Field of the invention:

The present invention provides a process for the preparation of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine compound represented by the following structural formula-1 and its pharmaceutically acceptable salts.

Formula-1 The present invention further relates to crystalline form of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine hydrochloride salt compound of formula-la.

Background of the invention:

2-Amino-4,4-disubstituted-4H-3,l-benzoxazine compounds and process for their preparation was first disclosed in US3725404A, herein after referred as '404' patent. The disclosed process involves the reaction of 2-amino-5-chloro benzophenone with methyl magnesium iodide to provide l-(2-amino-5-chlorophenyl)-l-phenylethanol, which on further reaction with isothiocyanatoethane in ether provides (Z)-N-(4-chloro-2-(l-hydroxy-1-phenylethyl)phenyl)-N'-ethylcarbamimidothioic acid. The resulting compound on cyclization with mercury oxide in refluxing ethanol produces 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,1-benzoxazine.

This patent generically discloses the conversion of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine compounds into their pharmaceutically acceptable acid addition salts such as hydrochloride salt. Further this patent didn't provide the process for the preparation of said acid addition salts.

The process disclosed in the above said '404' patent involves the usage of mercury oxide for the cyclization step, which is a toxic reagent. It has effects on kidneys resulting in kidney impairment. Mercury oxide on heating produces highly toxic mercury fumes and oxygen, which increases the fire hazard. Further mercury oxide is a costly reagent. Hence, it is not suggestible to use mercury oxide on industrial scale in safety and economic point of view.

Hence there is a need in the art to develop a process for the preparation of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine by utilizing safer and inexpensive reagents.

Polymorphs are distinct solids having the same molecular formula yet having distinct advantageous physical properties compared to other polymorphic forms of the same compound. The difference in the physical properties of different polymorphic forms results from the orientation and intermolecular interactions of adjacent molecules in the bulk solid.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphic forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption and solid state NMR spectrum. One polymorphic form may give rise to thermal behavior different from that of another polymorphic form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) as well as content of solvent in the polymorphic form, which have been used to distinguish polymorphic forms.

Till date no polymorphic forms are reported for 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine hydrochloride. Hence there is a need in the art to provide polymorphs of the same, which shows advantageous properties in the formulation process such as flowability, solubility, and chemical purity; stability such as storage stability, polymorph stability, low hygroscopicity and low content of residual solvents.

Brief description of the invention:

The first aspect of the present invention is to provide a process for the preparation of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine hydrochloride compound of formula-la, comprising of;

a) Reaction of 2-amino-5-chloro benzophenone compound of formula-2 with methyl
magnesium halide (halogen= Cl, Br or I) in a suitable solvent to provide l-(2-amino-5-chlorophenyl)-l-phenylethanol compound of formula-3,

b) reacting the compound of formula-3 with isothiocyanatoethane in a suitable solvent to provide (Z)-N-(4-chloro-2-(1 -hydroxy-1-phenylethyl)phenyl)-N'-ethylcarbamimidothioic acid compound of formula-4,

c) cyclization of (Z)-N-(4-chloro-2-(l-hydroxy-l-phenylethyl)phenyl)-N'-ethylcarbamimidothioic acid compound of formula-4 in presence of manganese dioxide in a suitable solvent to provide 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine compound of formula-1,

d) converting the compound of formula-1 into its hydrochloride salt compound of formula-la by treating it with a suitable HC1 source in a suitable solvent.

The second aspect of the present invention is to provide a process for the preparation of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine compound of formula-1, comprising of cyclization of (Z)-N-(4-chloro-2-(l-hydroxy-l-phenylethyl)phenyl)-N'-ethyl carbamimidothioic acid compound of formula-4 in presence of manganese dioxide in a suitable solvent to provide 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine compound of formula-1.

The third aspect of the present invention is to provide Etifoxine hydrochloride in crystalline form.
The fourth aspect of the present invention is to provide a process for the purification of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine hydrochloride salt compound of formula-la.
The fifth aspect of the present invention is to provide a process for the preparation of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine hydrochloride salt compound of formula-la, comprising of treating the 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine compound of formula-1 with a suitable HC1 source in a suitable solvent.

Brief description of the drawings:

Figure-1: Illustrates the X-Ray powder diffraction pattern of crystalline form-M of
Etifoxine hydrochloride.

