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-pyrirnidine 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:

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

A co-pending Indian patent application filed on July 1st, 2013 discloses an improved process for the preparation of Avanafil and its purification methods. The present inventor surprisingly found the advantageous by modifying the process. The modified process proceeds through novel salt of its intermediate compound which enhances the yield of intermediate compound as well as final compound.
Brief description of the invention:

The first aspect of the present invention is to provide an improved process for the preparation of Avanafil compound of formula-1.

The second 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.

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

The fourth aspect of the present invention relates to (3-chloro-4-methoxyphenyl) methanamine malate compound of formula-6b, a novel intermediate of Avanafil.

The fifth aspect of the present invention is to provide crystalline solid of (3-chloro-4-methoxyphenyl)methanamine malate compound of formula-6b, herein designated as crystalline form-S. Further the fifth aspect of the present invention also provides a process for the preparation of crystalline solid of (3-chloro-4-methoxyphenyl)methanamine malate compound of formula-6b.
The sixth aspect of the present invention is to provide a process for the preparation of crystalline form-M of Avanafil.

The seventh aspect of the present invention is to provide a process for the preparation of pyrimidin-2-ylmethanamine compound of formula-12 (or) its acid addition salts.

The eighth aspect of the present invention relates to 2,4-bis(3-chloro-4-methoxybenzyl amino)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide (herein after designated as diamine impurity) and N-(3-chloro-4-methoxybenzyl)-4-(3-chloro-4-methoxybenzylamino)-2-((S)-2-(hydroxymethyl)pyrrolidin-1 -yl)-N-(2-((S)-2-(hydroxymethyl)pyrrolidin-1 -yl)-5-(pyrimidin-2- ylmethylcarbamoyl)pyrimidin-4-yl)pyrimidine-5-carboxamide (herein after designated as dimer impurity), which are observed as impurities during the synthesis of Avanafil.
Brief description of the drawings:

Figure-1: Illustrates the PXRD pattern of crystalline form-S of (3-chloro-4-methoxyphenyl) methanamine malate compound of formula-6b.

Figure-2: Illustrates the DSC thermogram of crystalline form-S of (3-chloro-4-methoxyphenyl) methanamine malate compound of formula-6b.

Detailed description of the 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, 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" used herein is selected from sodium hypochlorite {NaOCl}; calcium hypochlorite {Ca(OCl)2}; sodium bromate {NaBrOs}; 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 term "phase transfer catalyst" used herein is selected from tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabuty ammonium tribromide, tetrabutyl ammonium trifluoro methanesulfonate, tetrabutyl ammonium bisulfate, tetrabutyl ammonium nitrate and the like.

The term "acid addition salts" used herein refers to a salt which is formed by reacting the compound with an acid selected from inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; (or) organic acids such as malic acid, oxalic acids, maleic acid, fumaric acid, acetic acid and the like.

As used herein "Avanafil substantially free of dimer and diamine impurities" refers to Avanafil containing dimer impurity and diamine impurity, each one, in an amount of less than about 0.1 area% as measured by HPLC. Specifically, Avanafil as disclosed herein containing diamine and dimer impurity, each one, in an amount less than 0.07 area% by HPLC, more specifically less than about 0.05 area% by HPLC.

The first aspect of the present invention provides an improved 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 an inorganic base such as alkali metal carbonate and bicarbonate, preferably sodium carbonate in a suitable solvent provides ethyl 4-hydroxy-2-(methylthio)pyrimidine-5-carboxylate compound of formula-4,

b) reacting the 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,

c) reacting the compound of formula-5 in-situ with (3-chloro-4-methoxyphenyl) methanamine compound of formula-6 (or) its acid addition salts in presence of an inorganic base in a suitable solvent, optionally in presence of a phase transfer catalyst provides Ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio)pyrimidine-5-carboxylate compound of formula-7,

d) optionally purifying the compound of formula-7 with a suitable solvent to provide pure compound of formula-7,

e) oxidizing the 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,

f) reacting the compound of formula-8 in-situ with (S)-pyrrolidin-2-ylmethanol compound of formula-9 in presence of a suitable base in a suitable solvent, optionally isolating the obtained compound with a suitable solvent provides (S)-ethyl 4-(3-chloro-4-methoxy benzylamino)-2-(2-(hydroxymethyl)pyrrolidin-1 -yl)pyrimidine-5-carboxylate compound of formula-10,

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

h) optionally purifying the compound of formula-11 in a suitable solvent to provide pure compound of formula-11, i) reacting the compound of formula-11 with pyrimidin-2-yl methanamine compound of formula-12 (or) its acid addition salts in presence of l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, hydroxybenzotriazole and triethylamine in dimethylformamide provides avanafil compound of formula-1, j) optionally, purifying the compound of formula-1 from a suitable solvent provides pure Avanafil.

