DESC:“CRYSTALLINE FORM I OF CENOBAMATE”

FIELD OF THE INVENTION

The present invention relates to crystalline Form I of Cenobamate. The present invention also relates to a process for the preparation of crystalline Form I of Cenobamate with high purity and yield.

BACKGROUND OF THE INVENTION

Cenobamate is a novel new antiepileptic drug, which can be used in the treatment of disorders of the central nervous system, especially as anxiety, depression, convulsion, epilepsy, migraine, bipolar disorder, drug abuse, smoking, ADHD, obesity, sleep disorder, neuropathic pain, stroke, cognitive impairment, neurodegeneration, stroke and muscle spasm.

Cenobamate was approved in US under the brand name Xcopri. Cenobamate is chemically known as [(1R)-1-(2-Chlorophenyl)-2-(tetrazol-2-yl) ethyl] carbamate. Its molecular formula is C10H10ClN5O2, and its molecular weight is 267.67 g/mol with the following structure:

Cenobamate was first reported in US 8501436, assigned to SK Holdings. This patent discloses a process for preparing Cenobamate from (R)-2-chlorostyrene oxide. The final Cenobamate is purified by column chromatography using a mixture of ethyl acetate and hexane, followed by recrystallization from dichloromethane and diethyl ether.

US 8501436 and US 8404461, assigned to SK Holdings, discloses a process for preparing Cenobamate from 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone. The final Cenobamate crystallization using isopropanol/heptane.

The above-mentioned prior art documents do not specify the crystal form information of Cenobamate. Nor has any characterization data, such as PXRD and DSC.

CN115716810A of Jiangsu alicorn pharmaceutical describes crystal form of Cenobamate characterized in that, X-ray powder diffraction spectrum is 12.51 ± 0.2°, 13.78 ± 0.2°, 13.78 ± 0.2°, 14.97±0.2°, 16.42±0.2°, 17.13±0.2°, 18.47±0.2°, 19.47±0.2°, 21.10±0.2°, 22.20±0.2°, 25.13±0.2°, 25.78±0.2°, 26.00±0.2°, 28.62±0.2° and 28.82±0.2°.

Therefore, there is a need to develop stable crystalline form of Cenobamate having better physicochemical properties and relatively higher solubility; there is also a constant need for a low cost and industrial friendly process for preparing the crystalline form of Cenobamate.

In view of the foregoing, the present inventors have provided herewith the crystalline Form I of Cenobamate and its purification process with commercially suitable reaction conditions with high yield and purity. The process is simple, efficient more economical for the preparation of Cenobamate crystalline Form I.

The present invention relates to crystalline Form I of Cenobamate. The present invention also relates to a process for the preparation of crystalline Form I of Cenobamate with high purity and yield.

SUMMARY OF THE INVENTION

The present invention relates to crystalline Form I of Cenobamate. The present invention also relates to a process for the preparation of crystalline Form I of Cenobamate with high purity and yield.

One aspect of the present invention is to provides crystalline Form I of Cenobamate, which is characterized by its Powder X-Ray Diffraction pattern (PXRD) having peaks at about 10.11°±0.2, 12.45°±0.2, 13.51°±0.2, 14.8°±0.2, 20.35°±0.2, 24.18°±0.2 and 26.55°±0.2 degrees of two-theta describes in Fig-1.

One aspect of the present invention provides crystalline Form I of Cenobamate, which is further characterized by its Powder X-Ray Diffraction pattern (PXRD) having peaks at about 10.11°±0.2, 12.45°±0.2, 13.51°±0.2, 14.8°±0.2, 16.58°±0.2, 17.12°±0.2, 18.41°±0.2, 20.35°±0.2, 21.92°±0.2, 23.13°±0.2, 24.18°±0.2, 25.28°±0.2, 26.55°±0.2, 27.06°±0.2, 30.08°±0.2 and 30.62°±0.2 degrees of two-theta describes in Fig-1.

Another aspect of the present invention provides crystalline Form I of Cenobamate, which is characterized by a Differential scanning calorimetry (DSC) exhibiting an onset temperature at about 92? to 102? and a peak temperature at about 94? to 104?, as described in Fig-2.

The second aspect of the present invention is to provides a process for the preparation of crystalline Form I of Cenobamate, comprising the steps of:

a) dissolving Cenobamate crude in a solvent;
b) heating the obtained solution at about 60-85°C;
c) cooling the solution obtained in step b); and
d) isolating crystalline Form I of Cenobamate.

