DESC:Field of the Invention:
The present invention relates to a process for 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl]amino]- 2,4(1H,3H)- pyrimidinedione compound of formula-I and polymorphs thereof, which is represented by the following structural formula:

Formula-I

Background of the Invention:
Mavacamten having chemical name of 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl] amino]- 2,4(1H,3H)- pyrimidinedione. It is approved by US FDA in April-2022 under the brand name of CAMZYOS capsules for oral use and is a cardiac myosin inhibitor indicated for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms, and also approved in Europe in 2023.

The US patent US9181200B2 (herein after referred as US’200) first reported 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl] amino]- 2,4(1H,3H)- pyrimidinedione and its preparation and intermediates thereof.
The PCT application publication WO2021092598A1 (herein after referred as WO’598) reported polymorphs for 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl] amino]- 2,4(1H,3H)- pyrimidinedione and intermediate’s process thereof.
The PCT application publication WO2021154904 (herein referred as WO’709) reported various crystalline forms for 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl] amino]- 2,4(1H,3H)- pyrimidinedione.
Based on drawbacks in the prior art process and certain limitations, there is a need for providing an improved process for the preparation of mavacamten, which involves simple experimental procedures, well suited to industrial production, which avoids the use of column chromatography purification, and which affords highly pure mavacamten.
The present invention provides an improved process for preparation of mavacamten and intermediates thereof and free from other impurities or isomers and nitroso amine impurities. The present invention involves cost effective key starting material, reagents and solvents, and suitable industrial production.
The present invention provides an improved process for preparation of 3-(1-methyl ethyl)-6-[[(1S)-1-phenylethyl]amino]- 2,4(1H,3H)- pyrimidinedione and intermediates thereof.

Brief Description:
The first aspect of the present invention is to provide a process for 3-(1-methyl ethyl)-6-[[(1S)-1-phenylethyl]amino]- 2,4(1H,3H)- pyrimidinedione compound of formula-I.
The second aspect of the present invention is to provide a purification process for the preparation of 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl]amino]- 2,4(1H,3H)-pyrimidine dione compound of formula-I.
Brief description of the drawings:
Figure 1: Illustrates the PXRD pattern of crystalline form of 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl]amino]- 2,4(1H,3H)- pyrimidinedione HCl obtained as per example-5.
Figure 1: Illustrates the PXRD pattern of crystalline form of 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl]amino]- 2,4(1H,3H)- pyrimidinedione obtained as per example-6.

Detailed Description:
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 dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, 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, 1,2-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), dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbontetra chloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile 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-methoxy ethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
As used herein the present invention the term “suitable base” refers to inorganic or organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium 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 ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases such as like dimethylamine, diethylamine, diisopropyl amine, diisopropyl ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine (DMAP), N-methyl morpholine (NMM), or mixtures thereof.

The first aspect of the present invention provides an improvised process for the preparation of 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl]amino]-2,4(1H,3H)-pyrimidi nedione compound of formula-I.

Formula-I
Comprising of,
a) reacting the compound of formula-1 with

suitable reagent, solvent to provide the compound of formula-2,

b) reacting the compound of formula-2 with suitable reagent, solvent to provide the compound of formula-3, or optionally purifying the compound of formula-3,

c) reacting the compound-3 obtained in step-b) with suitable reagent, solvent to provide the compound of formula-4 or an acid addition salt,

[4]
d) treating compound of formula-4 with suitable acid followed by suitable base treatment with suitable solvent to provide compound of formula-I,
e) optionally purifying the compound obtained in step c) or d) using suitable solvent to provide pure compound of formula-I
Wherein in step-a) suitable reagents are diethylmalonate, dimethylmalonate, inorganic base, organic base such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, dimethylamine, diethylamine, diisopropyl amine, diisopropyl ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine (DMAP), N-methyl morpholine (NMM) and mixture thereof.
Wherein in step-b) the suitable reagents are phosphorous oxychloride.
Wherein in step c) suitable reagent is (S)-1-phenylethanamine and suitable bases are sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, dimethylamine, diethylamine, diisopropyl amine, diisopropyl ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine (DMAP), N-methyl morpholine (NMM) and mixture thereof.
Wherein in step d) the suitable acids and base are hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, toluene sulphonic acid, benzene sulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid, HCl in alcohol, HCl in organic ethyl acetate, HCl in ether solvents, organic bases, inorganic bases and mixture thereof;

