WO2019064310A1

WO2019064310A1 - An improved process for the preparation of elbasvir and its salt thereof

Info

Publication number: WO2019064310A1
Application number: PCT/IN2018/050032
Authority: WO
Inventors: Suthrapu Sashikanth; Tankasala NAVEENA; Andru VEMAN REDDY; Karicheti MARUTHINATH; Ravi JANAKI RAMA RAO; Konakanchi DURGA PRASAD; Muddasani Pulla Reddy; Nannapaneni Venkaiah Chowdary
Original assignee: Natco Pharma Ltd
Current assignee: Natco Pharma Ltd
Priority date: 2017-09-26
Filing date: 2018-01-22
Publication date: 2019-04-04
Anticipated expiration: 2020-03-26

Abstract

The present invention relates to an improved process for the preparation of Elbasvir compound of Formula-I through its novel salt.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF ELBASVIR

AND ITS SALT THEREOF

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of Elbasvir compound of Formula-I from its novel salt. The compound of Formula- I is represented by the following structural formula:

Formula-I BACKGROUND OF THE INVENTION:

Elbasvir is chemically known as Dimethyl N,N'-([(6S)-6-phenylindolo [l,2-c][l,3]benzoxazine-3,10-diyl]bis{ lH-imidazole-5,2-diyl-(2S)-pyrrolidine- 2,l-diyl[(2S)-3-methyl-l-oxobutane-l,2 diyl] })dicarbamate and it is an inhibitor of the Hepatitis C Virus (HCV) Non-Structural protein 5A (NS5A).

Elbasvir and related compounds are disclosed in US patent No 8,871,759. The international patent application publications Nos. WO2012040923, WO2015065821, WO2016196932 are disclosed the various processes for preparing Elbasvir.

According to WO2012040923, the process for the preparation of Elbasvir is given in Scheme-I as below:

Scheme-I

According to WO2015065821, Elbasvir is prepared as shown in Scheme-II:

Scheme-II In the above mentioned prior art processes, the purity of the obtained

Elbasvir is not satisfactory and also unacceptable amounts of impurities are formed along with Elbasvir at various stages of the process that will impact the purity of final compound. Thus, there remains a need to prepare compound of Formula-I with high purity and in good yield while overcoming the drawbacks presented by the previously described processes.

SUMMARY OF THE INVENTION:

In one aspect of the present invention is to provide a process for the preparation of Elbasvir compound of formula-I.

In another aspect of the present invention is to provide novel salt of Elbasvir compound of formula-I and its process for the preparation.

Yet another aspect of the present invention is to provide a process for the preparation of pure Elbasvir compound of formula-I through novel salt of Elbasvir. BRIEF DESCRIPTION OF THE DRAWINGS

FIG-1: XRPD pattern of amorphous form of Elbasvir prepared from example- 1. FIG-2: XRD pattern of Elbasvir Bis mandelate prepared from example-2.

FIG-3: DSC of Elbasvir Bis mandelate prepared from example-2.

FIG-4: XRPD pattern of amorphous form of Elbasvir prepared from example-3.

DETAILED DESCRIPTION OF THE INVENTION

Aspects and preferred embodiments of the present invention will be described in further detail below, noting however that such aspects as well as embodiments and examples are presented for illustrative purposes only and shall not limit the invention in any way.

In one aspect of the present invention to provide a process for the preparation of Elbasvir compound of formula-I, comprising the steps of:

a) reacting the compound of Int-2 with int-7 in presence of Pd₂(dba)3 , Am-Phos and base in an organic solvent;

b) heating the reaction mixture of step-(a) up to dissolution;

c) cooling the reaction mixture and filtering;

d) optionally, treating the filtrate obtained in step-(c) with resin and/or charcoal; e) distilling off of the solvent to obtain the Elbasvir.

The base used in step a) is selected from inorganic base, such as sodium hydroxide, potassium hydroxide, sodium carbonates, potassium carbonates, sodium bicarbonate, potassium bicarbonate preferably potassium carbonate.

The organic solvent used in step a) is selected from alcohols, such as methanol, ethanol, propanol, isopropanol, t-butanol, n-butanol, preferably n- butanol.

The temperature used in step b), is up to get the clear solution of reaction mixture.

The cooling temperature in step c) may be about to 0 to 10°C, 20 to 25 °C, 25 to 30 °C preferably 25 to 30 °C. The resin used in step d) is selected from macro porous polystyrene resins such as macro porous trimercaptotriazine, macro porous thiourea preferably MP- TMT, MP-TMT-Fine, Si-TMT, MP-Thiourea, MP-Thiourea-Fine, Si-Thiourea more preferably MP-TMT.

