Briefly, the process for the preparation of Metopimazine comprises reaction of 2-(methylthio)-lOTf-phenothiazine of Formula-II with sodium amide followed by acetic anhydride to provide l-(2-(methylmio)-10//-phenothiazin-10-yl)ethanone of Formula-Ill, which on oxidation with metachloroperbenzoic acid followed by treatment with sodium hydroxide affords the 2-(methylsulfonyl)10#-phenothiazine of Formula-IV. The said Formula-IV on reaction with l-bromo-3-chloropropane provides 10-(3-chlorop!ropyl)-2-(methylsulfonyl)-10//-phenothiazine of Formula-V, which on condensation with piperidine-4-carboxamide provides Metopimazine of Formula-I. However, this patent does not mention the nature of Metopimazine obtained through this process.

Karel Sindelar et. al, Collect. Czech. Chemical Communications, 55(6), 1586-601; 1990 discloses a process for the preparation of Metopimazine which comprises reduction of 4(2-fluorophenylthio)-3-nitrophenyl methylsulfone of Formula-VI with hydrazine hydrate in boiling ethanol in the presence of ferric chloride and carbon or with iron in boiling aqueous acetic acid yielding 2-(2-fluorophenylthio)-5-(methylsulfonyl)aniline of Formula-VII; cyclization of compound of Formula-VII in DMSO with 80% NaH gives 2-(methylsulfonyl)phenothiazine of Formula-VIII which on reaction with l-(3 chloropropyl)piperidine-4-carboxmide of Formula-IX yields Metopimazine of compound of Formula-I. The process is depicted in scheme-II given below: Indian patent application No. 360/CHE/2010 discloses two different processes for the preparation of Metopimazine, which are depicted in scheme-Ill given below: The process comprises acylation of compound of Formula-II with acetyl chloride in toluene provides compound of formula-Ill; oxidation of compound of formula-Ill with hydrogen peroxide in presence of a catalyst like ammonium molybdate in the presence of phase transfer catalyst followed by hydrolysis of the obtained compound with sodium hydroxide provides compound of Formula-VIII, which on reaction with 1,3-dihalo compound in presence of suitable base affords the compound of Formula-Va, condensation of the compound of Formula-Va with piperidine-4-carboxamide in presence of a suitable base provides Metopimazine of compound of Formula-I; optionally purifying the compound of Formula-I using a suitable solvents provides pure compound of Formula-I.

Alternatively, the compound of Formula-Va is prepared through a novel intermediate compound of Formula-X, which comprises reaction of compound of Formula-II with 1,3-dihalo propane in presence of a suitable base to provide the compound of Formula-X, which on oxidation with hydrogen peroxide in presence of catalyst like ammonium molybdate, in presence of a phase transfer catalyst in a suitable solvent provides the compound of Formula-Va.

This application also discloses a novel crystalline form of Metopimazine characterized by its PXRD having peaks at 4.37, 8.75, 9.76, 13.16, 17.59, 19.10,19.62, 19.92,21.73,22.05,26.05 and 31.06 ± 0.2° 20 and by its DSC showing endothermic peak at 173.65°C. 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 polymorphs having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One polymorph mayj give rise to thermal behaviour different from that of another polymorph. Thermal behaviour can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC"), which have been used to distinguish polymorphic forms. The differences in the physical properties of different polymorphs results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other polymorphs of the same composition or complex. Hence there remains a need for polymorphic forms which have properties suitable for pharmaceutical processing on a commercial scale. The inventors of the present invention during their continuous efforts developed a high melting stable crystalline Form of Metopimazine.

Objective of the Invention

The main objective of the present invention is to provide novel crystalline Form of Metopimazine.

Detailed Description of the Invention

The present invention provides a novel high melting crystalline Form T of Metopimazine of the Formula-I having a DSC thermogram spectrum, showing endothermic peak at about 186-188°C as depicted in Figure 1. The novel high melting crystalline Form T of Metopimazine is also characterized by X-ray powder diffraction pattern with peaks at 12.05, 13.46, 16.35, 18.36 and 18.90 ± 0.2° 20 values. The novel crystalline Form T of Metopimazine is further characterized by X-ray powder diffraction pattern having additional peaks at 4.24, 12.97, 17.35, 19.55, 20.30, 20.76, 21.74, 23.82, 24.39, 25.28 and 25.68 ± 0.2° 29 values as depicted in Figure 2.

