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

Even before the first synthesis of Phenoxazine, reported in 1887 by Bernthsen (Ber.

Deut. Chem. Ges. 20,942,1887) two dye stuffs with phenoxazine ring system, Meldola's blue and gallocyanine were commercially available. After its discovery, however the chemistry of the phenoxazines remained dormant for nearly half a century. Only during the last 5 years this class of compounds have aroused renewed interest, as evidenced by the discovery of a biologically active novel antidiabetic compounds.

The classical method for preparation of lOH-phenoxazine, based upon Bernthsen's first synthesis is the pyrolytic condensation of 2-aminophenol of the formula (2) with catechols. Kehrmann and Neil (Ber. Deut. Chem. Ges., 47,3102,1914) pointed out, as early as 1914, that lOH-phenoxazine can be obtained by heating simply an equimolar mixture of 2-aminophenol and 2-aminophenol HC1 salt without catechol.

It was demonstrated later that the pyrolytic reaction takes place always between two molecules of 2-aminophenol and experimental evidence for this was obtained by the isolation of intermediate 2,2'-dihydroxy diphenylamine of the formula (3) [Compt.

Rend., 252,3274 (1961) ; Bull. Soc. Chim. France p2871 (1963)]. The reaction is shown in Scheme-1 below:

Scheme-1 By investigating the influence of the acid strength of various proton donor catalysts on the kinetics of the reaction, [Compt. Rend. 252,3274 (1961)] showed that the reaction rate increases with decreasing pka, however the yields of lOH-phenoxazine did not exceed 30 %.

A better and more recent procedure for the synthesis of unsubstituted 1OH- phenoxazine involves auto condensation of 2-aminophenol in the presence of iodine, with elimination of ammonia and water. This reaction is also assumed to proceed through an intermediate diphenylamine of the formula (3) [J. Org. Chem., 24,37 (1959); Zh obshch. Khim. 31,1492, (1961)] The following disadvantages have been observed during the scale up of the process for the preparation of the compound of the formula (1).

1. The preparation of lOH-phenoxazine although starts from neat reaction of 2- aminophenol of the formula (2) and 2-aminophenol HC1 at 280-290 °C, both 2- aminophenol and resulting lOH-phenoxazine of the formula (1) sublimes at this temperature and deposits on the necks, walls of the flasks which results in choking the vent thus making the process unsafe for scale-up operations as well as adversely effecting the efficiency of the process.

2. The reaction mass becomes very hard, pasty black mass, making it practically impossible to stir the mixture which results in the decomposition of the reaction mixture to some extent. Such a situation also adversely effects the efficiency of the process.

3. The work up of the reaction mixture involves pouring the mixture into a mortar and the solid obtained on cooling was ground and extracted with toluene. The toluene layer was washed with aqueous solution of sodium hydrogen sulfite, then several times with aqueous NaOH to remove any unreacted 2-aminophenol and finally with water. This workup methodology is time consuming, laborious leading to the formation of highly dark colored emulsion at washing stage which inturn makes the separation of the layer very difficult.

4. lOH-phenoxazine obtained has to be purified by either column chromatography or by vacuum distillation of the residue obtained after concentration. This step is an additional one making the process expensive. Further, the problem of sublimation of lOH-phenoxazine during the distillation stage still exists.

Poland patent PL 154807 describes a method for the preparation of 1OH- phenoxazine by photolysis. According to this method, lOH-phenoxazine of the formula (I) is prepared by irradiation of 10~1 to 10-4 mol/cc solution of (ß5- cyclopentadienyl) (16-phenoxazine) iron hexafluorophosphate in deoxygenated polar solvents like MeOH, DMSO or THF with light in the ? = 200-720 nm range for atleast 10 h. This process has the following disadvantages. i) Photolysis of solution at (P5-cyclopentadienyl) (P6-phenoxazine) iron hexafluorophosphate is carried out under very large dilution. Requirement of such a large dilution makes the process practically impossible for using it on a commercial scale. ii) The resultant lOH-phenoxazine has to be purified by column chromatography which is not only an additional step but also impractical for commercial scale application.

Objective of the invention The main objective of the present invention is to provide a process for the preparation of lOH-phenoxazine of the formula (1), which is simple and efficient avoiding the sublimation of the starting materials and the l OH-phenoxazine formed.

Still another objective of the present invention is to provide an improved process for the preparation of 10H-phenoxazine of the formula (1) avoiding the employment of column chromatography, thereby making the process simple and economical.

