This application claims the benefit of priority of our Indian patent application numbers 202141015993 filed on 05 April 2021 and 202141018048 filed on 19 April 2021 which is incorporated herein by reference.

Field of the Invention:

The present invention relates to solid state forms of (S)-quinuclidin-3-yl (2-(2-(4- fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate or salts and process for its preparation thereof.

The present invention also relates to crystalline form of (S)-quinuclidin-3-yl (2-(2-(4- fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate oxalate and process for its preparation thereof.

Background of the Invention:

Venglustat is chemically known as (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4- yl)propan-2-yl)carbamate represented by the following structural formula.

Formula- 1

Venglustat oxalate is chemically known as (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl) thiazol-4-yl)propan-2-yl)carbamate oxalate represented by the following structural formula.

Formula- la

Venglustat is a small-molecule glucosylceramide synthase (GCS) inhibitor designed to reduce the production of glucosylceramide (GL-1) and thus is expected to substantially reduce formation of glucosylceramide -based glycosphingolipids. Because of its effect on glycosphingolipid formation, GCS inhibition has therapeutic potential across many disorders affecting glycosphingolipid metabolism.

(S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate or a pharmaceutically acceptable salt was disclosed in US9126993 B2 (herein after described as US ‘993).

US ‘993 discloses process for the preparation of (S)-quinuclidin-3-yl (2-(2-(4-fluoro phenyl)thiazol-4-yl)propan-2-yl)carbamate.

Crystalline forms of (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl) carbamate salts and its process was disclosed in US9518049 B2.

Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different X-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.

Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances.

Brief description of the Invention:

The present invention relates to solid state forms of Venglustat or its salts and process for preparation thereof. The present invention also relates to novel intermediate compounds useful in the preparation of Venglustat or its salts.

The present invention also relates to Venglustat oxalate of formula- la and crystalline form of Venglustat oxalate of formula- la and process for preparation thereof.

Brief description of Drawings:

Figure 1: Illustrates the PXRD pattern of crystalline Form-M of Venglustat.

Figure-2: Illustrates the PXRD pattern of amorphous Form of Venglustat.

Figure-3: Illustrates the PXRD pattern of amorphous Form of Venglustat L-malate.

Figure 4: Illustrates the PXRD pattern of crystalline Form-M of Venglustat oxalate.

Detailed description of the Invention:

As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyro nitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2- methoxyethanol, 1, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t- pentyl alcohol, diethylene glycol, monoethyl ether, cyclohexanol, benzyl alcohol or glycerol and the like; “polar solvents” such as water or mixtures thereof.

The “suitable base” as used in the present invention is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; ammonia; and organic bases such as “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; triethyl amine, methyl amine, ethylamine, 1,8-diaza bicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5- ene (DBN), lithiumdiiso propylamide (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethylamino pyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1 -methyl imidazole, 1,2,4-triazole, l,4-diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.

In the first embodiment, the present invention provides crystalline Form-M of Venglustat of formula- 1 characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 5.7, 11.4 and 13.9 ± 0.2 degrees of 2-theta.

The crystalline Form-M of Venglustat of formula- 1 is further characterized by the X-ray powder diffraction (XRD) pattern as illustrated in figure- 1.

In the second embodiment, the present invention provides a process for the preparation of crystalline Form-M of Venglustat, which comprises: a) contacting Venglustat with diisopropyl ether; and b) isolating the crystalline Form-M of Venglustat.

In the process of the second embodiment, isolation of crystalline Form-M of Venglustat can be carried out by any methods known in the art or crystalline Form-M of Venglustat can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.

In the process of the second embodiment, drying the crystalline Form-M of Venglustat by suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In the third embodiment, the present invention provides an amorphous form of Venglustat of formula- 1.

In the fourth embodiment, the present invention provides a process for the preparation of amorphous form of Venglustat of formula- 1, which comprises: a) providing a solution of Venglustat of formula- 1 in a suitable solvent or a mixture of solvents; and b) isolating the amorphous form of Venglustat of formula- 1.

