Field of the Invention:

The present invention relates to an improved process for the preparation of (S)-4-[(3-chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-l-pyrrolidinyl]-N-(2-pyrimidinyl methyl)-5-pyrimidine carboxamide which is represented by the following structural formula-1.

(S)-4-[(3-Chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-l-pyrrolidinyl]-N-(2-pyrimidinylmethyl)-5-pyrimidine carboxamide is commonly known as "Avanafil". It is a PDE5 inhibitor used for the treatment of erectile dysfunction. It acts by inhibiting a specific phosphodiesterase type 5 enzyme which is found in various body tissues, but primarily in the corpus cavernosum penis, as well as the retina. It is developed by Vivus and marketed under the brand name "Stendra ".

Background of the Invention:

Avanafil and its process for the preparation were first disclosed in US6656935. The process disclosed in US6656935 is depicted in the following scheme: Scheme-1:

In nearly all the stages of the process chromatographic separation is involved which being very tedious is not compatible for a large scale commercial process.

As of now, there is no simple purification method available for Avanafil. Henceforth there is a need in the art to provide a simple purification method for Avanafil, which avoids tedious work-up process and provides a cost-effective process.

In general, the solvents utilized in the reaction play an important role in the cost effectiveness of a process. Hence there is a need to develop process which can minimize the use of solvents or use solvents which can be recycled and reused.

Therefore there is a need for developing a synthetic process which can take into account the above facts and can also be scaled up to an industrial level.

Brief description of Invention:

The first aspect of the present invention is to provide a process for the preparation of ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio) pyrimidine-5-carboxylate compound of formula-7, comprising of:

a) Chlorinating ethyl 4-hydroxy-2-(methylthio)pyrimidine-5-carboxylate compound of formula-4 with a suitable chlorinating agent in a suitable solvent provides ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate compound of formula-5,

b) reacting the compound of formula-5 in-situ with (3-chloro-4-methoxyphenyl) methanamine compound of formula-6 or its hydrochloride salt compound of formula-6a in presence of aqueous inorganic base to provide ethyl 4-(3-chloro-4-methoxybenzyl amino)-2-(methylthio)pyrimidine-5-carboxylate compound of formula-7.

The second aspect of the present invention is to provide a process for the preparation of (S)-4-(3 -chloro-4-methoxybenzylamino)-2-(2-(hydroxymethyl)pyrrolidin-1 -yl)pyrimidine-5-carboxylic acid compound of formula-11,comprising of:

a) Oxidizing the 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio)pyriniidine-5-carboxylate compound of formula-7 with a suitable oxidizing agent in a suitable solvent to provide ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylsulfinyl) pyrimidine-5-carboxylate compound of formula-8,

b) reacting the compound of formula-8 in-situ with (S)-pyrrolidin-2-ylmethanol compound
of formula-9 in presence of a suitable base, optionally purifying the obtained compound with a suitable solvent provides (S)-ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(2-(hydroxymethyl)pyrrolidin-1 -yl)pyrimidine-5-carboxylate compound of formula-10, c) hydrolyzing the compound of formula-10 in presence of an aqueous base provides (S)-4-(3-chloro-4-methoxybenzylamino)-2-(2-(hydroxymethyl)pyrrolidin-1 -yl) pyrimidine-5-carboxylic acid compound of formula-11.

The third aspect of the present invention provides an improved process for the preparation of Avanafil compound of formula-1.

The fourth aspect provides a crystalline solid of avanafil. The crystalline solid of Avanafil obtained by the present invention, herein designated as crystalline form-M, characterized by:

a) its powder X-ray diffractogram pattern in accordance with figure-1, and

b) its DSC thermogram showing an endotherm peak at 164.1°C.

The fifth aspect of the present invention is to provide a process for the purification of Avanafil compound of formula-1, comprising the following steps of:

a) Dissolving the compound of formula-1 in a suitable solvent by heating to reflux temperature,

b) cooling the reaction mixture and stirring the reaction mixture,

c) filtering the precipitated solid, washing with a suitable solvent and then drying to get pure compound of formula-1.

The sixth aspect of the present invention provides a process for the purification of Avanafil compound of formula-1, comprising of:

a) Dissolving compound of formula-1 in a suitable chloro solvent,

b) adding the above solution to hydrocarbon solvent,

c) stirring the reaction mixture,

d) filtering the precipitated solid, washing with a suitable hydrocarbon solvent and then drying to get pure Avanafil compound of formula-1.