Figure-2: Illustrates the DSC thermogram of crystalline form-M of Etifoxine hydrochloride.

Detailed description of the invention:

The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethylether, diethylether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate and the like; "polar-aprotic solvents" such as dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, dioxane, acetonitrile and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, t-butanol and the like; "polar solvents" such as water; and/or their mixtures thereof.

As used herein the present invention the term "suitable base" refers to "alkali metal carbonates" such as sodium carbonate, potassium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium tert.butoxide and the like; "alkali metal phosphates" such as disodium hydrogen phosphate, dipotassium hydrogen phosphate and "organic bases" like diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine and the like.

The first aspect of the present invention provides a process for the preparation of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine hydrochloride compound of formula-la, comprising of;

a) Reaction of 2-amino-5-chloro benzophenone compound of formula-2

Formula-2 with methyl magnesium halide (halogen= Cl, Br or I) in a suitable solvent to provide l-(2-amino-5-chlorophenyl)-l-phenylethanol compound of formula-3,

Formula-3

b) reacting the compound of formula-3 with isothiocyanatoethane in a suitable solvent to provide (Z)-N-(4-chloro-2-(1 -hydroxy-1-phenylethyl)phenyl)-N'-ethylcarbamimidothioic acid compound of formula-4,

Formula-4
c) cyclization of (Z)-N-(4-chloro-2-(l-hydroxy-l-phenylethyl)phenyl)-N'-ethylcarbamimidothioic acid compound of formula-4 in presence of manganese dioxide in a suitable solvent to provide 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine compound of formula-1,
d) converting the compound of formula-1 into its hydrochloride salt compound of formula-la by treating it with a suitable HC1 source in a suitable solvent.

Formula-la
Wherein, in step-a) the suitable solvent can be selected from ether solvents, hydrocarbon solvents, chloro solvents, ester solvents and/or their mixtures thereof;

in step-b) the suitable solvent can be selected from hydrocarbon solvents, ether solvents, ester solvents and/or their mixtures thereof;

in step-c) the suitable solvent can be selected from alcoholic solvents, polar-aprotic solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents and/or their mixtures thereof;

in step-d) the suitable HC1 source is selected from HC1 gas, dry HC1, aq.HCl, ethyl acetate-HCl, isopropyl alcohol-HCl; and the suitable solvent can be selected from ketone solvents, ester solvents, alcoholic solvents, polar-aprotic solvents and/or their mixtures thereof.

A preferred embodiment of the present invention provides a process for the preparation of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine hydrochloride compound of formula-la, comprising of;

a) Reaction of 2-amino-5-chloro benzophenone compound of formula-2 with methyl magnesium chloride in tetrahydrofuran to provide l-(2-amino-5-chlorophenyl)-l-phenylethanol compound of formula-3,

b) reacting the compound of formula-3 with isothiocyanatoethane in cyclohexane to provide (Z)-N-(4-chloro-2-(1 -hydroxy-1 -phenylethyl)phenyl)-N'-ethylcarbamimidothioic acid compound of formula-4,

c) cyclization of (Z)-N-(4-chloro-2-(l-hydroxy-l-phenylethyl)phenyl)-N'-ethylcarbamimidothioic acid compound of formula-4 in presence of manganese dioxide in acetonitrile or methanol to provide 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine compound of formula-1,

d) converting the compound of formula-1 into its hydrochloride salt compound of formula-la by treating it with ethyl acetate-HCl in a mixture of cyclohexane and acetone.

The following impurities were observed during the synthesis of Etifoxine as per the present invention.

Des chloro impurity Methyl impurity Olefin impurity

Des methyl impurity Thioic acid impurity

All the above impurities are well controlled in the final compound synthesized as per the present invention.

The 2-amino-5-chloro benzophenone compound of formula-2 used as starting material in the above process can be synthesized by any of the methods known in the art, for example it can be synthesized by the methods as disclosed in JP1987-116549A, JP1987-114944A and the like.

The second aspect of the present invention provides a process for the preparation of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine compound of formula-1, comprising of cyclization of (Z)-N-(4-chloro-2-(l-hydroxy-l-phenylethyl)phenyl)-N'-ethylcarbamimidothioic acid compound of formula-4 in presence of manganese dioxide in a suitable solvent selected from alcoholic solvents, polar-aprotic solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents and/or their mixtures to provide 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine compound of formula-1.