In the process of fourth embodiment, the suitable solvent used in step-a) is selected from alcohol solvents.

In the process of the fourth embodiment, providing a solution of Venglustat comprises dissolving Venglustat in a suitable solvent at a suitable temperature of about 30°C and above. Optionally, the solution may be filtered to make it particle free.

In the process of the fourth embodiment, isolation of amorphous form of Venglustat can be carried out by any methods known in the art or amorphous form of Venglustat can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.

In the process of the fourth embodiment, drying the amorphous form of Venglustat by suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In the fifth embodiment, the present invention provides an amorphous form of Venglustat L-malate of formula- lb.

In the sixth embodiment, the present invention provides a process for the preparation of amorphous form of Venglustat L-malate of formula-lb, which comprises: a) providing a solution of Venglustat, b) adding a solution of L-malic acid to the solution obtained in step-a), c) isolating the amorphous form of Venglustat L-malate of formula- lb.

In the process of the sixth embodiment, providing a solution of Venglustat, comprises dissolving Venglustat in a suitable solvent or a mixture of solvents at a suitable temperature of about 30°C and above. Optionally, the solution can be filtered to make it particle free.

In the process of sixth embodiment, the suitable solvent used in step-a) and b) is selected from alcohol solvents.

In the process of the sixth embodiment, isolation of amorphous form of Venglustat L- malate of formula- lb can be carried out by any methods known in the art or amorphous form of Venglustat L-malate of formula- lb can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.

In the process of the sixth embodiment, drying the amorphous form of Venglustat L- malate of formula- lb by suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In the seventh embodiment, the present invention provides a process for the preparation of Venglustat of formula- 1 or its salts, which comprises: a) reacting compound of formula-4 with methyl iodide in the presence of suitable base in a suitable solvent to provide compound of formula-3 ;

Formula-4 Formula-3 b) reacting compound of formula-3 with hydrazine hydrate to provide compound of formula-

2; and c) converting compound of formula-2 to Venglustat of formula- 1 or its salts.

In the process of the seventh embodiment, the suitable base used in step-a) is selected from inorganic base or organic base; and the suitable solvent is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

In the eighth embodiment, the present invention provides a process for the preparation of Venglustat of formula- 1 or its salts, which comprises: a) reacting compound of formula- 11 with methyl iodide in the presence of alkali metal amides in a suitable solvent to provide compound of formula- 10; and b) converting compound of formula- 10 to Venglustat of formula- 1 or its salts.

In the process of the eighth embodiment, the suitable alkali metal amides used in step-a) is selected from sodium amide, potassium amide, lithium amide, lithium diisopropyl amide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide, lithium bis(trimethysilyl)amide (LiHMDS) and the like; and the suitable solvent is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

In the ninth embodiment, the present invention provides a process for the preparation of Venglustat of formula- 1 or its salts, which comprises: a) reacting compound of formula- 12 with compound of formula-7 to provide compound of formula- 10; and

Formula- 12 Form -7 Formula- 10 b) converting compound of formula- 10 to Venglustat of formula- 1 or its salts.

In the process of the ninth embodiment, the suitable solvent used in step-a) is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

In the tenth embodiment, the present invention provides novel intermediate compound of formula-3 represented by the following structural formula.

The above mentioned novel intermediate compound of formula-3 is useful in the preparation of Venglustat of formula- 1 or its salts.

Venglustat or its salts obtained according to the present invention can be purified using a suitable solvent selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof. The process of the present invention can be represented schematically as follows:

Scheme-1

Formula- 13 Formula-7 Formula- 11

Methyl iodide

Formula- 12 Formula-7 Formula-10

Hydrolysis In the eleventh embodiment, the present invention provides Venglustat oxalate of formula- la.

In the twelfth embodiment, the present invention provides crystalline form of Venglustat oxalate of formula- la.

In first aspect of twelfth embodiment provides crystalline form of Venglustat oxalate of formula- la characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 9.9, 13.7 and 18.2 ± 0.2 degrees of 2-theta herein after designated as Form-M.

