Field of the Invention:

The present invention relates to identification, synthesis and structural studies of new rearranged impurity in novel crystalline Form of Metopimazine. Further, the present invention also relates to new rearranged impurity formation mechanism while preparing novel crystalline Form of Metopimazine.

Formula-1

Background of the invention:

Metopimazine is a dopamine D2 receptor antagonist and is indicated for the treatment of nausea and vomiting. Metopimazine has been marketed under the brand name Vogalene® in France. Metopimazine is chemically known as l-[3-[2-(methylsulfonyl)-1 OH-phenothiazin-10-yl]propyl]-4-piperidinecarboxamide and is represented by the structural Formula-I and 3-(Methylsulfonyl)-10H-phenothiazine (Impurity-E) is represented by the structural Formula-II.

Metopimazine is first disclosed in German patent No. 1 092 476. This patent also disclosed a process for the preparation of Metopimazine, which is as depicted in scheme-I given below:

Objective of the Invention:

The main objective of the present invention is to provide pure Metopimazine compound of formula-I.

Another objective of the present invention is to provide process for the preparation of pure Metopimazine compound of formula-I and its new rearranged impurity (Formula II).

Brief Description of the Invention:

Accordingly, the present invention provides a process for the preparation of pure Metopimazine compound of the Formula-I.

In another embodiment, the present invention provides a process for the preparation of novel new rearranged impurity of Metopimazine of Formula-II.

In another embodiment, the present invention provides metopimazine compound of the Formula-I containing less than 1.0% of compound of Formula-II.

Detailed Description of the Invention:

Metopimazine has been synthesized by Tyche Industries Ltd in two stages from 2-(methylsulfonyl)-lOH-phenothazine as given in Scheme-II.

Scheme-II:

Stage-1:10-(3-Chloropropyl)-2-(methyIsulfonyl)-10H-phenothiazine (MTP-1)

The review of the synthetic scheme suggests that there is potential for the formation of the following impurities:

But, in practice an additional impurity at RRT of about 1.45 in the range 0.08 -0.12% was observed at a level of 2.0% and the same is unknown. Various crystallization methods were perused to eliminate/reduce this impurity by using different solvents without fruitful result.

Alternatively, it was proposed to identify the impurity. Based on the structure of the molecule there is possibility of formation of N-oxides and/or S-oxides. Hence we synthesized mixture of N- and S-oxides from metopimazine, 10-(3-chloropropyl)-2-methylsulfonyl)-10H-Phenothiazine (MTP-1) and 2-(methylsulfonyl)-10H-phenothiazine (SM). We found that the unknown impurity is not matching with any one of them.

At this stage we have gone through the literature to find alternate possibilities for the formation of impurities under the conditions used in the synthetic Scheme-1 and observed that Smiles rearrangement is possible in Phenothiazines under basic conditions (Houben-Weyl, Vol E9, pp 533-35 and J Heterocyclic Chem, Vol 35, 843, 1998). Since our reaction is under basic conditions, there is possibility of Smiles rearrangement in the process and conducted detailed studies in this direction.

Accordingly, Smiles rearrangement, 2-sulfonyl group can be rearranged to 3-sulfonyl group resulting in the formation of 3-(methylsulfonyl)-10H-phenothiazine. To conform whether the impurity present in the metopimazine is 3-isomer, it is proposed to synthesize 3-(methylsulfonyl)-10H-phenothiazine from l,2-Dichloro-4-(methyl sulfonyl) benzene. The synthetic route is given in Scheme-Ill

The compound, 3-(methylsulfonyl)-10H-phenothiazine was synthesized as per scheme-3 and subjected HPLC under the conditions used for metopimazine. It was observed that a peak at RRT of 1.45 coinciding exactly with that observed in the metopimazine API. Hence further studies namely IR absorption proton, proton NMR, Carbon-13 NMR and mass spectroscopy were conducted to establish the structure of the compound and the details are presented below:

Please insert HPLC method: Structure Elucidation:

Infrared (IR) absorption:

The infrared spectrum of Metopimazine impurity 3-(Methylsulfonyl)-10H-Phenothiazine (Impurity-E, MTR-3) as a potassium bromide disc was recorded on a JASCO-640+ FTIR spectrophotometer in the range of 4000 cm"1 to 750 cm"1. The spectral results are interpreted as shown in table-1

Table-1: Interpretation of IR absorption spectrum of 3-(MethylsuIfonyl)-10H-Phenothiazine (Impurity-E, MTR-3)

NMR SPECTRA (Proton and C-13):

The *H and 13C NMR spectra of Metopimazine impurity, 3-(Methylsulfonyl)-lOH-Phenothiazine (Impurity-E, MTR-3) were recorded in DMSO-d6 at 300 MHZ on Bruker 300MHZ Avance NMR spectrometer. The'H and 13C chemical shifts are reported on 5 scale in ppm,relative to TMS(8 Q.OOppm) as internal standard. The chemical shifts assignments are as given below in table-2.

Mass Spectrum:

The mass spectrum of Metopimazine, impurity, 3-(Methylsulfonyl)-10H-Phenothiazine (Impurity-E, MTR-3) was recorded on Agilent 1100 SeriesLC-MSD-TRAP-SL system. The deprotonated molecular ion at m/z 276 (M-l) confirms the mass of Metopimazine, impurity (MTR/IMP-E) as 277 corresponds to molecular formula of C13H11NO2S2 and the data is given in table-3.

Table-3: Mass Spectral data of 3-(Methylsulfonyl)-10H-Phenothiazine (Impurity-E, MTR).
1 1 -J

From the above IR/H NMR, ,JC NMR, mass spectral data, the structure of the compound can be represented as shown below:

In LC-MS of the drug, the M+ ion of the peak at RRT 1.45 appearing at 277, further confirmed the structure of impurity at RRT 1.45 is nothing but 3-(methylsulfonyl)-10H-phenothiazine (MTR-3).

To further confirm the structure of impurity at RRT 1.45 an attempt has been made to synthesize the impurity from 10-(3-chloropropyl)-2-methylsulfonyl)-10H-Phenothiazine (MTP-1) by subjecting the latter to standard conditions used for the synthesis of metopimazine as shown in Scheme-3 without using isonipecotamide and the resulting compound was subjected HPLC analysis under the same conditions used for the API analysis. The HPLC analysis revealed the presence of peak at RRT 1.45, which was not present in MTP-1 confirming that the impurity at RRT 1.45 is 3-(methylsulfonyl)-lOH-phenothiazine. A possible mechanism for its formation is shown in Scheme-IV.

Scheme-IV:

Purified metopimazine as specified in the description is defined as metopimazine having impurity E (Compound II) content of less than 0.5%.

Pharmaceutical formulations like tablet, capsule, suspension, solution, injection are prepared using purified metopimazine of Formula I.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:

Example-1:10-(3-chloropropyl)-2-(methyIsulfonyl)-10H-phenothiazine.

A solution of 2-(methyl sulfonyl)-10H-phenothiazine (10 g) in a mixture of Toluene (100 ml) and N,N-Dimethyl Formamide (30 ml) was cooled to 0 to 5°C and slowly added to a suspension of sodiumhydride (2.8 g) in toluene (50 ml) under nitrogen atmosphere at 0 to 5°C. The reaction mixture was stirred for 1 hour at 0 to 5°C and temperature was raised to 25 to 35°C and maintained for 2 hours. The reaction mixture was quenched into water. The layers were separated and the organic layer was distilled under vacuum. The residue with toluene was cooled to 0 to 5°C. Filtered and dried to obtain 10-(3-chloropropyl)-2-(methylsulfonyl)-10H-phenothiazine (10 g, purity 95%) which was used in the next stage without any further purification.

Example-2: Process for the preparation of Metopimazine.

A mixture of 10-(3-chloropropyl)-2-(methylsulfonyl)-10H-phenothiazine (10 g), potassium carbonate (4 g). Sodium iodide (0.5 g), Isonipecotamide (4.0 g) in methyl ethyl ketone (80 ml) was refluxed for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered. The solids on the funnel were

washed with water to remove the inorganic salts. The crude product was recrystallized from methanol to obtain the highly pure metopimazine (7.0 g, Purity 99.8%). The purified metopimazine is analyzed for related substances content using HPLC method and the results are follows:

Example-3: Step-1: [2-chloro-4-(methyl sulfonyl)phenyl] [2-aminophenyl]sulfide.