Brief description of the figures:

Figure-1: Represents DSC thermogram of crystalline Form T of Metopimazine

Figure-2: Represents X-ray powder diffraction pattern of crystalline Form T of Metopimazine. In yet another embodiment, the present invention provides a process for the preparation of Metopimazine of Formula-I which comprises reacting compound of Formula-XI Formula-XI wherein L is halogen or a leaving group such as mesylate, tosylate, triflate, with piperidine-4-carboxamide of Formula-XII or acid addition salt in a suitable solvent in the presence of a base and a catalyst. Is In a preferred embodiment, the present invention provides a process for the preparation of Metopimazine of Formula-I which comprises reacting 10-(3-chloropropyl)-2-(methylsulfonyl)-1 OH-phenothiazine of Formula-V Formula-V with piperidine-4-carboxamide of Formula-XII or an acid addition salt in a suitable solvent in the presence of a base and a catalyst.

Suitable solvents used for reaction are selected from alcohols, esters, hydrocarbon solvents, chloro solvents, ketones, amides, nitriles or mixtures thereof. Suitable bases used for the reaction are inorganic or organic bases selected from alkali metal carbonates like sodium carbonate, potassium carbonate; alkali metal hydroxide like sodium hydroxide, potassium hydroxide; alkali metal bicarbonates like sodium bicarbonate, I potassium bicarbonate and the like; organic base selected from triethylamine, tributyl amine, pyridine, 4-dimethylaminopyridine, N-methyl morpholine and diisopropylethyl amine and the like. The catalyst used in the reaction is for facilitating the speed of the reaction and also to reduce the formation of impurities. Suitable catalyst used is iodide catalyst selected frorn sodium iodide, potassium iodide and the like.

In yet another embodiment, the present invention provides a process for the preparation of novel high melting crystalline Form T of Metopimazine, which comprises:

i) reacting 10-(3-chloropropyl)-2-(methylsulfonyl)-10H-phenothiazine of Formula-V, or an acid addition salt in a suitable solvent in the presence of a base and a catalyst,

ii) isolating crude Metopimazine of Formula-I,

iii) dissolving crude Metopimazine in a mixture of solvents,

iv) crystallizing Metopimazine obtained in the step (iii) and

iv) isolating crystalline Metopimazine. i

In yet another embodiment, the present invention provides a process for the preparation of novel high melting crystalline Form T of Metopimazine, which comprises: i) providing a solution of crude Metopimazine in a mixture of solvents, ii) crystallizing Metopimazine from the solution obtained in step (i) and iii) isolating crystalline Metopimazine. In a preferred embodiment, the present invention provides a process for the preparation of l novel high melting crystalline Form T of Metopimazine, which comprises:

i) providing a solution of crude Metopimazine in a mixture of solvents,

ii) heating the reaction mass to reflux temperature,

iii) optionally leaching the reaction mass,

iv) crystallizing Metopimazine obtained in the step (iii) and

v) isolating crystalline Metopimazine.

The isolation of crude Metopimazine of Formula-I according to the present invention is carried out using conventional methods used for isolation of compounds known in the field. Suitable mixture of solvents used for the crystallization are selected from protic solvents such as alcohols selected from methanol, ethanol, isopropanol, n-propanol, n-butanol; apr6tic polar solvents such as tetrahydrofuran, dioxane, dimethylformamide N,N-dimethylacetamide, N-methylpyrrolidinone (NMP), acetonitrile, dimethyl sulfoxide, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate; water or combination thereof.

Alternatively, Metopimazine used as the starting material for crystallization can be prepared by any of the processes reported in the literature. The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limitative and relate to solutions which have been particularly effective on a bench scale.

Example 1 Preparation of Metopimazine Mixture of 10-(3-chloropropyl)-2-(methylsulfonyl)-10H-phenothiazine (10 g), potassium carbonate (8.0 g), sodium iodide (1 g), piperidine-4-carboxamide (7.5 g) in acetone (100 ml) and DMF (10 ml) were heated to reflux temperature at 55-60°C for about 24 hrs. Cooled the reaction mixture to 35°C and filtered the reaction mass. The solid obtained was washed with acetone and water and dried. Yield (6.5 g).