Wherein in step-a), b), c), d) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ketone solvent, ether solvents, polar aprotic solvents, polar protic solvents, ester solvent, nitrile solvent, alcohol solvent, water and any mixture thereof;
The suitable temperature is 0 to 150°C, preferably 5-140°C.
The preferred embodiment of aspect of the present invention provides an improvised process for the preparation of 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl]amino]- 2,4(1H,3H)- pyrimidinedione compound of formula-I.

Formula-I
Comprising of,
a) reacting the compound of formula-1 with

diethyl malonate, in presence of sodium methoxide in methanol to provide the compound of formula-2,

b) reacting the compound of formula-2 with phosphorous oxychloride in acetonitrile to provide the compound of formula-3,

c) reacting the compound-3 obtained in step-b) with (S)-1-phenyl ethanamine in n-butanol and further treated with IPA-HCl to provide the compound of formula-4a 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl]amino]- 2,4(1H,3H)- pyrimidinedione hydrochloric acid)

[4a]
d)treating compound of formula-4a with aq. sodium hydroxide in water to provide compound of formula-I,
The second aspect of the present invention provides a purification process for 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl]amino]- 2,4(1H,3H)- pyrimidinedione compound of formula-I comprising less than 0.15 % R-isomer and other related impurities

Process comprising of:
a) stirring the compound of 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl]amino]- 2,4(1H,3H)- pyrimidinedione in a suitable acid, solvent at a suitable temperature,
b) isolating the compound obtained in step-a) at suitable temperature,
c) treating the compound obtained in step-b), with suitable base, solvent to provides pure form of 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl]amino]- 2,4(1H,3H)- pyrimidinedione compound of formula-I.

Wherein in step-a, b, c) the suitable temperature is 0 to 150°C, preferably 10-140°C;
Wherein in step-a, b, c) The suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvent, ether solvents, ketone solvents, nitrile solvents, polar aprotic solvents, polar protic solvents, alcohol solvents, polar solvent like acetic acid, water or any mixture thereof; in step c) the suitable temperature is below 40°C.

Wherein in step-a, c) the suitable acids and base are hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, toluene sulphonic acid, benzene sulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, HCl in alcohol, HCl in organic ethyl acetate, HCl in ether solvents, and benzoic acid, organic bases, inorganic bases and mixture thereof;

The process developed by the present invention produces highly pure 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl]amino]- 2,4(1H,3H)- pyrimidinedione compound of formula-I, which is devoid of nitroso amine impurities with good yield. All the related substances and residual solvents are controlled well within the limits as suggested by ICH guidelines and most of the related substances are controlled in non-detectable levels.

The other aspect of the present invention provides a stable crystalline form-M of 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl]amino]-2,4(1H,3H)- pyrimidinedione Hydrochloride salt is characterized by its powder X-Ray diffraction pattern having characteristic peaks at about 7.5, 15.1 and 17.3. The said crystalline form-M is further characterized by its powder X-Ray diffraction pattern substantially in accordance with figure-1. Further, the crystalline form-M of Mavacamten hydrochloride may be characterized by the PXRD pattern having peaks at 7.5, 11.5, 13.8, 15.1, 16.3, 17.3, 19.4, 22.2, 22.7, 23.0, 24.3, 24.8, 27.6, 28.1, 28.7, 29.1, 29.6, 30.4, 30.9, 31.2, 31.7, 34.6, 34.9, 35.3, 36.2, 36.6, 37.8, 38.1, 40.6, 41.6, 42.2, 45.2, 45.5, 46.9 and 47.8 ± 0.2° 2?.
The other aspect of the present invention compound of formula-I is having particle size distribution of D90 <300 µm, D50 <150 µm. D10 <75 µm.
The compound of formula-I produced by the process of the present invention has purity of at least about 95%; preferably of at least about 97%; more preferably of at least about 98%; most preferably of at least about 99 % as measured by HPLC.
The other isomer of compound of formula-I is having preferably < 0.5 %, more preferably < 0.15 %; and other related impurities are preferably < 0.5 %, more preferably < 0.15 % in compound of formula-I of the present invention.