Therefore, we directed our research work to develop a process for the preparation of the said compound of formula (1) with the objective of developing efficient, economical and commercially viable process employing cheap and easily available raw materials, involving simple reaction steps.

The present invention is based on our finding that the self condensation of 2- aminophenol is solvent and temperature specific. Accordingly, we observed that if the self condensation of 2-aminophenol is effected in the presence of iodine and diphenyl ether, the process becomes simple and economical and the sublimation is almost completely avoided. Further, we also observed that if the above reaction mixture contains additionally high boiling polar protic solvents such as polyethylene glycol and polypropylene glycol, the sublimation can be completely avoided. It is also observed that this reaction is also proceeded through the formation of an intermediate diphenylamine of the formula (3).

The above finding is pertinent, considering the fact that self condensation of 2- aminophenol did not occur solely in the presence of polar, protic high boiling organic solvents like polyethylene glycol, polypropylene glycol at the temperature of 250-280 °C. Similarly, the self condensation of 2-aminophenol does not also take place, in the presence of inert solvents like 1,2-dichlorobenzene at a temperature of 180-190 °C. In the case of paraffin oil the reaction of self condensation even though

initiated, the problem of sublimation and decomposition of reaction mixture persisted, as the oil has poor vaporization property. In the case of solvent like sulfolan, the self condensation of 2-aminophenol of the formula (2), even though proceeded well and addressed the problem of sublimation but for all practical purposes this solvent cannot be employed for commercial application as it is very expensive and also produces a foul sulfur smell during the reaction.

Further research on the preparation of lOH-phenoxazine yielded interesting results with high power microwave irradiation. It was observed that subjecting, either 2- aminophenol or a mixture of 2-aminophenol and an equimolar quantity of its hydrochloride salt to high power microwaves yielded 10H-phenoxazine in-30-40 % yield in just 5-10 minutes. Furthermore, this microwave technology was further extended from a batch process to a continuous process employing a focused microwave reactor. Microwave technique was found to be equally competent in neat as well as in the presence of a solvent. Solvents such as polyethylene glycols, sulfolan, diphenylether and mixtures thereof can be employed for microwave irradiation.

Accordingly, the present invention provides an improved process for the preparation of lOH-phenoxazine of the formula (1), which comprises : (i) self condensing 2-aminophenol of the formula (2) or condensing 2- aminophenol of the formula (2) with 2-aminophenol hydrochloride in the presence of iodine and diphenyl ether (as a solvent) with or without additional high boiling polar protic solvents at a temperature in the range of 250 to 280 °C and (ii) recovering the resulting lOH-phenoxazine in a known manner by soxhlet or liquid-liquid extraction.

In a preferred embodiment of the present invention the reaction in step (i) may be effected in the presence of high boiling polar protic solvents such as diethylene glycol, polyethylene glycol, polypropylene glycol and the like. The amount of high boiling polar protic solvents employed may range from 2 to 5 %.

In a preferred embodiment of the present invention the compound of formula (2) and diphenyl ether is used in the ratio of 1 : 1 to 1 : 1.25 In another embodiment of the present invention there is provided an alternate process for the preparation of 1OH-phenoxazine of the formula (1), which comprises (i) self condensing 2-aminophenol of the formula (2) or condensing 2- aminophenol of the formula (2) with 2-aminophenol hydrochloride in the presence or absence of a solvent using a microwave reactor and (ii) recovering the resulting lOH-phenoxazine in a known manner by soxhlet or liquid-liquid extraction.

In a preferred embodiment of the present invention the reaction in step (i) may be effected in the presence or absence of solvents such as diphenyl ether, diethylene glycol, polyethylene glycol, polypropylene glycol and the like.

The soxhlet extraction may be effected employing agents such as silica gel and neutral alumina. The solvent used for soxhlet extraction may be selected from petroleum ether, toluene, pet ether, ethyl acetate and the like or mixtures thereof. Out of all solvents employed for Soxhlet extraction, petroleum ether is the preferred solvent in terms of yield and purity of lOH-phenoxazine isolated. Similarly, the liquid-liquid extraction may be carried out by dissolving in methanol containing 5 % water.

