises N-alkylating the 10H-phenoxazine with 2-haloethanol or ethylene oxide to get [phenoxazin-10-yl]ethanol, mesylating the 2-[phenoxazin-10-yl]ethanol to the compound of formula (1) by treating with methane sulphonyl chloride in the presence of an organic base and an organic solvent and isolating the compound of formula (1) by conventional methods.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF 2- [PIffiNOXAZm-10-YL]ETHYLMETHANE SULPHONATE

FILED OF THE INVENTION The present invention relates to an improved process for the preparation of 2- [phenoxazin-10-yl]ethylmethane sulphonate of the formula (1).

The compound of formula (1) is an intermediate for the preparation of many pharmaceutically active compounds.

Consequent to the importance gained for 2-[phenoxazin-10-yl]ethylmethane sulphonate of formula (1) several synthetic processes have been reported for the preparation of 2-[phenoxazin-10-yl]ethanol of the formula (2), which is an important intermediate in the preparation of 2-[phenoxazin-10-yl]ethylmethane sulphonate of formula (1).

H.Linde [Arch. Pharm. 293, 537, (I960)] described a process for the preparation of 2-[phenoxazin-10-yl]ethanol of the formula (2) which comprises reaction of phenoxazine of the formula (3) with ethylene oxide in CO₂ filled autoclave at very high temperature of 230 °C in about 30 minutes. The residue resulting from the reaction is extracted with ether and the ether layer was washed with acid and alkali.

The reaction is shown in scheme 1.

Scheme-1

This process has the following disadvantages:

Ethylene oxide used for N-alkylation of phenoxazine of the formula (3) is a low boiling solvent and will polymerise easily into polyethylene oxides, which poses handling problem in bulk quantities.

The reaction is carried out at a temperature of 230 °C in an autoclave filled with carbon dioxide gas, which demands special equipment for carrying out the reaction and other safety precautionary measures while carrying out the reaction.

Ether used for extraction is a low boiling, highly inflammable solvent and has a poor recovery for recycling. For all practical commercial purposes it is no more used for extraction.

The product of the reaction is purified by column chromatography, which is time consuming and adds to the cost of the production.

V.G.Samolovova, T.V.Gortinskaya and M.N.Shehukina [Zh.obshhc. Khim. 32, 1085 (1962)] have reported a process for the preparation of 2-(phenoxazin-10-yl)ethanol of the formula (2), in which phenoxazine of the formula (3) is reacted with ethylene oxide of the formula (4) in toluene in presence of sodamide at a temperature of 100 °C in a sealed tube. This reaction is shown in Scheme II

Scheme-2

This process has the following drawbacks :

This process employs sodamide as a base for the reaction in a sealed tube. Sodamide is a very moisture sensitive pyrophoric reagent and needs careful handling. To carryout sealed tube reactions in a commercial scale is very difficult. The reaction product is purified by column chromatography, which is time consuming and adds to the cost of the production.

The main objective of the present invention is therefore to provide an improved process for the preparation of 2-[phenoxazin-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-[phenoxazin-10-yl]ethylmethane sulphonate of the formula (1), avoiding high temperature reactions, pyrophoric reagents and autoclaves, thereby making the process easy to operate commercially .

The objective of the present invention have been achieved by employing polar aprotic solvent such as DMF, DMSO and avoiding column chromatography.

Detailed Description of the Invention Accordingly, the present invention provides an improved process for the preparation of 2-[phenoxazin-10-yl]ethylmethane sulphonate of the formula (1) which comprises

i). N-alkylating the lOH-phenoxazine of the formula (3) with 2-haloethanol of the formula (5) in the presence of a polar aprotic solvent and a nucleophilic organic or inorganic base to get 2-[phenoxazin-10-yl]ethanol of the formula (2), ii) mesylating the 2-[phenoxazin-10-yl]ethanol of the formula (2) obtained in step (i) to the 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 the Scheme III