R-isomer

3-(1-methylethyl)-6-[[(1S)-1-phenylethyl]amino]- 2,4(1H,3H)- pyrimidinedione compound of formula-I 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, 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 an improved process for 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl]amino]- 2,4(1H,3H)- pyrimidinedione compound of formula-I as mentioned in the schematic representation-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: Preparation of compound of formula-1 (1-isopropylurea)
A round bottom flask was charged with isopropylamine (100 g) and 1N hydrochloric acid (75.6 mL) at 0-10°C and stirred for 15 min at 10-20°C. Further, charged potassium cyanate (302 g) to the above solution and heated to 70-80°C, and stirred for 16 hr at same temperature. Cooled the reaction mixture to 25-35°C, and stirred for 3 hr. The resulting solid was filtered and washed with n-heptane to get the wet compound. Further, the wet compound was charged with isopropanol and stirred for 1 hr. The solution was filtered through hyflow and washed with isopropanol. The filtrate solution was distilled-off completely and charged with n-heptane and stirred for 3 hr at 10-20°C. Filtered the solid and dried to get the title compound.
Yield: 78 g; Purity by HPLC: >99.5
Example-2: Preparation of compound of formula-2 (1-isopropylpyrimidine-2,4,6(1H, 3H,5H)-trione)
A round bottom flask was charged with compound-1 (100 g), methanol (600 mL) and stirred for 5-10 min at 25-35°C. To the reaction mixture charged dimethyl malonate (155 g) and sodium methoxide (27 % solution, 529 g), heated to 60-70°C and stirred for 24 hr at same temperature. The reaction mixture was distilled-off completely, quenched with water at 25-35°C and stirred for 30 min. The reaction solution pH was adjusted to 3 using dil HCl and stirred for 2 hr. The precipitated solid was filtered and washed with water to get the wet compound. The wet compound was stirred in water for 2 hr and filtered the solid compound and washed with water and dried to get the title compound.
Yield: 105.5 g
Example-3: Preparation of compound of formula-3 (6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione)
A round bottom flask was charged with compound-2 (100 g) and acetonitrile (200 mL) under nitrogen atmosphere stirred for 10 min at 25-35°C. Cooled the reaction mass to 5-15°C charged phosphorous oxychloride (180 g) and stirred for 14 hr at 55-65°C. Cooled the reaction mixture to 5-15°C quenched with ice cold water and stirred for 1 hr. Filtered the solid compound and washed with water to get the wet compound. Further, the wet compound was stirred in water for 1 hr and filtered and dried to get the title compound.
Yield: 75 g
Example-4: Preparation of compound of formula-4
A round bottom flask was charged with compound-3 (100 g) and n-butanol (200 mL) and stirred for 10 min at 25-35°C. Cooled the reaction mass to 5-15°C, charged (S)-1-phenyl ethanamine (128.5 g) and stirred the reaction at 110-125°C for 14 hr. Cooled the reaction mass to 20-30°C and stirred for 2 hr and filtered the compound and washed with n-butanol. Further, the obtained compound was charged with ethyl acetate and diluted HCl and stirred at 25-35° for 2 hr, both the layers were separated, organic layer was dried and distilled-off completely to get the title compound.
Yield: 85.6 g; Purity by HPLC: 99.1 %
Example-5: Preparation of compound of formula-4a ((S)-3-isopropyl-6-(1-phenylethyl amino) pyrimidine-2,4(1H,3H)-dione hydrochloric acid)