The Elbasvir obtained from step e) is mixture of crystalline and amorphous form of Elbasvir.

In a preferred embodiment of the present invention provides a process for the preparation of Elbasvir compound of formula-I, comprising the steps of:

a) reacting the compound of Int-2 with int-7 in presence of Pd₂(dba)3 , Am-Phos and potassium carbonate in n-butanol;

b) heating the reaction mixture of step-(a) to 80-85°C,

c) cooling the reaction mixture and filtering;

d) treating the filtrate obtained in step-(c) with MP-TMT resin and/or charcoal; e) distilling off of the solvent to obtain the Elbasvir compound of formula-I.

In another aspect of the present invention is to provide Bis mandelate salt of Elbasvir com ound of formula-I, comprising the steps of:

a) dissolving Elbasvir in a solvent or mixture of solvents;

b) adding S-(+)-Mandelic acid solution to the step-a) reaction mixture;

c) heating the reaction mixture to reflux;

d) cooling the reaction mixture to obtain the Elbasvir Bis mandelate. The solvent mixture used in step a) is selected from ketone and alcohol mixture such as acetone, methyl ethyl ketone and methyl isobutyl ketone and alcohols such as methanol, ethanol, propanol, isopropanol, t-butanol, n-butanol preferably a mixture of acetone and methanol.

The organic solvent used in step b) for dissolving Mandelic acid is selected from aliphatic ketones, aliphatic esters and aliphatic alcohols. Preferably aliphatic ketones more preferably acetone.

The ratio of organic solvent mixture used in step a) is 4: 1, 5: 1 preferably 4:1.

The cooling temperature in step d) may be about to 0 to 10 °C, 20 to 25 °C, 25 to 30 °C preferably 25 to 30 °C.

In a preferred embodiment of the present invention provides Bis mandelate salt of Elbasvir compound of formula-I, comprising the steps of:

a) dissolving Elbasvir in a mixture of acetone and methanol,

b) adding S-(+)-Mandelic acid in acetone solution to the step-a) reaction mixture,

c) heating the reaction mixture to reflux,

d) cooling the reaction mixture to obtain the Elbasvir Bis mandelate.

Yet another aspect of the present invention is to provide a process for the preparation of pure Elbasvir compound of formula-I from Elbasvir Bis mandelate, comprising the steps of:

a) dissolving the Elbasvir Bis mandelate in a first organic solvent,

b) adding a base to the step-a) reaction mixture,

c) stirring the reaction mixture,

d) separating the organic layer and filtering,

e) adding the filtrate obtained in step-d) to a second organic solvent, f) stirring the reaction mixture, g) filtering the precipitated solid and drying to get pure Elbasvir compound of formula-I.

The first organic solvent used in step a) is selected from ester solvents like methyl acetate, ethyl acetate, isopropyl acetate, propyl acetate preferably ethyl acetate.

The basic used step-b) is selected from inorganic base solution such as sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution, potassium hydroxide solution preferably potassium carbonate solution.

The second organic solvents used in step-e) is selected from hydrocarbons solvent such as benzene, xylene, toluene, n-hexane, n-heptane preferably n-heptane.

The Elbasvir obtained from above step-g) is pure amorphous form.

In a preferred embodiment of the present invention provides a process for the preparation of pure Elbasvir compound of formula-I from Elbasvir Bis mandelate, comprising the steps of:

a) dissolving the Elbasvir Bis mandelate in ethyl acetate,

b) adding aqueous potassium carbonate to the step-a) reaction mixture, c) stirring the reaction mixture,

d) separating the organic layer and filtering,

e) adding the filtrate obtained in step-d) to n-heptane,

f) stirring the reaction mixture,

g) filtering the precipitated solid and drying to get pure Elbasvir compound of formula-I.

The Elbasvir compound of formula-I obtained from the above step-g) is further purified with a mixture of ethyl acetate and n-heptane to get high pure Elbasvir. HPLC method of Analysis:

The Elbasvir compound of formula-I and Elbasvir Bis mandelate produced according to the present invention was analysed by HPLC under the following conditions:

Apparatus: A liquid chromatograph equipped with variable wavelength UV detector; Column: Kromasil-5-C-18, (250x4.6 mm), Column temperature: 30°C; Wave length: 220 nm; Elution: Gradient; Diluent: Acetonitrile: Methanol (1: 1); Injection volume: 20 pL; Run Time: 65 minutes; Mobile phase-A: 0.5% triethylamine in 1 litre water adjusted pH to 3.0 with orthophophoric acid; Flow: 1.0 ml/min; Mobile phase-B: Acetonitrile [Sample cone: 0.5. mg/ml]; Sample cooler Temp: 5°C.

