WO2015001567A1

WO2015001567A1 - Process for the preparation of (s)-4-[(3-chloro-4-methoxybenzyl)amino]-2-[2- (hydroxymethyl)-1-pyrrolidinyl]-n-(2-pyrimidinyl methyl-5-pyrimidine carboxamide

Info

Publication number: WO2015001567A1
Application number: PCT/IN2014/000436
Authority: WO
Inventors: Srinivasan Thirumalai Rajan; Sajja Eswaraiah; Komati Satyanarayana
Original assignee: MSN Laboratories Pvt Ltd
Current assignee: MSN Laboratories Pvt Ltd
Priority date: 2013-07-01
Filing date: 2014-06-30
Publication date: 2015-01-08
Anticipated expiration: 2016-01-01

Abstract

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

Description

Process for the preparation of (S)-4-f(3-chloro-4-methoxybenzyl)aminol-2-i2- (hydroxymethyl)-l-pyrrolidinyll-N-(2-pyrimidinvi methyl)-5-pyrimidine carboxamide Related Application:

This application claims the benefit of priority of our Indian patent applications 2915/CHE/2013 filed on 1^st July 2013 and 888/CHE/2014 filed on 24^th Feb 2014 which are incorporated herein by reference. 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 ethyl)-5-pyrimidine carboxamide which is represented by the following structural formula- 1.

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:

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

As on date, there is no simple purification method available for Avanafil. Henceforth there is a need in the art to develop 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 a 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 the 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.

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-l -yl)pyrimidine- 5-carboxylic acid compound of formula- 1 1. The third aspect of the present invention is to provide an improved process for the preparation of Avanafil compound of formula- 1.

The fourth aspect of the present invention is to provide a crystalline solid of Avanafil, herein after designated as crystalline form-M.

The fifth aspect of the present invention is to provide a process for the purification of Avanafil. The sixth aspect of the present invention is to provide another process for the purification of Avanafil.

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

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

The ninth 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 tenth 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-M of Avanafil compound of formula- 1.

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

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

Figure-4: 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, 2-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 {NaBr0₃} ; 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 "suitable chlorinating agent" used in the present invention is phosphoryl chloride or thionyl chloride.

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 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 acid addition salts 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 usage of number of solvents being used like for example carrying out two or three stages of the process 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 hydrochloride compound of formula-6a in presence of aqueous sodium carbonate provides ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio) pyrimidine-5-carboxylate compound of formula-7.

The (3-chloro-4-methoxyphenyl) methanamine hydrochloride compound of formula- 6a used in step-(b) of the above 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.

Another 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:

b) reacting the compound of formula-5 in-situ with (3-chloro-4-methoxyphenyl) methanamine malate compound of formula-6b in presence of an aqueous sodium carbonate and tetrabutylammonium bromide 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 & purity of compound of formula-7, which in-turn enhances the yield as well as purity of the final compound.

The second 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-chloro-4-methoxybenzylamino)-2-(methylthio)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-chloro-4-methoxybenzylamino)-2-(2-(hydroxymethyl)pyrrolidin- l-yl) pyrimidine-5-carboxylic acid compound of formula-1 1 ,

d) optionally 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 obtained compound is in-situ 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 and the obtained ester compound of formula- 10 is hydrolyzed using an aqueous sodium hydroxide to provide compound of formula- 11 which is further purified by using tetrahydrofuran to provide pure compound of formula-1 1. 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 third 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 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-methoxybenzylamino)-2-(2-(hydroxymethyl)pyrrolidin-l -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- 1 1 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-dimethylamino propyl)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 aqueous sodium carbonate 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 aqueous sodium carbonate and tetrabutylammonium bromide 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-(methyl sulfinyl)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-(hydroxymethyl)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-l-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- 1 1 with pyrimidin-2-ylmethanamine hydrochloride compound of formula- 12a in presence of l-ethyl-3-(3-dimethylamino propyl)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.

Another 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-methoxy phenyl) methanamine hydrochloride compound of formula-6a in presence of aqueous sodium carbonate provides ethyl 4-(3-chloro-4-methoxybenzylamino)-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 sulfinyl)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, isolating the obtained compound with cyclohexane provides (S)-ethyl 4-(3-chloro-4-methoxybenzylamino)- 2-(2-(hydroxymethyl)pyrrolidin- 1 -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-1 1 , 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 dimethyl formamide provides compound of formula- 1 ,

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

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, 1 1.9, 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 provides 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 or its mixture with water by heating to reflux temperature,

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

c) filtering the precipitated solid 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 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.

