DESC:FIELD OF THE INVENTION

The present invention relates to novel crystalline form L of daclatasvir, process for its preparation and its conversion to a pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

Daclatasvir is an inhibitor of HCV nonstructural protein 5A (NS5A). It is used for the treatment of patients with chronic hepatitis C virus (HCV) genotype 3 infection. It is developed and marketed by Bristol-Myers Squibb under the trade name Daklinza® as Daclatasvir dihydrochloride . The chemical name for daclatasvir is N,N'-[[1,1'-biphenyl]-4,4'-diylbis[1H-imidazole-5,2-diyl-(2S)-2,1-pyrrolidinediyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl]]]bis-carbamic acid, C,C'-dimethyl ester. Daclatasvir (I) has the following structural formula:

Daclatasvir and its pharmaceutically acceptable salts are described in the PCT application WO 2008021927. The PCT applications WO 2017021904 and WO 2016075588 describe daclatasvir in an amorphous form.

The present invention provides novel crystalline form L of daclatasvir, process for its preparation and its conversion to a pharmaceutically acceptable salt thereof.

SUMMARY OF THE INVENTION

The present invention provides novel crystalline form L of daclatasvir characterized by diffraction peak at 7.9, 11.8, 14.0, 15.6, 15.8, 18.1 and 18.8 ± 0.2 degree two theta in an X-ray diffraction pattern. The present invention further provides process for preparation of crystalline form L of daclatasvir and its conversion to pharmaceutically acceptable salt thereof.

DESCRIPTION OF DRAWINGS

Figure 1 – X-ray powder diffraction pattern of crystalline form L of daclatasvir.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel crystalline form L of daclatasvir and process for its preparation and its conversion to a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides crystalline form L of daclatasvir.

The crystalline form L of daclatasvir having characteristic diffraction peaks at 7.9, 11.8, 14.0, 15.6, 15.8, 18.1 and 18.8 ± 0.2 degree two theta in an X-ray diffraction pattern. The crystalline form L of daclatasvir having characteristic diffraction peaks at 7.9, 11.8, 12.8, 14.0, 15.6, 15.8, 16.1, 18.1, 18.8, 19.3, 20.5, 22.0, 22.5 and 23.9 ± 0.2 degree two theta in an X-ray diffraction pattern.

The crystalline form L of daclatasvir having characteristic X-ray powder diffraction pattern as depicted in Figure 1. The X-ray powder diffraction pattern was recorded at room temperature using PANalytical X’Pert PRO diffractogram with Cu Ka radiation (? = 1.54060 Å), running at 45 kV and 40 mA.

The crystalline form L of daclatasvir having characteristic infrared absorption spectra at 3350, 2964, 1721, 1649, 1631, 1541, 1448, 1247, 1105 and 1022 ± cm-1 The infrared absorption spectrum was obtained using a Perkin Elmer Precisely Spectrum 400 instrument using KBr pellet method.

The crystalline form L of daclatasvir having characteristic differential scanning calorimetry peak at about 174°C. The Differential Scanning Calorimetry thermogram was obtained using Perkin Elmer Diamond DSC instrument having pan with lid pin pierced .The analysis was carried out under a flow of nitrogen gas at temperature range of 30°C to 250°C at a constant rate of temperature increase of 10°C/min.

It has been observed that crystalline form L of daclatasvir is stable and do not get converted to any other polymorphic form over a period of time and the impurity profile also remains consistent in the hold time study.

In another embodiment, the present invention provides a process for the preparation of crystalline form L of daclatasvir comprising the steps of:

a) dissolving daclatasvir in a solvent,
b) optionally adding seed crystals,
c) stirring the mixture and
d) isolating crystalline form L of daclatasvir.

The solvent can be selected from polar solvent, non-polar solvents or mixtures thereof. Polar solvent can be selected from alcohols like methanol, ethanol, butanol, n-propanol, isopropanol; nitriles like acetonitrile, propionitrile, butyronitrile; ethers like tetrahydrofuran, dioxane, dimethoxyethane; esters like ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; other polar solvents like dimethylformamide, dimethyl sulfoxide, water and mixtures thereof. Non-polar solvents can be selected from hydrocarbon like hexane, cyclohexane, n-heptane, pentane, cyclopentane, toluene; chlorinated solvents methylene chloride, ethylene chloride, chloroform, carbon tetrachloride and mixtures thereof.