A preferred embodiment 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) reacting 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-methoxyphenyl) methanamine malate compound of formula-6b in presence of sodium carbonate and tetrabutylammonium bromide in water provides ethyl 4-(3-chloro-4-methoxy benzylamino)-2-(methylthio)pyrimidine-5-carboxylate compound of formula-7,

d) purifying the compound obtained in step-c) using water to get pure compound of formula-7,

e) oxidizing the compound of formula-7 with m-chloroperbenzoic acid in dichloromethane to provide ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylsulfinyl) pyrimidine-5-carboxylate compound of formula-8,

f) reacting the compound of formula-8 in-situ with (S)-pyrrolidin-2-ylmethanol compound of formula-9 in presence of triethyl amine, isolating the obtained compound with cyclohexane to provide (S)-ethyl 4-(3-chloro-4-methoxy benzylamino)-2-(2-(hydroxy methyl)pyrrolidin-l-yl)pyrimidine-5-carboxylate compound of formula-10,

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

h) purifying the compound of formula-11 using tetrahydrofuran to provide pure compound of formula-11, i) reacting the compound of formula-11 with pyrimidin-2-ylmethanamine hydrochloride compound of formula-12a in presence of l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, hydroxybenzotriazole and triethylamine in dimethylformamide provides avanafil compound of formula-1, j) purifying the compound of formula-1 from aqueous isopropanol provides pure Avanafil compound of formula-1.

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

a) Reacting 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 acid addition salts in presence of an inorganic base in a suitable solvent, optionally in presence of phase transfer catalyst to provide ethyl 4-(3 -chloro-4-methoxybenzylamino)-2-(methylthio)pyrimidine-5-carboxylate compound of formula-7,

c) optionally purifying the compound of formula-7 using a suitable solvent to provide pure compound of formula-7.

In the above aspect of the present invention, the condensation of compound of formula-5 with compound of formula-6 (or) its hydrochloride salt is carried out in presence of inorganic base such as alkali metal hydroxides, alkoxides, carbonates and bicarbonates, preferably sodium carbonate in place of organic base such as triethyl amine, which is reported in prior art.

The main advantage of the present invention is that it minimizes the number of 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 avoided 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.

A preferred embodiment of the present invention provides a process for the preparation of ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio)pyrimidine-5-carboxylate compound of formula-7, comprising of:

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

4 with phosphoryl chloride in toluene 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 malate compound of formula-6b in presence of sodium carbonate and tetra-butylammonium bromide in water provides ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio)pyrimidine-5-carboxylate compound of formula-7,

c) purifying the compound obtained in step-b) using water to provide pure compound of formula-7.

The use of malate salt compound of formula-6b in the condensation reaction with compound of formula-5 will substantially increase the yield of compound of formula-7, which in-turn enhances the yield of the final compound.

The third aspect of the present invention provides 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-cUoro-4-memoxybenzylarnmo)-2-(memyltliio)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 in a suitable solvent, optionally isolating the obtained compound with a suitable solvent provides (S)-ethyl 4-(3-chloro-4-methoxy benzylamino)-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-cUoro-4-methoxybenzylamino)-2-(2-(hydroxymethyl)pyn,olidin-l-yl)pyrimidine-5-carboxylic acid compound of formula-11,

d) purifying the compound of formula-11 in a suitable solvent to provide pure compound of formula-11.

In the above aspect oxidation of ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methyl thio)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 which is further purified by using tetrahydrofuran to provide pure 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 by using cyclohexane thereby avoiding column chromatography.

The formation of diamine impurity during the synthesis of product of interest cannot be eliminated, and the same always present in significant quantities in the Avanafil produced. The problem solved by the present invention through the purification method which utilizes tetrahydrofuran.

The fourth aspect of the present invention provides (3-chloro-4-methoxyphenyl) methanamine malate compound of formula-6b, useful compound in the synthesis of Avanafil.

The fifth aspect of the present invention provides a crystalline solid of (3-chloro-4-methoxyphenyl)methanamine malate compound of formula-6b, herein designated as crystalline form-S. The crystalline form-S is characterized by

a) its powder XRD having peaks at about 5.6, 12.5, 13.1, 15.0, 20.8, 22.4, 22.7, 24.5, 25.1, and 26.5± 0.2 degrees two-theta,

b) its PXRD pattern in accordance with figure-1,

c) its DSC thermogram showing endothermic peak at 177.6°C in accordance with figure-2.

