FORM 2
THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13)
1. TITLE OF THE INVENTION:
A process for the preparation of Avanafil and its intermediate.
2. APPLICANT (S)
(a) NAME: Wanbury Ltd.
(b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956.
(c) ADDRESS:
Wanbury Ltd., BSEL Tech park, B-wing, 10th floor, sec -30A, opp. Vashi Railway station, Vashi, Navi- Mumbai-400703, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field of the invention
The present invention relates to an acylated derivative of Avanafil (hereafter referred to as acylated Avanafil) of Formula (II).
Furthermore, the present invention relates to a process for purification of avanafil of Formula (I) through formation of acylated Avanafil of Formula (II).

Wherein R is C1 to C4 alkyl group.
Background of the invention
Avanafil is chemically known as 4-[(3-Chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)-l-pyrrolidinyl]-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide.
Avanafil is a FDA approved drug used for treatment of erectile dysfunction. It belongs to a group of medicines called phosphodiesterase 5 (PDE5) inhibitors and is said to exert a more rapid effect compared to other PDE5 inhibitors.
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this

specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
A process for preparation of Avanafil was first disclosed in US 6,797,709 (depicted in Scheme I), wherein 4-chloro-5-ethoxycarbonyl-2-methylthio-pyrimidine is coupled with 3-chloro-4-methoxybenzylamine in presence of triethylamine to provide compound of Formula (A), which on oxidization provides a sulfonyl compound of Formula (B). Said compound of Formula (B) is reacted with L-prolinol and exert compound of Formula (C). The resulting compound of Formula (C) undergoes column chromatographic purification and crystallization, while further subjected to hydrolysis to obtain compound of Formula (D). The compound of Formula (D) is coupled with 2-aminomethylpyrimidine to obtain Avanafil of Formula (I). The final product obtained is purified by column chromatography. The need to purify the intermediate compound of Formula (C) and final product, by column chromatography makes this process cumbersome, time consuming and unviable for large scale production thereby contributing to main disadvantages of the process.


CN 103254179, discloses a process for preparation of Avanafi, wherein 3-chloro-4-methoxybenzylhalide is coupled with cytosine to result compound of Formula (E), later on condensation with L-prolinol yields 4-[(3-chloro-4-methoxy benzyl)amino-2-(2-hydroxymethyl)-l-pyrrolinyl]pyrimidine of Formula (F). The compound of

Formula (F) is then condensed with N-(2-pyrimidylmethyl)formamide to obtain Avanafil of Formula (I). Process is depicted in Scheme II

CN 103254180, describes an alternate process for preparation of Avanafil of Formula
(I), wherein a substitution reaction on 6-amino-l,2-dihydropyrimidine-2-keto-5-
carboxylic acid, ethyl ester and 3-chloro-4-methoxybenzylchloride provides 6-(3-
chloro-4-methoxybenzylamino)-l,2-dihydropyrimidine-2-keto-5-carboxylic acid,
ethyl ester of Formula (G) which on condensation with L-prolinol generates 6-(3-
chloro-4-methoxybenzylamino)-l,2-dihydropyrimidine-2-keto-5-carboxylic acid
ethyl ester of Formula (H). The compound of Formula (H) is then hydrolysed and coupled with N-(2-pyrimidylmethyl)formamide to obtain Avanafil of Formula (I). Process is depicted in Scheme III


CN 103483323, discloses a synthetic method for preparation of avanafil, wherein amidation of pyrimidine-5-carbonyl chlorides with 2-(aminomethyl)pyrimidine at temperature ranging from -10 to 5°C resulted an amide (intermediates A); which underwent condensation with 3-chloro-4-methoxybenzylamine at the temperature ranging from 0 -3°C to give 4-[(3-chloro-4-methoxybenzyl)amino]-5-pyrimidinecarboxamides (intermediates B), which further on condensation with L-prolinol gave avanafil.. The process is depicted in Scheme IV.