Process for the preparation of crystalline form L of daclatasvir comprises dissolving daclatasvir in the solvent by heating the mixture to a temperature of 35°C to the reflux temperature of the solvent, optionally adding seed crystals, stirring the mixture for 8 to 10 hours at a temperature of 25 to 30°C and isolating crystalline form L of daclatasvir by techniques known in art like filtration, concentration, solvent evaporation, distillation, cooling, drying on rotavapor and the like.

In yet another embodiment, the present invention provides a process for the preparation of crystalline form L of daclatasvir comprising the steps of:

a) treating compound of formula (II)

with N-methoxycarbonyl-L-valine in the presence of base, coupling reagent and first solvent,
b) removing the first solvent,
c) adding second solvent to prepare a solution,
d) optionally adding seed crystals,
e) stirring the mixture and
f) isolating crystalline form L of daclatasvir.

The coupling reagent can be selected from 1,1'-carbonyldiimidazole, N-(3-dimethylaminopropyl)-N-ethyl carbodiimide, diisopropylcarbodiimide , N,N-dicyclohexylcarbodiimide in combination with 2-hydroxy pyridine-1-oxide, 1-hydroxybenzotriazole and the like.

The base can be selected from organic base like primary, secondary and tertiary amines such as trimethyl amine, triethyl amine, tertiary butyl amine, diisopropyl amine, diisopropyl ethylamine, N-methylmorpholine, N,N-dimethylpiperazine, N-methylpiperidine, pyridine, 4-dimethylaminopyridine and mixtures thereof.

The first solvent can be selected from organic solvent selected from nitriles like acetonitrile, propionitrile, butyronitrile; ethers like tetrahydrofuran, dioxane, dimethoxyethane, other solvent like dimethylformamide, methylene chloride, toluene and mixtures thereof.

The second solvent can be selected from polar solvent, non-polar solvents or mixtures thereof. Polar solvent can be selected from alcohols like methanol, ethanol, butanol, n-propanol, isopropanol; nitriles like acetonitrile, propionitrile, butyronitrile; ethers like tetrahydrofuran, dioxane, dimethoxyethane; esters like ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; other polar solvents like dimethylformamide, dimethyl sulfoxide, water and mixtures thereof. Non-polar solvents can be selected from hydrocarbon like hexane, cyclohexane, n-heptane, pentane, cyclopentane, toluene; chlorinated solvents methylene chloride, ethylene chloride, chloroform, carbon tetrachloride and mixtures thereof.

The reaction of compound of formula (II) with N-methoxycarbonyl-L-valine in the presence of base, coupling reagent and first solvent can be carried out at a temperature of 0 to 10°C, the first solvent can be removed by techniques known in art like filtration, concentration, solvent evaporation, distillation, cooling, drying on rotavapor and the like. The second solvent is added and a solution can be formed by heating the mixture to a temperature of 35°C to the reflux temperature of the solvent, optionally adding seed crystals, stirring the mixture for 8 to 10 hours at a temperature of 25 to 30°C and isolating crystalline form L of daclatasvir by techniques known in art like filtration, concentration, solvent evaporation, distillation, cooling, drying on rotavapor and the like.

Compound (II) which is used for preparation of crystalline form L of daclatasvir of the present invention can be prepared by methods known in the literature.

In a further embodiment, the present invention provides conversion of crystalline form L of daclatasvir to its pharmaceutically acceptable salt. The present invention provides conversion of crystalline form L of daclatasvir to its pharmaceutically acceptable salt comprising reacting crystalline form L of daclatasvir with an acid.

The pharmaceutically acceptable salt can be selected from inorganic salt such as hydrochloride, hydrobromide, sulphate and the like; organic salt such as tosylate, mesylate, besylate, tartrate, citrate, maleate, fumarate, oxalate and the like.

The corresponding acid can be selected from inorganic acid such as hydrochloric, hydrobromic, sulphuric and the like; organic acid such as p-toluenesulphonic acid, methanesulphonic acid, benzenesulfonic acid, tartrate, citrate, maleate, fumarate, oxalate and the like.

The present invention provides conversion of crystalline form L of daclatasvir to its dihydrochloride salt comprising reacting crystalline form L of daclatasvir with hydrochloric acid.

The conversion of crystalline form L of daclatasvir to its pharmaceutically acceptable salt can be carried out by reaction of crystalline form L of daclatasvir with the acid in presence of polar solvent selected from alcohols like methanol, ethanol, butanol, n-propanol, isopropanol; water or mixtures thereof at a temperature of 25-30°C, followed by isolation of daclatasvir dihydrochloride by techniques known in the art.

The present invention is further illustrated by the following representative examples and does not limit the scope of the invention.

