PROCESS FOR PREPARATION OF MIDODRINE AND INTERMEDIATES THEREOF

1 . A process for the preparation of midodrine or pharmaceutically acceptable salts thereof, the process comprising:

(a) reacting 1,4-dimethoxybenzene (VII) with chloroacetyl chloride to obtain 2-chloro-1-(2,5-dimethoxyphenyl)ethan-1-one (VI);

(b) reacting 2-chloro-1-(2,5-dimethoxyphenyl)ethan-1-one (VI) with phthalimide or a salt thereof to obtain 2-[2-(2,5-dimethoxyphenyl)-2-oxoethyl]-1H-isoindole-1,3(2H)-dione (V);

(c) converting 2-[2-(2,5-dimethoxyphenyl)-2-oxoethyl]-1H-isoindole-1,3(2H)-dione (V) into 2-amino-1-(2′,5′-dimethoxyphenyl)ethanol (III);

(d) converting 2-amino-1-(2′,5′-dimethoxyphenyl)ethanol (III) into midodrine; and

(e) optionally, converting midodrine into its pharmaceutically acceptable salt.

2 . The process according to claim 1 , wherein the reaction at step (a) is performed in the presence of a Lewis acid selected from AlCl 3 , AlBr 3 , FeCl 3 , and FeBr 3 .

3 . The process according to claim 1 , wherein the reaction at step (b) is performed using potassium phthalimide or sodium phthalimide.

4 . The process according to claim 1 , wherein the conversion of the compound of Formula (V) into the compound of Formula (IV) at step (c) is performed in the presence of a base or an acid.

5 . The process according to claim 4 , wherein the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, caesium carbonate, methylamine, ethylamine, dimethylamine, diethylamine, methylethylamine, triethylamine, ammonium hydroxide, and hydrazine hydrate.

6 . The process according to claim 4 , wherein the acid is selected from hydrochloric acid, hydrobromic acid, acetic acid, trichloroacetic acid, and trifluoroacetic acid.

7 . The process according to claim 1 , wherein the conversion of the compound of Formula (IV) into the compound of Formula (III) at step (c) is performed in the presence of a reducing agent selected from lithium aluminium hydride, lithium borohydride, sodium borohydride, zinc borohydride, calcium borohydride, sodium cyanoborohydride, diisobutylaluminium hydride, L-selectride, diborane, diazene, aluminum hydride, Red-Al, and sodium triacetoxyborohydride.

8 . The process according to claim 1 , wherein the conversion of the compound of Formula (III) into the compound of Formula (II) at step (d) is performed by reacting 2-amino-1-(2′,5′-dimethoxyphenyl)ethanol (III) with N-boc-glycine.

9 . The process according to claim 8 , wherein the conversion is performed in the presence of a coupling reagent selected from N,N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and N,N′-diisopropyl carbodiimide (DIC).

10 . The process according to claim 8 , wherein the conversion is performed in the presence of one or more solvents selected from dichloromethane, dichloroethane, chloroform, CCl 4 , benzene, toluene, and xylene.

11 . The process according to claim 1 , wherein the conversion of the compound of Formula (II) into the compound of Formula (I) at step (d) is performed by reacting the compound of Formula (II) with an acid selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, tartaric acid, mandelic acid, benzene sulfonic acid, and toluene sulfonic acid.

12 . A process for the preparation of desglymidodrine of Formula (III),

the process comprising:

(i) reacting 2-chloro-1-(2,5-dimethoxyphenyl)ethane-1-one (VI) with phthalimide or a salt thereof to obtain 2-(2-(2,5-dimethoxyphenyl)-2-oxoethyl)isoindoline-1,3-dione (V);

(ii) reacting 2-(2-(2,5-dimethoxyphenyl)-2-oxoethyl)isoindoline-1,3-dione (V) with a base or an acid to obtain 2-amino-1-(2,5-dimethoxyphenyl)ethane-1-one (IV) or its salt; and

(iii) reducing 2-amino-1-(2,5-dimethoxyphenyl)ethane-1-one (IV) or its salt to obtain desglymidodrine (III).

