DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR PREPARATION OF DEUTETRABENAZINE”

Glenmark Life Sciences Limited
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of deutetrabenazine.

BACKGROUND OF THE INVENTION
Deutetrabenazine, also known as (RR,SS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one, is represented by the structure of formula I.
I
Deutetrabenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor indicated for the treatment of chorea associated with Huntington’s disease.

SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of deutetrabenazine, a compound of formula I,
I
the process comprising:
(ai) reacting a compound of formula V or salt thereof,
V
with a dehydrogenating reagent to give a compound of formula IV or salt thereof;
IV
(aii) reacting the compound of formula IV or salt thereof, with a deuterated methylating agent to give a compound of formula II or salt thereof;
II
or
(bi) reacting a compound of formula V or salt thereof,
V
with a deuterated methylating agent to give a compound of formula VI or salt thereof;
VI
(bii) reacting the compound of formula VI or salt thereof with a dehydrogenating reagent to give a compound of formula II or salt thereof; and
(c) reacting the compound of formula II or salt thereof obtained in (aii) or (bii), with a compound of formula IIIa or IIIb,
IIIa IIIb
to give deutetrabenazine, the compound of formula I.
In another embodiment, the present invention provides a compound of formula VI or salt thereof,
VI.
In another embodiment, the present invention provides use of a compound of formula VI or salt thereof in the preparation of deutetrabenazine.
In another embodiment, the present invention provides use of a compound of formula V or salt thereof in the preparation of deutetrabenazine.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is the proton NMR spectrum of hydrochloride salt of compound of formula VI as obtained in Example 4.
Figure 2 is the proton NMR spectrum with D2O exchange of hydrochloride salt of compound of formula VI as obtained in Example 4.
Figure 3 is the proton NMR spectrum of tartrate salt of compound of formula II as obtained in Example 3.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of deutetrabenazine, a compound of formula I,
I
the process comprising:
(ai) reacting a compound of formula V or salt thereof,
V
with a dehydrogenating reagent to give a compound of formula IV or salt thereof;
IV
(aii) reacting the compound of formula IV or salt thereof, with a deuterated methylating agent to give a compound of formula II or salt thereof;
II
or
(bi) reacting a compound of formula V or salt thereof,
V
with a deuterated methylating agent to give a compound of formula VI or salt thereof;
VI
(bii) reacting the compound of formula VI or salt thereof with a dehydrogenating reagent to give a compound of formula II or salt thereof; and
(c) reacting the compound of formula II or salt thereof obtained in (aii) or (bii), with a compound of formula IIIa or IIIb,
IIIa IIIb
to give deutetrabenazine, the compound of formula I.
In the present application, the term “room temperature” means a temperature of about 25°C to about 30°C.
In (ai) of the above process, the compound of formula V or salt thereof is reacted with a dehydrogenating reagent to give the compound of formula IV or salt thereof.
A suitable dehydrogenating reagent includes, but is not limited to N-bromosuccinimide, manganese dioxide, p-toluene sulfonic acid in presence of zinc iodide and oxygen gas, tris(triphenylphosphine)ruthenium(II) dichloride in presence of tert-butyl hydroperoxide, by purging oxygen into reaction mixture comprising the compound of formula IV.
In one embodiment, the reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride and the like; nitriles such as acetonitrile and the like.
In one embodiment, the reaction may be carried out at a temperature of about 0°C to about room temperature. The stirring time may range from about 30 minutes to about 10 hours, or longer.
In one embodiment, the compound of formula V or salt thereof is reacted with N-bromosuccinimide to give the compound of formula IV or salt thereof.
In one embodiment, the compound of formula V or salt thereof is reacted with N-bromosuccinimide in the presence of a base to give the compound of formula IV.
A suitable base includes but is not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate.
In one embodiment, step (ai) comprises reacting the compound of formula V or salt thereof, with a dehydrogenating reagent to give the compound of formula IV and reacting the compound of formula IV with an acid to give a salt of the compound of formula IV.
A suitable acid includes but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, lactic acid, mandelic acid, salicylic acid, citric acid, malonic acid, malic acid.
In one embodiment, the compound of formula IV is reacted with hydrochloric acid to give hydrochloride salt of the compound of formula IV.
In one embodiment, the compound of formula IV is reacted with hydrobromic acid to give hydrobromide salt of the compound of formula IV.
In one embodiment, the compound of formula IV is reacted with L-tartaric acid to give tartrate salt of the compound of formula IV.
In (aii) of the above process, the compound of formula IV or salt thereof, is reacted with a deuterated methylating agent to give the compound of formula II.
A deuterated methylating agent is a deuterium containing methylating agent and selected from the group consisting of deuterated methyl iodide, deuterated methyl bromide, deuterated dimethyl sulfate, deuterated dimethyl carbonate, deuterated methoxy(diphenyl)phosphine, deuterated trimethoxyphosphine, deuterated trimethyl sulfonium hydroxide, deuteriated methyl 2,2,2-trichloroacetate, deuterated methanol optionally in presence of catalyst selected from azodicarboxylate such as diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD) and triphenylphosphine.