In second aspect of twelfth embodiment, the crystalline Form-M of Venglustat oxalate of formula- la is further characterized by the X-ray powder diffraction (XRD) pattern as illustrated in figure-4.

In the thirteenth embodiment, the present invention provides a process for the preparation of crystalline Form-M of Venglustat oxalate of formula- la, which comprises: c) providing a solution of Venglustat of formula- 1 in acetone; d) adding oxalic acid to solution obtained in step-a); and e) isolating the crystalline Form-M of Venglustat oxalate of formula- la.

In the process of the thirteenth embodiment, Venglustat dissolved in a suitable solvent at a suitable temperature of about 30°C and above. Optionally, the solution may be filtered to make it particle free.

In the process of the thirteenth embodiment, isolation of crystalline Form-M of Venglustat oxalate of formula- la can be carried out by any methods known in the art or crystalline Form-M of Venglustat oxalate of formula- la can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.

In the process of the thirteenth embodiment, drying of the crystalline Form-M of Venglustat oxalate of formula- la by suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

Venglustat of formula- 1 obtained according to the present invention is having R-isomer of Venglustat impurity less than 0.05% as measured by HPLC.

R-isomer of Venglustat

The Venglustat used in the present invention can be obtained by any of the processes known in the art.

Venglustat oxalate of formula- la is useful in the preparation of Venglustat free base or Venglustat malate.

Venglustat prepared according to the present invention is micronized or milled in conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that are used for particle size reduction include, but not limited to ball milling, roll milling and hammer milling, and jet milling. Milling or micronization is performed before drying, or after the completion of drying of the product.

The invention also encompasses pharmaceutical compositions comprising crystalline form of Venglustat oxalate of the present invention. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

The present invention also encompasses pharmaceutical composition comprising Amorphous Venglustat and its pharmaceutical acceptable salts one or more pharmaceutically acceptable excipients. The present invention also encompasses pharmaceutical composition comprising Venglustat oxalate and its pharmaceutical acceptable salts one or more pharmaceutically acceptable excipients.

The present invention also encompasses pharmaceutical composition comprising Amorphous Venglustat L-malate and its pharmaceutical acceptable salts one or more pharmaceutically acceptable excipients.

As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

P-XRD Method of Analysis: PXRD analyses of compounds produced by the present invention were carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A°.

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: Preparation of crystalline Form-M of Venglustat.

Tetrahydrofuran (621 ml) was added to 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methyl propanoic acid of formula-9 (25.0 gms) at 25-30°C under nitrogen atmosphere and stirred for 10 minutes. Cooled the mixture to 0-5°C. Triethylamine (26.1 ml) and isobutyl chloroformate (18.65 ml) were slowly added to the mixture at 0-5°C and stirred for 15 minutes. Sodium azide (12.5 gms) and water (125 ml) were slowly added to the mixture at 0-5°C and stirred for 1 hour. Raised the temperature of the mixture to 25-30°C and stirred for 20 hours. Water was added to mixture at 25-30°C and stirred for 10 minutes. Ethyl acetate was added to mixture at 25-30°C and stirred for 10 minutes. Layers were separated and extracted the aqueous layer with ethyl acetate. Combined the organic layers, washed with sodium bicarbonate solution. Layers were separated and organic layer was washed with sodium chloride solution. Layers were separated and organic layer was washed with water. Distilled off the organic layer at 50°C and co-distilled with toluene. To the obtained compound, toluene (625 ml) was added at 25-30°C. Heated the mixture to 115-120°C and stirred for 2 hours. (S)-Quinuclidin-3-ol (24.18 gms) was added to the mixture at 115-120°C and stirred for 17 hours. Cooled the mixture to 25-30°C. Water (250 ml) was added to the mixture at 25-30°C and stirred for 30 minutes. Layers were separated and organic layer was washed with water. Water was added to organic layer at 25-30°C and stirred for 10 minutes. Aqueous hydrochloric acid solution was slowly added to the mixture at 25-30°C and stirred for 1 hour. Layers were separated and organic layer was washed with aqueous hydrochloric acid solution. Layers were separated. Combined the total aqueous layers and washed with toluene at 25-30°C. Layers were separated. Isopropyl acetate (625 ml) was added to aqueous layers at 25-30°C. Cooled the mixture to 20°C. Sodium hydroxide solution was slowly added to the mixture at 20°C and stirred for 15 minutes. Layers were separated and extracted aqueous layer with isopropyl acetate at 25-30°C. Combined the organic layers and washed with water at 25-30°C. Distilled off the organic layer below 50°C and co-distilled with diisopropyl ether. To the obtained compound, diisopropyl ether (625 ml) was added at 25-30°C and stirred for 2 hours. Filtered the solid, washed with diisopropyl ether and dried to get the title compound. Yield: 22.0 gms.

