DESC:FIELD OF THE INVENTION
The present invention relates to improved process for the preparation of Tetrabenazine and d6-Tetrabenazine.
BACKGROUND OF THE INVENTION
Tetrabenazine (XENAZINE®) is a hexahydro-dimethoxy-benzoquinoline derivative and a vesicular monoamine transporter-2 (VMAT2) inhibitor. The U.S. Food and Drug Administration (FDA) approved Tetrabenazine for the treatment of Huntington's disease.
Tetrabenazine has the chemical name rac-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a] quinolizin-2-one and has the following structural Formula (I); wherein X is H:

Formula (I)
d6-Tetrabenazine (AUSTEDOTM®) is a deuterated analog of Tetrabenazine (I) which has improved pharmacokinetic properties when compared to the non-deuterated drug. The U.S. Food and Drug Administration (FDA) approved d6-Tetrabenazine for the treatment of chorea associated with Huntington disease and and Tardive dyskinesia in adults.
d6-Tetrabenazine has the chemical name (RR, SS)-1, 3, 4, 6, 7, 11b-hexahydro-9, 10-di (methoxy-d3)-3-(2-methylpropyl)¬-2H-benzo[a]quinolizin-2-one and has the following structural Formula (I);wherein X is D:

Formula (I)
US 3,045,021 discloses process for preparation of Tetrabenazine and patent US 8,524,733 (IN1728/DELNP/2011) discloses d6-Tetrabenazine.
US 3,045,021 provides process for preparation of Tetrabenazine which comprises condensation of 6,7-dimethoxy-3,4-dihydroisoquinoline with 3-methylene-5- methyl-2-hexanone (VI) in an alkaline medium.
Another patent GB 999095 described process for preparation of Tetrabenazine which involves reaction of 3,4-dihydro-6,7-dimethoxyisoquinoline and (2-acetyl-4-methyl- pentyl)-tri methyl -ammonium iodide (V) in alcohol.
US 8,524,733 (IN1728/DELNP/2011) provides process for preparation of d6-Tetrabenazine by reaction of d6-6,7-Dimethoxy-3,4-dihydroisoquinoline and (2-acetyl-4-methyl-pentyl)- tri methyl -ammonium iodide (V) in ethanol.
Another patent application US2015/0152099A1 (IN201617021735A) describes process for preparation of d6-Tetrabenazine by reaction of d6-6,7-Di methoxy-3,4-dihydroisoquinoline and (2-acetyl-4-methyl-pentyl)-trimethyl-ammonium iodide (V) in one or more solvents selected from water, methanol, ethanol and its mixture thereof.
The present invention provides improved process for preparation of Tetrabenazine (I); wherein X is H and d6-Tetrabenazine (I); wherein X is D which is efficient, industrially viable and cost effective that can afford desired products with substantially free of diastereomeric impurities.
SUMMARY OF THE INVENTION
In one aspect of the present invention provides improved process for the preparation of compound of formula (I), comprising the steps of:

Formula (I)
Wherein X is H or D ;
reacting 6,7dimethoxy-3,4-dihydroisoquinoline compound of formula (II) or a salt thereof

Formula (II)
with (2-acetyl-4-methyl-pentyl)-trimethyl-ammonium iodide (III)

Formula (III)
in presence of solvent such as polyhydroxy alcohol and optionally in the presence of base.
Salt of dimethoxy isoquinoline compound (II) can be selected from inorganic salts such as hydrochloric, hydrobromic or organic salt like oxalate, maleate, fumarate and the like.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect of the present invention provides improved process for the preparation of compound of formula (III), wherein X is H or D;
comprising the steps of:

Formula (I)
reacting dimethoxy isoquinoline compound (IV) or a salt thereof

Formula (II)
with (2-acetyl-4-methyl-pentyl)-trimethyl-ammonium iodide (V)

Formula (III)
in presence of solvent such as polyhydroxy alcohol and optionally in the presence of base.
Polyhydroxy alcohol solvent of the present invention may be selected from ethylene glycol, propylene glycol, butylene glycol, glycerol and the like.
Base can be selected form organic or inorganic base; organic base can be selected form alkyl amines like triethyl amine or tributyl amine etc. inorganic bases include hydroxide, alkoxides or carbonates, bicarbonates of alkali or alkaline earth metal like sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate etc.
In another aspect of the present invention provides improved process that can afford desired products with good yield and free of impurities.
Reaction of present invention is carried out in the temperature range of 20 to 70oC, preferably 20 to 50 oC, and more preferably at 25 to 40 oC.
Solvent ratio of the present invention is between and about 2 and about 10 times the mass of the compound of formula (I) or (II).
In other embodiment, a compound of the present invention where in X is D, has an isotopic enrichment factor for each designated deuterium atom of at least 50% deuterium incorporation at each designated deuterium atom, at least 60% deuterium incorporation, at least 70% deuterium incorporation , at least 80% deuterium incorporation, at least 90% deuterium incorporation at least 99 % deuterium incorporation, at least 99.5% deuterium incorporation; preferably greater than 99%.
Following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope of the invention.
1H NMR spectra are recorded at 300 MHz on a Bruker Advance III instrument. Dimethyl sulfoxide (99.8% D) is used as solvent, and tetramethylsilane (TMS) is used as internal reference standard.
Examples
Preparation of Tetrabenazine (Formula I; Wherein X is H)
Example 1:
To ethylene glycol (1000 ml) 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (100 gm) and (2-acetyl-4-methyl-pentyl)-trimethyl-ammonium iodide (149 gm) were added at 25 oC and stirred for about 10-15 min. To the reaction mixture potassium carbonate (61 gm) was added and stirred for about 48-50 hours followed by the addition of water (2500 ml). The obtained solid was filtered, washed with water and dried under vacuum.