In one embodiment, the deuterated methylating agent is deuterated methanol.
In one embodiment, the reaction may be carried out in the presence of catalyst selected from azodicarboxylate such as diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD) and triphenylphosphine.
In one embodiment, the deuterated methylating agent is deuterated methanol in presence of catalyst selected from azodicarboxylate such as diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD) and triphenylphosphine.
In one embodiment, the deuterated methylating agent is deuterated methyl iodide.
In one embodiment, the reaction may be carried out in the presence of a catalyst.
A suitable catalyst includes, but is not limited to crown ethers such as 18-crown-6, dibenzo-18-crown-6 and the like.
In one embodiment, the reaction may be carried out in the presence of a base. The suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate; alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate; amines such as triethylamine, diisopropylethylamine; or mixtures thereof. Preferably the base selected is potassium carbonate.
In one embodiment, the reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; nitriles such as acetonitrile and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane and the like; dimethylformamide; dimethyl sulfoxide; or mixtures thereof.
In one embodiment, the reaction may be carried out at a temperature of about 0°C to about 80°C. The stirring time may range from about 30 minutes to about 40 hours, or longer.
In one embodiment, step (aii) comprises reacting the compound of formula IV or salt thereof, with a deuterated methylating agent to give a compound of formula II and reacting the compound of formula II with an acid to give a salt of the compound of formula II.
A suitable acid includes but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, lactic acid, mandelic acid, salicylic acid, citric acid, malonic acid, malic acid.
In one embodiment, the compound of formula II is reacted with hydrochloric acid to give hydrochloride salt of the compound of formula II.
In one embodiment, the compound of formula II is reacted with hydrobromic acid to give hydrobromide salt of the compound of formula II.
In one embodiment, the compound of formula II is reacted with L-tartaric acid to give tartrate salt of the compound of formula II.
In (bi) of the above process, the compound of formula V or salt thereof, is reacted with a deuterated methylating agent to give the compound of formula VI or salt thereof.
A deuterated methylating agent is a deuterium containing methylating agent and selected from the group consisting of deuterated methyl iodide, deuterated methyl bromide, deuterated dimethyl sulfate, deuterated dimethyl carbonate, deuterated methoxy(diphenyl)phosphine, deuterated trimethoxyphosphine, deuterated trimethyl sulfonium hydroxide, deuteriated methyl 2,2,2-trichloroacetate, deuterated methanol optionally in presence of catalyst selected from azodicarboxylate such as diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD) and triphenylphosphine.
In one embodiment, the deuterated methylating agent is deuterated methanol.
In one embodiment, the reaction may be carried out in the presence of catalyst selected from azodicarboxylate such as diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD) and triphenylphosphine.
In one embodiment, the deuterated methylating agent is deuterated methanol in presence of catalyst selected from azodicarboxylate such as diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD) and triphenylphosphine.
In one embodiment, the deuterated methylating agent is deuterated methyl iodide.
In one embodiment, the reaction may be carried out in the presence of a catalyst.
A suitable catalyst includes, but is not limited to crown ethers such as 18-crown-6, dibenzo-18-crown-6 and the like.
In one embodiment, the reaction may be carried out in the presence of a base. The suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate; alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate; amines such as triethylamine, diisopropylethylamine; or mixtures thereof. Preferably the base selected is potassium carbonate.
In one embodiment, the reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; nitriles such as acetonitrile and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane and the like; dimethylformamide; dimethyl sulfoxide; or mixtures thereof.
In one embodiment, the reaction may be carried out at a temperature of about 0°C to about 80°C. The stirring time may range from about 30 minutes to about 40 hours, or longer.
In one embodiment, step (bi) comprises reacting the compound of formula V or salt thereof, with a deuterated methylating agent to give a compound of formula VI and reacting the compound of formula VI with an acid to give a salt of the compound of formula VI.
A suitable acid includes but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, lactic acid, mandelic acid, salicylic acid, citric acid, malonic acid, malic acid.
In one embodiment, the compound of formula VI is reacted with hydrochloric acid to give hydrochloride salt of the compound of formula VI.
In one embodiment, the compound of formula VI is reacted with hydrobromic acid to give hydrobromide salt of the compound of formula VI.
In (bii) of the above process, the compound of formula VI or salt thereof is reacted with a dehydrogenating reagent to give the compound of formula II or salt thereof.