Brief description of the drawings:

Figure-1: Illustrates the PXRD pattern of crystalline form-M of Avanafil compound of formula-
1.

Figure-2: Illustrates the DSC thermogram of crystalline form-M of Avanafil compound of formula-1.

Detailed description of Invention:

The term "suitable solvent" used in the present invention is selected from, but not limited to "ester solvents" such as ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate and the like; "ether solvents" such as tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane and the like; "hydrocarbon solvents" such as toluene, hexane, heptane, pet.ether, benzene, xylene, cyclohexane and the like; "polar aprotic solvents" such as dimethyl acetamide, dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol and the like; "chloro solvents" such as dichloromethane, chloroform, dichloroethane, carbon tetrachloride and the like; "nitrile solvents" such as acetonitrile, butyronitrile, isobutyronitrile and the like; "protic solvent" such as acetic acid; "polar solvent" such as water or mixtures thereof.

The term "suitable base" used herein 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; organic bases such as triethyl amine, tribenzylamine, isopropyl amine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethylaminopyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1-methylimidazole, 1,2,4-triaozle or mixtures thereof.

The "suitable oxidizing agent" is selected from sodium hypochlorite {NaOCl}; calcium hypochlorite {Ca(OCl)2}; sodium bromate {NaBrO3}; Dess-Martin periodinane (DMP); oxalyl chloride/dimethyl sulfoxide (Swern oxidation); trichloroisocyanuric acid; TEMPO; pyridiniumchlorochromate (PCC); potassium dichromate; manganese dioxide; oxone; chromium trioxide; N-chlorosuccinimide/dimethylsulfide; Peracids such as metachloro perbenzoic acid, performic acid, peracetic acid and perbenzoic acid.

The first aspect of the present invention provides an improved process for the preparation of ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio)pyrimidine-5-carboxylate compound of formula-7,comprising of:

a) Chlorinating ethyl 4-hydroxy-2-(methylthio)pyrimidine-5-carboxylate compound of formula-4,

Formula-4 with a suitable chlorinating agent in a suitable solvent provides ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate compound of formula-5,

Formula-5 b) reacting the compound of formula-5 in-situ with (3-chloro-4-methoxyphenyl) methanamine compound of formula-6 or its hydrochloride salt compound of formula-6a in presence of aqueous inorganic base provides compound of formula-7.

Formula-7
In the present aspect of the invention the condensation of compound of formula-5 with compound of formula-6 or compound of formula-6a is carried out by using inorganic base like sodium carbonate in place organic base such as triethyl amine, which is reported in prior art.

The main advantage of the present aspect of the invention is that it minimizes the solvents used by carrying out two or three steps in a single solvent. In the above aspect the suitable solvent used is toluene. In the conversion of compound of formula-4 to compound of formula-7, toluene is used as a solvent which is carried over into next stage as the reaction mixture. Hence the use of multiple solvents is negated and further the toluene solvent can be recycled and reused. This has a great impact during scale-up.

The "suitable chlorinating agent" used in step-a) of the above aspect is phosphoryl chloride or thionyl chloride.

The (3-chloro-4-methoxyphenyl) methanamine hydrochloride compound of formula-6a used in step-(b) of the first aspect of the present invention is prepared by chlorination of the (4-methoxyphenyl) methanamine with sulfuryl chloride in acetic acid provides compound of formula-6a.

The second aspect of the present invention is to provide a process for the preparation of (S)-4-(3-chloro-4-methoxybenzylamino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrimidine 5-carboxylic acid compound of formula-11,comprising of:

a) Oxidizing 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio)pyrimidine-5-carboxylate compound of formula-7 with a suitable oxidizing agent in a suitable solvent provides ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylsulfinyl) pyrirnidine -5-carboxylate compound of formula-8,

Formula-8 b) reacting the compound of formula-8 in-situ with (S)-pyrrolidin-2-ylmethanol compound of formula-9 in presence of a suitable base, optionally purifying the obtained compound with a suitable solvent provides (S)-ethyl 4-(3-chloro-4-methoxybenzylarnino)-2-(2-(hydroxymethyl)pyrrolidin-l-yl)pyrimidine-5-carboxylate compound of formula-10,

Formula-10 c) hydrolyzing the compound of formula-10 in presence of an aqueous base provides (S)-4-(3-chloro-4-methoxybenzylamino)-2-(2-(hydroxymethyl) pyrrolidin-1 -yl) pyrimidine-5-carboxylic acid compound of formula-11.