Example 2:
To propylene glycol (1000 ml) 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (100 gm) and (2-acetyl-4-methyl-pentyl)-trimethyl-ammonium iodide (149 gm) were added at 35 oC and stirred for about 10-15 min. To the reaction mixture potassium carbonate (61 gm) was added and stirred for about 48-50 hours followed by the addition of water (2500 ml). The obtained solid was filtered, washed with water and dried under vacuum.
Example 3:
To glycerol (1000 ml) 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (100 gm) and (2-acetyl-4-methyl-pentyl)-trimethyl-ammonium iodide (149 gm) were added at 30 oC and stirred for about 10-15 min. To the reaction mixture potassium carbonate (61 gm) was added and stirred for about 48-50 hours followed by the addition of water (2500 ml). The obtained solid was filtered, washed with water and dried under vacuum.

Example 4:
To propylene glycol (1000 ml) 6,7-dimethoxy-3,4-dihydroisoquinoline (100 gm) and (2-acetyl-4-methyl-pentyl)-trimethyl-ammonium iodide (149 gm) were added at 30 oC and stirred for about 48-50 hours followed by the addition of water (2500 ml). The obtained solid was filtered, washed with water and dried under vacuum.

Preparation of d6-Tetrabenazine (Formula I; Wherein X is D)
Example 5:
To ethylene glycol (1000 ml) d6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (100 gm) and (2-acetyl-4-methyl-pentyl)-trimethyl-ammonium iodide (149 gm) were added at 35 oC and stirred for about 10-15 min. To the reaction mixture potassium carbonate (61 gm) was added and stirred for about 48-50 hours followed by the addition of water (2500 ml). The obtained solid was filtered, washed with water and dried under vacuum.

Example 6:
To propylene glycol (1000 ml) d6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (100 gm) and (2-acetyl-4-methyl-pentyl)-trimethyl-ammonium iodide (149 gm) were added at 30 oC and stirred for about 10-15 min. To the reaction mixture potassium carbonate (61 gm) was added and stirred for about 48-50 hours followed by the addition of water (2500 ml). The obtained solid was filtered, washed with water and dried under vacuum.

Example 7:
To glycerol (1000 ml) d6-6,7-dimethoxy-3,4-dihydroisoquinoline oxalate (100 gm) and (2-Acetyl-4-methyl-pentyl)-trimethyl-ammonium iodide (149 gm) were added at 40 oC and stirred for about 10-15 min. To the reaction mixture potassium carbonate (61 gm) was added and stirred for about 48-50 hours followed by the addition of water (2500 ml). The obtained solid was filtered, washed with water and dried under vacuum.
1H NMR: (300 MHz, CDCI3) d 6.61 (s, 1H), 6.55 (s, 1H), 3.49 (br dd, 1H), 3.28 (dd, 1H), 3.11 (m, 2H), 2.88 (dd, 1H), 2.75 (m, 2H), 2.57 (m, 2H), 2.35 (t, 1H), 1.81 (ddd, 1H), 1.65 (m, 1H), 1.02 (ddd, 1H), 0.92 (d, 3H), 0.90 (d, 3H) ppm.
13C NMR: (75 MHz, CDCI3) d 210.09, 147.77, 147.45, 128.48, 126.01, 111.40, 107.78, 62.44, 61.46, 50.54, 47.58, 47.51, 35.04, 29.33, 25.37, 23.21, 22.07 ppm.
Example 8:
To propylene glycol (1000 ml) d6-6,7-dimethoxy-3,4-dihydroisoquinoline (100 gm) and (2-acetyl-4-methyl-pentyl)-trimethyl-ammonium iodide (149 gm) were added at 35 oC and stirred for about 10-15 min. and reaction mixture was stirred for about 48-50 hours followed by the addition of water (2500 ml). The obtained solid was filtered, washed with water and dried under vacuum.

,CLAIMS:We Claim:
1. A process for the preparation of compound of formula (I), comprising the steps of:

Formula (I)
wherein X is H or D ;
reacting 6,7dimethoxy-3,4-dihydroisoquinoline compound of formula (II) or a salt
thereof;

Formula (II)
with (2-acetyl-4-methyl-pentyl)-trimethyl-ammonium iodide (III)

Formula (III)
at the temperature range of at 25-40 oC in presence of solvent such as polyhydroxy alcohol and optionally in the presence of base.
2. The process as claimed in claim 1, wherein polyhydroxy alcohol is selected from group comprising of ethylene glycol, propylene glycol, butylene glycol and glycerol.

3. The process as claimed in claim 1, base is selected form the group comprising of triethyl amine, tributyl amine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
4. The process as claimed in claim 1, wherein the compound of formula (II) or its salt is

5. The process as claimed in claim 1, wherein the compound of formula (II) or its salt is

6. The process as claimed in claim 5, wherein the salt is selected from hydrochloride, hydrobromide, oxalate, sulphate and maleate.
7. The process as claimed in claim 5, wherein the compound of formula (II) has deuterium enhancement greater that 95%.
Dated this 13th May 2019
Dr. S. Ganesan