A suitable dehydrogenating reagent includes, but is not limited to N-bromosuccinimide, manganese dioxide, p-toluene sulfonic acid in presence of zinc iodide and oxygen gas, tris(triphenylphosphine)ruthenium(II) dichloride in presence of tert-butyl hydroperoxide, by purging oxygen into reaction mixture comprising the compound of formula VI.
In one embodiment, the reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride and the like; nitriles such as acetonitrile and the like.
In one embodiment, the reaction may be carried out at a temperature of about 0°C to about 80°C. The stirring time may range from about 30 minutes to about 10 hours, or longer.
In one embodiment, the compound of formula VI or salt thereof is reacted with N-bromosuccinimide to give the compound of formula II or salt thereof.
In one embodiment, the compound of formula VI or salt thereof is reacted with N-bromosuccinimide in presence of a base to give the compound of formula II.
A suitable base includes but is not limited to, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, or mixtures thereof. Preferably the base selected is sodium hydroxide.
In one embodiment, step (bii) comprises reacting the compound of formula VI or salt thereof, with a dehydrogenating reagent to give the compound of formula II and reacting the compound of formula II with an acid to give a salt of the compound of formula II.
A suitable acid includes but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, lactic acid, mandelic acid, salicylic acid, citric acid, malonic acid, malic acid.
In one embodiment, the compound of formula II is reacted with hydrochloric acid to give hydrochloride salt of the compound of formula II.
In one embodiment, the compound of formula II is reacted with hydrobromic acid to give hydrobromide salt of the compound of formula II.
In one embodiment, the compound of formula II is reacted with L-tartaric acid to give tartrate salt of the compound of formula II.
In (c) of the above process, the compound of formula II or salt thereof obtained in (aii) or (bii), is reacted with the compound of formula IIIa or IIIb to give deutetrabenazine.
In one embodiment, the reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol, ethylene glycol, and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; water or mixtures thereof.
In one embodiment, the compound of formula II or salt thereof, is reacted with the compound of formula IIIa or IIIb in ethylene glycol-water mixture to give deutetrabenazine.
In one embodiment, the compound of formula II or salt thereof, is reacted with the compound of formula IIIa or IIIb under biphasic conditions to give deutetrabenazine.
In one embodiment, the biphasic conditions include reacting the compound of formula II or salt thereof with the compound of formula IIIa or IIIb in a mixture of water and water-immiscible solvent.
The water-immiscible solvent includes but is not limited to hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like.
In one embodiment, the compound of formula II or salt thereof, is reacted with the compound of formula IIIa or IIIb under biphasic conditions comprising of n-heptane-water mixture to give deutetrabenazine.
In one embodiment, the hydrochloride salt of the compound of formula II is reacted with the compound of formula IIIb under biphasic conditions comprising of n-heptane-water mixture to give deutetrabenazine.
In one embodiment, the compound of formula II is reacted with the compound of formula IIIb under biphasic conditions comprising of n-heptane-water mixture in presence of hydrochloric acid to give deutetrabenazine.
In one embodiment, the present invention provides a compound of formula VI or salt thereof,
VI.
In one embodiment, the present invention provides a hydrochloride salt of the compound of formula VI characterized by a proton NMR spectrum having peaks at d 9.64 (s,2H), 6.80 (s,1H), 6.78 (s,1H), 4.11 (s,2H), 3.28 (t,2H), 2.91 (t,2H).
In one embodiment, the present invention provides a compound of formula VI characterized by mass spectrum having M/Z = 200.14 (M+H).
In one embodiment, the present invention provides use of compound of formula VI or salt thereof in the preparation of deutetrabenazine.
In one embodiment, the present invention provides use of compound of formula V or salt thereof in the preparation of deutetrabenazine.
In one embodiment, the present invention provides a tartrate salt of the compound of formula II characterized by a proton NMR spectrum having peaks at d 8.38 (s,1H), 7.15 (s,1H), 6.9 (s,1H), 4.2 (s,2H), 3.64 (t,2H), 2.70 (t,2H).
In one embodiment, the present invention provides use of tartrate salt of the compound of formula II in the preparation of deutetrabenazine.
In one embodiment, the present invention further provides a process for purification of deutetrabenazine comprising:
(i) reacting deutetrabenazine with an acid selected from the group of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, lactic acid, mandelic acid, salicylic acid, citric acid, malonic acid, malic acid in a solvent to form salt of deutetrabenazine; and
(ii) treating the salt of deutetrabenazine with a base to give deutetrabenazine.
A suitable base includes but is not limited to an alkali or an alkaline earth metal hydroxide, an alkali or an alkaline earth metal carbonate and the like, an alkali or an alkaline earth metal bicarbonate for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.
In one embodiment, the deutetrabenazine obtained by the process described herein, has a purity of at least 99.5% and wherein the level of RS-isomer and SR-isomer of deutetrabenazine is less than 0.1%, preferably absent.
In one embodiment, the present invention further provides a process for the preparation of deutetrabenazine represented schematically in Scheme 1.