The details of the process of the present invention is described in the examples 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 A mixture of 2-aminophenol (300 g), Iodine (3 g) and diphenyl ether (300 ml) were taken into 2 L, 4 necked round bottom flask fitted with a mechanical stirrer, Dean stark apparatus and a reflux condenser. The reaction mass was slowly heated to 260- 270 °C under stirring and. the reaction mixture was maintained at this temperature for 20-24 h, with frequent removal of water. As the reaction progresses, ammonia vapors are evolved. The reaction was monitored by TLC. The reaction mixture was brought to 80-100 °C temperature and methanol (500 ml) was added for homogenization of the reaction mass. 60-120 Mesh silica gel (300 g) was added to this homogenised mixture under stirring and methanol was concentrated under reduced pressure at 60-70 °C. The uniformly dispersed reaction mass on silica gel free from methanol is packed into a thimble made of nylon filtration cloth of mesh 150 and extracted with petroleum ether and ethyl acetate mixture (97: 3) (5 L) using soxhlet apparatus for about 10-12 h, monitoring the extract on TLC. The petroleum ether, ethyl acetate mixture was concentrated on rotavapor at 60-70 °C/150-200 mm vacuum to a volume of 250-400 ml. The concentrated layer was cooled to 0-5 °C under stirring for 30 min and the precipitated solid was filtered, washed with chilled petroleum ether (200-250 ml), dried in hot air oven at 60-70 °C to yield 10H- phenoxazine appeared as dull white solid, (weighed about 90-100 g, yield 36-40 %, m. p. 154-156 °C (rep: 156 °C), purity 98-99 % by HPLC).

The petroleum ether washings and mother liquor were mixed, concentrated under reduced pressure at 60-70 °C. The residue was cooled to 0-5 °C, under stirring, for 30 min. The precipitated solid was filtered and dried. lOH-phenoxazine isolated as crop II appeared as dull white solid, weighed about 15-25 g, yield 6-10 %, m. p. 152-

154 °C (rep 156 °C), purity 96-98 % by HPLC. The filtrate was distilled at a temperature of 110-120 °C under vacuum 5-10 mm and the vapour of diphenyl ether was collected at 85-90 °C. Diphenyl ether (230 ml) was recovered (75 % recovery), which was of purity 99 % by GC, 0.2 % MC. The recovered diphenyl ether was good enough to use for the next reaction.

Example-2 2-Aminophenol (300 g), Iodine (3 g) and 300 ml mixture of diphenyl ether and polyethylene glycol 200 in 98: 2 ratio were taken into 2 L, 4 necked round bottom flask fitted with a mechanical stirrer, Dean stark apparatus and a reflux condenser.

The reaction mass was slowly heated to 260-270 °C under stirring and the reaction mixture was maintained at this temperature for 20-24 h, with frequent removal of water. As the reaction progresses, ammonia vapors are evolved. The reaction was monitored by TLC. The reaction mixture was brought to 80-100 °C temperature and methanol (500 ml) was added for homogenization of the reaction mass. 60-120 Mesh silica gel (300 g) was added to this homogenised mixture under stirring and methanol was concentrated under reduced pressure at 60-70 °C. The uniformly dispersed reaction mass on silica gel free from methanol was packed into a thimble made of nylon filtration cloth of mesh 150 and extracted with 5 L petroleum ether and ethyl acetate mixture (97: 3) using Soxhlet apparatus for about 10-12 h, monitoring the extract on TLC. The petroleum ether, ethyl acetate mixture was concentrated on rotavapor at 60-70 °C/150-200 mm vacuum to a volume of 250- 400 ml. The concentrated layer was cooled to 0-5 °C under stirring for 30 min and the precipitated solid was filtered, washed with chilled petroleum ether (200-250 ml), and dried in hot air oven at 60-70 °C to yield lOH-phenoxazine appeared as dull white solid, (weighed about 90-100 g, yield 36-40 %, m. p. 154-156 °C (rep: 156 °C), purity 97-99 % by HPLC).

The petroleum ether washings and mother liquor were mixed, concentrated under reduced pressure at 60-70 °C. The residue was cooled to 0-5 °C, under stirring, for 30 min. The precipitated solid was filtered and dried. lOH-phenoxazine isolated as crop II appeared as dull white solid, weighed about 15-25 g, yield 6-10 %, m. p. 152- 154 °C (rep 156 °C), purity 96-98 % by HPLC. The filtrate was distilled at a temperature of 110-120 °C under vacuum 5-10 mm and the vapors of diphenyl ether were collected at 85-90 °C. Diphenyl ether (230 ml) was recovered (75 % recovery), which was of purity 99 % by GC, 0.2 % MC. The recovered diphenyl ether was good enough to use for the reaction.