Further the fifth aspect of the present invention also provides a process for the preparation of crystalline (3-chloro-4-methoxyphenyl)methanamine malate compound of formula-6b, comprising of:

a) Adding sulfuryl chloride to 4-methoxybenzylamine in a suitable solvent such as acetic acid and stirring it,

b) isolating the (3-chloro-4-methoxyphenyl) methanamine hydrochloride as a solid using a suitable ether solvent,

c) adding a suitable solvent selected from hydrocarbon solvents and chloro solvents to the wet solid obtained in step-(b),

d) basifying the reaction mixture to provide (3-chloro-4-methoxyphenyl) methanamine using a suitable base such as alkali metal hydroxide,

e) separating the organic and aqueous layers,

f) distilling off the solvent from the organic layer completely,

g) adding a suitable alcoholic solvent to the compound obtained in step-(f),

h) adding malic acid to the reaction mixture,

i) heating the reaction mixture and stirring the reaction mixture, j) cooling the reaction mixture and stirring the reaction mixture, k) filtering the precipitated solid,

1) optionally purifying the obtained solid using a suitable solvent selected from alcoholic solvents, polar solvents or their mixtures to get crystalline compound of formula-6b.

A preferred embodiment of the present invention provides a process for the preparation of crystalline (3-chloro-4-methoxyphenyl)methanamine malate compound of formula-6b, comprising of:

a) Adding sulfuryl chloride to 4-methoxybenzylamine in acetic acid and stirring it,

b) isolating the (3-chloro-4-methoxyphenyl)methanamine hydrochloride as a solid using methyl tert-butyl ether,
c) adding toluene to the wet solid obtained in step-(b),

d) basifying the reaction mixture to provide (3-chloro-4-methoxyphenyl)methanamine using 20% aqueous sodium hydroxide solution,

e) separating the organic and aqueous layers,

f) distilling off the solvent from the organic layer completely,

g) adding methanol to the compound obtained in step-(f),

h) adding malic acid to the reaction mixture,

i) heating the reaction mixture to 60-65°C and stirring the reaction mixture,

j) cooling the reaction mixture to 25-30°C and stirring the reaction mixture,

k) filtering the precipitated solid,

1) purifying the obtained solid using water to provide crystalline compound of formula-6b.

The sixth aspect of the present invention provides a process for the preparation of crystalline form-M of Avanafil, comprising of:

a) Adding a mixture of alcoholic solvent and water to Avanafil,

b) heating the reaction mixture,

c) stirring the reaction mixture,

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

e) filtering the precipitated solid and drying to get crystalline form-M of Avanafil.

A preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of Avanafil, comprising of:

a) Adding aqueous isopropanol to Avanafil,

b) heating the reaction mixture to 65-70°C,

c) stirring the reaction mixture,

d) cooling the reaction mixture to 0-5°C and stirring the reaction mixture,

e) filtering the precipitated solid and drying to get crystalline form-M of Avanafil.

The above purification method minimizes the formation of degradation impurities and thereby enhances the purity of avanafil.

The seventh aspect of the present invention provides a process for the preparation of pyrimidin-2-ylmethanamine compound of formula-12 (or) its acid addition salts, comprising of

a) Hydrogenating the 2-cyanopyrimidine in presence of Raney nickel in an alcoholic solvent to provide pyrimidin-2-ylmethanamine compound of formula-12,

b) optionally, converting the compound of formula-12 into its acid addition salt by treating with a suitable acid in a suitable solvent.

Wherein, the alcoholic solvent is selected from methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol and 2-butanol. Further the conversion of compound of formula-12 into its acid addition salt is carried out by treating the compound of formula-12 with a suitable acid selected from inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; (or) organic acids such as malic acid, oxalic acid, maleic acid, furmaric acid and acetic acid.

The present invention is represented schematically as follows:

The eighth aspect of the present invention provides diamine impurity and dimer impurity, which are observed as impurities during the synthesis of Avanafil.

The diamine and dimer impurities are represented by the following structural formulae:

The Diamine and Dimer impurities are characterized by H NMR, IR and Mass spectral data.

The Dimer impurity is observed at 1.75 RRT in HPLC and it is synthesized according to the scheme represented below.

The Diamine impurity is observed at 1.79 RRT in HPLC and it is prepared according to the scheme represented below.

Along with the above said two impurities (Dimer and Diamine impurities), the following impurities are formed during the synthesis of Avanafil.

PXRD analysis of the crystalline Avanafil as well as malate salt of the compound of formula-6b 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 0.037min.