In one embodiment, the present invention provides a process for the preparation of tetrabenazine, a compound of formula VIII,
VII
the process comprising:
(ai) reacting a compound of formula V or salt thereof,
V
with a dehydrogenating reagent to give a compound of formula IV or salt thereof;
IV
(aii) reacting the compound of formula IV or salt thereof, with a methylating agent to give a compound of formula VIII or salt thereof;
VIII
or
(bi) reacting a compound of formula V or salt thereof,
V
with a methylating agent to give a compound of formula IX or salt thereof;
IX
(bii) reacting the compound of formula IX or salt thereof with a dehydrogenating reagent to give a compound of formula VIII or salt thereof; and
(c) reacting the compound of formula VIII or salt thereof obtained in (aii) or (bii), with a compound of formula IIIa or IIIb,
IIIa IIIb
to give tetrabenazine, the compound of formula VII.
The reaction conditions are as discussed supra in preparation of deutetrabenazine, the compound of formula I.
In one embodiment, the present invention provides pharmaceutical compositions comprising deutetrabenazine or salt or solvate thereof obtained by the processes herein described, having a D90 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns.
In one embodiment, the present invention provides pharmaceutical compositions comprising deutetrabenazine or salt or solvate thereof obtained by the processes herein described, having a D50 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns.
The particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state deutetrabenazine or salt or solvate thereof into any of the foregoing desired particle size range.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES

EXAMPLE 1: Preparation of 6,7-(dimethoxy-d6)-3,4-dihydroisoquinoline
To a stirred mixture of 6,7-(dimethoxy-d6)-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.2g) in dichloromethane (12mL) at about 5°C to about 10°C, was added aqueous ammonia to adjust pH to about 12. The two layers were separated and the organic layer was washed with water and dried over sodium sulphate. To this solution, N-bromosuccinimide (1.1g) was added portion wise over about 45min and the reaction mixture was stirred for about 1h at about 0°C to about 10°C. The temperature of the reaction mixture was raised to about 10°C to about 15°C and the mixture was stirred for about 1h. Aqueous sodium hydroxide was added to the reaction mixture which was stirred for about 30min at about room temperature. The two layers were separated and the organic layer was concentrated under vacuum to give 6,7-(dimethoxy-d6)-3,4-dihydroisoquinoline as brown oil.
Yield: (0.8g, 80%)
1H NMR (400MHz, DMSO): d 8.21 (s,1H), 7.03 (s,1H), 6.85 (s,1H), 3.58 (t,2H), 2.60 (t,2H)
Mass: M/Z = 198.19 (M+H)

EXAMPLE 2: Preparation of 6,7-(dimethoxy-d6)-3,4-dihydroisoquinoline
To a mixture of 6,7-dimethoxy-3,4-dihydroisoquinoline (10g) in tetrahydrofuran (80mL), methanol-d6 (21.4g) and triphenylphosphine (47g) was added a solution of diisopropyl azodicraboxylate (DIAD) (36.2g) in tetrahydrofuran (20mL) at about 20°C to about 25°C. The temperature of the reaction mixture was raised to about room temperature and the mixture was stirred for about 6h. Ethyl acetate (100mL) was added to the reaction mixture which was then filtered. To the filtrate, water (100mL) was added and the pH was adjusted to about 2-3 by adding acetic acid. The two layers were separated and the organic layer extracted with water (50ml). Ethyl acetate was added to combined aqueous layers and the pH was adjusted to about 9 to 10 by adding liquid ammonia. The mixture was extracted with ethyl acetate and concentrated.
Yield: 7g

EXAMPLE 3: Preparation of 6,7-(dimethoxy-d6)-3,4-dihydroisoquinoline tartrate
To the solution of L-Tartaric acid (3.8g) in methanol (6mL), was drop wise added 6,7-(dimethoxy-d6)-3,4-dihydroisoquinoline (5g) in ethyl acetate (25mL). The reaction mixture was stirred for about 3h, filtered, washed with ethyl acetate and dried.
Yield: 6g
1H NMR (400MHz, DMSO): d 8.38 (s,1H), 7.15 (s,1H), 6.9 (s,1H), 4.2 (s,2H), 3.64 (t,2H), 2.70 (t,2H)
Mass: M/Z = 198 (M+H)

EXAMPLE 4: Preparation of 6,7-(dimethoxy-d6)-1,2,3,4-tetrahydroisoquinoline hydrochloride
To a mixture of 6,7-(dimethoxy-d6)-1,2,3,4-tetrahydroisoquinoline in ethyl acetate, HCl gas was purged for about 2h. The precipitated solid was filtered and dried under vacuum at about 50°C to about 55°C for about 12h to give 6,7-(dimethoxy-d6)-1,2,3,4-tetrahydroisoquinoline hydrochloride as white solid.