PXRD Method of Analysis:

PXRD analysis of Elbasvir compound of formula-I and Elbasvir Bis mandelate produced by the present invention were carried out using PANalytical X'pert PRO/DY-3248 X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406°A with a step size of 0.026 ° and step time of 93.84s.

DSC Method of Analysis:

The differential scanning calorimetric (DSC) analysis was performed on a Meltler Toledo 823e calorimeter with aluminium pans. Samples held in a closed pan were analysed as a heating rate of 10°C/min under nitrogen atmosphere.

The following examples are provided for illustration purpose only and are not intended to limit the scope of the invention. EXAMPLES

Examples- 1: Process for the preparation of amorphous Elbasvir of formula I:

Int-2 (70 g, 0.127 moles) and Int-7 (104.65 g, 0.280 moles) was dissolved in degassed n-butanol (735 mL) under nitrogen atmosphere at 25-30°C. The reaction mixture was stirred and degassed for 30 min under nitrogen atmosphere at 25-30°C. Degassed aq. potassium carbonate solution (prepared by dissolving 105.67 g, 0.764 moles of potassium carbonate in 385.0 mL of water) was charged to the above reaction mixture. The reaction mixture was stirred and degassed for 30 min under inert atmosphere at 25-30°C. To the above reaction mixture, added the Pd₂(dba)₃ (2.91 g, 0.003 moles), Am-Phos (1.7 g, 0.006 moles) and degassed n- butanol solution (175 mL) at 25-30°C. The reaction mixture was stirred and degassed for 30 min under inert atmosphere at 25-30°C. The reaction mixture was slowly heated to 80-85°C and stirred for 4 hours. Then the reaction mixture was cooled to 25-30°C, salts were filtered off and washed with n-butanol (70 mL). Water (700 mL) was added to the filtrate and stirred the reaction mixture for 30 min at 25-30°C. Separated the organic layer and washed with 10% sodium sulphite solution (350 mL) and sodium chloride solution (350 mL) followed by washed with ft-butanol (140 mL). MP-TMT resin (70 g) and activated carbon (14 g) were added to the above organic layer and stirred for 1 hour at 25-30°C. Filtered the obtained compound and washed with n-butanol (140 mL). Distilled-off the solvent completely under vacuum at < 50°C to get amorphous Elbasvir as a residue foamy solid. Purity by HPLC: 91.6 %. Example-2: Process for the preparation of Elbasvir Bis mandelate:

The Elbasvir (60 g) obtained in Example- 1 was dissolved in acetone (70 mL) and distilled-off the solvent completely under vacuum to get crude Elbasvir. The Crude Elbasvir was dissolved in the solvent mixture of acetone (630 ml) and methanol (70 mL) and reaction mixture was heated to 45-50°C. The solution of (5)- (+)-mandelic acid (77.5 g, 0.509 moles) in acetone (210 mL) was added to the above reaction mixture over a period of 2 hours and stirred for 4 hours at 45-50°C. Then the reaction mixture was cooled to 25-30°C and stirred for 1 hour. Filtered the solid and washed with solvent mixture of acetone (168 mL) and methanol (42 mL). Acetone (1050 mL) was added to the above wet solid and heated to reflux and maintained for 1 hour at reflux temperature. Then the reaction mixture was cooled to 25-30°C and stirred for 1 hour. Filtered the solid, washed with acetone (140 mL) and dried at 55-60°C to obtain Elbasvir Bis mandelate as white solid (91.5 g). Purity by HPLC: 99.67%. Example-3: Process for the preparation of pure Elbasvir of Formula-I:

A mixture of Elbasvir Bis mandelate (91 g), ethyl acetate (28 mL) and water (364 mL) were stirred for 10 min at 25-30°C. 2M aqueous potassium carbonate solution (96 mL) (prepared by dissolving 26.5 g of potassium carbonate in 96 mL of water) was added to the above reaction mixture and stirred for 10 min at 25- 30°C. The organic layer was separated and washed with 10% sodium chloride (455 mL) and water (455 mL). The organic layer was separated and dried over sodium sulphate (9.1 g) and filtered. The obtained filtrate was added to the n-heptane (1456 mL) over a period of 2 hours and stirred for 2 hours at 25-30°C. The resulting precipitated solid was filtered and washed with the solvent mixture of ethyl acetate (45.5 mL) and n-heptane (136.5 mL) and dried under vacuum at 55-60°C to obtain amorphous Elbasvir as an off-white solid (60 g, 88.6%). Purity by HPLC: 99.81 %.