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: Purospher star RP 18 endcapped, 250 x 4.0 mm, 5 um or equivalent; Flow rate: 1.5 ml/minute; Elution: Gradient; Wavelength: 245 nm; Column temperature: 30°C; Injection volume: 5 uL; Run time: 60 minutes; Needle wash: Diluent; Diluent: Acetonitrile: Buffer (40:60 v/v); Mobile phase A: Buffer (100%); Mobile phase B: Acetonitrile : Water: Methanol (75: 20: 5 v/v); Buffer preparation: Transfer about 1.0 ml of trifluoro acetic acid in 1000 ml of mill-Q-water, allow to dissolve, then add 1.0 ml of triethylamine and mix well.

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 preferably below 20um 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 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 malate (Formula-6b)

4-methoxybenzylamine (100 g) was added to acetic acid (850 ml) at 25-30°C and stirred for 10 minutes. Sulfuryl chloride (147.58 g) was slowly added to the reaction mixture at 25-30°C and stirred for 6 hours. Methyl tert-butyl ether (850 ml) was added to the reaction mixture at 25-30°C. The reaction mixture was cooled to 10-15°C and stirred for 1 Vi hour. Filtered the precipitated solid and washed with methyl tertiary butylether. Water (600 ml), followed by toluene (400 ml) were added to the precipitated solid and basified using 20% aqueous sodium hydroxide solution at 25-30°C. Separated the organic and aqueous layers, the organic layer was washed with water followed by with 25% aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure. Methanol (200 ml) followed by Malic acid (83.08 g) were added to the obtained compound and heated to 60-65°C and stirring the reaction mixture for 15 minutes. Cooled the reaction mixture to 25-30°C and stirred for 60 minutes. Filtered the precipitated solid and washed with methanol. The obtained solid was dissolved in water (300 ml) by heating to 85-90°C. Cooled the reaction mixture to 0-5°C and stirred for 1 lA hour. Filtered the precipitated solid, washed with water and then dried to get title compound. Yield: 140 g; MR: 161-166°C; Purity by HPLC: 99.3%; *H NMR (D20, 300 MHz) 5 2.55-2.81 (m, 2H), 3.87 (s, 3H), 4.08 (s, 2H), 4.32-4.36 (q, 1H), 7.09-7.11 (d, 1H), 7.36-7.33 (d, 1H), 7.46 (s, 1H). XL EI/CIMSD m/z = 171. FTIR: v 3392.24 cm"1.

The crystalline solid obtained here is designated as crystalline form-S. PXRD, DSC of crystalline form-S herein is represented in figure-1 and figure-2 respectively. Example-2: Preparation of ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio) pyrimidine-5-carboxyIate(FormuIa-7)

Step-a) 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), sodium carbonate (98.04 g) and water (1000 ml) at 25-30°C and stirred for 18 hours at 25-30°C. The reaction mixture was poured into pre-cooled dilute hydrochloric acid solution (150 ml) at 10-15°C and stirred for 1 hour at 10-15°C. Filtered the precipitated solid and washed with chilled water. Step-b): Preparation of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (Formula-5)

The wet solid obtained in step-a) was dissolved in toluene (800 ml) by heating the reaction mixture to 85-90°C. The reaction mixture was kept aside for 15 minutes and both the organic and aqueous layers were separated. The organic layer was heated to 110-115°C to remove water from it. Cooled the reaction mixture to 55-60°C. Phosphoryl chloride (106.36 g) was added to the organic layer at 55-60°C, heated the reaction mixture to 100-105°C and then stirred for 4 hours. The reaction mixture was cooled to 0-5°C and then quenched with water at a temperature below 40°C. The reaction mixture was heated to 40-45°C and separated both the organic and aqueous layers. The organic layer was washed with 5% sodium carbonate solution followed by water. The organic layer containing the title compound is taken to the next step. Step-c) Preparation of ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio)pyrimidine-5-carboxylate (FormuIa-7)

(3-Chloro-4-methoxyphenyl)methanamine malate compound of formula-6b (113.1 g) was added to the organic layer containing ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate compound of formula-5. Water (200 ml), followed by sodium carbonate (147.06 g) and tetrabutyl ammonium bromide (4.47 g) were added to the reaction mixture at 25-30°C and stirred for 8 hours at the same temperature. Water was added to the reaction mixture at 25-30°C. The reaction mixture was heated to 40-45°C. Separated the both organic and aqueous layers. The organic layer was washed with water. Distilled off the solvent from the organic layer under reduced pressure. 600 ml of cyclohexane: ethyl acetate (in 9:1 ratio) was added to the obtained compound. The reaction mixture was heated to 65-70°C and stirred 15 minutes. The reaction mixture was cooled to 10-15°C and stirred for 3 hours. Filtered the precipitated solid and washed with cyclohexane. Water (1000 ml) was added to the wet solid. Heated the reaction mixture to 60-65°C and stirred for 30 minutes. Cooled the reaction mixture to 25-30°C and stirred for 60 minutes. Filtered the precipitated solid, washed with water and then dried to get the title compound. Yield: 102 gms; Melting range: 80-84°C; Purity by HPLC: 99.25%