A preferred embodiment of the present invention provides a process for the preparation of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,1-benzoxazine compound of formula-1, comprising of cyclization of (Z)-N-(4-chloro-2-(l-hydroxy-l-phenylethyl)phenyl)-N'-ethylcarbamimidothioic acid compound of formula-4 in presence of manganese dioxide in methanol or acetonitrile to provide 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine compound of formula-1.

The third aspect of the present invention provides Etifoxine hydrochloride in crystalline form, herein designated as crystalline form-M characterized by the PXRD pattern having peaks at about 11.3, 12.3, 14.1, 20.7, 23.5, 24.1, 25.8, 27.3, 29.3 ± 0.2 degrees of 2-theta values. This crystalline form-M is further characterized by the PXRD pattern having peaks at about 13.7, 17.7, 18.4, 19.7, 20.0, 23.0, 29.8, 31.1, 34.0, 42.6 ± 0.2 degrees of 2-theta values. The PXRD pattern of crystalline form-M is illustrated in figure-1. The crystalline form-M of Etifoxine hydrochloride is further characterized by its DSC pattern as illustrated in figure-2.

The fourth aspect of the present invention provides a process for the purification of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine hydrochloride compound of formula-la, comprising of;

a) Adding acetonitrile to 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine hydrochloride,

b) heating the reaction mixture,

c) stirring the reaction mixture,

d) treating the reaction mixture with charcoal,

e) cooling the reaction mixture,

f) filtering the solid followed by washing with acetonitrile to provide pure 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine hydrochloride compound of formula-la.

The fifth aspect of the present invention provides a process for the preparation of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine hydrochloride salt compound of formula-la, comprising of treating the 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l- benzoxazine compound of formula-1 with a suitable HC1 source selected from HC1 gas, dry HC1, aq.HCl, ethyl acetate-HCl and isopropyl alcohol-HCl in a suitable solvent selected from hydrocarbon solvents, ketone solvents, alcoholic solvents, ester solvents and/or their mixtures thereof.

A preferred embodiment of the present invention provides a process for the preparation of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine hydrochloride salt compound of formula-la, comprising of treating the 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine compound of formula-1 with ethyl acetate-HCl in a mixture of cyclohexane and acetone

The PXRD analysis of the crystalline Etifoxine hydrochloride of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using CuKα radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.

Differential scanning calorimetric (DSC) analysis was performed with Q10 V9.6 Build 290 calorimeter. Samples of about 2 to 3 milligrams, held in a closed pan, were analyzed at a heating rate of 10°C per minute.

The particle size distribution of Etifoxine hydrochloride is measured using Malvern Mastersizer 2000 instrument.

Etifoxine hydrochloride of the present invention was analyzed by HPLC under the following conditions;
Apparatus: A liquid chromatograph equipped with variable wavelength UV-detector; Column: Symmetry C18, 250x4.6 mm, 5μm or equalent; Flow rate: l.0mL/min; Wavelength: 258 nm; Column temperature: 25°C; Injection volume: 20μL; Run time: 35 min (for reference solution), 70 min (for blank, SST and test solution); Diluent: Buffer: Acetonitrile (25:75 v/v); Elution: Isocratic; Buffer: Transfer lmL of ortho phosphoric acid in 1000 mL of milli-Q water and adjust pH 6.5 with triethyl amine. Filter this solution through 0.22μm Nylon membrane filter paper; Mobile phase: Buffer: Acetonitrile (50:50 v/v).

Etifoxine hydrochloride produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball mills, roller and hammer mills and jet mills. Milling or micronization may be performed before drying or after the completion of drying of the product. The present invention is schematically represented as follows.

Synthetic scheme:
Here 'X' represents Cl, Br or I.

The best mode of carrying out the present invention is illustrated by the below mentioned examples.

These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.