All the reactions mentioned in prior art results in the formation of additional byproducts which lead to low overall yield and low purity that fails to comply with the pharmaceutical standards. The above mentioned drawbacks call for an alternative and novel process for the purification of Avanafil, which should be cost effective, eco-friendly, commercially viable, reproducible on industrial scale and meet the needs of regulatory agencies.
Like any synthetic compound, Avanafil can contain extraneous compounds or
impurities. These impurities may be, for example, starting materials, by-products of

the reaction, products of side reactions, or degradation products.
Prior art processes disclose several processes for the preparation of pure Avanafil by column chromatography, crystallization etc. But it was found by the present inventors that certain identified and unidentified impurities do not go away with the purification techniques reported in prior arts per se. solvent purification and crystallization.
Hence, there is a long-felt need for the industrially applicable and consistently reproducible purification process to provide highly pure Avanafil having acceptable levels of certain impurities, which complies with the requirements of pharmacopoeias.
The present invention is thus directed to an industrially advantageous process for the purification of Avanafil which improves the economics by employing less expensive and less hazardous raw materials and is more productive.
Object of the invention
1. The main object of the present invention is to provide a novel compound of Formula (II) i.e. acylated Avanafil, and process for preparation thereof.
2. Another object of present invention is to provide a process for purification of avanafil of Formula (I) through formation of acylated Avanafil of Formula
(II).
3. Yet another object of present invention is to provide a process for preparation of Avanafil of Formula (I), in high yield and purity using a novel compound of Formula (II).
4. Yet another object of the present invention to provide simple, economic and industrially scalable process for the preparation of Avanafil of Formula (I).

Summary of the invention
According to an aspect of present invention, there is provided a novel compound of Formula (II).

wherein R is C1 to C4 alkyl group.
According to another aspect of present invention, there is provided a process for purifying Avanafil of Formula (I), comprising steps of:
i) reacting crude Avanafil with an acylating agent in presence of an organic base in a water immiscible solvent(s) to form reaction mixture comprising acylated Avanafil of Formula (II);


wherein R is C1 to C4 alkyl group
ii) reducing the acidity of the reaction mixture of step a) by extracting with water followed by separating an organic layer;
iii) subjecting the organic layer to distillation/evaporation to obtain a reaction mass;
iv) dissolving the reaction mass in a polar protic solvent by heating at 60-65°C
v) cooling the solution obtained in step iv) to 25-30°C to precipitate out acylated Avanafil of Formula (II)
vi) treating acylated Avanafil of Formula (II) with base and solvent to obtain Avanafil of Formula (I).
According to yet another aspect of present invention, Avanafil of Formula (I) is obtained in high purity and yield.

Detailed Description of the Invention
According to an embodiment of present invention, there is provided a novel compound of Formula (II).

wherein R is C1 to C4 alkyl group
According to another embodiment of present invention, there is provided a process for purifying Avanafil of Formula (I), comprising steps of
i) reacting crude avanafil with an acylating agent in presence of an organic base in a water immisicible solvent to form a reaction mixture comprising acylated Avanafil of Formula (II);


Formula (II)
wherein R is C1 to C4 alkyl group
ii) reducing the acidity of the reaction mixture of step a) by extracting with water followed by sequentially washing thus formed organic layer with dilute hydrochloric acid, dilute aqueous ammonia solution and water;
iii) subjecting the resultant organic layer to distillation/evaporation to obtain a reaction mass;
iv) dissolving the reaction mass in a polar protic solvent by heating at 60-65°C;
v) cooling the solution obtained in step iv) to 25-30°C to precipitate out acylated avanafil of Formula (II);
vi) treating acylated Avanafil of Formula (II) with base and solvent to obtain Avanafil of Formula (I).
For the purpose of this specification the meaning of "crude Avanafil" is Avanafil having purity of less than 99%. The impurities identified in this present invention are mainly Des-methoxy Avanfil of formula (III), Des-chloro-Avanafil of formula (IV) and many more.


The said impurities are having the structural similarity to Avanafil and carried forward in final product so, in such case to get rid of theses impurities is very critical in order to pass the final product as per ICH guideline. So the present invention overcomes this drawback by employing the technique such as preparing the derivative of Avanafil per se acetyl Avanafil. According to an embodiment of present invention, the acylating agent used in step i) is selected from acyl halide or acyl anhydride.The organic bases like dimethylaminopyridine, triethylamine or ethyldiisopropyl amine is used in acylation, preferably dimethylaminopyridine is used.
The water immiscible organic solvent used in step i) is selected from group comprising aromatic hydrocarbon, chlorinated hydrocarbon or ester. The examples of aromatic hydrocarbon include but not limited to toluene, xylene, benzene and the like. The examples of chlorinated hydrocarbons include but not limited to dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture thereof. The example of ester include but not limited to ethylacetate and like or mixture thereof.
According to another embodiment of the present invention, the polar protic solvent used in step iv)of the process is selected from propanol, methanol, ethanol, butanol, water or mixture thereof, preferably methanol is used. According to an embodiment of present invention, step vi) of reaction is carried out in presence of a inorganic base in polar protic solvent selected from propanol, methanol, ethanol, butanol, water or mixture thereof.
The inventors of present inventions found that acylating crude Avanafil contain compound formula (III) and compound formula (IV) and many impurities is converted to acetyl Avanfil by using acylating agent. And finally treated with base in solvent to obtain pure Avanafil (purity above 99.5%). The detail of the invention