Example-3: Preparation of (S)-ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(2-(hydroxyl methyl)pyrrolidin-l-yl)pyrimidine-5-carboxylate(Formula-10)

Step-a) Preparation of ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylsulfinyl) pyrimidine-5-carboxyIate (Formula-8)

A mixture of Ethyl 4-(3-cWoro-4-memoxybenzylamino)-2-(methylthio)pyrimidine-5-carboxylate compound of formula-7 (65 g) and dichloromethane (325 ml) was cooled to 0 to 5°C. 70% meta-chloroperbenzoic acid (43.5 g) was added slowly to the reaction mixture in a lot wise at 0-5°C and stirred for 1 hour at the same temperature. Quenched the reaction mixture with 10% aqueous sodium bicarbonate solution and separated the organic and aqueous layers. The organic layer containing title compound was washed with 10% aqueous sodium sulphite solution at a temperature below 10°C.

Step-b) 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-(methyl sulfinyl)pyrimidine-5-carboxylate compound of formula-8 was cooled to 0-5°C. L-prolinol solution (25.02 g of L-prolinol in 65 ml of dichloromethane), followed by triethyl amine (17.88 g) was added slowly to the reaction mixture at 0-5°C and stirred for 8 hours. Quenched the reaction mixture with 10% aqueous sodium carbonate solution. Separated the organic and aqueous layers, the solvent from the organic layer was completely distilled off and then co-distilled with cyclohexane. To the obtained residue cyclohexane (325 ml) was added at 25-30°C and stirred for 2 hours. Filtered the solid, washed with cyclohexane and then dried to get title compound. Yield: 65 g. MR: 79-84°C; Purity by HPLC: 91.06 %.

Example-4: Preparation of (S)-4-(3-chloro-4-methoxybenzylamino)-2-(2-(hydroxylmethyl) pyrrolidin-l-yl)pyrimidine-5-carboxyIic acid (Formula-11)

A mixture of (S)-ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(2-(hydroxymethyl) pyrrolidin-l-yl)pyrimidine-5-carboxylate compound of formula-10 (35 g), water (175 ml) and sodium hydroxide (8.31 g) was stirred for 10 minutes at 25-30°C. Heated the reaction mixture to 95-100°C and stirred for 8 hours. Cooled the reaction mixture to 45-50°C and washed with toluene. The reaction mixture was further cooled to 25-30°C and isopropanol (35 ml) was added to it. Acidifying the reaction mixture with acetic acid (52.5 ml) at 25-30°C and stirred for 2 hours. Filtered the obtained solid and washed with water. Tetrahydrofuran (122.5 ml) was added to the obtained wet solid, heated the reaction mixture to 60-65°C and stirred for 15 minutes. Cooled the reaction mixture to 25-30°C and stirred for 1 lA hour at 25-30°C. Filtered the solid, washed with tetrahydrofuran and then dried to get title compound. Yield: 23 g; MR: 180-185°C; Purity by HPLC: 98.91%. Example-5: Preparation of Avanafil (Formula-1)

Hydroxybenzotriazole (51.6 g) followed by (S)-4-(3-chloro-4-methoxybenzylamino)-2-(2-(hydroxymethyl)pyrrolidin-l-yl) pyrimidine-5-carboxylic acid (150 g) and l-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (128.1 g) were added to a pre-cooled mixture of pyrimidin-2-ylmethanamine hydrochloride compound of formula-12a (72.3 g), triethylamine (77.3 g) and dimethylformamide (750 ml) at 0-5°C and stirred for 14 hours at 0-5°C. Quenched the reaction mixture with 5% aqueous potassium carbonate solution (3.75 lit) at a temperature below 30°C and stirred for 3 hours at 25-30°C. Filtered the solid and washed with water. Water followed by dichloromethane was added to the obtained solid and separated the organic and aqueous layers. Carbon (7.5 g) was added to the organic layer. Filtered the reaction mixture, washed with dichloromethane and distilled off the solvent completely from the filtrate. Methanol (1500 ml) was added to the obtained solid 30-35°C. Heated the reaction mixture to 65-70°C and stirred for 10 minutes. Cooled the reaction mixture to 25-30°C and stirred for 1 lA hour. Filtered the solid, washed with methanol and then dried to get title compound. Yield: 145 g; Melting range: 158-163°C; Purity by HPLC: 99.6%, Particle Size Distribution: D90: 52.006 um.