Examples:
Example-1: Process for the preparation of l-(2-amino-5-chlorophenyl)-l-phenylethanol (Formula-3)

A solution of 2-amino-5-chloro benzophenone (100 gm) dissolved in tetrahydrofuran (400 ml) was slowly added to a mixture of methyl magnesium chloride (400 gm) in tetrahydrofuran (100 ml) at 0-5°C under N2 atmosphere and stirred for 2 hrs at the same temperature. After the completion of the reaction, the reaction mixture was quenched with 10% ammonium chloride solution. The pH of the reaction mixture was adjusted to 6.0-6.5 with 10% acetic acid solution at 0-10°C. Raised the temperature of the reaction mixture to 25-35°C and extracted with methylene chloride. Both the organic and aqueous layers were separated, washed the organic layer with water and dried over sodium sulfate. Distilled off the organic layer and cyclohexane (100 ml) was added. Distilled off the solvent under reduced pressure and cyclohexane (200 ml) was added. Heated the reaction mixture to reflux and stirred for 30 min at the same temperature. The reaction mixture was cooled to 20-3 0°C and stirred for 2 hrs at the same temperature.

Filtered the precipitated solid, washed with cyclohexane and dried to get the title compound. Yield: 91.5 gm.

Example-2: Process for the preparation of (Z)-N-(4-chIoro-2-(l-hydroxy-l-phenylethyI)phenyl)-N'-ethylcarbamimidothioic acid (Formula-4)

A mixture of cyclohexane (60 ml), l-(2-amino-5-chlorophenyl)-l-phenylethanol (20 gm) and isothiocyanatoethane (14.06 gm) was heated to 50-55°C and stirred for 8 hrs at the same temperature. After the completion of the reaction, cooled the reaction mixture to 25-30°C and stirred for 10 hrs at the same temperature. Water (20 ml) was added to the reaction mixture at 25-30°C, cooled to 10-15°C and stirred for 1 hr at the same temperature. Filtered the precipitated solid, washed with a mixture of cyclohexane and water and then dried to get the title compound. Yield: 24.0 gm.

Example-3: Process for the preparation of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,1-benzoxazine (Formula-1)

A mixture of acetonitrile (125 ml), (Z)-N-(4-chloro-2-(l-hydroxy-l-phenylethyl)phenyl)-

N'-ethylcarbamimidothioic acid (25 gm) and manganese dioxide (13 gm) was heated to 50-55°C and stirred for 3 hrs at the same temperature. After the completion of the reaction, filtered the reaction mixture through hyflow bed and distilled off the solvent from the filtrate under reduced pressure. Cooled the reaction mixture to 25-35°C, dichloromethane (75 ml) followed by water (25 ml) were added and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated, water (25 ml) was added to the organic layer and stirred for 30 min. Separated the organic layer and dried over sodium sulfate and distilled off the solvent under reduced pressure. Cyclohexane (25 ml) was added to the obtained residue and distilled off the solvent completely under reduced pressure.

Example-4: Process for the preparation of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,1-benzoxazine hydrochloride from acetonitrile (Formula-la)

Cyclohexane (125 ml) was added to the residue obtained in example-3 and cooled the reaction mixture to 25-35°C. Acetone (6 ml) was added to the reaction mixture and the pH of the reaction mixture was adjusted to 1.0-2.0 using ethyl acetate-HCl at 25-35°C and stirred for 14 hrs at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 1 hr at the same temperature. Filtered the precipitated solid and washed with cyclohexane. Water (100 ml) was added to the obtained compound at 25-30°C and stirred for 45 min at the same temperature. Filtered the solid, washed with water and then dried to get the title compound. Yield: 18.0 gm.

Exampie-5: Process for the preparation of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,1-benzoxazine hydrochloride from acetonitrile (Formula-la)

A mixture of acetonitrile (500 ml), (Z)-N-(4-chloro-2-(l-hydroxy-l-phenylethyl)phenyl)-N'-ethylcarbamimidothioic acid (100 gm) and manganese dioxide (51.92 gm) was heated to 50-55°C and stirred for 3 hrs at the same temperature. After the completion of the reaction, filtered the reaction mixture through hyflow bed and distilled off the solvent from the filtrate under reduced pressure. Cooled the reaction mixture to 25-35°C, dichloromethane (300 ml) followed by water (100 ml) were added and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated, water (100 ml) was added to the organic layer and stirred for 30 min. Separated the organic layer and dried over sodium sulfate and distilled off the solvent under reduced pressure. Cyclohexane (100 ml) was added to the obtained residue and distilled off the solvent completely under reduced pressure. Cyclohexane (500 ml) was added to the obtained residue and cooled the reaction mixture to 25-35°C. Acetone (25 ml) was added to the reaction mixture and the pH of the reaction mixture was adjusted to 1.0-2.0 using ethyl acetate-HC1 at 25-35°C and stirred for 14 hrs at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hr at the same temperature. Filtered the precipitated solid and washed with cyclohexane. Water (400 ml) was added to the obtained compound at 25-30°C and stirred for 45 min at the same temperature. Filtered the solid, washed with water and then dried to get the title compound. Yield: 74.0 gm.