EXAMPLE 5: Preparation of deutetrabenazine
To a mixture of 6,7-(dimethoxy-d6)-3,4-dihydroisoquinoline tartrate (10g) in water (30mL), was added 3-(N,N-dimethylaminomethyl)-5-methyl-2-hexanone (5.42g) in n-heptane (15mL) and the reaction mixture was stirred for about 48h at about 35°C. The solids were filtered, washed with water and dried under vacuum to get deutetrabenazine (Yield: 7.5g)

EXAMPLE 9: Preparation of deutetrabenazine
2-Acetyl-N,N,N,4-tetramethyl-1-pentanaminium iodide (9.48g) was added to a suspension of 6,7-(dimethoxy-d6)-3,4-dihydroisoquinoline tartrate (10g), and potassium carbonate (7.95g) in ethylene glycol (30mL) and water (15mL) at about room temperature. The reaction mixture was stirred at about 40°C to about 45°C for about 30h. The reaction mixture was cooled and water was added to it. The reaction mass was filtered and the solid obtained was washed with water and dried for about 12h at about 50°C to about 55°C.
Yield: 6.5g.

EXAMPLE 10: Preparation of deutetrabenazine
2-Acetyl-N,N,N,4-tetramethyl-1-pentanaminium iodide (0.79g) was added to a suspension of 6,7-(dimethoxy-d6)-3,4-dihydroisoquinoline (0.5g), ethylene glycol (2.25mL) and water (0.75mL) at about room temperature. The reaction mixture was stirred at about 40°C to about 45°C for about 30h. The reaction mixture was cooled and water was added to it. The reaction mass was filtered and the solid obtained was washed with water and dried for about 12h at about 50°C to about 55°C.
Yield: 0.49g

EXAMPLE 11: Preparation of deutetrabenazine
To a mixture of 6,7-(dimethoxy-d6)-3,4-dihydroisoquinoline (10g) in water (30mL), was added 3-(N,N-dimethylaminomethyl)-5-methyl-2-hexanone (6.7g) in n-heptane (15mL) and the reaction mixture was stirred for about 50h at about 25°C to 35°C. The solid was filtered, washed with water and dried under vacuum.
Yield: 11.2g

EXAMPLE 12: Preparation of deutetrabenazine
To a mixture of 6,7-(dimethoxy-d6)-3,4-dihydroisoquinoline (10g) in water (30mL), was added 3-(N,N-dimethylaminomethyl)-5-methyl-2-hexanone (8.3g) in n-heptane (15mL) followed concentrated hydrochloric acid (4mL) and the reaction mixture was stirred for about 40h at about 25°C to 35°C. The solid was filtered, washed with water and dried under vacuum.
Yield: 8.4g

EXAMPLE 13: Preparation of deuterated methyl iodide
A mixture of deuterated methanol (50g), hydroiodic acid (55-57%, 500mL) and water (50mL) was heated to about 40°C to about 45°C for about 2h and at about 45°C to about 50°C for another 2h. The reaction mixture was then cooled to about 30°C and concentrated at atmospheric pressure to give 150g of deuterated methyl iodide as a colorless liquid which was dried over sodium sulphate and stored at about 2°C to about 8°C using copper as stabilizer.

EXAMPLE 14: Preparation of 6,7-(dimethoxy-d6)-1,2,3,4-tetrahydroisoquinoline hydrochloride
A solution of tert-butyl-6,7-dihydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (3g), potassium carbonate (4.68g) and dibenzo-18-crown-6 (0.164g) in acetone (30mL) was stirred at about 35°C to about 40°C for about 30min to about 45min. Methyl-d3 iodide (4.92g) was added and the reaction mixture was stirred at about the same temperature for about 18h. An additional methyl-d3 iodide (1.64g) was added to the reaction mixture which was stirred for about 18h. The reaction mixture was cooled to about room temperature and was filtered. The filtrate was concentrated under vacuum. The solid obtained was dissolved in water and extracted with ethyl acetate. The organic layers were combined and concentrated under vacuum. To the solid obtained, was added ethyl acetate and HCl gas was purged into the reaction mixture for about 2h. The precipitated solid was filtered and dried under vacuum at about 50°C to about 55°C for about 12h to give 6,7-(dimethoxy-d6)-1,2,3,4-tetrahydroisoquinoline hydrochloride as white solid.
Yield: (2.13g, 80%)
1H NMR (400MHz, DMSO): d 9.64 (s,2H), 6.80 (s,1H), 6.78 (s,1H), 4.11 (s,2H), 3.28 (t,2H), 2.91 (t,2H)
Mass: M/Z = 200.14 (M+H)
1H NMR (400MHz, DMSO+D2O): d 6.76 (s,1H), 6.75 (s,1H), 4.12 (s,2H), 3.30 (t,2H), 2.90 (t,2H)