Example-3 2-Aminophenol (300 g), Iodine (3 g) and 300 ml mixture of diphenyl ether and polyethylene glycol 200 in 98: 2 ratio were taken into 2 L, 4 necked round bottom flask fitted with a mechanical stirrer, Dean stark apparatus and a reflux condenser.

The reaction mass was slowly heated to 260-270 °C under stirring and the reaction mixture was maintained at this temperature for 20-24 h, with frequent removal of water. As the reaction progresses, ammonia vapors are evolved. The reaction was monitored by TLC. The reaction mixture was brought to 80-100 °C temperature and 2.5 L 95 % methanol, water mixture was added for dissolution of the reaction mixture and this solution was passed through celite bed for removal of any insoluble particles. The aqueous methanol layer was extracted with petroleum ether (5-7 L) using liquid/liquid extractor of 20 L capacity for about 10-12 h, monitoring the extracts on TLC. The petroleum ether was concentrated on rotavapor at 60-70 °C/ 150-200 mm vacuum to a volume of 250-400 ml. The concentrated layer was cooled to 0-5 °C under stirring for 30 min and the precipitated solid was filtered, washed with chilled petroleum ether (200-250 ml) and dried in hot air oven at 60-70 °C to yield lOH-phenoxazine appeared as dull white solid, (weighed about 105-110 g, yield 42-44 %, m. p. 154-156 °C (rep: 156 °C), purity 98-99 % by HPLC).

The petroleum ether washings and mother liquor were mixed, concentrated under reduced pressure at 60-70 °C. The residue was cooled to 0-5 °C, under stirring, for 30 min. The precipitated solid was filtered and dried. l OH-phenoxazine isolated as crop II appeared as dull white solid, weighed about 15-25 g, yield 6-10 %, m. p. 152- 154 °C (rep 156 °C), purity 96-98 % by HPLC. The filtrate was distilled at a temperature of 110-120 °C under vacuum 5-10 mm and the vapour of diphenyl ether was collected at 85-90 °C. Diphenyl ether (230 ml) was recovered (75 % recovery), which was of purity 99 % by GC, 0.2 % MC. The recovered diphenyl ether was good enough to use for the reaction.

Example-4 2-Aminophenol (300 g) in a loosely capped petri dish was subjected to microwave irradiation at high power setting for a period of 4-6 minutes during which period the contents of the petri dish became a viscous liquid and the reaction was found to be complete by TLC. The reaction mixture was brought to 80-100 °C temperature and 2.5 L of 95 % methanol, water mixture was added for dissolution of the reaction mixture and this solution was passed through celite bed for removal of any insoluble particles. The aqueous methanol layer was extracted with petroleum ether (5-7 L) using liquid/liquid extractor of 20 L capacity for about 10-12 h, monitoring the extracts on TLC. The petroleum ether was concentrated on rotavapor at 60-70 °C/ 150-200 mm vacuum to a volume of 250-400 ml. The concentrated layer was cooled to 0-5 °C under stirring for 30 min and the precipitated solid was filtered, washed with chilled petroleum ether (200-250 ml) and dried in hot air oven at 60-70 °C to yield 10H-phenoxazine appeared as dull white solid, (weighed about 75 g, yield 30 %, m. p. 154-155 °C (rep: 156 °C), purity 97-99 % by HPLC).

The petroleum ether washings and mother liquor were mixed, concentrated under reduced pressure at 60-70 °C. The residue was cooled to 0-5 °C, under stirring, for 30 min. The precipitated solid was filtered and dried. lOH-phenoxazine isolated as

crop II appeared as dull white solid, weighed about 15-25 g, yield 6-10 %, m. p. 152- 154 °C (rep 156 °C), purity 96-98 % by HPLC.

Example-5 A mixture of 2-aminophenol (150 g) and 2-aminophenol hydrochloride (200 g) in a loosely capped petri dish was subjected to microwave irradiation at high power setting for a period of 4-6 minutes during which period the contents of the petri dish became a viscous liquid and the reaction was found to be complete by TLC. The reaction mixture was brought to 80-100 °C temperature and 2.5 L of 95 % methanol, water mixture was added for dissolution of the reaction mixture and this solution was passed through celite bed for removal of any insoluble particles. The aqueous methanol layer was extracted with petroleum ether (5-7 L) using liquid/liquid extractor of 20 L capacity for about 10-12 h, monitoring the extracts on TLC. The petroleum ether was concentrated on rotavapor at 60-70 °C/150-200 mm vacuum to a volume of 250-400 ml. The concentrated layer was cooled to 0-5 °C under stirring for 30 min and the precipitated solid was filtered, washed with chilled petroleum ether (200-250 ml) and dried in hot air oven at 60-70 °C to yield 10H- phenoxazine appeared as dull white solid, (weighed about 105 g, yield 36 %, m. p.