Formula-11

In the above aspect oxidation of ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio)pyrimidine-5-carboxylate compound of formula-7 is carried out with meta chloro perbenzoic acid, in dichloromethane and the reaction mixture is used without distillation of the solvent, is reacted with (S)-pyrrolidin-2-ylmethanol compound of formula-9 in presence of triethylamine to provide compound of formula-10. The solvent is distilled off, ester compound of formula-10 is hydrolyzed using an aqueous sodium hydroxide in the absence of any solvent to provide compound of formula-11. Prior reported process involve column purification of compound of formula-10, whereas in the present aspect it is isolated directly from the dichloromethane solvent and purified using cyclohexane thereby avoiding column chromatography.

The third aspect of the present invention provides a process for the preparation of Avanafil compound of formula-1, comprising of:

a) Reacting diethyl 2-(ethoxymethylene)malonate compound of formula-2 with 2-methyl-2-pseudothiourea sulfate compound of formula-3 in presence of sodium carbonate in water provides ethyl 4-hydroxy-2-(methylthio)pyrimidine-5-carboxylate compound of formula-4,

b) chlorinating the compound of formula-4 with phosphoryl chloride in toluene provides ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate compound of formula-5,

c) reacting the compound of formula-5 in-situ with (3-chloro-4-methoxy phenyl) methanamine hydrochloride compound of formula-6a in presence of aqueous sodium carbonate provides ethyl 4-(3-chloro-4-methoxy benzylamino)-2-(methyl thio)pyrimidine-5-carboxylate compound of formula-7,

d) oxidizing the compound of formula-7 with m-chloroperbenzoic acid in dichloromethane provides ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methyl sulfmyl)pyrimidine-5-carboxylate compound of formula-8,

e) reacting the compound of formula-8 in-situ with (S)-pyrrolidin-2-ylmethanol compound of formula-9 in presence of triethyl amine, purifying the obtained compound with cyclohexane provides (S)-ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(2-(hydroxymethyl)pyrrolidin-l-yl)pyrimidine-5-carboxylate compound of formula-10,

f) hydrolyzing the compound of formula-10 in presence of aqueous sodium hydroxide provides (S)-4-(3-chloro-4-methoxybenzylamino)-2-(2-(hydroxy methyl)pyrrolidin-1 -yl)pyrimidine-5-carboxylic acid compound of formula-11,

g) reacting the compound of formula-11 with pyrimidin-2-yl methanamine hydrochloride compound of formula-12a in presence of l-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride, hydroxybenzotriazole and triethylamine in dimethylformamide provides compound of formula-1,

h) purifying the compound of formula-1 from methanol provides pure Avanafil compound of formula-1.

The pyrimidin-2-yl methanamine hydrochloride compound of formula-12a used in step-g) of the third aspect of the present invention is prepared by hydrogenating the pyrimidine-2-carbonitrile in presence of Raney nickel in 1,4-dioxane at a temperature ranging from 65 to about 70°C and at a pressure of 6-7 kg/cm2. Further the obtained compound is converted into its hydrochloride salt compound of formula-12a by treating it with hydrochloride source selected from ethylacetate-hydrochloride, isopropanol-hydrochloride, conchydrochloric acid, and aqueous hydrochloric acid.

The present invention is depicted in scheme-2.

Scheme-2
The fourth aspect provides a crystalline solid of (S)-4-[(3-chloro-4-methoxybenzyl) amino]-2-[2-(hydroxymethyl)-l-pyrrolidinyl]-N-(2-pyrimidinylmethyl)-5-pyrimidine carboxamide i.e. avanafil.

Avanafil obtained by the process of the present invention is a crystalline solid, which is designated as crystalline form-M. The crystalline form-M of the present invention is characterized by:

a) Its powder X-ray diffractogram having peaks at 5.9, 8.4, 11.9, 14.7, 16.1, 17.5, 18.7,19.3,
19.8, 20.4, 20.7, 21.0, 22.3, 23.3, 24.6, 25.6, 26.1, 28.0, 29.8 and 30.1± 0.2 degrees of 2- theta.

b) its powder X-ray diffractogram pattern in accordance with figure-1, and

c) its DSC thermogram showing an endotherm peak at 164.1°C.