Scheme-3

The N-alkylation lOH-phenoxazine of the formula (3) with 2-haloethanol of formula (5) wherein X represents halogen atom such as chlorine, fluorine, bromine or iodine in step (i) may be carried out using reagents such as 2-bromoethanol, 2- chloroethanol or 2-iodoethanol. This N-alkylation step may be affected in the presence of polar aprotic solvents such as DMF, DMSO, DMAc and the like in the presence of nucleophilic organic bases such as t-BuOK, sodium methoxide and the like; or inorganic bases such as sodium hydride, KOH or NaOH. The base NaH is used in ratio of 1:2 to 1:5 preferably using 1:2 M and 2-haloethanol is employed in the ratio of 1:3 to 1:2. The yield of the resultant 2-[phenoxazin-10-yl]ethanol of the formula (2) 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-[phenoxazine- 10-yl]ethanol of the formula (2) with methane sulphonyl chloride in step (ii) may be carried out in the presence of solvent such as DCM, toluene, ethylacetate and the like and a base such as triethylamine, tributylamine and the like. The final compound namely 2-[phenoxazin-10-yl]ethyhnethane sulphonate of the formula (1) is obtained in quantitative yield and purity of 99 %.

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

Example 1

Step (i) : Preparation of 2-rphenoxazin-lO-yllethanol of the formula (2) : Sodium hydride (44 g) (60 % dispersion in oil) was taken into 2 L, 4 necked round bottom flask and thoroughly washed with hexane (300 ml) under N₂ atmosphere with stirring. DMF (150 ml) was added to the washed sodium hydride freed from oil and hexane. lOH-phenoxazine (100 g) in DMF (150 ml) was added dropwise to the mixture at 60 °C in about 30 minutes. 2-Bromoethanol (137 g) was added dropwise at 60 °C in about 1.5 hour under N₂ atmosphere with stirring. After addition the reaction mass was maintained at room temperature for 1 hour, monitoring the reaction by TLC. Methanol (100 ml) was added slowly to quench the unreacted hydride and the DMF, methanol was distilled from the reaction mixture to rotavapor at 90-95 °C / 5-10 mm vacuum. Toluene (500 ml) was added to the residue and the toluene layer was washed with water (3 x 300 ml), decolorized with activated charcoal. The decolorized toluene layer was concentrated on rotavapor at 80-90 °C/150 mm to a minimal volume of 200 ml. The concentrated solution was cooled to 0-5 °C under stirring and the precipitated solid was filtered and dried in a vacuum desiccator to yield 2-[phenoxazin-10-yl]ethanol of the formula (6) appears as a white crystalline solid (weighs about 72-80 g, yield 58-64 %, mp. 105-107 °C ( rep. 105 °C as HC1 salt), purity 99 % by HPLC). The IR, 1H-NMR data are consistent with assigned structure.

Step (ii) : Preparation of 2-rphenoxazin-lO-yllethylmethane sulphonate of the formula (1) :

In a 2 L, 4 necked round bottom flask fitted with a mechanical stirrer and condenser 2-[phenoxazin-10-yl]ethanol (114 g) obtained as described in step (i) above and ethylacetate were added (500 ml) under N₂ atmosphere with stirring. Triethylamine (75.75 g ~ 105 ml) was added portion wise under N₂ atmosphere in about 10 minutes at room temperature with stirring. Methane sulphonyl chloride (71.2 g ~ 48.5 ml) was added to the reaction mixture at 5-10 °C under stirring in about 30 minutes. The reaction mass was maintained at 25 °C for 3 h, monitoring the reaction by TLC. Demineralised water (200 ml) was added, followed by fresh ethylacetate (600 ml) and stirred for 30 minutes. The organic layer was separated, washed with demineralised water (2 x 200 ml), dried the ethylacetate layer over Na₂SO₄ and concentrated under reduced pressure in a rotavapor to a volume of ~ 300 ml. Hexane (~ 500 ml) was added to a cone, solution of ethylacetate layer at 10-15 °C under stirring. The precipitated solid was filtered and dried in a vacuum dessicator to yield 2-[phenoxazin-10-yl]ethylmethane sulphonate of the formula (1) (weighs about 147- 149 g, yield 96-97 %, mp. 81-82 °C, purity 98.8-99 % by HPLC). The IR, 1H-NMR data are consistent with assigned structure.

