FIELD OF THE INVENTION
The present invention relates to a process for preparation of deutetrabenazine (3S,11bS)-3-(2-methylpropyl)-9,10-bis(trideuteriomethoxy)-1,3,4,6,7,11b-hexahydrobenzo[a] quinolizin-2-one of Formula I.

BACKGROUND OF THE INVENTION
Deutetrabenazine is a deuterated analog of tetrabenazine (I) which has improved pharmacokinetic properties when compared to the non-deuterated drug. Deutetrabenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor indicated for the treatment of chorea associated with Huntington’s disease.

Deutetrabenazine is chemically known as (3S,11bS)-3-(2-methylpropyl)-9,10-bis(trideuteriomethoxy)-1,3,4,6,7,11b-hexahydrobenzo[a]quinolizin-2-one.

US 3,045,021 discloses process for preparation of tetrabenazine. The patent US 8,524,733 discloses deutetrabenazine and process for the preparation by reaction of d6-6,7-Dimethoxy-3,4-dihydroisoquinoline and (2-acetyl-4-methyl-pentyl)- trimethylammonium iodide (V) in ethanol. The product is isolated by column chromatography with yields of 35%. The intermediate d6-6,7-Dimethoxy-3,4-dihydroisoquinoline is prepared by series of reaction wherein (E)-4-(2-nitrovinyl)benzene-1,2-diol is reacted with d3-Iodomethane to produce d6-(E)-1,2-Dimethoxy-4-(2-nitrovinyl)benzene which undergoes reduction in presence of lithium aluminum hydride to give 2-(3,4-d6-dimethoxyphenyl) ethanamine which further reacts with hexamethylenetetramine in presence of acetic acid/ trifluoroacetic acid to give the intermediate d6-6,7-dimethoxy-3,4-dihydroisoquinoline. The major drawback of the above said process is utilization of expensive reagents like d3-Iodomethane, tedious technique of column chromatography resulting in low yields hence is not industrially feasible.

Another patent application US 20150152099, describes process for the preparation of deutetrabenazine by reaction of d6-6,7-dimethoxy-3,4-dihydroisoquinoline and (2-acetyl- 4-methyl-pentyl)-trimethylammonium iodide in various solvents. The intermediate d6-6,7-Dimethoxy-3,4-dihydroisoquinoline is prepared by series of reaction wherein dopamine hydrochloride reacts with ethyl formate to give N-(2-(3,4-dihydroxy-phenyl)-ethyl)-formamide which reacts further with d3-Iodomethane to produce deuterated compound which is cyclized in presence of phosphoryl chloride to give d6-6,7-Dimethoxy-3-dihydro isoquinoline hydrochloride. The major drawback of the above said process is utilization of expensive reagents like d3-Iodomethane.

Although several methods are known in prior published references for the synthesis of compound of Formula I, the present invention is concentrated towards the development of a new method for synthesizing compound of Formula I which is efficient, industrially viable wherein reaction conditions are mild and simple for operation, less expensive cost effective process.

The present invention will now be explained in details. While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims.

The process for preparing compound of Formula I, and other object of the present invention as disclosed in the following embodiments are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein.

OBJECT OF THE INVENTION
A primary object of the present invention is to provide a novel process for the preparation of (3S,11bS)-3-(2-methylpropyl)-9,10-bis(trideuteriomethoxy)-1,3,4,6,7,11b-hexahydrobenzo [a]quinolizin-2-one (deutetrabenazine) of Formula I and pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide amorphous, and crystalline forms of deutetrabenazine.

Another object of the present invention is to provide amorphous solid dispersion of deutetrabenazine.

SUMMARY OF THE INVENTION
In one aspect, the present invention provides a process for the preparation of deutetrabenazine compound of Formula I comprising steps of:
a) methylating compound of Formula A to get deuterated compound of Formula B in presence of deuterated agent,

wherein R is selected from Boc and -CHO, or
methylating compound of Formula XI to get d6-6,7-Dimethoxy-3,4-dihydroisoquinoline compound of Formula VII and/ or salt thereof, in presence of deuterating agent,
,
wherein said deuterating agent is represented as compound of Formula XIII,
,
wherein Y2 is selected from the group consisting of hydroxyl, halogen, alkyl sulfate, alkyl sulfonate, halosulfonate, perhaloalkyl sulfonate, aryl sulfonate, alkylaryl sulfonate, dialkyloxonium, alkylphosphate, and alkylcarbonate, any of which may be optionally substituted; and
b) converting compound of Formula B or VII to deutetrabenazine of Formula I.

In another aspect, compound of Formula A is represented as compound of Formula III and IX;
, and .

In another aspect, compound of Formula B is represented as compounds of Formula IV or Formula VI;
, and .

