Process for the preparation of benzimidazole derivatives and its salts

1. A process for preparing dabigatran etexilate compound of Formula-1

or a salt thereof, the process comprising:

a) reacting a compound of Formula-2

with a compound of Formula-3

in a solvent selected from an ester solvent, an ether solvent, a hydrocarbon solvent, a polar aprotic solvent, a ketone solvent, an alcoholic solvent, a chloro solvent, a nitrile solvent or a nitro solvent, or a mixture thereof, to provide a compound of Formula-4,

b) reacting the compound of Formula-4 with a compound of Formula-5

or a compound of Formula-6

in the presence of a base selected from an inorganic base or an organic base, or a mixture thereof, in a solvent selected from an ester solvent, an ether solvent, a hydrocarbon solvent, a polar aprotic solvent, a ketone solvent, an alcoholic solvent, a chloro solvent, a nitrile solvent or a nitro solvent, or a mixture thereof, to provide the compound of Formula-1.

2. The process according to claim 1 , wherein

the solvent used in step (a) is a chloro solvent, ester solvent, ether solvent, ketone solvent or polar aprotic solvent; and

the solvent used in step (b) is ether solvent, ester solvent, ketone solvent, polar aprotic solvent or nitrile solvent; and

the base is an alkali metal carbonate or an alkali metal bicarbonate.

3. The process according to claim 1 , wherein

the solvent used in step (a) is in an amount ranging from 2-10 volumes of solvent to 1 g of compound of Formula-5 or compound of Formula-6; and

the solvent used in step (b) is in an amount ranging from 5-50 volumes of solvent to 1 g of compound of Formula-5 or compound of Formula-6.

4. The process according to claim 1 , wherein the mole proportions of base, compound of Formula-3 and compound of Formula-2 are in an amount ranging between 0.8-10, 0.8-6 and 0.8-6, respectively, per one mole of compound of Formula-5 or compound of Formula-6.

5. The process according to claim 1 , wherein:

step (a) is performed in dichloromethane; and

step (b) is performed by reacting the compound of Formula-4 with the compound of Formula-5 or the compound of Formula-6a

in the presence of potassium carbonate in aqueous acetonitrile to provide the compound of Formula-1.

6. The process according to claim 1 , wherein the compound of Formula-4 is used in step (b) without isolation.

7. The process according to claim 1 , further comprising:

a) treating the compound of Formula-5 with oxalic acid in ethanol to provide a compound of Formula-6a,

b) treating the compound of Formula-6a with potassium carbonate to provide the compound of Formula-5 and isolating the compound of Formula-5 to provide pure compound of Formula-5.

8. The process according to claim 1 , further comprising:

a) reacting a compound of Formula-16

with sodium 2-chloroacetate in presence of a base selected from alkali metal hydroxides, alkali metal carbonates or alkali metal bicarbonates in presence of tertiary butyl ammonium bromide in a solvent selected from alcohol solvents, ketone solvents, polar solvents or mixtures thereof to provide a compound of Formula-13,

b) condensing the compound of Formula-13 with a compound of Formula-12

in the presence of carbonyldiimidazole in a suitable solvent selected from ether solvents, hydrocarbon solvents, ester solvents, ketone solvents or mixtures thereof to provide a compound of Formula-14,

c) reacting the compound of Formula-14 with ammonium carbonate in presence of a Lewis acid selected from aluminium chloride(AlCl 3 ), aluminium bromide(AlBr 3 ), boron trichloride (BCl 3 ), boron trifluoride (BF 3 ), Iron(III) chloride(FeCl 3 ), Tin(IV) chloride (SnCl 4 ), calcium chloride dihydrate (CaCl 2 .2H 2 O), or calcium chloride (CaCl 2 ), and in presence of hydrochloride gas in a solvent selected from alcohol solvents, ether solvents, ketone solvents or mixtures thereof, to provide a compound of Formula-17a,

d) converting the compound of Formula-17a into compound of Formula-5 by treating the compound of Formula-17a with a base selected from alkali metal hydroxides, alkali metal carbonates or alkali metal bicarbonates or triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine or pyridine in a solvent selected from alcohol solvents, ether solvents, ketone solvents, ester solvents, hydrocarbon solvents, chloro solvents, polar solvents or mixtures thereof.

9. The process according to claim 1 , wherein the acid in the compound of Formula-6 is oxalic acid, 2,5-dihydroxy benzoic acid, benzene sulfonic acid, cyclamic acid, ethanedisulfonic acid, ethane sulfonic acid, D-glucaronoic acid, glycolic acid, mandelic acid, palmitic acid, oleic acid, stearic acid, cinnamic acid, camphor sulfonic acid, adipic acid, naphthalene-2-sulfonic acid or naphthalene-1,5-disulfonic acid.

10. The process according to claim 9 , wherein the compound of Formula-6 is represented by a compound of Formula-6a,

11. The process according to claim 10 , wherein the compound of Formula- 6 a is a crystalline solid herein designated as crystalline form-M and is characterized by:

a) its powder XRD pattern having peaks at about 7.6, 11.7, 14.5, 18.0, 18.2, 22.8, 24.8 and 25.3±0.2 degrees of two-theta; or

b) its DSC thermogram showing endotherm at about 203.53° C.

12. The process according to claim 10 , further comprising:

a) treating a compound of Formula-5 with an acid in a solvent selected from alcohol solvents, chloro solvents, ether solvents, nitro solvents, ketone solvents, ester solvents, nitrile solvents or hydrocarbon solvents and;

b) isolating the solid obtained in step (a) to provide the compound of Formula-6.

13. The process according to claim 1 , wherein the compound of Formula-1 is dabigatran etexilate mesylate and is characterized by:

a) having a purity greater than 99.50% by HPLC; or

b) having a purity greater than 99.75% by HPLC; or

c) having a purity greater than 99.95% by HPLC; or

d) containing less than 0.05% of Impurity-X and Impurity-Y by HPLC; or

e) containing less than 0.01% of Impurity X and Impurity Y by HPLC; or

f) containing less than 0.1% by HPLC of an acid impurity represented by the following structural formula:

and an N-oxide impurity represented by the following structural formula:

Or

g) containing less than 0.05% by HPLC of the acid impurity and the N-oxide impurity; or

h) containing less than 0.01% by HPLC of the acid impurity and the N-oxide impurity.

14. The process according to claim 5 , wherein the compound of Formula-4 is used in step (b) without isolation.

15. The process according to claim 5 , further comprising:

a) treating the compound of Formula-5 with oxalic acid in ethanol to provide compound of Formula-6a,

b) treating the compound of Formula-6a with potassium carbonate to provide the compound of Formula-5 and isolating the compound of Formula-5 to provide pure compound of Formula-5.

16. The process according to claim 2 , wherein:

in step (a), the chloro solvent is dichloromethane, chloroform or dichloroethane; the ester solvent is ethyl acetate, methyl acetate or isopropyl acetate; the ether solvent is tetrahydrofuran, diethyl ether or methyl tert-butyl ether; the ketone solvent is acetone, methylethylketone, propanone or methylisobutylketone; and the polar aprotic solvent is dimethylformamide or acetonitrile; and

in step (b), the ether solvent is tetrahydrofuran, methyl tert-butyl ether or diethyl ether; the ester solvent is methyl acetate, ethyl acetate or isopropyl acetate; the ketone solvent is acetone, propanone, methyl ethyl ketone or methylisobutylketone; the polar aprotic solvent is dimethylformamide or dimethylacetamide; and the nitrile solvent is acetonitrile, propionitrile or its mixtures with water.