Examples

1. Process for preparation of crystalline form L of daclatasvir.

A mixture of 2-hydroxy pyridine-1-oxide (35.1 g) and acetonitrile (450 ml) was cooled to 0-10°C and N-(3-dimethylaminopropyl)-N-ethyl carbodiimide (90.7 g), N- methoxycarbonyl-L-valine (82.8 gm), compound (II) (90 g) and diisopropyl amine (136 ml) was added to it. The reaction mixture was stirred for 4-5 hours at 0-10°C. Water (450 ml) was added to the reaction mixture followed by addition of dichloromethane (630 ml). Organic layer separated and washed with 3% sodium hydroxide solution and sodium chloride solution. Organic layer was concentrated under vacuum and methanol (630 ml) was added to it, the solution was again concentrated under vacuum to reduce the volume of solution. This solution was added to water (900 ml) and the slurry was stirred for about 2 hours. The solid was filtered and dried. The solid was taken up in a mixture of isopropanol (270 ml) and water (360 ml) and the mixture was heated to 60-65°C and stirred for an hour. Seed crystals (0.18g) were added to it. The slurry was gradually cooled to 25-27°C under stirring over a period of 5-6 hours. The solid was filtered, washed with isopropanol-water mixture and dried under vacuum.

2. Process for preparation of crystalline form L of daclatasvir.

A mixture of daclatasvir (25 g), isopropanol (75 ml) and water (100 ml) was heated to 73-75°C and stirred for an hour. The solution was cooled to about 65°C and seed crystals (0.10g) were added to it. The slurry was gradually cooled to 25-27°C under stirring over a period of 5-6 hours. The solid was filtered, washed with isopropanol-water mixture and dried under vacuum. Yield: 22 g.

3. Process for preparation of daclatasvir dihydrochloride.

A mixture of daclatasvir (30 g), as prepared in example 1 or 2 and water (180 ml) was stirred at 25-30°C and concentrated hydrochloric acid (8.4 ml) was added to the mixture. The solution was subjected to carbon treatment. The solution was heated to 45-50°C and was gradually cooled to 27-29°C under stirring over a period of 2-3 hours. The solid was filtered and dried under vacuum. Yield: 28 g.
,CLAIMS:1. A crystalline form L of daclatasvir having characteristic diffraction peaks at 7.9, 11.8, 14.0, 15.6, 15.8, 18.1 and 18.8 ± 0.2 degree two theta in an X-ray diffraction pattern.

2. A crystalline form L of daclatasvir of claim 1, having characteristic diffraction peaks at 7.9, 11.8, 12.8, 14.0, 15.6, 15.8, 16.1, 18.1, 18.8, 19.3, 20.5, 22.0, 22.5 and 23.9 ± 0.2 degree two theta in an X-ray diffraction pattern.

3. A crystalline form L of daclatasvir of claim 1, having characteristic X-ray powder diffraction pattern as depicted in Figure 1.

4. A process for the preparation of crystalline form L of daclatasvir of claim 1, comprising the steps of:
a) dissolving daclatasvir in a solvent,
b) optionally adding seed crystals,
c) stirring the mixture and
d) isolating crystalline form L of daclatasvir.

5. The process according to claim 4 wherein, solvent is alcohol, nitrile, ether, ester, ketone, dimethylformamide, dimethyl sulfoxide, hydrocarbon, chlorinated hydrocarbon, water and mixtures thereof.

6. A process for the preparation of crystalline form L of daclatasvir of claim 1, comprising the steps of:
a) treating compound of formula (II)

with N-methoxycarbonyl-L-valine in the presence of base, coupling reagent and first solvent,
b) removing the first solvent,
c) adding second solvent to prepare a solution,
d) optionally adding seed crystals,
e) stirring the mixture and
f) isolating crystalline form L of daclatasvir.

7. The process according to claim 6 wherein, base is an organic base selected from primary, secondary and tertiary amine.

8. The process according to claim 6 wherein, coupling reagent is 1,1'-carbonyldiimidazole, N-(3-dimethylaminopropyl)-N-ethyl carbodiimide, diisopropylcarbodiimide , N,N-dicyclohexylcarbodiimide in combination with 2-hydroxy pyridine-1-oxide and 1-hydroxybenzotriazole.

9. The process according to claim 6 wherein, solvent is alcohol, nitrile, ether, ester, ketone, dimethylformamide, dimethyl sulfoxide, hydrocarbon, chlorinated hydrocarbon and mixtures thereof.

10. A process for conversion of crystalline form L of daclatasvir of claim 1, to its dihydrochloride salt comprising reacting crystalline form L of daclatasvir with hydrochloric acid.