Example-6: Process for the preparation of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,1-benzoxazine hydrochloride from methanol (Formula-la)

A mixture of methanol (500 ml), (Z)-N-(4-chloro-2-(l-hydroxy-l-phenylethyl)phenyl)-N'-ethylcarbamimidothioic acid (100 gm) and manganese dioxide (51.92 gm) was heated to 60-65°C and stirred for 3 hrs at the same temperature. After the completion of the reaction, filtered the reaction mixture through hyflow bed and distilled off the solvent completely from the filtrate under reduce pressure. Cooled the reaction mixture to 25-35°C, methylene chloride (300 ml) followed by water (100 ml) were added and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated. Water (100 ml) was added to the organic layer at 25-35°C and stirred for 30 min at the same temperature.

Separated the organic layer and dried over sodium sulfate and distilled off the solvent completely under reduced pressure. Cyclohexane (100 ml) was added to the obtained residue and distilled off the solvent completely under reduced pressure. 500 ml of cyclohexane was added to the obtained residue at below 45°C and cooled the reaction mixture to 25-35°C. Acetone (25 ml) was added to the reaction mixture and the pH of the reaction mixture was adjusted to 1.0-2.0 using ethyl acetate-HCl at below 25°C and stirred for 14 hrs at 25-35°C. Cooled the reaction mixture to 0-5°C and stirred for 1 hr at the same temperature. Filtered the reaction mixture and washed with cyclohexane. To the obtained compound, water (450 ml) was added at 25-35°C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with water and then dried to get the title compound. Yield: 84.0 gm; Purity by HPLC: 99.77%; Olefin impurity: 0.22%; Des chloro impurity: N/D;

Methyl impurity: N/D; Des methyl impurity: N/D; Thioic acid impurity: N/D

Example-7: Purification of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine hydrochloride (Formula-la)

To the 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine hydrochloride (75 gm) obtained in example-4, 300 ml of acetonitrile was added. Heated the reaction mixture to 55-60°C and stirred for 30 min at the same temperature. Carbon (5 gm) was added to the reaction mixture at 55-60°C and stirred for 30 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with acetonitrile. Cooled the filtrate to 25-35°C and stirred for 1 hr at the same temperature. The filtrate was further cooled to 0-5°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with acetonitrile and then dried to get pure title compound. The PXRD of the obtained compound is shown in figure-1. Yield: 70.0 gm;

Purity by HPLC: 99.97%; Des chloro impurity: N/D; Methyl impurity: N/D; Olefin impurity: 0.02%; Des methyl impurity: N/D; Thioic acid impurity: N/D Particle Size Distribution: D(0.1) is 21.06 μm; D(0.5) is 71.46 μm; D(0.9) is 153.57 μm.

We Claim:

1. A process for the preparation of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine hydrochloride compound of formula-la, comprising of; a) Reaction of 2-amino-5-chloro benzophenone compound of formula-2

Formula-2 with methyl magnesium halide (halogen= Cl, Br or I) in a suitable solvent selected from ether solvents, hydrocarbon solvents, chloro solvents, ester solvents and/or their mixtures thereof to provide l-(2-amino-5-chlorophenyl)-l-phenylethanol compound of formula-3,

Formula-3 b) reacting the compound of formula-3 with isothiocyanatoethane in a suitable solvent selected from hydrocarbon solvents, ether solvents, ester solvents and/or their mixtures thereof to provide (Z)-N-(4-chloro-2-(l-hydroxy-l-phenylethyl)phenyl)-N'-ethylcarbamimidothioic acid compound of formula-4,
Formula-4

c) cyclization of (Z)-N-(4-chloro-2-(l-hydroxy-l-phenylethyl)phenyl)-N'-ethyl carbamimidothioic acid compound of formula-4 in presence of manganese dioxide in a suitable solvent selected from alcoholic solvents, polar-aprotic solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents and/or their mixtures thereof to provide 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine compound of formula-1,