Another preferred embodiment of the present invention provides a process for the purification of Avanafil, comprising of:

a) Dissolving Avanafil in aqueous isopropanol by heating to 65-70°C,

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

c) filtering the precipitated solid and drying to get pure Avanafil.

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

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 and then drying to get pure Avanafil compound of formula-1.

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

Formula-6b

The eighth 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-3,

c) its DSC thermogram showing endothermic peak at 177.6°C in accordance with figure-4.

Further the eighth aspect of the present invention also provides a process for the preparation of crystalline form-S of (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 form-S of (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 ninth 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. 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 tenth aspect of the present invention relates to 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 formula

Diamine impurity Dimer Impurity

The Diamine and Dimer impurities are characterized by Ή 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.

Deschloro impurity Acid Impurity Dichloro Impurity

Deschlorodesmethoxy Impurity Aminomethyl Impurity PXRD analysis of the crystalline Avanafil and its intermediate compounds 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. HPLC method of Analysis:

Avanafil and its related substances were analyzed by HPLC with the following chromatographic conditions:

Apparatus: A liquid chromatograph is equipped with variable wavelength UV-detector and integrator; Column: Kromasil C-18, 250x4.6mm, 5 μηι or equivalent; Flow rate: 1.5 mL/minute; Elution: Gradient; Wavelength: 245 nm; Column temperature: 30°C; Injection volume: 5 μΐ,; 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 Trifluroacetic acid in 1000 ml of mill-Q-water, allow dissolving, then adding 1.0 ml of triethylamine and mixing well. Filter this solution through 0.22 μπι filter paper.

Avanafil and its related substances can also be analyzed by 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 μηι or equivalent; Flow rate: 1.5 ml/minute; Elution: Gradient; Wavelength: 245 nm; Column temperature: 30°C; Injection volume: 5 μί; 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 and its related substances can also be analyzed by chiral HPLC with the following chromatographic conditions:

Apparatus: A liquid chromatograph is equipped with variable wavelength UV-detector; Column: Chiral pack-IA-3, 250 x 4.6 mm, 3 μπι or equivalent; Flow rate: 1.5 ml/minute; Elution: Isocratic; Wavelength: 236 nm; Column temperature: 35°C; Injection volume: 20 μί; Run time: 60 minutes; Diluent: Methanol:Solution-A(l :9 v/v); Solution-A: n- Hexane:Ethanol: Diethyl amine (60:40:0.1 v/v/v): Needle wash: Methanol; Concentration: 1.0 mg/mL; Solution-B: Ethanol:Isopropyl alcohol (45:55 v/v): Mobile phase composition: n- Hexane:Solution-B:Diethylamine:Trifluoroacetic acid (80:20:0.2:0.1 v/v.

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. The present invention is represented schematically as follows:

Avanafil

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-chIoro-4-methoxyphenyl)methanamine hydrochloride (Formuia-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. Sulfiiryl 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 ½ hour at the same temperature. Filtered the precipitated solid, washed with methyl tertiary butyl ether and then dried to get title compound. Yield: 1 18 g

Example-2: Preparation of 3-Chloro-4-niethoxyphenyl)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 ½ 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 ½ 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%; Ή NMR (D₂0, 300 MHz) δ 2.55-2.81 (m, 2H), 3.87 (s, 3H), 4.08 (s, 2H), 4.32-4.36 (q, 1 H), 7.09-7.11 (d, 1H), 7.36-7.33 (d, 1H), 7.46 (s, 1 H). 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-3 and figure-4 respectively. ExampIe-3: Preparation of p rimidin-2-ylmethanamine hydrochloride (Formula- 12 a)

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 25-30°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-4: 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 precipitated solid, washed with ethyl acetate and then dried to get title compound.

Yield: 22 g; Decomposition: 207-213°C; Purity by HPLC: 99.1%.

ExampIe-5: Preparation of ethyl 4-(3-chloro-4-methoxybenzyIamino)-2-(methylthio) pyrimidine-5-carboxylate (Formula-7)

Step-a) Preparation of ethyl 4-hydroxy-2-(methyIthio)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.

Step-b) Preparation of ethyl 4-chIoro-2-(methyIthio)pyrimidine-5-carboxylate (Formula-5)

The wet solid obtained in step-a) 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.