PXRD & DSC of the obtained compound is similar to the figure-1 and figure-2 of a co-pending application No.:2915/CHE/2013. Example-6: Purification of Avanafil (Formula-1)

A mixture of Avanafil (80 g), isopropanol (832 ml) and water (208 ml) was heated to 65-70°C and stirred for 15 minutes. Carbon (24 g) was added to the reaction mixture at 65-70°C and stirred for 15 minutes. Filtered the reaction mixture through hyflo bed and washed the bed with aqueous isopropanol. The filtrate was cooled to 0-5°C and stirred for 1 V2 hour. Filtered the precipitated solid, washed with isopropanol and then dried to get pure Avanafil. Yield: 68.5 g; MR: 160-163°C; Purity by HPLC: 99.76 %; Deschloro impurity: 0.01%; Acid impurity: 0.04%; Dichloro Impurity: 0.01%, Dimer Impurity: 0.05%; Diamine impurity:0.05%, Particle Size Distribution: D90: 88.658 um; PXRD & DSC of the obtained compound is similar to the figure-1 and figure-2 of a co-pending application No.: 2915/CHE/2013. Example-7: Preparation of pyrimidin-2-ylmethanamine hydrochloride (Formula-12a)

Raney nickel (18 g) was added to a mixture of 2-cyanopyrimidine (30 g) and 2-butanol (150 ml) in an autoclave and applied 4-5 kg/cm2 hydrogen pressure. The reaction mixture was heated to 75-80°C and stirred for 15 hours. Cooled the reaction mixture to 25-30°C and hydrogen gas pressure was released. Filtered the reaction mixture through hyflo bed and washed with 2-butanol. Carbon (1.5 g) was added to the filtrate at 25-30°c and stirred for 15 minutes. Filtered the reaction mixture through hyflo bed and washed with 2-butanol. Adjusted the pH of the reaction mixture to 3 with 2-butanolic hydrochloride at 25-30°C and stirred for 1 hour. Filtered the solid and washed with 2-butanol. Methanol (60 ml) was added to the obtained solid, heated the reaction mixture 65-70°C and stirred for 15 minutes. Cooled the reaction mixture to 25-30°C, ethyl acetate (90 ml) was added to it and stirred for 1 1/2 hour at 25-30°C. Filtered the solid, washed with ethyl acetate and then dried to get title compound. Yield: 22 g; Decomposition: 207-213°C; Purity by HPLC: 99.1%. Example-8: Preparation of Dimer Impurity

A mixture of l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (48.8 g), Hydroxy benzotriazole (17.1 g), pyrimidin-2-ylmethanamine hydrochloride (12.9 g) and triethylamine (25.75 g) was added to a mixture of (S)-4-(3-chloro-4-methoxybenzylamino)-2-(2-(hydroxy methyl)pyrrolidin-l-yl) pyrimidine-5-carboxylic acid compound of formula-11 (50 g) and ethyl acetate (500 ml) at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 6 hours. Cooled the reaction mixture to 25-30°C and water followed by ethyl acetate were added to the reaction mixture. Separated the organic and aqueous layers and washed the organic layer with water. Distilled off the solvent from the organic layer and then co-distilled with methanol. Methanol (150 ml) was added to the obtained compound at 25-30°C and stirred for 45 minutes. The solvent was decanted from the reaction mixture and water (500 ml) was added to the reaction mixture and stirred for 5 hours. Filtered the precipitated solid, washed with water and then dried to get the title compound. The obtained compound was further purified by preparative HPLC to get pure title compound. Yield: 40 g; Purity by HPLC: 96%. *H NMR (CHC13, 300 MHz) 5 1.62-2.16 (m, 9H), 3.48-3.77 (m, 6H), 3.82-3.87 (d, 7H), 4.77-4.78 (d, 2H), 4.24-4.27 (d, 2H), 4.43-4.45 (d, 2H), 4.57-4.59 (d, 4H), 4.78-4.79 (d, 2H), 6.79-6.87 (d, 2H), 7.15-7.18 (d, 2H), 7.26-7.46 (m, 4H), 8.43 (s, 1H), 8.49 (s, 1H), 8.71-8.72 (d, 2H), 9.0-9.04 (t, 1H). EIMS (M+l) m/z = 858.3. FTIR: v 3339.55, 1678.41 cm"1.