The fifth aspect of the present invention providea a process for the purification of Avanafil compound of formula-1, comprising the following steps of:

a) Dissolving the compound of formula-1 in a suitable solvent by heating to reflux temperature,

b) cooling the reaction mixture and stirring the reaction mixture,

c) filtering the precipitated solid, washing with a suitable solvent and then drying to get pure compound of formula-1.

Wherein, the suitable solvent is selected from ester solvents, ketone solvents, nitrile solvents, hydrocarbon solvents and alcoholic solvents, preferably ethyl acetate, acetone, acetonitrile, toluene and methanol.

A preferred embodiment of the present invention provides a process for the purification of Avanafil compound of formula-1, comprising of:

a) Dissolving the compound of formula-1 in ethyl acetate by heating to reflux temperature,

b) cooling the reaction mixture and stirring the reaction mixture,

c) filtering the precipitated solid, washing with ethyl acetate and then drying to get pure compound of formula-1.

Another preferred embodiment of the present invention provides a process for the purification of Avanafil compound of formula-1,comprising of

a) Dissolving the compound of formula-1 in methanol by heating to reflux temperature,

b) cooling the reaction mixture and stirring the reaction mixture,

c) filtering the precipitated solid, washing with methanol and then drying to get pure compound of formula-1.

The sixth aspect of the present invention provides a process for the purification of Avanafil compound of formula-1, comprising of:

a) Dissolving compound of formula-1 in a suitable chloro solvent,

b) adding the above solution to hydrocarbon solvent,

c) stirring the reaction mixture,

d) filtering the precipitated solid, washing with a suitable hydrocarbon solvent and then drying to get pure Avanafil compound of formula-1.

The following impurities are formed during the synthesis of Avanafil are represented by the following structural formulae.

Deschloro desmethoxy Impurity Deschloro impurity Amino methyl impurity

Acid impurity R-Avanafil impurity

Avanafil obtained by the present invention is having purity about 99.7% by HPLC. Even though the process of the present invention is not proceeding through chromatographic purification, controls all the impurities to below ICH limits in which few of them are controlled to not detected level.

Avanafil obtained 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.

PXRD analysis of the crystalline Avanafil of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.

Differential scanning calorimetric (DSC) analysis was performed with Q10 V9.6 Build 290 calorimeter. Samples of about 2 to 3 milligrams held in a closed pan were analyzed at a heating rate of 10°C per minute.

Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 2000 instrument.

Avanafil and its related substances are measured by using HPLC with the following chromatographic conditions:

Apparatus: A liquid chromatograph is equipped with variable wavelength UV-detector and integrator;

Column: Kromasil C-18,125x4.0 mm, 5μm or equivalent; Flow rate: l.0mL/minute; Elution: Gradient; Wavelength: 245 nm; Column temperature: 25°C; Injection volume: 10 uL; Run time: 42 minutes; Needle wash: Diluent; Diluent: Acetonitrile:water (50:50 v/v); Mobile phase A: Buffer;

Mobile phase B: Acetonitrile + Water (90:10 v/v);

Buffer preparation: Transfer about 1.0 ml of Trifluroacetic acid in 100 ml of mill-Q-water, allow dissolving, then adding 1.0 ml of triethylamine and mixing well. Filter this solution through 0.22 μm filter paper

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation of the scope of the invention.

Examples:

Example-1: Preparation of (3-chloro-4-methoxyphenyl)methanamine hydrochloride

(Formula-6a)

Acetic acid (100 ml) was added to 4-methoxybenzylamine (100 g) at 25-30°C. Again acetic acid (750 ml) was added to the reaction mixture. Sulfuryl chloride (87.84 ml) was added slowly to the reaction mixture at 20-25°C and stirred for 6 hours at the same temperature. Methyl tertiary butyl ether (850 ml) was added to the reaction mixture at 25-30°C. The reaction mixture was cooled to 15-20°C and stirred for 1 1/2 hour at the same temperature. Filtered the precipitated solid, washed with methyl tertiary butyl ether and then dried to get title compound. Yield: 118 g.