13 . The process according to claim 12 , wherein 2-chloro-1-(2,5-dimethoxyphenyl)ethane-1-one (VI) at step (i) is reacted with potassium phthalimide or sodium phthalimide.

14 . The process according to claim 12 , wherein the base at step (ii) is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, caesium carbonate, methylamine, ethylamine, dimethylamine, diethylamine, methylethylamine, triethylamine, ammonium hydroxide, and hydrazine hydrate.

15 . The process according to claim 12 , wherein the acid at step (ii) is selected from hydrochloric acid and acetic acid.

16 . The process according to claim 12 , wherein the reduction reaction at step (iii) is performed using a reducing agent selected from lithium aluminium hydride, lithium borohydride, sodium borohydride, zinc borohydride, calcium borohydride, sodium cyanoborohydride, diisobutylaluminium hydride, L-selectride, diborane, diazene, aluminum hydride, Red-Al, and sodium triacetoxyborohydride.

17 . A process for the preparation of desglymidodrine of Formula (III),

the process comprising:

(i) reacting 1,4-dimethoxybenzene (VII) and chloroacetyl chloride in the presence of a Lewis acid to obtain 2-chloro-1-(2,5-dimethoxyphenyl) ethane-1-one (VI);

(ii) reacting 2-chloro-1-(2,5-dimethoxyphenyl) ethane-1-one (VI) with phthalimide or a salt thereof to obtain 2-(2-(2,5-dimethoxyphenyl)-2-oxoethyl) isoindoline-1,3-dione (V);

(iii) reacting 2-(2-(2,5-dimethoxyphenyl)-2-oxoethyl) isoindoline-1,3-dione (V) with a base or an acid to obtain 2-amino-1-(2,5-dimethoxyphenyl) ethane-1-one (IV) or its salt; and

(iv) reducing the 2-amino-1-(2,5-dimethoxyphenyl) ethane-1-one (IV) or its salt to obtain desglymidodrine.

18 . The process according to claim 17 , wherein the reaction at stage (i) is performed in the presence of a Lewis acid selected from AlCl 3 , AlBr 3 , FeCl 3 , and FeBr 3 .

19 . The process according to claim 17 , wherein the reaction at stage (ii) is performed using potassium phthalimide or sodium phthalimide.

20 . The process according to claim 17 , wherein the base at step (iii) is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, caesium carbonate, methylamine, ethylamine, dimethylamine, diethylamine, methylethylamine, triethylamine, ammonium hydroxide, and hydrazine hydrate.

21 . The process according to claim 17 , wherein the acid at step (iii) is selected from hydrochloric acid, hydrobromic acid, acetic acid, trichloroacetic acid, and trifluoroacetic acid.

22 . The process according to claim 17 , wherein the reduction of 2-amino-1-(2,5-dimethoxyphenyl) ethane-1-one (IV) or its salt at stage (iv) is performed in the presence of a reducing agent selected from lithium aluminium hydride, lithium borohydride, sodium borohydride, zinc borohydride, calcium borohydride, sodium cyanoborohydride, diisobutylaluminium hydride, L-selectride, diborane, diazene, aluminum hydride, Red-Al, and sodium triacetoxyborohydride.

23 . A crystalline Form A of midodrine hydrochloride, characterized by X-ray powder diffraction pattern having at least two peaks expressed in degrees 2θ selected from 5.4°, 12.0°, 15.2°, and 21.6°±0.2°.

24 . A process for the preparation of crystalline Form A of midodrine hydrochloride, the process comprising:

(a) providing a solution of midodrine hydrochloride in one or more solvents;

(b) optionally treating with charcoal;

(c) cooling the solution; and

(d) removing the solvent from the solution to obtain crystalline Form-A of midodrine hydrochloride.

25 . The process according to claim 24 , wherein the one or more solvent at step (a) is selected from water, ethyl acetate, isopropyl acetate, methanol, ethanol, propanol, isopropanol, and butanol.

26 . The process according to claim 24 , wherein the cooling at step (c) is performed at −5° C. to 20° C.

27 . The process according to claim 24 , wherein the removal of the solvent at step (d) is performed by one or more of distillation, distillation under reduced pressure, filtration, decantation, evaporation and centrifugation.