Formula-1 d) converting the compound of formula-1 into its hydrochloride salt compound of formula-la by treating it with a suitable HC1 source selected from HC1 gas, dry HC1, aq.HCl, ethyl acetate-HCl, isopropyl alcohol-HCl in a suitable solvent selected from ketone solvents, ester solvents, alcoholic solvents, polar-aprotic solvents and/or their mixtures thereof.

Formula-la
2. A process for the preparation of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine hydrochloride compound of formula-la, comprising of;

a) Reaction of 2-amino-5-chloro benzophenone compound of formula-2 with methyl magnesium chloride in tetrahydrofuran to provide l-(2-amino-5-chlorophenyl)-l-phenylethanol compound of formula-3,

b) reacting the compound of formula-3 with isothiocyanatoethane in cyclohexane to provide (Z)-N-(4-chloro-2-( 1 -hydroxy-1 -phenylethyl)phenyl)-N'-ethylcarbamimidothioic acid compound of formula-4,

c) cyclization of (Z)-N-(4-chloro-2-(l-hydroxy-l-phenylethyl)phenyl)-N'-ethylcarbamimidothioic acid compound of formula-4 in presence of manganese dioxide in acetonitrile and/or methanol to provide 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,1-benzoxazine compound of formula-1,

d) converting the compound of formula-1 into its hydrochloride salt compound of formula-la by treating it with ethyl acetate-HCl in a mixture of cyclohexane and acetone.

3. Crystalline Etifoxine hydrochloride.

4. Crystalline form-M of Etifoxine hydrochloride characterized by its PXRD pattern having peaks at about 11.3, 12.3, 14.1, 20.7, 23.5, 24.1, 25.8, 27.3, 29.3 ± 0.2 degrees of 2-theta values, which is further characterized by the PXRD pattern having peaks at about 13.7, 17.7, 18.4, 19.7, 20.0, 23.0, 29.8, 31.1, 34.0, 42.6 ± 0.2 degrees of 2-theta values.

5. A process for the preparation of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine compound of formula-1, comprising of cyclization of (Z)-N-(4-chloro-2-(l-hydroxy-1-phenylethyl)phenyl)-N'-ethylcarbamimidothioic acid compound of formula-4 in presence of manganese dioxide in a suitable solvent selected from alcoholic solvents, polar-aprotic solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents and/or their mixtures thereof to provide 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine compound of formula-1.

6. A process for the preparation of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine compound of formula-1, comprising of cyclization of (Z)-N-(4-chloro-2-(l-hydroxy-l-phenylethyl)phenyl)-N'-ethylcarbamimidothioic acid compound of formula-4 in presence of manganese dioxide in methanol and/or acetonitrile to provide 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine compound of formula-1.

7. A process for the purification of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine hydrochloride compound of formula-la, comprising of;

a) Adding acetonitrile to 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine hydrochloride,

b) heating the reaction mixture,

c) stirring the reaction mixture,

d) Treating the reaction mixture with charcoal,

e) cooling the reaction mixture,

f) filtering the solid followed by washing with acetonitrile to provide pure 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine hydrochloride compound of formula-la.

8. A process for the preparation of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine hydrochloride compound of formula-la, comprising of treating the 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine compound of formula-1 with a suitable HC1 source selected from HC1 gas, dry HC1, aq.HCl, ethyl acetate-HCl and isopropyl alcohol-HCl, preferably ethyl acetate-HCl in a suitable solvent selected from hydrocarbon solvents, ketone solvents, alcoholic solvents, ester solvents and/or their mixtures thereof; preferably in a mixture of cyclohexane and acetone.

9. Etifoxine hydrochloride having purity of greater than 99.90%, preferably 99.95%, more preferably 99.97% by HPLC.

10. Particle size distribution of 2-ethylamino-4-methyl-4-phenyl-6-chloro-4H-3,l-benzoxazine hydrochloride having D90 value less than 250 μm, more preferably less than 200 μm, most preferably less than 160 μm.