Step-c) 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 step-b). Water (100 ml), followed by sodium carbonate (110.3 g) were added to the reaction mixture at 25-30°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 precipitated 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-methoxybenzyIamino)-2-(methylthio) pyrimidine-5-carboxylate (Formula-7)

Step-a) Preparation of ethyl 4-hydroxy-2-(methylthio)pyrimidine-5-carboxyIate (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-methoxybenzy.amino)-2- (methylthio)pyrimidine-5-carboxylate (Formula-7)

(3-Chloro-4-methoxyphenyl)methanamine malate compound of formula-6b (1 13.1 g) was added to the organic layer containing ethyl 4-chloro-2-(methylthio)pyrimidine-5- carboxylate compound of formula-5 obtained in step-(b). 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 and then co-distilled with cyclohexane. Cooled the obtained compound to 25-30°C and 600 ml of cyclohexane: ethyl acetate (in 9: 1 ratio) was added to it at the same temperature. 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-7: Preparation of (S)-ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(2- (hydroxymethyl) pyrrolidin-l-yI)pyrimidine-5-carboxylate (Formula-10)

Step-a) Preparation of ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methyIsulfinyl) pyrimidine-5-carboxyIate (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.

Step-b): Preparation of (S)-ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(2- (hydroxyraethyl) pyrrolidin-l-yl)pyrimidine-5-carboxylate (FormuIa-10)

The organic layer containing ethyl 4-(3-chIoro-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) were 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. Cooled the residue to 30-35°C and cyclohexane (250 ml) was added and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with cyclohexane and then dried to get title compound.

Yield: 50 gms; Melting range: 80-85°C. Example-8: Preparation of (S)-ethyl 4-(3-chIoro-4-methoxybenzyIamino)-2-(2-(hydroxyl methyl)pyrrolidin-l-yI)pyrimidine-5-carboxylate (Formula-10)

Step-a) Preparation of ethyl 4-(3-chIoro-4-methoxybenzylamino)-2-(methyIsulfinyl) pyriniidine-5-carboxyIate (Formula-8)

A mixture of Ethyl 4-(3-chloro-4-methoxybenzylamino)-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-chIoro-4-methoxybenzylamino)-2-(2- (hydroxymethyl) pyrrolidin-l-yI)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-9: Preparation of (S)-4-(3-chloro-4-methoxybenzyIamino)-2-(2-(hydroxyl methyl)pyrrolidin-l-yI)pyrimidine-5-carboxyIic acid (Formula-11)

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 were 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-10: Preparation of (S)-4-(3-chloro-4-methoxybenzylamino)-2-(2-(hydroxyI methyl)pyrrolidin-l-yI)pyrimidine-5-carboxylic 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 toluene was added to the reaction mixture. Both the organic and aqueous layers were separated. The aqueous layer was 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 ½ hour at 25-30°C. Filtered the precipitated solid, washed with tetrahydrofuran and then dried to get title compound.

Yield: 23 g; MR: 180-185°C; Purity by HPLC: 98.91%.

Example-ll: 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-1 1 (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 25-35°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 ½ 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-12: Preparation of Avanafil (Fortnula-l)

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 were 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 and co-distilled with methanol. Cooled the obtained compound to 30-35°C and methanol (1500 ml) was added to it. 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 ½ 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: D(0.1): 5.501 μιη; D(0.5): 20.469 um; D(0.9): 52.006 um; D(4,3): 25.457 μηι.

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

Example-13: Purification of Avanafil using methanol

Avanafil (50 g) was dissolved in methanol (1 100 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 and DSC patterns of the obtained compound are similar to the PXRD and DSC patterns of the compound obtained in example- 12.

Particle size distribution: D (0.1): 2.88μηι; D(0.5): 1 1.62μιη; and D (0.9): 37.99 μπι; Specific surface area: 1.05 m2/g.

Example-14: 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 of the obtained compound are similar to the PXRD and DSC patterns of the compound obtained in Example- 12.

Example-15: Purification of Avanafil using toluene

Avanafil (2.0 g) was dissolved in toluene (20 ml) at 105-1 10°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 of the obtained compound are similar to the PXRD and DSC patterns of the compound obtained in Example- 12. Example-16: 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 of the obtained compound are similar to the PXRD and DSC patterns of the compound obtained in Example- 12. Example-17: 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

Example-18: Purification of Avanafil (Formula-l)

A mixture of Avanafil (80 g), isopropanol (832 ml) and water (208 ml) was heated to

65-70°C and stirred for 15 minutes. The reaction mixture was cooled to 40-450°C and carbon (24 g) was added to it. The reaction mixture was heated to 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 ½ 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: 0.03%; Dichloro Impurity: 0.01%, Dimer Impurity: 0.05%; Diamine impurity:0.05%; Particle Size Distribution: D(0.1 ): 7.2 μιη; D(0.5): 29.3 μπι; D(0.9): 82.3 μπι.