In another aspect, the present invention provides a process for the preparation of deutetrabenazine compound of Formula I comprising steps of:
a) adding 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline of Formula VII and/or salt thereof, with compound of Formula VIII in presence of solvent to obtain deutetrabenazine compound of Formula I,
,
wherein R1, R2, R3 are independently selected from (un)substituted C1-C6 alkyl, (un)substituted cycloalkyl, (un)substituted cycloheteroalkyl, (un)substituted aryl, (un)substituted alkaryl, (un)substituted heteroaryl; X is selected from halogen, alkyl sulfate, alkyl sulfonate, halosulfonate, perhaloalkyl sulfonate, aryl sulfonate, alkylaryl sulfonate, dialkyloxonium, alkylphosphate, and alkylcarbonate, any of which may be optionally substituted; and
vii) optionally purifying compound of Formula I.

In another aspect, the present invention provides a process for the preparation of deutetrabenazine compound of Formula I comprising steps of:
a) formylating 2-(3,4-bis(methoxy-d3)phenyl)ethan-1-amine of Formula V in presence of formylaing agent to get d6-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide of Formula VI,
, or
formylating dopamine hydrochloride compound of Formula II with formylating agent to get N-(3,4-dihydroxyphenethyl)formamide of Formula IX,
,
wherein said formylating agent is represented by Formula XII or C1-C6 alkyl orthoformate,

wherein Y represents group consisting of hydroxyl, acetoxy, alkoxy, halogen, haloalkoxy, perhaloalkoxy, heteroalkoxy, and aryloxy, any of which may be optionally substituted, NR4R5, wherein R4 and R5 are independently selected from hydrogen, (un)substituted alkyl and the like;
and R is selected from the group consisting of hydrogen and deuterium; and
b) converting compound of Formula VI or Formula IX to deutetrabenzine of Formula I.

In another aspect, the present invention provides a process of preparing deutetrabenzine wherein said process comprises the steps of:
(i) cyclizing N-(3,4-dihydroxyphenethyl)formamide of Formula IX in presence of dehydrating agent to obtain 6,7-dihydroxy-3,4-dihydroisoquinoline compound of Formula XI,
; or
cyclizing N-(3,4-bis(methoxy-d3)phenethyl-d6)formamide of Formula VI in presence of dehydrating agent to obtain d6-6,7-dimethoxy-3,4-dihydroisoquinoline compound of Formula VII and/or salt thereof,
;
wherein said dehydrating agent is selected from phosphorous oxy chloride, phosphorus pentachloride, and thionyl chloride,
(ii) methylating 6,7-dihydroxy-3,4-dihydroisoquinoline compound of Formula XI with deuterating agent to obtain d6-6,7-Dimethoxy-3,4-dihydroisoquinoline compound of Formula VII and/ or salt thereof,
;
(iii) reacting d6-6,7-Dimethoxy-3,4-dihydroisoquinoline compound of Formula VII and/or salt thereof obtained from step (i) or (ii), with compound of Formula VIII in presence of solvent to obtain deutetrabenazine compound of Formula I,
,
wherein R1, R2, R3 and X are as defined above; and
(iv) optionally purifying compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION
Definitions:
The term “suitable base” or “base” as used in the context of the present invention refers to the group comprising of¬ organic and inorganic base such as alkali metal alkoxides, alkali metal hydroxides, alkali metal hydrides, alkali metal carbonates, inorganic and organic amines and is selected from, but not limited to, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium carbonate, potassium carbonate, sodium bicarbonate and the like.

The term “solvent” or “suitable solvent” as used in the context of the present invention refers to the group comprising of dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform, benzene, toluene, methanol, ethanol, propanol, butanol, acetonitrile, propionitrile, acetone, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, sulfolane, glycol, dioxane, propanediol, butanediol, polyethylene glycol, water or mixture thereof.

The “pharmaceutically acceptable excipient” as used in the context of the present invention may include, but not limited to an inorganic oxide such as silicon dioxide, titanium dioxide, zinc oxide, zinc dioxide, aluminium dioxide and zeolite; and organic polymers such as polyvinyl pyrrolidinone, cross linked cellulose acetate phthalate, microcrystalline cellulose, polyethylene/polyvinyl alcohol copolymer, polyethyle/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, povidone, povidone K-30, povidone K-60, Povidone K-90, polyvinyl pyrrolidone vinyl acetate, polyvinyl alcohol, polysorbate 80, polyethylene glycol, methyl cellulose, Eudragit S-100, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, gelucire 44/14, ethyl cellulose, D-alphatocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcellulose, cellulose derivatives; polyethylene glycol, cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like.