The PXRD pattern of the obtained compound is illustrated in Figure- 1.

Example-2: Preparation of crystalline Form-M of Venglustat.

Tetrahydrofuran (4000 ml) was added to 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methyl propanoic acid of formula-9 (160 gms) at 25-30°C under nitrogen atmosphere and stirred for 10 minutes. Cooled the mixture to 0-5°C. Triethylamine (122 gms) and isobutyl chloroformate (125.20 gms) were slowly added to the mixture at 0-5°C and stirred for 80 minutes. Sodium azide (78.40 gms) and water (800 ml) were slowly added to the mixture at 0-5°C and stirred for 2 hours. Raised the temperature of the mixture to 25-30°C and stirred for 15 hours. Water (4000 ml) and ethyl acetate (2.0 lit) were added to mixture at 25-30°C and stirred for 1 hour. Layers were separated and extracted the aqueous layer with ethyl acetate. Combined the organic layers, washed with sodium bicarbonate solution at 25-30°C. Layers were separated and organic washed with sodium chloride solution at 25-30°C. Layers were separated and organic layer washed with water at 25-30°C. Distilled off the organic layer under vacuum and co-distilled with toluene. To the obtained compound, toluene (4000 ml) was added at 25-30°C. Heated the mixture to 120°C and stirred for 2 hours. (S)-Quinuclidin-3-ol (154.75 gms) was added to the mixture at 120°C and stirred for 15 hours. Cooled the mixture to 25-30°C. Water (1600 ml) was added to the mixture at 25-30°C and stirred for 20 minutes. Layers were separated and organic layer washed with water at 25-30°C. Water (4000 ml) was added to organic layer at 25-30°C. Aqueous hydrochloric acid solution was slowly added to the mixture at 25-30°C and stirred for 30 minutes. Layers were separated and organic layer washed with aqueous hydrochloric acid solution at 25-30°C. Layers were separated. Combined the total aqueous layers and washed with toluene at 25-30°C. Layers were separated. Isopropyl acetate (4000 ml) was added to aqueous layers at 25-30°C. Cooled the mixture to 20°C. Sodium hydroxide solution was slowly added to the mixture at 20°C and stirred for 10 minutes. Layers were separated and extracted aqueous layer with isopropyl acetate at 25- 30°C. Combined the organic layers and washed with water at 25-30°C. Distilled off the organic layer below 50°C and co-distilled with diisopropyl ether. To the obtained compound, diisopropyl ether (800 ml) as added at 25-30°C and stirred for 20 minutes. Filtered the solid, washed with diisopropyl ether and dried to get the title compound. Yield: 90 gms.

The PXRD pattern of the obtained compound is illustrated in Figure- 1.

Example-3: Preparation of amorphous form of Venglustat.

Methanol (25 ml) was added to Venglustat (1.0 gm) at 25-30°C and stirred for 30 minutes. Filtered the mixture through filter paper and washed with methanol. Distilled off the mixture under vacuum to get the title compound. Yield: 970 mg.

The PXRD pattern of the obtained compound is illustrated in Figure-2.