PXRD and DSC patterns of the obtained compound are similar to the PXRD and

DSC patterns of the compound obtained in Example-12.

Example-19: 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-l 1 (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 reaction mixture 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%. Ή NMR (CHC1₃, 300 MHz) δ 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, 1 H), 8.71-8.72 (d, 2H), 9.0-9.04 (t, 1 H). EIMS (M+l) m/z = 858.3. FTIR: v 3339.55, 1678.41 cm^'1.

Example-20: 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 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 hours. Quenched the reaction mixture with aqueous sodium bicarbonate solution at a temperature below 10°C. Separated organic and aqueous layers, the organic layer was washed with 10% aqueous sodium sulfite. 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 precipitated solid, washed with water and then dried to get title compound.

Yield: 42 g.

Example-21: Preparation of 2,4-bis(3-chloro-4-methoxybenzyIamino)pyrimidine-5- carboxylic acid (FormuIa-14)

10% aqueous sodium hydroxide (24.5 g) 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 were added to the reaction mixture at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred for 3 hours. Filtered the precipitated solid, washed with water and then dried to get title compound. Yield: 30 g.

Example-22: 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 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 reaction mixture at 30-35°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 ½ hour. Filtered the precipitated solid, washed with methanol and then dried to get title compound. Yield: 12.0 g; Ή NMR (CDC1₃, 300 MHz) δ 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, 1 H). EIMS (M+l )) m/z = 554.2. FTIR: v 3325.22, 1639.9 cm^"1.

Claims

We Claim:

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

Formula-4

b) reacting the compound of formula-4 with a chlorinating agent in a suitable solvent provides 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-methoxyphenyl) methanamine compound of formula-6 (or) its acid addition salts

Formula-6

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,

Formula-7

Formula-8

f) reacting the compound of formula-8 in-situ with (S)-pyrrolidin-2-ylmethanol compound of formula-9

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-methoxybenzyl amino)-2-(2-(hydroxymethyl)pyrrolidin- 1 -yl)pyrimidine-5-carboxylate compound of formula- 10,

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

Formula- 11

h) optionally purifying the compound of formula-1 1 in a suitable solvent to provide pure compound of formula- 1 1 ,

i) reacting the compound of formula- 11 with pyrimidin-2-yl methanamine compound of formula- 12 (or) its acid addition salts

Formula- 12

in presence of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, hydroxy benzotriazole and triethylamine in dimethylformamide provides compound of formula-1 , j) optionally, purifying the compound of formula- 1 from a suitable solvent provides pure Avanafil.

2. A process for the preparation of Avanafil, comprising of:

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 aqueous sodium carbonate and a tetrabutyl ammonium bromide 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,

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 provides (S)-4-(3-chloro-4-methoxybenzylamino)-2-(2-(hydroxymethyl) pyrrolidin-l -yl) pyrimidine-5-carboxylic acid compound of formula- 1 1 ,

h) purifying the compound of formula- 11 using tetrahydrofuran to provide pure compound of formula- 1 1 ,

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 dimethyl formamide provides compound of formula- 1 ,

3. The process according to claim- 1 , comprising of:

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-methoxy phenyl) methanamine hydrochloride compound of formula-6a in presence of aqueous sodium carbonate provides ethyl 4-(3-chloro-4-methoxy benzylamino)-2-(methylthio) pyrimidine-5-carboxylate compound of formula-7,

e) 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 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 ,

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

b) reacting the compound of formula-5 in-situ with (3-chloro-4-methoxyphenyl) methanamine compound of formula-6 or its acid addition salt in presence of an inorganic base in a suitable solvent, optionally in presence of a phase transfer catalyst to provide ethyl 4-(3-chloro-4-methoxybenzyl amino)-2-(methylthio)pyrimidine-5- carboxylate compound of formula-7,

The process according to claim-4, 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 an aqueous sodium carbonate and tetrabutylammonium bromide provides ethyl 4-(3-chloro-4- methoxybenzylamino)-2-(methylthio)pyrimidine-5-carboxylate compound of formula-7,

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

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 acid addition salt in presence of an inorganic base in a suitable solvent, optionally in presence of phase transfer catalyst to provide compound of formula-7.

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-(methylthio)pyrimidine-5- carboxylate compound of formula-7 with a suitable oxidizing agent in a suitable solvent to provide ethyl 4-(3-chloro-4-metho¾ybenzylamino)-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, 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,

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

9. 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 or its mixture with water by heating to reflux temperature,

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

c) filtering the precipitated solid and then drying to get pure Avanafil.