Example-2: Preparation of pyrimidin-2-ylmethanamine hydrochloride (Formula-12a) 1,4-dioxane (500 ml) followed by Raney nickel (60 g) was added to pyrimidine-2-carbonitrile (100 gms). Hydrogen gas was passed into the vessel at a pressure of 7 kg/cm2. The reaction mixture was heated to 65-70°C and stirred for 50 hours. After completion of the reaction, the reaction mixture was cooled to 30-35°C and released the hydrogen gas pressure. Filtered the reaction mixture through hyflow bed, washed with dioxane. Distilled off the solvent from the filtrate to obtain a residue. The obtained residue was cooled to 30-35°C and added methanol (400 ml) into it. pH of the reaction mixture was adjusted to below 1 with ethyl acetate-HC1 at 25-30°C. Ethyl acetate (400 ml) was added to the reaction mixture at 25-30°C and the reaction mixture was stirred for 2 hours. Filtered the obtained solid, washed with ethyl acetate. To the above wet solid again added methanol (700 ml) and heated to reflux temperature. Filtered the reaction mixture through hyflow bed and washed with methanol. To the obtained filtrate again added ethyl acetate (600 ml) at 25-3 0°C and stirred for 2 hours. Filtered the precipitated solid, washed with ethyl acetate and the dried to get title compound. Yield: 50 gms; Melting range: 207-210°C (decomposition).

Example-3: Preparation of ethyl 4-hydroxy-2-(methylthio)pyrimidine-5-carboxylate (Formula-4) Diethyl 2-(ethoxymethylene)malonate compound of formula-2 (100 g) was added to a mixture of 2-methyl-2-pseudothiourea sulfate compound of formula-3 (77.24 g) and water (300 ml) at 25-30°C. Sodium carbonate solution (98.04 g of sodium carbonate in 300 ml of water) was slowly added to the reaction mixture at 25-30°C and stirred for 12 hours at the same temperature. After completion of the reaction, quenching the reaction mixture with dilute hydrochloric acid and stirred for 1 hour at 15-20°C. Filtered the precipitated solid and washed with water to obtain title compound. This wet solid taken into next step.

Example-4: Preparation of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (Formula-5) The wet solid obtained in example-3 was dissolved in toluene (800 ml) at 85-90°C. The reaction mixture was kept aside for 15 minutes and both the organic and aqueous layers were separated. Phosphoryl chloride (106.36 g) was added to the organic layer at 85-90°C. The reaction mixture was further heated to 100-105°C and stirred for 6 hours. After completion of the reaction, the reaction mixture was cooled to 35-40°C and quenched with water. Both the organic and aqueous layers were separated; the aqueous layer was extracted with toluene (600 ml). All the organic layers were combined and washed with water. This organic layer containing ethyl 4-chloro-2-(methylthio) pyrimidine-5-carboxylate compound of formula-5 was taken to the next step without distillation.

Example-5: Preparation of ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio) pyrimidine-5-carboxylate(Formula-7) (3-Chloro-4-methoxyphenyl) methanamine hydrochloride compound of formula-6a (76.98 g) was added to the organic layer containing ethyl 4-chloro-2-(methylthio) pyrimidine-5-carboxylate compound of formula-5, which is obtained in example-4. Water (100 ml), followed by sodium carbonate (110.3 g) was added to the reaction mixture at 25-3 0°C and stirred for 4 hours at the same temperature. After completion of the reaction, water was added to it. Both the organic and aqueous layers were separated; the aqueous layer was extracted with toluene. All the organic layers were combined and washed with water. Distilled off the solvent from the organic layer under reduced pressure. The reaction mixture was cooled to 30-35°C. 700 ml of cyclohexane: ethyl acetate (in 9.5:5 ratio) was added to the reaction mixture. The reaction mixture was heated to 70-75°C and stirred until complete dissolution. The reaction mixture was cooled to 10-15°C and stirred for 3 hours. Filtered the solid, washed with cyclohexane and then dried to get title compound. Yield: 90 gms; Melting range: 81-84°C; Purity by HPLC: 95.3%.