To a solution of 2-aminothiophenol (10 gm), 1,2 - Dichloro-4-(methyl sulfonyl) benzene in methanol (80 ml) was added 30% NaOH solution (12 g). The reaction mixture was heated to reflux and maintain for 10 hours. Methanol was distilled off under vaccum. Cooled to room temperature and added water and stirred for 1 hour. The separated solid was filter to obtain crude product which was recrystallized from methanol to get the 2-chloro-4-(methylsulfonyl)phenyl] [2-aminophenyl]sulfide (13 g, purity 99.5%).

Example-4: 3-(methyl sulfonyl)-10H-Phenothiazine.

A mixture of [2-chloro-4-(methylsulfonyl)phenyl] [2-aminophenyl] sulfide (10 g) and potassium carbonate (10 g) in N,N-Dimethylformamide were stirred for 12 hr at reflux.

Cooled to room temperature and filtered to remove the salts. Solvent was distilled off under vaccum arid added water to the residue and stirred for 30 min. The separated product was filtered to get the crude product. It was taken in dichloromethane (30 ml) and stirred for 30 minutes, filtered and dried to get 3-(methylsulfonyl)-10 H- Phenothiazine (6.0 g, Purity 99.3%)

Example 5:

Pharmaceutical formulations like tablets, capsules, solutions, suspensions, injections are prepared using metopimazine containing less than 0.5% of compound II.
Tablets:
Manufacturing Process: Metopimazine, microcrystalline cellulose, sodium starch glycolate are first sieved and then blended in blender for 15 minutes and then added magnesium stearate and Colloaidol silicon dioxide, then finally blended for 5 minutes. The final blend is compressed into tablets.
Orodispersible Tablets:

Manufacturing Process: Metopimazine, mannitol, and Sachhrin sodium are first sieved, then loaded sieved Metopimazine, mannitol, Sachhrin sodium and Peppermint flavor in blender and blended for 20 minutes and then added magnesium stearate to the blend, then finally blended for 5 minutes. The final blend is compressed into tablets.

We Claim:

1. A compound having the structural formula:

Formula-II

2. A process for the preparation of 3-(methylsulfonyl)-10H-phenothiazine
compound of formula-II, comprising of:

a) Reacting the 2-aminobenzenethiol with 1,2-dichloro-4-(methylsulfonyl)benzene in a suitable base in suitable 'solvent to provide 2-(2-chloro-4-(methylsulfonyl)phenylthio)aniline

b) reacting the 2-(2-chloro-4-(methylsulfonyl)phenylthio)aniline in presence of
a suitable base in a suitable solvent to provide 3-(methylsulfonyl)-10H-
phenothiazine compound of formula-II.

3. The process for the preparation of 3-(methylsulfonyl)-10H-phenothiazine
compound of formula-II, comprising of:

a) Reacting the 2-aminobenzenethiol with 1,2-dichloro-4-(methylsulfonyl)benzene in presence of sodium hydroxide in methanol to provide 2-(2-chloro-4-(methylsulfonyl) phenylthio)aniline,

b) reacting the 2-(2-chloro-4-(methylsulfonyl)phenylthio)aniline in presence of potassium carbonate in N,N-Dimethylformamide to provide 3-(methylsulfonyl)-lOH-phenothiazine compound of formula-II.

4. Metopimazine compound of formula-I having less than 1.0% of the 3-(methylsulfonyl)-1 OH-phenothiazine compound of formula-II.

5. Pharmaceutical formulations of Metopimazine compound of formula-I having less than 1.0% of the 3-(methylsulfonyl)-l OH-phenothiazine compound of formula-II.

6. Pharmaceutical formulations of metopimazine as claimed in Claim 5, wherein pharmaceutical formulations are selected from tablet, capsule, solution, suspension, injection.