DESC:ACID ADDITION SALTS OF VELPATASVIR, ITS PREPARATION AND USE THEREOF

FIELD OF THE INVENTION
The present invention provides acid addition salts of Velpatasvir, its preparation and use in the preparation of Velpatasvir of Formula (I).

Formula (I)

BACKGROUND OF THE INVENTION
Velpatasvir is chemically described as Methyl {(1R)-2-[(2S,4S)-2-(5-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methyl pyro lidine-2-yl]-1,11-di hydro[2]benzopyrano[4',3':6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxy methyl) pyrrolidin-1-yl]-2-oxo-1-phenyl ethyl} carbamate having the structural Formula (I).

Velpatasvir in combination with Sofosbuvir has been approved in both in US and Europe for the treatment of adult patients with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infections.
US 8,940,718; US 8,575,135 and US 8,921,341 discloses new HCV therapeutic agents such as Velpatasvir of Formula A and its intermediate and processes for preparation thereof.
Different salts of Velpatasvir such as hydrochloride, phosphate, tartrate and hydrobromide are disclosed in WO 2015/191431 A1 (F: US 9,630,972, US 9,884,873 and US 2019/270750).
Discovering new salts, solid state forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate form that facilitate conversion to other salts or polymorphic forms.
New polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). For at least these reasons, there is a need for additional solid state forms (including solvated forms or salts) of Velpatasvir. Therefore, it would be desirable to provide acid addition salt of Velpatasvir and process for preparation, and use thereof.
OBJECT OF THE INVENTION
In one aspect, the present invention provides acid addition salts of Velpatasvir, its preparation and use in preparation of Velpatasvir of Formula (I).

Formula (I)
In another aspect, the present invention provides process for the preparation of acid addition salt of Velpatasvir comprising the following steps:
a) obtaining solution or suspension of Velpatasvir in a suitable solvent(s);
b) adding suitable acid to reaction mixture obtained in step (a) or adding reaction mixture obtained in step (a) to suitable acid; and
c) isolating acid addition salt of Velpatasvir .
wherein suitable acid used is selected from group consisting of sulfuric acid, ethyl phosphonic acid, methyl phosphonic acid, meta phosphoric acid, methane sulfonic acid, ethane sulfonic acid, trifluoro methane sulfonic acid, fluoro sulfonic acid, phenyl sulfonic acid, succinic acid, fumaric acid, malonic acid, glutaric acid, cinnamic acid, malic acid, mandelic acid, oxalic acid, adipic acid, maleic acid, citric acid, lactic acid, p-tolyl tartaric acid, p-benzoyl tartaric acid, glutaric acid, pimelic acid, glucoheptanoic acid, glycerophosphoric acid, glutamic acid, camphor sulfonic acid, p-toluene sulfonic acid, boric acid, phenyl boronic acid, salicylic acid.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides acid addition salt of Velpatasvir, its preparation and use in preparation of Velpatasvir of formula (I).

Formula (I)
In an embodiment of the present invention, the Velpatasvir used in step (a) is prepared by conventional process. Either isolated Velpatasvir or directly from the reaction mass is used in step (a). The solution of Velpatasvir in step (a) is obtained by optionally heating the Velpatasvir in suitable solvent(s).
In one embodiment of the present invention, wherein in step (b) suitable acid is added to reaction mixture either in the form of solid or solution of an acid dissolved in a suitable solvent. The reaction mixture after addition of acid is stirred for 30 minutes to several hours at a temperature in the range of 5 °C to reflux temperature of the solvent used.
In another embodiment of the present invention, the suitable acid used in the present process is in an amount of 1-10 moles per mole of Velpatasvir.
In another embodiment of the present invention, the solution of step (b) is optionally treated with activated carbon before isolation. The acid addition salt is isolated by conventional techniques such as cooling, anti-solvent addition, filtration, distillation, evaporation, freeze drying, centrifugation, and the like manner and dried by convention methods
The acid used in preparation of Velpatasvir acid addition salt is selected from sulfuric acid, ethyl phosphonic acid, methyl phosphonic acid, meta phosphoric acid, methane sulfonic acid, ethane sulfonic acid, trifluoro methane sulfonic acid, fluoro sulfonic acid, phenyl sulfonic acid, succinic acid, fumaric acid, malonic acid, glutaric acid, cinnamic acid, malic acid, mandelic acid, oxalic acid, adipic acid, maleic acid, citric acid, lactic acid, p-tolyl tartaric acid, p-benzoyl tartaric acid, glutaric acid, pimelic acid, glucoheptanoic acid, glycerophosphoric acid, glutamic acid, camphor sulfonic acid, p-toluene sulfonic acid, boric acid, phenyl boronic acid, salicylic acid and like.
The suitable solvent(s) in any of the step of the present invention may be protic or aprotic polar or non-polar solvents selected from the group comprising of water, alcohols, esters, ketones, acids, amides, ethers, nitriles, halogenated hydrocarbons, hydrocarbons, sulfolane, dimethyl sulphoxide, N-methyl pyrrolidone or mixtures thereof.
Alcohol solvents such as methanol, ethanol, n-propanol, 2-propanol, ethylene glycol, butanol, n-butanol and like; ester solvents such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate and like; ketone solvents such as acetone, methyl ethyl ketone, cyclohexanone and the like and ether solvents such as tetrahydrofuran, dioxane and the like; halogenated hydrocarbons include dichloromethane, chloroform; 1, 2-dichloroethane and like and hydrocarbons include hexane, heptane, benzene, toluene and like; nitrile such as acetonitrile, benzonitrile and like; amides such as N, N-dimethylformamide, ?, ?-dimethylacetamide and like.