Example-6: Preparation of ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylsulfinyl) pyrimidine-5-carboxylate(Formula-8) A mixture of Ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio) pyrimidine-5-carboxylate compound of formula-7 (50 g) and dichloromethane (350 ml) was cooled to 0 to 5°C. 70% meta-chloroperbenzoic acid (33.5 g) was added slowly to the reaction mixture and stirred for 1 hour at 0 to 5°C. After completion of the reaction, quenched the reaction mixture with 10% aqueous sodium bicarbonate solution. Both the organic and aqueous layers were separated; the aqueous layer was extracted with dichloromethane (200 ml). Organic layers were combined and washed with 10% aqueous sodium sulphite solution at 0-5°C. This organic layer containing ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylsulfinyl) pyrimidine-5-carboxylate compound of formula-8 was taken to the next step without distillation.

Example-7: Preparation of (S)-ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(2- (hydroxymethyl)pyrrolidin-l-yl)pyrimidine-5-carboxylate (Formula-10) The organic layer containing ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylsulfinyl) pyrimidine-5-carboxylate compound of formula-8 obtained in example-6 was taken into a clean & dry RBF and cooled to 5-10°C. L-prolinol solution (19.24 g of L-prolinol in 50 ml of dichloromethane), followed by triethyl amine (15.81 g) was added slowly to the reaction mixture at 5-10°C. The reaction mixture was stirred for 8 hours at 5-10°C. After completion of the reaction, quenched the reaction mixture with 10% aqueous sodium bicarbonate solution. Both the organic and aqueous layers were separated. The solvent from the organic layer was completely distilled off and then co-distilled with cyclohexane. To the obtained residue cyclohexane (250 ml) was added at 30-35°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with cyclohexane and then dried to get title compound. Yield: 50 gms; Melting range: 80-85°C.

Example-8: Preparation of (S)-4-(3-chloro-4-methoxybenzyIamino)-2-(2-(hydroxyl methyl)pyrrolidin-l-yl)pyrimidine-5-carboxylicacid(Formula-ll) To a mixture of (S)-ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(2-(hydroxyl methyl)pyrrolidin-l-yl)pyrimidine-5-carboxylate compound of formula-10 (50 g) and water (500 ml), 10% aqueous sodium hydroxide solution (37.5 gms of sodium hydroxide in 150 ml of water) was added slowly to the reaction mixture at 30-35°C. The temperature of the reaction mixture was raised to 95-100°C and stirred for 6 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 30-35°C and washed the reaction mixture with toluene. Isopropyl alcohol followed by acetic acid was added to the reaction mixture at 30-35°C and stirred for 2 hours at the same temperature. Filtered the obtained solid, washed with water and then dried to get title compound. Yield: 39 gms; Melting range: 180-185°C.

Example-9: Preparation of Avanafil (Formula-1) A mixture of (S)-4-(3-chloro-4-methoxybenzylamino)-2-(2-(hydroxymethyl) pyrrolidin-l-yl)pyrimidine-5-carboxylic acid compound of formula-11 (50 g), l-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (36.6 g), hydroxybenzotriazole (24.07 g) and dimethylformamide (500 ml) was cooled to 0-5°C. Pyrimidin-2-ylmethanamine hydrochloride compound of formula-12a (24.09 g), followed by triethyl amine (35.4 ml) was added to the reaction mixture at 0-5°C. The reaction mixture was stirred for 3 hours at 0-5°C. Triethyl amine (8.87 ml) was added to the reaction mixture at 0-5°C and stirred for 2 hours. l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (24.39 g), followed by hydroxybenzotriazole (17.19 g) and triethyl amine (23.59 ml) was again added to the reaction mixture at 0-5°C. The reaction mixture further stirred for 18 hours at 0-5°C. Water was added to the reaction mixture at below 10°C and the temperature of the reaction mixture was raised to 25-30°C. Reaction mixture was extracted with ethyl acetate. Washed the organic layer with 10% aqueous potassium carbonate solution, followed by sodium chloride solution. The solvent from the organic layer was completely distilled under reduced pressure. To the obtained solid ethyl acetate (50 ml) was added at 25-3 5°C. The reaction mixture was heated to 75-80°C and stirred until complete dissolution. The reaction mixture was cooled to 25-30°C and stirred for 1 1/2 hour at 25-30°C. Filtered the precipitated solid, washed with ethyl acetate and then dried to get title compound. Yield: 53 gms; Melting range: 159-162°C; Purity by HPLC: 99.12%.

