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 Pharmaceuticals 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:
(a) reacting a compound of formula IV or salt thereof,
IV
with a dehydrogenating reagent to give a compound of formula II;
II
(b) optionally, reacting the compound of formula II with an acid to give a salt of the compound of formula II; and
(c) reacting the compound of formula II or salt thereof, 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 IV or salt thereof,
IV.
In another embodiment, the present invention provides a compound of formula IV 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 IV as obtained in Example 2.
Figure 2 is the proton NMR spectrum with D2O exchange of hydrochloride salt of compound of formula IV as obtained in Example 2.

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:
(a) reacting a compound of formula IV or salt thereof,
IV
with a dehydrogenating reagent to give a compound of formula II;
II
(b) optionally, reacting the compound of formula II with an acid to give a salt of the compound of formula II; and
(c) reacting the compound of formula II or salt thereof, 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 (a) of the above process, the compound of formula IV or salt thereof is reacted with a dehydrogenating reagent to give the compound of formula II.
A suitable dehydrogenating reagent includes, but is not limited to N-bromosuccinimide, 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 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 (b) of the above process, the compound of formula II is reacted 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 (c) of the above process, the compound of formula II or salt thereof, 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 compound of formula IV or salt thereof is prepared by a process comprising:
(a) reacting a compound of formula VI,
VI
wherein R is selected from the group consisting of Boc, Cbz, Fmoc, acetyl, trifluoroacetyl, benzyl, trityl, tosyl, mesyl,
with a deuterated methylating agent to give a compound of formula V;
V
(b) deprotecting the compound of formula V to give the compound of formula IV; and
(c) optionally, reacting the compound of formula IV with an acid to give a salt of the compound of formula IV.
In (a) of the above process, the compound of formula VI is reacted with a deuterated methylating agent to give the compound of formula V.
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 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 (b) of the above process, the compound of formula V is deprotected to give the compound of formula IV.
In one embodiment, the deprotection reaction process includes any of the following:
(x) where R is Boc, Fmoc, acetyl, trifluoroacetyl, trityl, tosyl, mesyl, the deprotection is performed using an acid or a base; or
(y) where R is Cbz, benzyl, the deprotection is performed via hydrogenation reaction using hydrogen in the presence of a metal catalyst.
The acids used for deprotection may be selected from mineral acids like hydrochloric acid, sulfuric acid, nitric acid or organic acids such as acetic acid, methanesulfonic acid, trifluoroacetic acid, p-toluene sulfonic acid and the like.
The bases used for deprotection may be selected from inorganic base or organic base. The inorganic base may be selected from the group consisting of alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; metal carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate and the like; metal bicarbonates such as sodium bicarbonate, potassium bicarbonate; metal hydrides such as lithium hydride, sodium hydride, potassium hydride and the like. The organic base may be selected from the group consisting of organic amines such as triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, pyridine, 4-dimethylaminopyridine, tri-n-butylamine, morpholine, N-methylmorpholine, piperidine, and the like.
In (c) of the above process, the compound of formula IV is reacted 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 VI is prepared by a process comprising reacting a compound of formula VII or salt thereof,
VII
with Boc anhydride (di-tert-butyl dicarbonate), Cbz chloride (benzylchloroformate), Cbz anhydride (dibenzyldicarbonate), Fmoc chloride (9-fluorenylmethylchloroformate), acetyl chloride, acetic anhydride, trifluoroacetyl chloride, trifluoroacetic anhydride, benzyl chloride, benzyl bromide, trityl chloride, tosyl chloride, or mesyl chloride to give the compound of formula VI.
In one embodiment, the reaction may be carried out in the presence of a base.
A suitable base includes but is not limited to inorganic base such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate; organic base such as triethylamine, diethylamine, diisopropylamine, diisopropylethylamine, pyridine; or mixtures thereof. Preferably, the base is selected from inorganic base and more preferably the base is sodium bicarbonate.
In one embodiment, the present invention provides a compound of formula IV or salt thereof,
IV.
In one embodiment, the present invention provides a hydrochloride salt of the compound of formula IV 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 IV characterized by mass spectrum having M/Z = 200.14 (M+H).
In one embodiment, the present invention provides a compound of formula IV or salt thereof 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 provides an amorphous form of deutetrabenazine.
In one embodiment, the amorphous form of deutetrabenazine is prepared by a method selected from the group consisting of lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.
In one embodiment, the present invention provides a solid amorphous dispersion of deutetrabenazine.
The term “solid amorphous dispersion” means the dispersion contains deutetrabenazine in a substantially amorphous solid state form. The term “substantially amorphous” means at least 80% of deutetrabenazine in the dispersion is in an amorphous form.
In one embodiment, the present invention provides a solid amorphous dispersion of deutetrabenazine with a pharmaceutically acceptable carrier.
The pharmaceutically acceptable carrier may comprise diluents, adjuvants, disintegrating agents, binders, excipients, lubricants, solubility enhancing agents and the like.
In one embodiment, the solid amorphous dispersion of deutetrabenazine is prepared by a method selected from the group consisting of lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.
In one embodiment, the present invention provides a process for the preparation of tetrabenazine, a compound of formula VIII,
VIII
the process comprising:
(a) reacting a compound of formula VI,
VI
wherein R is selected from the group consisting of Boc, Cbz, Fmoc, acetyl, trifluoroacetyl, benzyl, trityl, tosyl, mesyl,
with a methylating agent to give a compound of formula XI;
XI
(b) deprotecting the compound of formula XI to give the compound of formula X;
X
(c) optionally, reacting the compound of formula X with an acid to give a salt of the compound of formula X;
(d) reacting a compound of formula X or salt thereof, with a dehydrogenating reagent to give a compound of formula IX; and
IX
(e) optionally, reacting the compound of formula IX with an acid to give a salt of the compound of formula IX;
(f) reacting the compound of formula IX or salt thereof, with a compound of formula IIIa or IIIb,
IIIa IIIb
to give tetrabenazine, the compound of formula VIII.
In (a) of the above process, the compound of formula VI is reacted with a methylating agent to give the compound of formula XI.
A suitable methylating agent includes but is not limited to methyl iodide, methyl bromide, dimethyl sulphate, dimethyl carbonate.
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.
In (b) of the above process, the compound of formula XI is deprotected to give the compound of formula X.
The deprotecting reagents are as discussed supra in preparation of the compound of formula IV.
In (c) of the above process, the compound of formula X is reacted with an acid to give the salt of the compound of formula X.
The suitable acid is as discussed supra in preparation of the salt of the compound of formula IV.
In one embodiment, the compound of formula X is reacted with hydrochloric acid to give hydrochloride salt of the compound of formula X.
In (d) of the above process, the compound of formula X or salt thereof, is reacted with a dehydrogenating reagent to give the compound of formula IX.
A suitable dehydrogenating reagent includes, but is not limited to N-bromosuccinimide, 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 compound of formula IV.
In (e) of the above process, the compound of formula IX is reacted with an acid to give the salt of the compound of formula IX.
The suitable acid is as discussed supra in preparation of the salt of the compound of formula II.
In one embodiment, the compound of formula IX is reacted with hydrochloric acid to give hydrochloride salt of the compound of formula IX.
In (f) of the above process, the compound of formula IX or salt thereof, is reacted with the compound of formula IIIa or IIIb to give tetrabenazine.
In one embodiment, the reaction may be carried out in the presence of a suitable solvent. The suitable solvent is 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 tert-butyl-6,7-dihydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate
A solution of 1,2,3,4-tetrahydroisoquinoline-6,7-diol hydrobromide (5g), sodium bicarbonate (5.36g) and di-tert-butyl dicarbonate (4.88g) in 57.5mL tetrahydrofuran/water (5:1) was stirred at about 20°C to about 30°C for about 2h to about 3h. The reaction mixture was filtered and the filtrate was diluted with ethyl acetate. The two layers were separated and the organic layer was washed with water and concentrated under reduced pressure. To the residue, cyclohexane was added and the solid obtained was filtered and dried under vacuum to give tert-butyl-6,7-dihydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate as a pale yellow solid.
Yield: 4.31g