Example-4: Preparation of amorphous form of Venglustat L-malate.

Isopropanol (14 ml) was added to Venglustat (2.0 gms) at 25-30°C and stirred for 30 minutes. Filtered the mixture through filter paper. A solution of L-malic acid (0.689 gms) in isopropanol (13 ml) was slowly added to the filtrate at 25-30°C and stirred for 23-24 hours. Distilled off the solvent completely from the mixture below 50°C. To the obtained compound, methanol (50 ml) was added at 25-30°C and stirred for 30 minutes. Filtered the mixture through filter paper and washed with methanol. Distilled off the mixture under vacuum to get the title compound. Yield: 2.45 gms.

The PXRD pattern of the obtained compound is illustrated in Figure-3.

Example-5: Preparation of crystalline Form-M of Venglustat oxalate.

Acetone (5.0 ml) was added to Venglustat (200 mg) at 25-30°C and stirred for 20 minutes. Oxalic acid (71.2 mg) was added to the mixture at 25-30°C and stirred for 2 hours. Filtered the solid, washed with acetone and dried to get the title compound. Yield: 180 mg.

The PXRD pattern of the obtained compound is illustrated in Figure-4.

Example-6: Preparation of crystalline Form-M of Venglustat oxalate.

Acetone (10 ml) was added to Venglustat (500 mg) at 25-30°C and stirred for 20 minutes. Filtered the mixture to make it particle free. Oxalic acid solution (oxalic acid (169.8 mg) dissolved in acetone (5.0 ml)) was added to mixture at 25-30°C. N-heptane (15 ml) was added to mixture at 25-30°C and stirred for 90 minutes. Filtered the solid, washed with n-heptane and dried to get the title compound. Yield: 500 mg; Oxalic acid content: 18.51%.

The PXRD pattern of the obtained compound is illustrated in Figure-4.

Example-7: Preparation of ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)acetate of Formula-11.

Ethanol (40.0 ml) was added to 4-fhiorobenzothioamide of formula-7 (10.0 gm) at 25- 30°C and stirred for 10 minutes. Raised the temperature of the mixture to 50-55°C. Ethyl-4- chloro acetoacetate of formula- 13 (10.0 ml) was slowly added to the mixture at 50-55°C. Raised the temperature of the mixture to 75-80°C and stirred for 6 hours. Distilled off the mixture under vacuum at 75-80°C. Water (10.0 ml) and methyl tert-butyl ether (30.0 ml) were added to the obtained compound at 25-30°C and stirred for 30 minutes. Layers were separated and extracted aqueous layer with methyl tert-butyl ether. Combined the organic layers and washed with sodium bicarbonate solution at 25-30°C. Layers were separated and organic layer washed with water. Distilled off the organic layer below 55°C and co-distilled with n-heptane. n-Heptane (40.0 ml) was added to the obtained compound at 25-30°C and stirred for 3 hours. Filtered the solid, washed with n-heptane and stirred to get the title compound. Yield: 11.1 gm.

Example-8: Preparation of ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoate of Formula-10.

Tetrahydrofuran (70.0 ml) was added to potassium tert-butoxide (8.59 gm) at 25-30°C and stirred for 3 hours. Cooled the mixture to 0-5°C. Ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)acetate (5.0 gm) and tetrahydrofuran (10.0 ml) were slowly added to the mixture at 0-5°C and stirred for 90 minutes. Methyl iodide (10.69 gm) and tetrahydrofuran (12.0 ml) were slowly added to the mixture at 0-5°C and stirred for 1 hour. Sodium chloride solution was slowly added to the mixture at 0-5°C and stirred for 15 minutes. Aqueous hydrochloric acid was slowly added to the mixture at 0-5°C and stirred for 15 minutes. Layers were separated and extracted aqueous layer with tetrahydrofuran. Combined the organic layers. Distilled off the organic layer under vacuum at below 45°C to get the title compound. Yield: 6.2 gm.

Example-9: Preparation of 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoic acid of Formula-9.