10. 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 and then drying to get pure Avanafil.

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

a) Dissolving the Avanafil in aqueous isopropanol by heating to reflux temperature, b) cooling the reaction mixture and stirring the reaction mixture,

c) filtering the precipitated solid and drying to get pure Avanafil.

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

a) Dissolving Avanafil in a suitable chloro solvent,

b) adding the above solution to hydrocarbon solvent,

c) stirring the reaction mixture,

d) filtering the precipitated solid and then drying to get pure Avanafil.

13. The process according to claim- 12, comprising of:

a) Dissolving Avanafil in dichloromethane,

b) adding the above solution to n-pentane,

c) stirring the reaction mixture,

d) filtering the precipitated solid and then drying to get pure Avanafil.

14. A compound of formula

15. 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-3, and

c) its DSC thermogram showing endotherm peak at 177.6°C in accordance with figure- 4.

16. A process for preparation of crystalline (3-chloro-4-methoxyphenyl) methanamine malate compound of formula-6b, comprising of:

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

d) basifying the reaction mixture to provide (3-chloro-4-methoxyphenyl)methanamine using 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 and stirring the reaction mixture,

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

k) filtering the precipitated solid,

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

a) Hydrogenating the 2-cyanopyrimidine having structural formula

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.

18. The process according to claim- 17, comprising of:

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

b) converting the compound of formula- 12 into its hydrochloride salt by treating with 2- butanolic-HCl,

c) purifying the obtained compound with methanol provides pure pyrimidin-2- ylmethanamine hydrochloride compound of formula- 12a.

19. Diamine and Dimer impurities having the following structural formulae

Diamine impurity Dimer impurity

20. A process for the preparation of Diamine impurity, comprising of:

a) Oxidizing the ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio)pyrimidine-5- carboxylate compound of formula-7 with meta-chloro perbenzoic acid in dichloro methane to provide ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methyl sulfinyl)pyrimidine-5-carboxylate compound of formula-8,

b) reacting the compound of formula-8 with (3-chloro-4-methoxyphenyl) methanamine malate salt compound of formula-6b in presence of triethylamine in dichloromethane provides ethyl 2,4-bis(3-chloro-4-methoxybenzylamino) pyrimidine-5-carboxylate compound of formula- 13,

c) hydrolyzing the compound of formula- 13 with an aqueous sodium hydroxide in dimethylsulfoxide to provide 2,4-bis(3-chloro-4-methoxybenzylamino)pyrimidine-5- carboxylic acid compound of formula- 14,

d) reacting the compound of formula- 14 with pyrimidin-2-ylmethanamine hydrochloride compound of formula- 12a in presence of l-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride, hydroxy benzotriazole and triethylamine in dimethylformamide provides diamine impurity.

21. A process for the preparation of Dimer impurity, comprising of reacting the (S)-4-(3- chloro-4-methoxybenzylamino)-2-(2-(hydroxymethyl)pyrrolidin-l -yl)pyrimidine-5- carboxylic acid compound of formula- 1 1 with pyrimidin-2-ylmethanamine hydrochloride compound of formula- 12a in presence of l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride, hydroxy benzotriazole and triethylamine in a dimethyl formamide at a temperature greater than 10°C, preferably greater than 40°C provides Dimer impurity.

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

23. A process for the preparation of Avanafil less than 0.5% of dimer impurity comprising of reacting the compound of formula- 1 1 with pyrimidin-2-yl methanamine hydrochloride compound of formula- 12a in presence of a suitable coupling agent in presence of a suitable base in a suitable solvent at a temperature below 10°C.

24. A process for the preparation of Avanafil less than 0.5% of dimer impurity comprising of 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 at a temperature below 10°C.

25. A process for the preparation of Avanafil substantially free of dimer impurity comprising of reacting the compound of formula- 1 1 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 at a temperature 0-5°C.

26. Avanafil is having particle size distribution of D 0 less than 150 μπι, preferably less than 100 μιη, more preferably less than 50 μηι.

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

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

29. Use of compound claimed in claim- 14 in the synthesis of Avanafil.

30. Use of crystalline form-S of (3-chloro-4-methoxyphenyl)methanamine malate in the synthesis of Avanafil.

31. Avanafil obtained by the present invention is having purity greater than 99% by HPLC, more preferably greater than 99.5% by HPLC, most preferably greater than 99.7% by HPLC.