A round bottom flask was charged with compound-3 (100 g) and n-butanol (200 mL) and stirred for 10 min at 25-35°C. Cooled the reaction mass to 5-15°C, charged (S)-1-phenyl ethanamine (128.5 g) and stirred the reaction at 110-125°C for 14 hr. Cooled the reaction mass to 20-30°C and stirred for 2 hr and filtered the compound and washed with n-butanol. Further, the obtained compound was charged with isopropanol HCl and stirred at 65-75° for 2 hr and stirred for 2 hr at 20-30°C. The resulting solid was filtered and washed with isopropanol and dried to get the title compound.
Yield: 93.5 g; purity by HPLC: 99.8 %; R-isomer: not detected;
The obtained compound PXRD depicted in figure-1
Example-6: Preparation of compound of formula-I
A round bottom flask was charged with ((S)-3-isopropyl-6-(1-phenylethyl amino) pyrimidine-2,4(1H,3H)-dione Hydrochloric acid) (100 g) and water (800 mL) was stirred for 10 min at 25-35°C. The reaction mass was charged with aq. sodium hydroxide (13 g in water 30 mL) and stirred for 10 min at 25-35°C. Charged activated carbon (5 g) and stirred for 10 min, filtered through hyflow and washed with water. Further, the pH of the reaction was adjusted to 5.5 with HCl and stirred for 2 hr. Filtered the solid obtained and washed with water to get wet compound. The wet compound was charged with water and stirred for 1 hr at 45-55°C. Filtered the obtained solid and washed with water and dried to get the title compound.
Yield: 90.5 g; Purity by HPLC: 99.8%; R-isomer: not detected;
The obtained compound PXRD depicted in figure-2
Example-7: Purification of Preparation of ((S)-3-isopropyl-6-(1-phenylethyl amino) pyrimidine-2,4(1H,3H)-dione para-Toluenesulfonicacid)
A round bottom flask was charged with compound-4 (10 g) and methanol (20 mL) and stirred for 10 min at 25-35°C. Charged with para-Toluenesulfonicacid (1 eq) and stirred at 55-65° for 2 hr and stirred for 1 hr at 20-30°C. The resulting solid was filtered and washed with methanol and dried to get the title compound.
Yield: 11.5 g
Example-8: Purification of Preparation of ((S)-3-isopropyl-6-(1-phenylethyl amino) pyrimidine-2,4(1H,3H)-dione tartaric acid)
A round bottom flask was charged with compound-4 (10 g) and isopropanol (20 mL) and stirred for 10 min at 25-35°C. Charged with tartaric acid (1 eq) and stirred at 65-75° for 2 hr and stirred for 2 hr at 20-30°C. The resulting solid was filtered and washed with isopropanol and dried to get the title compound.
Yield: 10.5 g.
Example-9: Preparation of ((S)-3-isopropyl-6-(1-phenylethyl amino) pyrimidine-2,4(1H,3H)-dione) fumaric acid
A round bottom flask was charged with compound-4 (10 g) and isopropanol (20 mL) and stirred for 10 min at 25-35°C. Charged with fumaric acid (1 eq) and stirred at 65-75° for 5 hr and stirred for 1 hr at 20-30°C. The resulting solid was filtered and washed with isopropanol and dried to get the title compound.
Yield: 9.85 g.
Example-10: Preparation of compound of formula-1 (1-isopropylurea)
A round bottom flask was charged with isopropylamine (100 g), cooled the reaction mass to 0-10°C, stirred for 5 min at 0-10°C and charged with 1N hydrochloric acid (75.6 mL) slowly at 15°C, stirred for 15 min at 10-20°C. Further, charged potassium cyanate (302 g) to the above solution and heated to 70-80°C, and stirred for 14 hr at same temperature. Gradually cooled the reaction mixture to 15-25°C and stirred for 3 hr at same temperature. The resulting solid was filtered and washed with n-heptane (50 ml) to get the wet compound. Further, the wet compound was charged with isopropanol (700 ml) and stirred for 45 min. The solution was filtered through hyflo and washed with isopropanol. The filtrate solution was distilled off completely and cooled the reaction mass to 25-35°C and charged with n-heptane and stirred for 3 hr at 15-25°C. Filtered the solid and washed with n-heptane and dried to get the title compound.