Example 2

Step (i) : Preparation of 2-rphenoxazin-10-yl1ethanol of the formula (2) :

Sodium hydride (44 g) (60 % dispersion in oil) was taken into 2 L, 4 necked round bottom flask and thoroughly washed with hexane (300 ml) under N₂ atmosphere with stirring. Dimethylformamide (150 ml) was added to the washed sodium hydride freed from oil and hexane. 10-H-phenoxazine (100 g) in DMF (150 ml) was added dropwise to the mixture at 60 °C in about 30 minutes. 2-Chloroethanol (87.3 g ~ 72.8 ml) was added at 50-60 °C in about 1 hour. After addition the reaction mass was maintained at 60 °C for 1 hour, monitoring the reaction by TLC. Methanol (100 ml) was added slowly to quench the unreacted hydride and DMF, methanol was distilled from the reaction mixture to rotavapor at 90-95 °C / 5-10 mm vacuum. Toluene (500 ml) was added to the residue and the toluene layer was washed with water (3 x 300 ml), decolourised with activated charcoal. The decolourised toluene layer was concentrated on rotavapor at 80-90 °C/150 mm to a minimal volume of ~ 200 ml. The concentrated solution was cooled to 0-5 °C under stirring and the precipitated solid was filtered and dried in a vacuum dessicator to yield 2-[phenoxazin-10- yl]ethanol of the formula (6) appears as white crystalline solid (weighs about 71-76 g, yield 57-61 %, mp. 105-107 °C, purity 99 % by HPLC). The IR, 1H-NMR data are consistent with assigned structure.

Step (ii) : Preparation of 2-rphenoxazin-10-yl]ethylmethane sulphonate of the formula (1) :

In a 2 L, 4 necked round bottom flask fitted with a mechanical stirrer and condenser, 2-[phenoxazin-10-yl]ethanol (170 g) and ethylacetate (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 minutes at room temperature with stirring. Methane sulphonyl chloride (107 g ~ 73 ml) was added to the reaction mixture at 5-10 °C under stirring in about 30 minutes. The reaction mass was maintained at 25 °C for 3 hours monitoring the reaction by TLC. Demineralised water (300 ml) was added, followed by fresh ethylacetate (800 ml) and stirred for 30 minutes. The organic layer was separated, washed with demineralised water (2 x 200 ml), dried over Na SO₄ and concentrated under reduced pressure in a rotavapor to a volume of ~ 350 ml. Hexane (~ 600 ml) was added to a concentrated solution of organic layer at 10-15 °C under stirring. The precipitated solid was filtered and dried in a vacuum dessicator to yield 2-[phenoxazin-10-yl]ethylmethane sulphonate of the formula (1) (weighs about 222 g, yield 97.3 %, mp. 81-82 °C, purity 99 % by HPLC). The LR, 1H-NMR data are consistent with assigned structure.

5

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 chromatographic is totally avoided resulting in i o 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 15 quick preparation of the compounds of formula ( 1 ).

Claims

Claims :

1. An improved process for the preparation of 2-[phenoxazin-10- yl]ethylmethane sulphonate of the formula (1)

which comprises : i). N-alkylating the lOH-phenoxazine of the formula (3)

with 2-haloethanol of the formula (5)

,OH

X' ^ (5) wherein the X represents halogen atom in the presence of a polar aprotic solvent and a nucleophilic organic or inorganic base to get 2-[phenoxazin-10-yl]ethanol of the formula (2),

ii) mesylating the 2-[phenoxazin-10-yl]ethanol of the formula (2) obtained in step (i) to the 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.

2. The process as claimed in claim 1, wherein N-alkylation in step (i) is carried out using reagents such as 2-bromoethanol, 2-chloroethanol or 2-iodoethanol.

3. The process as claimed in claim 1 and 2, wherein the -alkylation in step (i) is carried out in the presence of polar aprotic solvents selected from the group consisting of DMF, DMSO or DMAc

4. The process as claimed in claims 1 to 3, wherein the nucleophilic base used in step (i) is selected from the group consisting of organic bases such as t-BuOK or sodium methoxide; inorganic bases such as sodium hydride, KOH or NaOH.

5. The process as claimed in claims 1 to 4, wherein in step (i) the base NaH is used in ratio of 1:2 to 1:5 and the 2-haloethanol is employed in the ration of 1:3 to

1:2.

6. The process as claimed in claims 1 to 5, wherein the mesylation in step (ii)is carried out in the presence of solvent such as DCM, toluene or ethylacetate

7. The process as claimed in claims 1 to 6, wherein the base used in step (ii) is selected from the group consisting of triethylamine or tributylamine.