Tetrahydrofuran (75.0 ml) was added to ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)-2- methylpropanoate of formula- 10 (5.0 gm) at 25-30°C and stirred for 10 minutes. Cooled the mixture to 15-20°C. Lithium hydroxide (1.75 gm) and water (24.0 ml) were slowly added to the mixture at 15-20°C and stirred for 15 minutes. Raised the temperature of the mixture to 65-70°C and stirred for 12 hours. Cooled the mixture to 25-30°C. Methyl tert-butyl ether (40.0 ml) was added to the mixture at 25-30°C and stirred for 20 minutes. Layers were separated and aqueous layer washed with methyl tert-butyl ether. Cooled the aqueous layer to 0-5°C. Methyl tert-butyl ether (50.0 ml) was added to the aqueous layer at 0-5°C. Aqueous hydrochloric acid was slowly added to the mixture at 0-5°C and stirred for 10 minutes. Layers were separated and extracted aqueous layer with methyl tert-butyl ether. Combined the organic layers and washed with water. Distilled off the organic layer under vacuum at below 50°C. n-Heptane (35.0 ml) was added to the obtained compound 25-30°C and stirred for 2 hours. Filtered the solid, washed with n-heptane and dried to get the title compound. Yield: 3.50 gm.

Example-10: Preparation of 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoic acid of Formula-9.

Tetrahydrofuran (700.0 ml) was added to potassium tert-butoxide (84.5 gm) at 25-30°C and stirred for 20 minutes. Cooled the mixture to 0-5°C. Ethyl 2-(2-(4-fluorophenyl)thiazol-4- yl)acetate (50.0 gm) and tetrahydrofuran (100.0 ml) were slowly added to the mixture at 0-5°C and stirred for 1 hour. Methyl iodide (106.9 gm) and tetrahydrofuran (120.0 ml) were slowly added to the mixture at 0-5°C and stirred for 10 minutes. Sodium chloride solution was slowly added to the mixture at 0-5°C and stirred for 10 minutes. Aqueous hydrochloric acid was slowly added to the mixture at 0-5°C and stirred for 10 minutes. Layers were separated and extracted aqueous layer with tetrahydrofuran. Combined the organic layers. Distilled off the organic layer under vacuum at below 65°C. Lithium hydroxide (20.0 gm) and water (500.0 ml) were slowly added to the mixture at 15-20°C. Raised the temperature of the mixture to 70-75°C and stirred for 16 hours. Cooled the mixture to 25-30°C. Methyl tert-butyl ether (100.0 ml) was added to the mixture at 25-30°C and stirred for 15 minutes. Layers were separated and extracted aqueous layer with methyl tert-butyl ether. Methyl tert-butyl ether (100.0 ml) was added to the aqueous layer at 25-30°C. Cooled the mixture to 0-5°C. Aqueous hydrochloric acid was slowly added to the mixture at 0-5°C and stirred for 10 minutes. Layers were separated and extracted aqueous layer with methyl tert-butyl ether. Combined the organic layers. Distilled off the organic layer under vacuum at below 50°C. n-Heptane (270.0 ml) was added to the obtained compound 25-30°C and stirred for 2 hours. Filtered the solid, washed with n-heptane and dried to get the title compound. Yield: 38.0 gm.

Example-11: Preparation of Venglustat.