Example-10: Purification of Avanafil using methanol Avanafil (50 g) was dissolved in methanol (1100 ml) at 65-70°C. Carbon (15 g) was added to the reaction mixture and stirred for 15 minutes at the same temperature. Filtered the reaction mixture through hyflow bed, washed with methanol. The reaction mixture was cooled to 0-5°C and stirred for 2 hours. Filtered the precipitated solid, washed with methanol and then dried to get title compound. Yield: 38 gms; Melting range: 160-163°C; and purity by HPLC: 99.7%; Deschloro impurity: 0.05%; Deschlorodesmethoxy impurity: Not detected; (R)-isomer: 0.07.

PXRD pattern of the obtained compound is represented in figure-1 and DSC thermogram of the obtained compound is represented in figure-2.

Particle size distribution: D (0.1): 2.88μm; D(0.5): 11.62μm; and D (0.9): 37.99 urn; Specific surface area: 1.05 m7g.

Example-11: Purification of Avanafil using acetonitrile

Avanafil (2.0 g) was dissolved in acetonitrile (40 ml) at 80-85°C. The reaction mixture was cooled to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with acetonitrile and then dried to get pure Avanafil.

Yield: 1 .6 gms; PXRD and DSC patterns are similar to the PXRD and DSC patterns of the compound obtained in Example-10. Example-12: Purification of Avanafil using toluene

Avanafil (2.0 g) was dissolved in toluene (20 ml) at 105-110°C. The reaction mixture was cooled to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with toluene and then dried to get pure Avanafil.

Yield: 1.6 gms; PXRD and DSC patterns are similar to the PXRD and DSC patterns of the compound obtained in Example-10. Example-13: Purification of Avanafil using acetone

Avanafil (2.5 g) was dissolved in acetone (85 ml) by heating the reaction mixture to 55-60°C. The reaction mixture was cooled to 0-5°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with acetone and then dried to get pure Avanafil. Yield: 1.5 gms; PXRD and DSC patterns are similar to the PXRD and DSC patterns of the compound obtained in Example-10. Example-14: Purification of Avanafil using dichloromethane and n-pentane

Avanafil (2.0 g) was dissolved in dichloromethane (20 ml) at 25-30°C. n-pentane (100 ml) was added to the above solution at 25-30°C and stirred for 10 hours at 25-30°. Filtered the precipitated solid, washed with n-pentane and then dried to get pure Avanafil. Yield: 1.8 gms

PXRD and DSC patterns are similar to the PXRD and DSC patterns of the compound obtained in Example-10.

We Claim:

1. A process for the preparation of ethyl 4-(3-chloro-4-methoxybenzylamino)-2- (methylthio) pyrimidine-5-carboxylate compound of formula-7, comprising of:

a) Chlorinating ethyl 4-hydroxy-2-(methylthio)pyrimidine-5-carboxylate compound of formula-4 with a suitable chlorinating agent in a suitable solvent provides ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate compound of formula-5,

b) reacting the compound of formula-5 in-situ with (3-chloro-4-methoxyphenyl) methanamine compound of formula-6 or its hydrochloride salt compound of formula-6a in presence of aqueous inorganic base to provide ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio)pyrimidine-5-carboxylate compound of formula-7.

2. A process for the preparation of (S)-4-(3-chloro-4-methoxybenzylamino)-2-(2- (hydroxymethyl)pyrrolidin-l-yl)pyrimidine-5-carboxylic acid compound of formula- 11,comprising of:

a) Oxidizing the 4-(3-chloro-4-methoxybenzylamino)-2-(methyltWo)pyrimidine-5-carboxylate compound of formula-7 with a suitable oxidizing agent in a suitable solvent to provide ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylsulfinyl) pyrimidine-5-carboxylate compound of formula-8,

b) reacting the compound of formula-8 in-situ with (S)-pyrrolidin-2-ylmethanol compound of formula-9 in presence of a suitable base, optionally purifying the obtained compound with a suitable solvent provides (S)-ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(2-(hydroxymethyl)pyrrolidin-l-yl)pyrimidine-5-carboxylate compound of formula-10,

c) hydrolyzing the compound of formula-10 in presence of an aqueous base provides (S)-4-(3 -chloro-4-methoxybenzylamino)-2-(2-(hydroxymethyl)pyrrolidin-1 -yl) pyrimidine-5-carboxylic acid compound of formula-11.

3. A process for the preparation of ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio)pyrimidine-5-carboxylate compound of formula-7, which comprises of reacting ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate compound of formula-5 with (3-chloro-4-methoxyphenyl) methanamine compound of formula-6 or its hydrochloride salt compound of formula-6a in presence of aqueous inorganic base in a suitable solvent to provide compound of formula-7.