Yield: 85.8 g;
Example-11: Preparation of compound of formula-2 (1-isopropylpyrimidine-2,4,6(1H, 3H,5H)-trione)
A round bottom flask was charged with compound-1 (100 g), methanol (600 mL) and stirred for 10 min at 25-35°C. To the reaction mixture charged dimethyl malonate (155.21 g) and sodium methoxide (27 % solution, 529.03 g), gradually heated to 60-70°C and stirred for 24 hr at same temperature. The reaction mixture was distilled off completely, quenched with water at 25-35°C. Cooled the reaction mass, adjusted the solution pH to 3.5 using dil HCl and stirred for 2 hr at 15-25°C. The precipitated solid was filtered and washed with water to get the wet compound. The wet compound was stirred in water for 2 hr at and filtered the solid compound and washed with water and dried to get the title compound.
Yield: 110.0 g
Example-12: Preparation of compound of formula-3 (6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione)
A round bottom flask was charged with compound-2 (30 g) and acetonitrile (60 mL) stirred the reaction mass for 10 min at 25-35°C. Cooled the reaction mass to 5-15°C, gradually charged phosphorous oxychloride (54.06 g) and stirred for 14 hr at 55-65°C. Cooled the reaction mixture to 5-15°C, quenched with ice cold water (150 ml) and stirred for 45 min. Filtered the solid compound and washed with water (30 ml) to get the wet compound. Further, the wet compound was stirred in water (90 ml) for 1 hr and filtered the solid and washed with water (30 ml) to get the wet compound.
Another RBF was charged with wet compound and dichloromethane (120 ml) at 25-35°C, raised the temperature of the reaction to 35-45°C and maintained for 45 min. The reaction mass was cooled to 25-35°C, maintained for 1 hr, filtered the solid and washed with dichloromethane and dried to get the title compound.
Yield: 28.0 g
Example-13: Preparation of compound of formula-4a ((S)-3-isopropyl-6-(1-phenylethyl amino) pyrimidine-2,4(1H,3H)-dione Hydrochloric acid).
A round bottom flask was charged with compound-3 (100 g) and n-butanol (200 mL) and stirred for 10 min at 25-35°C. Cooled the reaction mass to 5-15°C, charged (S)-1-phenyl ethanamine (128.5 g) and stirred the reaction at 110-125°C and maintained for 14 hr at 55-65°C. Cooled the reaction mass to 20-30°C and stirred for 2 hr at same temperature and filtered the obtained compound and washed with n-butanol. Further, the obtained wet compound was charged with IPA-HCl (400 ml) and maintained for 90 min at 65-75°C. Cooled the reaction mass to 25-35°C and maintained for 2 hr at same temperature. Filtered the solid and washed with isopropanol and dried to get the title compound.
Yield: 121.37 g;
Example-14: Preparation of crystalline form -A of compound of formula-I
A round bottom flask was charged with ((S)-3-isopropyl-6-(1-phenylethyl amino) pyrimidine-2,4(1H,3H)-dione Hydrochloric acid) (10 g) and aq. sodium hydroxide (5 g in water 100 mL) and stirred for 20 min at 15-25°C. Filtered through hyflow and washed with water . Cooled the reaction mass to 15-25°C and further, neutralized the reaction mixture and raised the reaction mass temperature to 25-35°C, maintained for 45 min at same temperature. Filtered the solid and washed with water to get wet compound.