Tetrahydrofuran (100.0 ml) was added to 2-(2-(4-fluorophenyl)thiazol-4-yl)-2- methylpropanoic acid of formula-9 (4.0 gm) at 25-30°C. Cooled the mixture to 0-5°C. Triethyl amine (3.05 gm) and isobutyl chloroformate (3.13 gm) were added to the mixture at 0-5°C and stirred for 15 minutes. Sodium azide (1.96) and water (20.0 ml) were added to the mixture at 0- 5°C and stirred for 10 minutes. Raised the temperature of the mixture to 25-30°C and stirred for 18 hours. Ethyl acetate (60.0 ml) and water (100.0 ml) were added to the mixture at 25-30°C. Layers were separated and extracted aqueous layer with ethyl acetate. Combined the organic layers and washed with sodium bicarbonate solution and sodium chloride solution. Distilled off the organic layer under vacuum at below 50°C. Toluene (100.0 ml) was added to the obtained compound at 40-45°C and stirred for 30 minutes. (S)-Quinuclidin-3-ol (3.83 gm) was added to the mixture at 40-45°C. Raised the temperature of the mixture to 60-65°C and stirred for 12 hours. Distilled off the mixture under vacuum at below 50°C. Isopropyl acetate (100.0 ml), sodium bicarbonate and water were added to the obtained compound at 25-30°C and stirred for 10 minutes. Layers were separated and organic layer washed with sodium sulphate solution. Distilled off the organic layer under vacuum at below 50°C to get the title compound. Yield: 2.5 gm.

Example-12: Preparation of Venglustat.

Tetrahydrofuran (621.0 ml) was added to 2-(2-(4-fluorophenyl)thiazol-4-yl)-2- methylpropanoic acid of formula-9 (25.0 gm) at 25-30°C and stirred for 10 minutes. Cooled the mixture to 0-5°C. Triethyl amine (26.1 ml) and isobutyl chloroformate (18.65 ml) were added to the mixture at 0-5°C and stirred for 1 hour. Sodium azide (12.5) and water (125 ml) were added to the mixture at 0-5°C. Raised the temperature of the mixture to 25-30°C and stirred for 20 hours. Water (625.0 ml) was added to the mixture at 25-30°C and stirred for 10 minutes. Ethyl acetate (375.0 ml) was added to the mixture at 25-30°C and stirred for 15 minutes. Layers were separated and extracted aqueous layer with ethyl acetate. Combined the organic layers and washed with sodium bicarbonate solution and sodium chloride solution. Distilled off the organic layer under vacuum at below 50°C and co-distilled with toluene. Toluene (625.0 ml) was added to the obtained compound at 25-30°C. Raised the temperature of the mixture to 110-115°C and stirred for 90 minutes. (S)-Quinuclidin-3-ol (24.18 gm) was added to the mixture at 115-120°C and stirred for 16 hours. Cooled the mixture to 25-30°C. Water (250.0 ml) was added to the mixture at 25-30°C and stirred for 1 hour. Layers were separated and organic layer washed with water. Water (— ) was added to the organic layer at 25-30°C. Aqueous hydrochloric acid was slowly added to the mixture at 25-30°C and stirred for 30 minutes. Layers were separated and organic layer washed with aqueous hydrochloric acid. Combined the aqueous layers and washed with toluene. Layers were separated. Toluene (625.0 ml) was added to aqueous layer at 25-30°C. Cooled the mixture to 20-25°C. Sodium hydroxide solution was slowly added to the mixture at 20-25°C. Layers were separated and extracted aqueous layer with isopropyl acetate. Combined the organic layers and washed with water. Distilled off the organic layer under vacuum at below 45°C and co-distilled with diisopropyl ether. Diisopropyl ether (625.0 ml) was added to the obtained compound at 25-30°C and stirred for 2 hours. Liltered the solid, washed with diisopropyl ether and dried to get the title compound. Yield: 22.0 gm.

Example-13: Preparation of Venglustat.