Example-9: Preparation of ethyl 2,4-bis(3-chloro-4-methoxybenzylamino)pyrimidine-5-carboxylate (Formula-13)

70% meta-chloro perbenzoic acid (36.9 g) was added to a pre-cooled mixture of ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio)pyrimidine-5-carboxylate compound of formula-7 (50 g) and dichloromethane (250 ml) at 0-5°C and stirred for 1 hour. Quenched the reaction mixture with aqueous sodium bicarbonate solution at a temperature below 10°C. Separated both organic and aqueous layers, the organic layer was washed with 10% aqueous sodium sulfite solution. The organic layer was cooled to 0-5°C and (3-chloro-4-methoxyphenyl) methanamine malate (58.2 g) was added to it. Triethylamine (25.75 g) was slowly added to the reaction mixture at 0-5°C and stirred for 8 hours. Quenched the reaction mixture with 10% aqueous sodium carbonate solution. At a temperature below 25°C.Filtered the solid, washed with water and then dried to get title compound. Yield: 42 g.

Example-10: Preparation of 2,4-bis(3-chloro-4-methoxybenzyIamino)pyrimidine-5-carboxylic acid (Formula-14)

10% aqueous sodium hydroxide (24.5 g sodium hydroxide dissolved in water) solution was added to a mixture of ethyl 2,4-bis(3-chloro-4-methoxybenzylamino)pyrimidine-5-carboxylate compound of formula-13 (35 g) and dimethyl sulfoxide (350 ml) at 25-30°C. Heated the reaction mixture to 95-100°C and stirred for 4 hours. Cooled the reaction mixture to 25-30°C. Water followed by acetic acid was added to the reaction mixture at 25-30°C. Cooled the reaction mixture to 0-5 °C and stirred for 3 hours. Filtered the solid, washed with water and then dried to get title compound. Yield: 30 g. Example-11: Preparation of Diamine Impurity

A mixture of 2,4-bis(3-chloro-4-methoxybenzylamino)pyrimidine-5-carboxylic acid compound of formula-14 (25 g) and dimethylformamide (500 ml) was stirred for 15 minutes at 25-30°C. Hydroxybenzotriazole (7.3 g) followed by l-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (18.14 g), pyrimidin-2-yl methanamine hydrochloride (10.24 g) and triethylamine (10.94 g) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 5 hours. Cooled the reaction mixture to 25-30°C, quenched the reaction mixture with 5% aqueous potassium carbonate solution and then stirred for 3 hours. Filtered the solid, washed with water. Dichloromethane (50 ml) was added to the obtained solid. Carbon (5 g) was added to it and stirred for 15 minutes. Filtered the reaction mixture, washed with dichloromethane and distilled off the solvent from the filtrate. Methanol (250 ml) was added to the obtained compound at 25-30°C, heated the reaction mixture to 60-65°C and stirred for 10 minutes. Cooled the reaction mixture to 25-30°C and stirred for 1 XA hour. Filtered the solid, washed with methanol and then dried to get title compound. Yield: 12.0 g; !H NMR (CDC13, 300 MHz) 5 3.86-3.87 (s, 6H), 4.51-4.55 (d, 4H), 4.78-4.80 (d, 2H), 6.81 (s, 2H), 7.09 (s, 2H), 7.22-7.3 (m, 5H), 8.32 (s, 1H), 8.72-8.73 (d, 2H), 9.12 (s, 1H). EIMS (M+l)) m/z = 554.2. FTIR: v 3325.22, 1639.9 cm1.

We Claim:

1. A process for the preparation of Avanafil, 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 an inorganic base such as alkali metal carbonate or bicarbonate in a suitable solvent provides ethyl 4-hydroxy-2-(methylthio)pyrimidine-5-carboxylate compound of formula-4,

b) reacting the 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,

c) reacting the compound of formula-5 in-situ with (3-chloro-4-methoxyphenyl) methanamine malate compound of formula-6b in presence an inorganic base in a suitable solvent, optionally in presence of a phase transfer catalyst provides ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio) pyrimidine-5-carboxylate compound of formula-7,

d) purifying the compound of formula-7 with a suitable solvent to provide pure compound of formula-7,

e) oxidizing the 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,

f) reacting the compound of formula-8 in-situ with (S)-pyrrolidin-2-ylmethanol compound of formula-P- in presence of a suitable base in a suitable solvent, optionally isolating the obtained compound with a suitable solvent provides (S)-ethyl 4-(3-chloro-4-methoxybenzyl amino)-2-(2-(hydroxymethyl)pyrrolidin-1 -yl)pyrimidine-5-carboxylate compound of formula-10,

g) 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,

h) purifying the compound of formula-11 in a suitable solvent to provide pure compound of formula-11,

i) reacting the compound of formula-11 with pyrimidin-2-yl methanamine compound of formula-12 (or) its acid addition salts in presence of l-ethyl-3-(3-dimethylaminopropyl)carbodumide hydrochloride, hydroxyl benzotriazole and triethylamine in dimethylformamide provides avanafil compound of formula-1,

j) purifying the compound of formula-1 from a suitable solvent provides pure Avanafil.