BRIEF DESCRIPTION OF THE DRAWINGS:

Fig 1: X-ray powder diffraction pattern (PXRD) of Cenobamate crystalline Form I.

Fig 2: Differential scanning calorimetry (DSC) of Cenobamate crystalline Form I.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to crystalline Form I of Cenobamate. The present invention also relates to a process for the preparation of crystalline Form I of Cenobamate with high purity and yield.

One embodiment of the present invention is to provides crystalline Form I of Cenobamate, which is characterized by its Powder X-Ray Diffraction pattern (PXRD) having peaks at about 10.11°±0.2, 12.45°±0.2, 13.51°±0.2, 14.8°±0.2, 20.35°±0.2, 24.18°±0.2, and 26.55°±0.2, as described in Fig-1.

In an embodiment of the present invention is to provides crystalline Form I of Cenobamate, which is further characterized by its Powder X-Ray Diffraction pattern (PXRD) having peaks at about 10.11°±0.2, 12.45°±0.2, 13.51°±0.2, 14.8°±0.2, 15.93°±0.2, 16.58°±0.2, 17.12°±0.2, 18.41°±0.2, 19.36°±0.2, 20.35°±0.2, 21.72°±0.2, 21.92°±0.2, 22.81°±0.2, 23.13°±0.2, 24.18°±0.2, 24.69°±0.2, 25.28°±0.2, 26.55°±0.2, 27.06°±0.2, 27.41°±0.2, 27.93°±0.2, 28.56°±0.2, 29.31°±0.2, 30.08°±0.2 and 30.62°±0.2, as describes in Fig-1.

Another embodiment of the present invention provides crystalline Form I of Cenobamate, which is characterized by its Differential scanning calorimetry (DSC) exhibiting an onset temperature at about 92? to 102? and a peak temperature at about 94? to 104?, as described in Fig-2.

The second embodiment of the present invention provides a process for the preparation of crystalline Form I of Cenobamate, comprising the steps of:

a) dissolving Cenobamate crude in a solvent;
b) heating the obtained solution at about 60-85°C;
c) cooling the solution obtained in step b); and
d) isolating crystalline Form I of Cenobamate.

In an embodiment of the present invention provides a process for the preparation of crystalline Form I of Cenobamate, which comprises crude Cenobamate was dissolved in a solvent at room temperature. The temperature is then raised to about 60-85°C. The reaction mass is stirred for about 20 minutes and then cooled to room temperature to isolate crystalline Form I of Cenobamate.

In an embodiment of the present invention provides Cenobamate crystalline Form I having a purity of about 99% to about 99.99%, as measured by HPLC.

According to an embodiment of the present invention. wherein the suitable solvent is selected sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutanol, tert-butanol; nitriles such as acetonitrile and propionitrile; ether solvent such as tetrahydrofuran, diisopropylether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and aromatic hydrocarbons such as toluene, anisole, heptane and xylene; esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone; halogenated hydrocarbons such as chloroform, dichloromethane; water; cyclohexane and N-methyl-2-pyrrolidone and or mixtures thereof.

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES

Example-1:

Preparation of crystalline Form I of Cenobamate

(R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanol (100 gm) and Ethyl acetate (1000 ml) and were added into reaction flask at room temperature, then cooled to 0-5°C. Slowly chlorosulfonyl isocyanate (110 gm) was added to the obtained reaction mixture at 0-10°C, stirred for 15-20 min, raised the temperature to 25-30°C and stir for 1-2 hours. After completion of the reaction, the mixture was cooled to 15-20°C. Purified water (500 ml) was added to the reaction mixture at below 30°C and the two layers were separated, pH was adjusted to 8.0-10.0 with sodium carbonate solution and then washed twice with sodium chloride then combined with silica gel (50 gm) and activated carbon (10 grams) in a flask. The mixture was filtered and washed with ethyl acetate. The entire filtered mass was collected in a flask. Finally, the solvent was removed from the flask using vacuum distillation at a temperature below 60°C to obtain the crude product.

Charge Toluene (200 ml) and isopropyl alcohol (20 ml) into flask. The mixture was stirred for 10-20 minutes at 60-65°C, then cooled to 20-25°C and stirred for 1-2 hours. The obtained reaction mixture was filtered and washed with toluene (100 ml). Methanol (300 ml) and wet material were added into flask. The temperature was raised to 50-55°C. Activated carbon (5.0 gm) added to the mixture and stirred for 20-30 min. The mixture was then filtered, and the filter cake was washed with methanol. The filtrate was concentrated under vacuum at a temperature below 60°C. Purified water was added to the concentrated mixture. The mixture was stirred for 15-20 minutes at 60-65°C. The mixture was then cooled to 25-30°C and stirred for 1-2 hours. The mixture was filtered, and the material was washed with purified water. Finally, the material was dried at 60-65°C to obtain the titled compound.