provided in the following example is given by the way of illustration only and should not be construed to limit the scope of the present invention.
Examples
Example 1: Preparation of acetyalated avanafil

To a mixture of lOOg of crude Avanafil (purity 98.5%) 30g of N,N-dimethylaminopyridine and 900ml of dichloromethane at 15-20°C was added a solution of acetyl chloride in 100ml of dichloromethane. The resultant mixture was maintained at 20-25°C for 2 hours. After completion of reaction, the reaction mixture was extracted with water, the organic layer was separated and sequentially washed with dilute hydrochloric acid (60ml of concentrated hydrochloric acid in 300ml of water), dilute aqueous ammonia ( 60ml of aqueous ammonia in 300ml of water) and 300ml of water. The organic layer thus obtained was then evaporated to gain a reaction mass which was stripped with methanol to remove any traces of dichloromethane. The reaction mass was then dissolved in 400ml of methanol by heating it to 64-68°C. The mixture was filtered and cooled to 25-30°C to precipitate acetylated avanafil of Formula (II); wherein R= C1 alkyl group. The product was isolated, washed with chilled methanol and dried at 35-40°C to obtain 108.78g of acetylated avanafil

Yield: 86.87%.
Example 2: Deacetylation of avanafil

lOOg of acetylated avanafil obtained in Example 1, was added to 400ml of methanol. To this mixture at 25-30°C was added sodium hydroxide and the resultant mixture was heated to 64-68°C for 2 hours. After completion of reaction, the mixture was cooled to 25-30°C to precipitate out the solid. The solid obtained was isolated and again heated to 64-68°C with 1200ml of methanol followed by charcoalization at same temperature. The charcoalized solution was cooled to 25-30°C to precipitate out product, which was dried at 60-65°C to obtain 84.97g of purified avanafil.
Yield: 86.50%
Purity: 99.8%

We Claim:
1. A compound of Formula (II).

Wherein R is C1 to C4 alkyl group.
2. A process for purifying Avanafil of Formula (I), comprising steps of:
i) reacting crude avanafil with an acylating agent in presence of an organic base in a water immiscible solvent to form a reaction mixture comprising acylated Avanafil of Formula (II);


Wherein R is C1 to C4 alkyl group
ii) reducing the acidity of the reaction mixture of step a) by extracting with water followed by sequentially washing thus formed organic layer with dilute hydrochloric acid, dilute aqueous ammonia solution and water;
iii) subjecting the resultant organic layer to distillation/evaporation to obtain a reaction mass;
iv) dissolving the reaction mass in a polar protic solvent by heating at 60-65°C;
v) cooling the solution obtained in step iv) to 25-30°C to precipitate out acylated avanafil of Formula (II);
vi) treating acylated Avanafil of Formula (II) with base and solvent to obtain Avanafil of Formula (I).
3. The process as claimed in claim 2, wherein the acylating agent used in step i) is
selected from acyl halide or acyl anhydride.
4. The process as claimed in claim 2, wherein the organic bases like
dimethylaminopyridine, triethylamine or ethyldiisopropyl amine is used in acylation,
but preferably dimethylaminopyridine is used.
5. The process as claimed in claim 2, wherein the water immiscible organic solvent
used in step i) is selected from group comprising aromatic hydrocarbon like toluene,
xylene or benzene , and chlorinated hydrocarbon like dichloromethane,
dichloroethane, chloroform, carbon tetrachloride, esters like ethylacetate or mixture
thereof.

6. The process as claimed in claim 2, wherein the polar protic solvent used in step iv) of the process is selected from propanol, methanol, ethanol, butanol, water or mixture thereof, but preferably methanol is used.
7. The process as claimed in claim 2, wherein step vi) of reaction is carried out in presence of a inorganic base in polar protic solvent selected from propanol, methanol, ethanol, butanol, water or mixture thereof.