2. The process for the preparation of avanafil, 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) reacting 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-methoxyphenyl) methanamine malate compound of formula-6b in presence of sodium carbonate and a tetrabutyl ammonium bromide in water provides ethyl 4-(3-chloro-4-methoxy benzylamino)-2-(methylthio)pyrimidine-5-carboxylate compound of formula-7,

d) purifying the compound of formula-7 with water to provide pure compound of formula-7,

e) oxidizing the compound of formula-7 with m-chloroperbenzoic acid in dichloromethane to provide ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylsulfinyl) pyrimidine-5-carboxylate compound of formula-8,

f) reacting the compound of formula-8 in-situ with (S)-pyrrolidin-2-ylmethanol compound of formula-9 in presence of triethyl amine, isolating the obtained compound with cyclohexane to provide (S)-ethyl 4-(3-chloro-4-methoxybenzyl amino)-2-(2-(hydroxymethyl)pyrrolidin-1 -yl)pyrimidine-5-carboxylate compound of formula-10,

g) hydrolyzing the compound of formula-10 in presence of an aqueous sodium hydroxide solution provides (S)-4-(3-cMoro-4-methoxybenzylamino)-2-(2-(hydroxymethyl) pyrrolidin-1-yl) pyrimidine-5-carboxylic acid compound of formula-11,

h) purifying the compound of formula-11 using tetrahydrofuran to provide pure compound of formula-11, i) 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 avanafil compound of formula-1, j) purifying the compound of formula-1 from aqueous isopropanol provides pure Avanafil compound of formula-1.

3. A compound of formula

4. A crystalline form-S of (3-chloro-4-methoxyphenyl)methanamine malate is characterized by:

a) its powder X-ray powder diffraction pattern having peaks at 5.6, 12.5, 13.1, 15.0, 20.8, 22.4, 22.7,24.5, 25.1, and 26.5 ± 0.2 degrees two-theta;

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

c) its DSC thermogram showing endotherm peak at 177.6°C in accordance with figure-2.

5. Process for the preparation of crystalline (3-chloro-4-methoxyphenyl) methanamine malate compound of formula-6b, comprising of:

a) Adding sulfuryl chloride to 4-methoxybenzylamine in acetic acid and stirring it,

b) isolating the (3-chloro-4-methoxyphenyl)methanamine hydrochloride as a solid using methyl tert-butyl ether,

c) adding toluene to the wet solid obtained in step-(b),

d) basifying the reaction mixture to provide (3-chloro-4-methoxyphenyl)methanamine using 20% aqueous sodium hydroxide solution,

e) separating the organic and aqueous layers,

f) distilling off the solvent from the organic layer completely,

g) adding methanol to the compound obtained in step-(f),

h) adding malic acid to the reaction mixture,

i) heating the reaction mixture to 60-65°C and stirring the reaction mixture,

j) cooling the reaction mixture to 25-30°C and stirring the reaction mixture,

k) filtering the precipitated solid,
1) purifying the obtained solid using water to provide crystalline compound of formula-6b.

6. A process for the preparation of crystalline form-M of Avanafil, comprising of:

a) Adding a mixture of alcoholic solvent and water to Avanafil,

b) heating the reaction mixture,

c) stirring the reaction mixture,

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

e) filtering the precipitated solid and drying to get crystalline form-M of Avanafil.

7. Aprocess for the preparation of pyrimidin-2-ylmethanamine compound of formula-12 (or) its
acid addition salt, comprising of:

a) Hydrogenating the 2-cyanopyrimidine in presence of Raney nickel in alcoholic solvent to provide compound of formula-12,

b) optionally converting the compound of formula-12 into its acid addition salt by treating with a suitable acid in a suitable solvent.

8. Diamine and Dimer impurities having the following structural formulae

9. Avanafil is substantially free of Dimer and Diamine impurities.

10. Avanafil is having particle size distribution of D90 less than 150 um, preferably less than 100 um.