EXAMPLE 15: Preparation of 6,7-dimethoxy-d6-1,2,3,4-tetrahydroisoquinoline
To a mixture of tetrahydrofuran (80mL), 1,2,3,4-tetrahydroisoquinoline-6,7-diol (10g), methanol-d6 (22g) and triphenyl phosphine (48g), was added a solution of diisopropyl azodicraboxylate (DIAD) (37g) in tetrahydrofuran (20mL) at about 20°C to about 25°C. The temperature of the reaction mixture was raised to about room temperature and the mixture was stirred for about 6h. Ethyl acetate was added to the reaction mixture which was then filtered. To the filtrate, water was added and the pH was adjusted to about 2-3 by adding acetic acid. The two layers were separated and the organic layer was extracted with water. Ethyl acetate was added to the combined aqueous layers and the pH was adjusted to about 9 to 10 by adding liquid ammonia. The mixture was extracted with ethyl acetate and concentrated.
Yield: 6.3g

EXAMPLE 16: Preparation of 6,7-(dimethoxy-d6)-3,4-dihydroisoquinoline
To a solution of 6,7-dimethoxy-d6-1,2,3,4-tetrahydroisoquinoline in methylene chloride, N-bromosuccinimide (5g) was added portion wise over about 45min and the reaction mixture was stirred for about 1h at about 0°C to 10°C. The temperature of reaction mixture was raised to about 10°C to 15°C and stirred for about 1h. Aqueous sodium hydroxide was added to the reaction mixture which was stirred for about 30min at about 25°C. The two layers were separated and the organic layer was concentrated under vacuum to give 6,7-(dimethoxy-d6)-3,4-dihydroisoquinoline as brown oil.

EXAMPLE 17: Preparation of 6,7-dimethoxy-d6-1,2,3,4-tetrahydroisoquinoline hydrochloride
To a mixture of tetrahydrofuran (50mL), tert-butyl-6,7-dihydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (10g), methanol d6 (14g) and triphenyl phosphine (30g), was added a solution of diisopropyl azodicraboxylate (DIAD) (23g) in tetrahydrofuran (25mL) at about room temperature. The temperature of the reaction mixture was raised to about room temperature and the mixture was stirred for about 5-10 hours. Ethyl acetate (75mL) was added to the reaction mixture which was then filtered. To the filtrate, dry HCl gas was purged and the mixture was stirred for about 3h. The solid obtained was filtered and dried.
Yield: 6.3g

WE CLAIM
1. A process for the preparation of deutetrabenazine, a compound of formula I,
I
the process comprising:
(ai) reacting a compound of formula V or salt thereof,
V
with a dehydrogenating reagent to give a compound of formula IV or salt thereof;
IV
(aii) reacting the compound of formula IV or salt thereof, with a deuterated methylating agent to give a compound of formula II or salt thereof;
II
or
(bi) reacting a compound of formula V or salt thereof,
V
with a deuterated methylating agent to give a compound of formula VI or salt thereof;
VI
(bii) reacting the compound of formula VI or salt thereof with a dehydrogenating reagent to give a compound of formula II or salt thereof; and
(c) reacting the compound of formula II or salt thereof obtained in (aii) or (bii), with a compound of formula IIIa or IIIb,
IIIa IIIb
to give deutetrabenazine, the compound of formula I.