EXAMPLE 2: 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)
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)
Mass: M/Z = 200.14 (M+H)

EXAMPLE 3: Preparation of 6,7-(dimethoxy-d6)-3,4-dihydroisoquinoline
To a 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 the pH of the reaction mixture to about 12. The two layers were separated and the organic layer was dried over sodium sulphate. N-bromosuccinimide (1.1g) was portion wise added to the organic layer over about 45min and the reaction mixture was stirred for about 1h at about 0°C to about 10°C and for another 1h at about 10°C to about 15°C. 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.
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 4: 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 5: 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 6: 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 7: 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.

CLAIMS:WE CLAIM

1.A process for the preparation of deutetrabenazine, a compound of formula I,
I
the process comprising:
(a) reacting a compound of formula IV or salt thereof,
IV
with a dehydrogenating reagent to give a compound of formula II;
II
(b) optionally, reacting the compound of formula II with an acid to give a salt of the compound of formula II; and
(c) reacting the compound of formula II or salt thereof, 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 (a) is selected from the group consisting of N-bromosuccinimide, p-toluene sulfonic acid.

3.The process as claimed in claim 1, wherein step (b) is carried out in the presence of solvent selected from alcohols, hydrocarbons, water, and mixtures thereof.

4.The process as claimed in claim 1, wherein the compound of formula IV or salt thereof is prepared by a process comprising:
(a) reacting a compound of formula VI,
VI
wherein R is selected from the group consisting of Boc, Cbz, Fmoc, acetyl, trifluoroacetyl, benzyl, trityl, tosyl, mesyl,
with a deuterated methylating agent to give a compound of formula V;
V
(b) deprotecting the compound of formula V to give the compound of formula IV; and
(c) optionally, reacting the compound of formula IV with an acid to give a salt of the compound of formula IV.

5.The process as claimed in claim 4, wherein the source of deuterated methyl of step (a) 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, and mixtures thereof.

6.The process as claimed in claim 4, wherein the compound of formula V is reacted with the source of deuterated methyl in the presence of a catalyst.

7.The process as claimed in claim 6, wherein the catalyst is selected from the group consisting of 18-crown-6, dibenzo-18-crown-6, and mixtures thereof.

8.A compound of formula IV or salt thereof,
IV.

9.Use of a compound of formula IV or salt thereof in the preparation of deutetrabenazine.