Claims

We Claim:

1. A process for the preparation of Elbasvir compound of formula-I, comprising the steps of:

a) reacting the compound of Int-2 with int-7 in presence of Pd₂(dba)3 , Am-

Phos and a base in an organic solvent;

b) heating the reaction mixture of step-(a) up to dissolution;

c) cooling the reaction mixture and filtering;

d) optionally, treating the filtrate obtained in step-(c) with resin and/or charcoal;

e) distilling off of the solvent to obtain the Elbasvir.

2. The process as claimed in claim- 1, wherein, the base used in step a) is selected from inorganic base, such as sodium hydroxide, potassium hydroxide, sodium carbonates, potassium carbonates, sodium bicarbonate, potassium bicarbonate preferably potassium carbonate; and the organic solvent used in step a) is selected from alcohols, such as methanol, ethanol, propanol, isopropanol, t- butanol, n-butanol, preferably n-butanol. 3. The process as claimed in claim- 1, wherein, the resin used in step d) is selected from macro porous polystyrene resins such as macro porous trimercaptotriazine, macro porous thiourea preferably MP-TMT, MP-TMT- Fine, Si-TMT, MP-Thiourea, MP-Thiourea-Fine, Si-Thiourea more preferably MP-TMT.

4. The process for the preparation of Elbasvir compound of formula-I, comprising the steps of:

a) reacting the compound of Int-2 with int-7 in presence of Pd₂(dba)3 , Am- Phos and potassium carbonate in n-butanol;

b) heating the reaction mixture of step-(a) to 80-85°C,

c) cooling the reaction mixture and filtering;

d) treating the compound obtained in step-(c) with MP-TMT resin and/or charcoal;

e) distilling off of the solvent to obtain the Elbasvir compound of formula-I. 5. A process for the preparation of Bis mandelate salt of Elbasvir compound of formula-I comprising the steps of:

a) dissolving Elbasvir in a solvent or mixture of solvents;

b) adding S-(+)-Mandelic acid solution to the step-a) reaction mixture;

c) heating the reaction mixture to reflux;

d) cooling the reaction mixture to obtain the Elbasvir Bis mandelate. 6. The process as claimed in claim-5, wherein, the solvent used in step a) is selected from ketone such as acetone, methyl ethyl ketone and methyl isobutyl ketone and alcohols solvents such as methanol, ethanol, propanol, isopropanol, t-butanol, n-butanol and mixtures thereof; preferably a mixture of acetone and methanol.

The process for the preparation of Bis mandelate salt of Elbasvir compound of formula-I, comprising the steps of: a) dissolving Elbasvir in a mixture of acetone and methanol,

c) heating the reaction mixture to reflux,

d) cooling the reaction mixture to obtain the Elbasvir Bis mandelate.

8. A process for the preparation of pure Elbasvir compound of formula-I from Elbasvir Bis mandelate, comprising the steps of:

a) dissolving the Elbasvir Bis mandelate in a first organic solvent, b) adding a base to the step-a) reaction mixture,

c) stirring the reaction mixture,

d) separating the organic layer and filtering,

e) adding the filtrate obtained in step-d) to a second organic solvent, f) stirring the reaction mixture,

9. The process as claimed in claim-8, wherein, the first organic solvent used in step a) is selected from ester solvents like methyl acetate, ethyl acetate, isopropyl acetate, propyl acetate preferably ethyl acetate; and the basic used step-b) is selected from inorganic base solution such as sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution, potassium hydroxide solution preferably potassium carbonate solution; and the second organic solvents used in step-e) is selected from hydrocarbons solvent such as benzene, xylene, toluene, n-hexane, n-heptane preferably n-heptane.

10. The process for the preparation of pure Elbasvir compound of formula-I from Elbasvir Bis mandelate, comprising the steps of:

a) dissolving the Elbasvir Bis mandelate in ethyl acetate,

b) adding aqueous potassium carbonate to the step-a) reaction mixture, c) stirring the reaction mixture, d) separating the organic layer and filtering,

e) adding the filtrate obtained in step-d) to n-heptane,

f) stirring the reaction mixture,

The compound having the structural formula:

1 1.

12. The crystalline Elbasvir Bis mandelate has an X-ray powder diffraction pattern substantially as shown in Figure.2

13 Use of Mandelate salt of Elbasvir for the preparation of highly pure Elbasvir compound of formula-I.

14 Use of Bis mandelate salt of Elbasvir for the preparation of highly pure Elbasvir compound of formula-I.

The process for the preparation of Elbasvir compound of formula-I according to any of the preceding claims, having purity more than 99%, preferably more than 99.5%, more preferably more than 99.8% by HPLC.