The wet compound was charged with water (100 ml) and stirred for 10 min at 40-50°C. for 45 min at the same temperature. Filtered the solid and washed with water to get the wet compound. The wet compound was washed with n-heptane and dried to get the title compound.
Yield: 7.5 g;
Example-15: Preparation of crystalline form -A of compound of formula-I
A round bottom flask was charged with ((S)-3-isopropyl-6-(1-phenylethyl amino) pyrimidine-2,4(1H,3H)-dione Hydrochloric acid) (100 g) and aq. sodium hydroxide (32.28 g in water 1000 mL) and stirred for 20 min at 15-25°C. Filtered through hyflow and washed with water (50 ml). Cooled the reaction mass to 15-25°C and further, neutralized the reaction mixture and raised the reaction mass temperature to 25-35°C, maintained for 45 min at same temperature. Filtered the solid and washed with water to get wet compound.

The wet compound was charged with water (1000 ml) and stirred for 10 min at 40-50°C. for 45 min at the same temperature. Filtered the solid and washed with water (50 ml) to get the wet compound. The wet compound was charged with isopropanol (700 ml) and stirred the reaction mass for 10 min at 25-35°C, heated to 65-75°C and maintained for 30 min at same temperature. The reaction mass was cooled and stirred for 2 hr and filtered the compound and washed with n-heptane and dried to get the title compound.
Yield: 80.30 g;
Example-16: Preparation of crystalline form -A of compound of formula-I
A round bottom flask was charged with ((S)-3-isopropyl-6-(1-phenylethyl amino) pyrimidine-2,4(1H,3H)-dione Hydrochloric acid) (100 g) and aq. sodium hydroxide (32.28 g in water 1000 mL) and stirred for 20 min at 15-25°C. Filtered through hyflow and washed with water (50 ml). Cooled the reaction mass to 15-25°C and further, neutralized the reaction and raised the reaction mass temperature to 25-35°C, maintained for 45 min at same temperature. Filtered the solid and washed with water to get wet compound.
The wet compound was charged with water (1000 ml) and stirred for 10 min at 40-50°C. for 45 min at the same temperature. Filtered the solid and washed with water (50 ml) to get the wet compound. The wet compound was charged with n-butanol (700 ml) and stirred the reaction mass for 10 min at 25-35°C, heated to 65-75°C and maintained for 30 min at same temperature. The reaction mass was cooled and filtered the compound and washed with n-heptane and dried to get the title compound.
Yield: 77.5 g;
The obtained compound PXRD is similar to the figure 2.
Particle size distribution of D90: 43 µm, D50 :19.6 µm. D10: 5.96 µm.
Example-17: Preparation of compound of formula-4a ((S)-3-isopropyl-6-(1-phenylethyl amino) pyrimidine-2,4(1H,3H)-dione hydrochloric acid)
A round bottom flask was charged with compound-3 (50 g) and isopropanol (100 mL) and stirred for 10 min at 25-35°C. Cooled the reaction mass to 5-15°C, charged (S)-1-phenyl ethanamine ( 65 g) and stirred the reaction at 70-80°C for 24 hr. Cooled the reaction mass to 20-30°C and stirred for 2 hr and filtered the compound and washed with isopropanol. Further, the obtained compound was charged with isopropanol- HCl and stirred at 60-70° for 2 hr and the resulting solid was filtered and washed with isopropanol and dried to get the title compound.
Yield: 42.5 g;

,CLAIMS:We claim:
1.An improved process for the preparation of 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl]amino]- 2,4(1H,3H)- pyrimidinedione compound of formula-I.

Formula-I
Comprising of,
a) reacting the compound of formula-1 with

diethyl malonate, in presence of sodium methoxide in methanol to provide the compound of formula-2,

b) reacting the compound of formula-2 with phosphorous oxychloride in acetonitrile to provide the compound of formula-3,

c) reacting the compound obtained in step-b) with (S)-1-phenyl ethanamine in n-butanol and further treated with IPA-HCl to provide the compound of formula-4a 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl]amino]- 2,4(1H,3H)- pyrimidinedione hydrochloric acid)

[4a]
d)treating compound of formula-4a with aq. sodium hydroxide in water to provide compound of formula-I.
2.A process for crystalline form-A of compound formula-I, Comprising of
a) stirring the compound of 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl]amino]- 2,4(1H,3H)- pyrimidinedione in a suitable acid, solvent at a suitable temperature,
b)isolating the compound obtained in step-a) at suitable temperature,
c)treating the compound obtained in step-b), with suitable base, solvent to provide pure 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl] amino]- 2,4(1H,3H)- pyrimidinedione compound of formula-I.
3.A process for preparation of crystalline form A of compound of formula-I as claimed in claim 2, Wherein in step-a, b, c) the suitable temperature is 0 to 150°C, preferably 10-140°C; Wherein in step-a, b, c) The suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvent, ether solvents, ketone solvents, nitrile solvents, polar aprotic solvents, polar protic solvents, alcohol solvents, polar solvent like acetic acid, water or any mixture thereof;
Wherein in step-a, c) the suitable acids and base are hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, toluene sulphonic acid, benzene sulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, HCl in alcohol, HCl in ethyl acetate, HCl in ether solvents, and benzoic acid, organic bases, inorganic bases and mixture thereof;

4. Mavacamten according to any of the preceding claims is having particle size distribution of D90 <300 µm, D50 <150 µm. D10 <75 µm., preferably D90 <100 µm, D50 <50 µm. D10 <20 µm
5. Mavacamten according to the preceding claims has purity of at least about 95%; preferably of at least about 97%; more preferably of at least about 98%; most preferably of at least about 99 % as measured by HPLC.