Tetrahydrofuran (4000.0 ml) was added to 2-(2-(4-fluorophenyl)thiazol-4-yl)-2- methylpropanoic acid of formula-9 (160.0 gm) at 25-30°C and stirred for 10 minutes. Cooled the mixture to 0-5°C. Triethyl amine (122.0 gm) and isobutyl chloroformate (125.20 gm) were added to the mixture at 0-5°C and stirred for 90 minutes. Sodium azide (78.40 gm) and water (800.0 ml) were added to the mixture at 0-5°C and stirred for 2 hours. Raised the temperature of the mixture to 25-30°C and stirred for 15 hours. Water (4000.0 ml) and ethyl acetate (2000.0 ml) were added to the mixture at 25-30°C. Layers were separated and extracted aqueous layer with ethyl acetate. Combined the organic layers and washed with sodium bicarbonate solution and sodium chloride solution. Distilled off the organic layer under vacuum at below 50°C and co-distilled with toluene. Toluene (4000.0 ml) was added to the obtained compound 25-30°C. Raised the temperature of the mixture to 110-115°C and stirred for 40 minutes. (S)-Quinuclidin-3-ol (154.75 gm) was added to the mixture at 115-120°C and stirred for 16 hours. Cooled the mixture to 25- 30°C. Water (1600.0 ml) was added to the mixture at 25-30°C and stirred for 10 minutes. Layers were separated and organic layer washed with water. Water (4000.0 ml) was added to the organic layer at 25-30°C. Aqueous hydrochloric acid was slowly added to the mixture at 25-30°C and stirred for 30 minutes. Layers were separated and organic layer washed with aqueous hydrochloric acid. Combined the aqueous layers and washed with toluene. Layers were separated. Isopropyl acetate (4000.0 ml) was added to aqueous layer at 20-25°C. Cooled the mixture to 15-20°C. Sodium hydroxide solution was slowly added to the mixture at 15-20°C. Layers were separated and extracted aqueous layer with isopropyl acetate. Combined the organic layers and washed with water. Distilled off the organic layer under vacuum at below 45°C and co-distilled with diisopropyl ether. Diisopropyl ether (800.0 ml) was added to the obtained compound at 25-30°C and stirred for 10 minutes. Filtered the solid, washed with diisopropyl ether and dried to get the title compound. Yield: 90.0 gm.

Example-14: Preparation of R-isomer of Venglustat.

Tetrahydrofuran (125.0 ml) was added to 2-(2-(4-fluorophenyl)thiazol-4-yl)-2- methylpropanoic acid of formula-9 (5.0 gm) at 25-30°C and stirred for 10 minutes. Cooled the mixture to 0-5°C. Triethyl amine (3.81 gm) and isobutyl chloroformate (3.91 gm) were added to the mixture at 0-5°C and stirred for 90 minutes. Sodium azide (2.45 gm) and water (25.0 ml) were added to the mixture at 0-5°C and stirred for 2 hours. Raised the temperature of the mixture to 25-30°C and stirred for 20 hours. Water (100.0 ml) and ethyl acetate (60.0 ml) were added to the mixture at 25-30°C and stirred for 20 minutes. Layers were separated and extracted aqueous layer with ethyl acetate. Combined the organic layers and washed with sodium bicarbonate solution and sodium chloride solution. Organic layer washed with water. Distilled off the organic layer under vacuum at below 50°C and co-distilled with toluene. Toluene (25.0 ml) was added to the obtained compound 25-30°C. Raised the temperature of the mixture to 115-120°C and stirred for 1 hour. (R)-Quinuclidin-3-ol (4.5 gm) was added to the mixture at 115-120°C and stirred for 16 hours. Cooled the mixture to 25-30°C. Water (50.0 ml) was added to the mixture at 25-30°C and stirred for 10 minutes. Layers were separated and organic layer washed with water. Water (50.0 ml) was added to the organic layer at 25-30°C. Aqueous hydrochloric acid was slowly added to the mixture at 25-30°C and stirred for 30 minutes. Layers were separated and organic layer washed with aqueous hydrochloric acid. Combined the aqueous layers and washed with toluene. Layers were separated. Isopropyl acetate (100.0 ml) was added to aqueous layer at 20- 25°C. Cooled the mixture to 20-25°C. Sodium hydroxide solution was slowly added to the mixture at 20-25°C. Layers were separated and extracted aqueous layer with isopropyl acetate. Combined the organic layers and washed with water. Distilled off the organic layer under vacuum at below 45°C and co-distilled with diisopropyl ether. Diisopropyl ether (35.0 ml) was added to the obtained compound at 25-30°C and stirred for 30 minutes. Filtered the solid, washed with diisopropyl ether and dried to get the title compound. Yield: 2.5 gm.