2. The process as claimed in claim 1, wherein the dehydrogenating reagent of step (ai) or step (bii) is selected from the group consisting of N-bromosuccinimide, manganese dioxide, p-toluene sulfonic acid.

3. The process as claimed in claim 1, wherein the deuterated methylating agent of step (aii) or step (bi) is selected from the group consisting of deuterated methyl iodide, deuterated methyl bromide, deuterated dimethyl sulfate, deuterated dimethyl carbonate, deuterated methoxy(diphenyl)phosphine, deuterated trimethoxyphosphine, deuterated trimethyl sulfonium hydroxide, deuteriated methyl 2,2,2-trichloroacetate, deuterated methanol optionally in presence of catalyst selected from azodicarboxylate such as diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD) and triphenylphosphine, and mixtures thereof.

4. The process as claimed in claim 1, wherein the deuterated methylating agent of step (aii) or step (bi) is deuterated methanol in presence of catalyst selected from azodicarboxylate such as diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD) and triphenylphosphine.

5. The process as claimed in claim 1, wherein the compound of formula II or salt thereof, is reacted with the compound of formula IIIa or IIIb, in the presence of a solvent selected from the group consisting of alcohols, hydrocarbons, water, and mixtures thereof.

6. A compound of formula VI or salt thereof,
VI.

Dated this 13th day of January, 2020

(Signed)____________________
DR. VARSHA SADEKAR
DEPUTY GENERAL MANAGER-IPM
GLENMARK LIFE SCIENCES LIMITED
,CLAIMS:WE CLAIM
1. A process for the preparation of deutetrabenazine, a compound of formula I,
I
the process comprising:
(ai) reacting a compound of formula V or salt thereof,
V
with a dehydrogenating reagent to give a compound of formula IV or salt thereof;
IV
(aii) reacting the compound of formula IV or salt thereof, with a deuterated methylating agent to give a compound of formula II or salt thereof;
II
or
(bi) reacting a compound of formula V or salt thereof,
V
with a deuterated methylating agent to give a compound of formula VI or salt thereof;
VI
(bii) reacting the compound of formula VI or salt thereof with a dehydrogenating reagent to give a compound of formula II or salt thereof; and
(c) reacting the compound of formula II or salt thereof obtained in (aii) or (bii), with a compound of formula IIIa or IIIb,
IIIa IIIb
to give deutetrabenazine, the compound of formula I.

2. The process as claimed in claim 1, wherein the dehydrogenating reagent of step (ai) or step (bii) is selected from the group consisting of N-bromosuccinimide, manganese dioxide, p-toluene sulfonic acid.

3. The process as claimed in claim 1, wherein the deuterated methylating agent of step (aii) or step (bi) is selected from the group consisting of deuterated methyl iodide, deuterated methyl bromide, deuterated dimethyl sulfate, deuterated dimethyl carbonate, deuterated methoxy(diphenyl)phosphine, deuterated trimethoxyphosphine, deuterated trimethyl sulfonium hydroxide, deuteriated methyl 2,2,2-trichloroacetate, deuterated methanol optionally in presence of catalyst selected from azodicarboxylate such as diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD) and triphenylphosphine, and mixtures thereof.

4. The process as claimed in claim 1, wherein the deuterated methylating agent of step (aii) or step (bi) is deuterated methanol in presence of catalyst selected from azodicarboxylate such as diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD) and triphenylphosphine.

5. The process as claimed in claim 1, wherein the compound of formula II or salt thereof, is reacted with the compound of formula IIIa or IIIb, in the presence of a solvent selected from the group consisting of alcohols, hydrocarbons, water, and mixtures thereof.

6. A compound of formula VI or salt thereof,
VI.

Dated this 13th day of January, 2020

(Signed)____________________
DR. VARSHA SADEKAR
DEPUTY GENERAL MANAGER-IPM
GLENMARK LIFE SCIENCES LIMITED