154-155 °C (rep: 156 °C), purity 97-99 % by HPLC).

The petroleum ether washings and mother liquor were mixed, concentrated under reduced pressure at 60-70 °C. The residue was cooled to 0-5 °C, under stirring, for 30 min. The precipitated solid was filtered and dried. lOH-phenoxazine isolated as crop II appeared as dull white solid, weighed about 15-25 g, yield 6-10 %, m. p. 152- 154 °C (rep 156 °C), purity 96-98 % by HPLC.

Example-6 2-Aminophenol (300 g) and diethylene glycol (300 ml) in a loosely capped petri dish was subjected to microwave irradiation at high power setting for a period of 4-6

minutes during which period the contents of the petri dish became a viscous liquid and the reaction was found to be complete by TLC. The reaction mixture was brought to 80-100 °C temperature and 2.5 L of 95 % methanol, water mixture was added for dissolution of the reaction mixture and this solution was passed through celite bed for removal of any insoluble particles. The aqueous methanol layer was extracted with petroleum ether (5-7 L) using liquid/liquid extractor of 20 L capacity for about 10-12 h, monitoring the extracts on TLC. The petroleum ether was concentrated on rotavapor at 60-70 °C/150-200 mm vacuum to a volume of 250- 400 ml. The concentrated layer was cooled to 0-5 °C under stirring for 30 min and the precipitated solid was filtered, washed with chilled petroleum ether (200-250 ml) and dried in hot air oven at 60-70 °C to yield lOH-phenoxazine appeared as dull white solid, (weighed about 75 g, yield 30 %, m. p. 154-155 °C (rep: 156 °C), purity 97-99 % by HPLC).

The petroleum ether washings and mother liquor were mixed, concentrated under reduced pressure at 60-70 °C. The residue was cooled to 0-5 °C, under stirring, for 30 min. The precipitated solid was filtered and dried. lOH-phenoxazine isolated as crop II appeared as dull white solid, weighed about 15-25 g, yield 6-10 %, m. p. 152- 154 °C (rep 156 °C), purity 96-98 % by HPLC.

Exaniple-7 A mixture of 2-aminophenol (150 g), 2-aminophenol hydrochloride (200 g) and diethylene glycol (300 ml) in a loosely capped petri dish was subjected to microwave irradiation at high power setting for a period of 4-6 minutes during which period the contents of the petri dish became a viscous liquid and the reaction was found to be complete by TLC. The reaction mixture was brought to 80-100 °C temperature and 2.5 L of 95 % methanol, water mixture was added for dissolution of the reaction mixture and this solution was passed through celite bed for removal of any insoluble particles. The aqueous methanol layer was extracted with petroleum ether (5-7 L)

using liquid/liquid extractor of 20 L capacity for about 10-12 h, monitoring the extracts on TLC. The petroleum ether was concentrated on rotavapor at 60-70 °C/ 150-200 mm vacuum to a volume of 250-400 ml. The concentrated layer was cooled to 0-5 °C under stirring for 30 min and the precipitated solid was filtered, washed with chilled petroleum ether (200-250 ml) and dried in hot air oven at 60-70 °C to yield lOH-phenoxazine appeared as dull white solid, (weighed about 105 g, yield 36 %, m. p. 154-155 °C (rep: 156 °C), purity 97-99 % byHPLC).

The petroleum ether washings and mother liquor were mixed, concentrated under reduced pressure at 60-70 °C. The residue was cooled to 0-5 °C, under stirring, for 30 min. The precipitated solid was filtered and dried. lOH-phenoxazine isolated as crop II appeared as dull white solid, weighed about 15-25 g, yield 6-10 %, m. p. 152- 154 °C (rep 156 °C), purity 96-98 % by HPLC.

Advantages of the present invention: 1. The process does not require washing with organic layer, aqueous NaOH and column purification/vacuum distillation of the product and thereby making the process simple and economical.

2. The process is very effective in terms of time wherein the reaction is complete in just 5-10 minutes by employing a microwave reactor.

3. The process is very safe as there is no problem of sublimation of 2- aminophenol.

4. The solvent used for soxhlet extraction or liquid/liquid extraction can be recycled. Further the column chromatography method of purification is not required. This makes the process economical.