Example 2 Preparation of Metopimazine Mixture of 10-(3-chloropropyl)-2-(methylsulfonyl)-10H-phenothiazine (10 g), potassium carbonate (8.0 g), sodium iodide (1 g), piperidine-4-carboxamide (7.5 g) in toluene (70 ml) and DMF (30 ml) were heated to reflux temperature at 100-105°C for about 10 hr$. Cooled the reaction mixture to 35°C and filtered the reaction mass. The solid obtained was washed with toluene and water and dried. Yield (8.5 g).

Example 3 Preparation of Metopimazine Mixture of 10-(3-chloropropyl)-2-(methylsulfonyl)-10H-phenothiazine (10 g), potassium carbonate (8.0 g), sodium iodide (1 g), piperidine-4-carboxamide (7.5 g) in methyl ethyl ketone (170 ml) were heated to 75-80°C for about 18 hrs. Cooled the reaction mixture to 35°C and filtered the reaction mass. The solid obtained was washed with methyl ethyl ketone and water and dried. Yield (8.5 g).

Example 4 Preparation of Crystalline Metopimazine Crude Metopimzine (8.0) g was dissolved in a mixture of DMF and methanol and heated the reaction mass to reflux temperature. Activated carbon was added to the reaction mass and filtered on hyflo bed. The obtained filtrate was concentrated to 50% of its volume and cooled to room temperature for about 1 hr. The solid obtained was filtered, washed with methanol and dried. Yield (6.5 g).

We Claim:

1. Novel high melting crystalline Form T of Metopimazine of formula I having a characteristic endothermic peak between 186-188°C in DSC thermogram spectrum. |

2. Novel crystalline Form T of Metopamzine characterized by X-ray powder diffraction pattern with peaks at 12.05,13.46,16.35,18.36 and 18.90 ± 0.2° 29 values.

3. Novel crystalline Form T of Metopamzine further characterized by X-rayj powder diffraction pattern having additional peaks at 4.24, 12.97, 17.35, 19.55, 20.30, 20.7^6, 21.74, 23.82, 24.39, 25.28 and 25.68 ± 0.2° 29 values. j

4. A process for the preparation of Metopimazine of formula I which comprises reacting compound of Formula-XI Formula-XI wherein L is halogen or a leaving group such as mesylate, tosylate, triflate, with piperidine-4-carboxamide of Formula-XII or acid addition salt in a suitable solvent in the presence of a base and a catalyst.

5. A process for the preparation of novel high melting crystalline Form T of Metopimazine of formula I which comprises:

i) providing a solution of crude Metopimazine in a solvent,

ii) crystallizing Metopimazine from the solution obtained in step (i) and

iii) isolating crystalline Metopimazine.

6. A process for the preparation of novel high melting crystalline Form T of Metopimazine of formula I which comprises:

i) providing a solution of crude Metopimazine in a solvent,

ii) heating the reaction mass to reflux temperature,

iii) optionally leaching the reaction mass,

iv) crystallizing Metopimazine obtained in the step (iii) and

v) isolating crystalline Metopimazine.

7. The process according to claims 4, wherein the solvent used in step (i) is selected from alcohols, esters, hydrocarbon solvents, chloro solvents, ketones, amides, nitriles or mixtures thereof.

8. The process according to claims 4, wherein the base used in step (i) is selected from inorganic or organic bases.

9. The process according to claims 4, wherein the catalyst used in step (i) is iodide catalyst selected from sodium iodide, potassium iodide and the like. j

10. The process according to claims 5&6, wherein the solvent used for the crystallization are selected from protic solvents such as alcohols selected from methanol, ethanol, isopropanol, n-propanol, n-butanol; aprotic polar solvents such as tetrahydrofuran, dioxane, dimethylformamide N,N-dimethylacetamide, N-methylpyrrolidinone (NMP), acetonitrile, dimethyl sulfoxide, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate; water or mixtures thereof.