Yield: 71.4%

Purity: 99.99%

Example-2:

Preparation of crystalline Form I of Cenobamate

Crude compound of Cenobamate (10 gm) and Purified water (50 ml) were added into a reaction flask at room temperature and then raised the temperature to 60-65°C. The obtained reaction mixture was stirred for 20 mins at the same temperature. Further, the reaction mixture was cooled to room temperature stirred again for 60 min, filtered and washed with purified water (10 ml) and then dried at 60-65°C to get the titled of the compound.

Yield: 9.8 gm.

Purity: 99.95%

Example-3:

Preparation of crystalline Form I of Cenobamate

Crude compound of Cenobamate (10 gm) and Toluene (50 ml) were added into a reaction flask at room temperature and raised the temperature to 80-85°C. The obtained reaction mixture was stirred for 20 min at the same temperature. Further, the reaction mixture was cooled to room temperature stirred again for 60 min, filtered and washed with toluene (5 ml) and then dried at 60-65°C to get the titled of the compound.

Yield: 9.5 gm.

Purity: 99.96%

Example-4:

Preparation of crystalline Form I of Cenobamate

Crude compound of Cenobamate (10 gm) and Isopropyl alcohol (10 ml) were added into a reaction flask at room temperature and raised the temperature to 60-65°C. The obtained reaction mixture was stirred for 20 min at the same temperature. Further, the reaction mixture was cooled to room temperature stirred again for 60 min. It was then further cooled to 10-15°C. The mixture was then filtered and washed with heptane. Finally, it was dried at 60-65°C to obtain the titled compound.

Yield: 9.3 gm.

Purity: 99.98%

Example-5:

Preparation of crystalline Form I of Cenobamate

Crude compound of Cenobamate (10 gm) and Ethyl acetate (10 ml) and were added into a reaction flask at room temperature The temperature was then temperature raised to 55-60°C. The obtained reaction mixture was stirred for 20 min at the same temperature. Further, the reaction mixture was cooled to room temperature stirred again for 60 min. It was further cooled to 10-15°C. Subsequently, the mixture was filtered and washed with heptane. Finally, the mixture was dried at 60-65°C to obtain the titled compound.

Yield: 9.0 gm

Purity: 99.98%
,CLAIMS:We Claim,

1. A crystalline Form I of Cenobamate, characterized by an X-ray powder diffraction pattern having characteristic peaks at about 10.11°±0.2, 12.45°±0.2, 13.51°±0.2, 14.8°±0.2, 20.35°±0.2, 24.18°±0.2, and 26.55°±0.2 degrees of two-theta.

2. The crystalline Form I of Cenobamate as claimed in claim 1, further characterized by an X-ray powder diffraction pattern having peaks at about 10.11°±0.2, 12.45°±0.2, 13.51°±0.2, 14.8°±0.2, 16.58°±0.2, 17.12°±0.2, 18.41°±0.2, 20.35°±0.2, 21.92°±0.2, 23.13°±0.2, 24.18°±0.2, 25.28°±0.2, 26.55°±0.2, 27.06°±0.2, 30.08°±0.2, and 30.62°±0.2 degrees of two-theta.

3. The crystalline Form I of Cenobamate as claimed in claim 1, characterized by a Differential Scanning Calorimetry (DSC) pattern as shown in Figure 2.

4. A process for the preparation of crystalline Form I of Cenobamate, comprising the following steps:

a) dissolving Cenobamate crude in a solvent;
b) heating the obtained solution at about 60-85°C;
c) cooling the solution obtained in step b); and
d) isolating crystalline Form I of Cenobamate.

5. The process as claimed in claim 6, wherein the suitable solvent is selected form methanol, ethanol, isopropyl alcohol, butanol, tert-butyl alcohol, propanol, toluene, hexane, ethyl acetate, methyl acetate, propyl acetate, acetone, cyclohexanone, tetrahydrofuran and water or mixtures thereof.

6. A crystalline Form I of Cenobamate, having a purity of about 99% to about 99.99%, as measured by HPLC.