The Velpatasvir used as starting material in above process can be obtained according to process known in US 8,940,718.

The acid addition salt of Velpatasvir obtained according to above process can be in any form such as crystalline, semi crystalline or amorphous. The acid addition salts of Velpatasvir obtained according to the present invention contain the counter ion of suitable acid in any stoichiometric ratio, for example 0.5 to 3 moles per mole of Velpatasvir.

The acid addition salt prepared by present invention is used for the preparation of highly pure Velpatasvir which free of impurities. The process of present invention is simple, commercially viable and economical.

In the foregoing section, embodiments are described by way of an example to illustrate the process of the invention. However, this is not intended in any way to limit the scope of the present invention. Several variants of the example would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.

EXAMPLES
Example 1: Preparation of Velpatasvir sulfate
Velpatasvir (25.0 g, 0.028 moles) in ethyl acetate (250 mL) was charged at 25-30°C. To this sulfuric acid (2.77 g, 0.028 moles) was charged at 25-30°C. The reaction mixture was heated at about 40-45°C and stirred for 1 hour. The reaction mixture was cooled to 25-30°C and stirred for about 30 min. The solid obtained was filtered, washed with ethyl acetate and dried to obtain product (21.0 g).
Example 2: Preparation of Velpatasvir sulfate
Velpatasvir (20.0 g, 0.022 moles) was charged in acetone (200 mL) at 25-30°C. To this sulfuric acid (2.15 g, 0.022 moles) was charged at 25-30°C. The reaction mixture was heated at about 35-40°C. The reaction mixture was cooled to 25-30°C and stirred for about 30 min. The solid obtained was filtered, washed with acetone and dried to obtain the product (14.2 g).
Example 3: Preparation of Velpatasvir sulfate
Velpatasvir (10.0 g, 0.011 moles) was charged in acetonitrile (150 mL) at 25-30°C. To this sulfuric acid (1.07 g, 0.022 moles) was charged at 25-30°C. The reaction mixture was heated at about 45-50°C and stirred for 1 hour. The reaction mixture was cooled to 25-30°C and stirred for about 30 min. The solid obtained was filtered, washed with acetonitrile and dried to obtain the product (5.3 g).

Example 4: Preparation of boric acid salt of Velpatasvir
Velpatasvir (10.0 g, 0.011 moles) was charged in acetonitrile (100 mL) and heated at about 80-85°C. To this boric acid (4.08 g, 0.066 moles) was charged at 80-85°C. The reaction mixture was stirred for 10 hour at same temperature and then reaction mixture was cooled to 45-50°C. The obtained solid was filtered, washed with acetonitrile and dried to obtain the product.

Example 5: Preparation of boric acid salt of Velpatasvir
Velpatasvir (2.0 g, 0.0022 moles) was charged in acetonitrile (150 mL) at 25-30°C. To this boric acid (0.4 g, 0.0067 moles) was charged at 25-30°C. The reaction mixture was heated at about 80-85°C. The reaction mixture was cooled to 25-30°C and stirred for about 15-30 min. The obtained solid was filtered, washed with acetonitrile and dried to obtain the product.
Other acid addition salt as disclosed in present invention can be prepared in similar manner as per the process of above examples.

Dated this 23rd day of Sep. 2019

Dr. S. Ganesan
,CLAIMS:We Claim:

1. Acid addition salts of compound of formula (I) :

wherein acid is selected from boronic acid and sulfuric acid.

2. The compound as claimed in claim1 wherein acid addition salt is boronic acid salt of Velpatasvir.

3. The compound as claimed in claim 1 wherein acid addition salt is sulfate salt of Velpatasvir.

4. A process for preparing acid addition salt of compound of formula (I) comprising of following steps:
(a) obtaining solution or suspension of Velpatasvir in a suitable solvent(s);
(b) adding suitable acid to reaction mixture obtained in step (a) or adding reaction mixture obtained in step (a) to suitable acid; and
(c) isolating acid addition salt of Velpatasvir .

5. The process as claimed in claim 4 further comprises converting acid addition salt of Velpatasvir in Velpatasvir free base.

6. The process as claimed in in step (a) of claim 4, wherein suitable solvent(s) are selected from esters, nitriles and ketones.

7. The process as claimed in step (b) of claim 4, wherein suitable acid is selected from sulfuric acid or boronic acid.

Dated this 23rd day of Sep. 2019

Dr. S. Ganesan