4. An improved process for the preparation of Avanafil compound of formula-1, comprising of: a) Reacting diethyl 2-(ethoxymethylene)malonate compound of formula-2 Formula-2 with 2-methyl-2-pseudothiourea sulfate compound of formula-3 Formula-3 in presence of sodium carbonate in water to provide ethyl 4-hydroxy-2-(methylthio) pyrimidine-5-carboxylate compound of formula-4, b) chlorinating the compound of formula-4 with phosphoryl chloride in toluene to provide ethyl 4-chloro-2-(methylthio) pyrimidine-5-carboxylate compound of formula-5, Formula-5 c) reacting the compound of formula-5 in-situ with (3-chloro-4-methoxy phenyl) methanamine hydrochloride compound of formula-6a in presence of an aqueous sodium carbonate provides ethyl 4-(3-chloro-4-methoxy benzylamino)-2-(methylthio)pyrimidine-5-carboxylate compound of formula-7, d) oxidizing the compound of formula-7 with meta chloro perbenzoic acid in dichloromethane provides ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methyl sulfinyl) pyrimidine-5-carboxylate compound of formula-8, Formula-8 e) reacting the compound of formula-8 in-situ with (S)-pyrrolidin-2-ylmethanol compound of formula-9 Formula-9 in presence of triethylamine, optionally purifying the obtained compound with cyclohexnae to provide (S)-ethyl 4-(3-chloro-4-methoxybenzyl amino)-2-(2-(hydroxymethyl)pyrrolidin-1 -yl)pyrimidine-5-carboxylate compound of formula-10, Formula-10 f) hydrolyzing the compound of formula-10 in presence of aqueous sodium hydroxide provides (S)-4-(3-chloro-4-methoxybenzylamino)-2-(2-(hydroxymethyl) pyrrolidin-1 -yl) pyrimidine-5-carboxylic acid compound of formula-11, Formula-11 g) reacting the compound of formula-11 with pyrimidin-2-yl methanamine hydrochloridecompound of formula-12a in presence of l-ethyl-3-(3-dimethyl aminopropyl)carbodiimide hydrochloride, hydroxybenzotriazole and triethylamine in dimethylformamide provides compound of formula-1, h) purifying the compound of formula-1 from methanol to provide pure Avanafil compound of formula-1.

5. A process for the purification of Avanafil, comprising the following steps of:

a) Dissolving avanafil in a suitable solvent selected from ketone solvents, nitrile solvents, hydrocarbon solvents, ester solvents and alcoholic solvents by heating to reflux temperature,

b) cooling the reaction mixture and stirring the reaction mixture,

c) filtering the precipitated solid, washing with a suitable solvent selected from ketone solvents, nitrile solvents, hydrocarbon solvents, ester solvents and alcoholic solvents and then drying to get pure Avanafil.

6. A process for the purification of Avanafil, comprising the following steps of:

a) Dissolving avanafil in methanol by heating to reflux temperature,

b) cooling the reaction mixture and stirring the reaction mixture,

c) filtering the precipitated solid, washing it with methanol and then drying to get pure Avanafil.

7. The crystalline form of Avanafil obtained by the process according to preceding claims, designated as crystalline form-M, characterized by:

a) Its X-ray powder diffraction pattern having peaks at 5.9, 8.4, 11.9, 14.7, 16.1, 17.5, 18.7, 19.3, 19.8, 20.4, 20.7, 21.0, 22.3, 23.3, 24.6, 25.6, 26.1, 28.0, 29.8 and 30.1 ± 0.2 degrees of 29,

b) its powder X-ray diffarctogram pattern in accordance with figure-1, and

c) its DSC thermogram showing endotherm peak at 164.1 °C .

8. Avanafil obtained by the process of the present invention is having particle size distribution of D (0.1): 2.88μm, D(0.5): 11.62μm, and D (0.9): 37.99 urn; and specific surface area: 1.05 m2/g.

9. Avanafil containing less than 0.1% each of deschloro impurity, deschlorodesmethoxy impurity and (R)-isomer.

10. Avanafil containing less than 0.2% in total of any combination of deschloro impurity, deschlorodesmethoxy impurity and (R)-isomer.