In one embodiment, the present invention provides a process for the preparation of deutetrabenazine compound of Formula I comprising the steps of:
a) methylating compound of Formula A to get deuterated compound of Formula B in presence of deuterated agent,

wherein R is selected from Boc and -CHO, or
methylating compound of Formula XI to get d6-6,7-Dimethoxy-3,4-dihydroisoquinoline compound of Formula VII and/ or salt thereof, in presence of deuterating agent,
,
wherein said deuterating agent is represented as compound of Formula XIII,
,
wherein Y2 is selected from the group consisting of hydroxyl, halogen, alkyl sulfate, alkyl sulfonate, halosulfonate, perhaloalkyl sulfonate, aryl sulfonate, alkylaryl sulfonate, dialkyloxonium, alkylphosphate, and alkylcarbonate, any of which may be optionally substituted; and
b) converting compound of Formula B or VII to deutetrabenazine of Formula I.

In another embodiment, compound of Formula A is represented as compound of Formula III and IX;
, and .

In another embodiment, compound of Formula B is represented as compounds of Formula IV or Formula VI;
, and .

In another embodiment, the present invention provides a process for the preparation of deutetrabenazine compound of Formula I comprising steps of:
a) adding 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline of Formula VII and/or salt thereof, with compound of Formula VIII in presence of solvent to obtain deutetrabenazine compound of Formula I,
,
wherein R1, R2, R3 are independently selected from (un)substituted C1-C6 alkyl, (un)substituted cycloalkyl, (un)substituted cycloheteroalkyl, (un)substituted aryl, (un)substituted alkaryl, (un)substituted heteroaryl; X is selected from halogen, alkyl sulfate, alkyl sulfonate, halosulfonate, perhaloalkyl sulfonate, aryl sulfonate, alkylaryl sulfonate, dialkyloxonium, alkylphosphate, and alkylcarbonate, any of which may be optionally substituted; and
vii) optionally purifying compound of Formula I.

In another embodiment, the present invention provides a process for the preparation of deutetrabenazine compound of Formula I comprising steps of:
a) formylating 2-(3,4-bis(methoxy-d3)phenyl)ethan-1-amine of Formula V in presence of formylaing agent to get d6-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide of Formula VI,
, or
formylating dopamine hydrochloride compound of Formula II with formylating agent to get N-(3,4-dihydroxyphenethyl)formamide of Formula IX,
,
wherein said formylating agent is represented by Formula XII or C1-C6 alkyl orthoformate,

wherein Y represents group consisting of hydroxyl, acetoxy, alkoxy, halogen, haloalkoxy, perhaloalkoxy, heteroalkoxy, and aryloxy, any of which may be optionally substituted, NR4R5, wherein R4 and R5 are independently selected from hydrogen, (un)substituted alkyl and the like;
and R is selected from the group consisting of hydrogen and deuterium; and
b) converting compound of Formula VI or Formula IX to deutetrabenzine of Formula I.

In a specific embodiment, Y is hydroxyl, acetoxy or C1-C5 alkoxy, NR4R5; wherein R4 and R5 are independently selected from hydrogen, (un)substituted alkyl and like;
wherein Y is specifically selected from the group comprising of hydroxyl, methoxy, propoxy, isopropoxy, butoxy, iso-butoxy, and dialkyl amine.

In another embodiment, the present invention provides a process for the preparation of deutetrabenazine compound of Formula I, comprising the steps of:
(i) reacting dopamine hydrochloride compound of Formula II with Boc-anhydride in presence of suitable solvent to get tert-butyl (3,4-dihydroxyphenethyl)carbamate of Formula III,
;
(ii) methylating compound of Formula III to get tert-butyl (3,4-bis(methoxy-d3)phenethyl)carbamate of Formula IV in presence of deuterated agent in a suitable solvent, wherein said deuterating agent is selected from deuterated methanol (CD3OD or CD3OH) and deuterated methyl iodide (CD3I),
;
(iii) deprotecting compound of Formula IV in presence of deprotecting agent to get 2-(3,4-bis(methoxy-d3)phenyl)ethan-1-amine of Formula V, wherein said deprotecting agent is selected from acid or base,
;
(iv) formylating compound of Formula V in presence of formylating agent and base to get d6-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide of Formula VI,
,
wherein said formylating agent is selected from formic acid, methyl formate, ethyl formate, isopropyl formate, and dimethyl formamide, trimethylorthoformate, triethylorthoformate;
(v) cyclizing compound of Formula VI in presence of dehydrating agent to get 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline of Formula VII and/or salt thereof, wherein said dehydrating agent is selected from the group consisting of phosphorous oxy chloride, phosphorus pentachloride, and thionyl chloride,
;
vi) reacting 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline of Formula VII and/or salt thereof, with compound of Formula VIII in presence of solvent to obtain deutetrabenazine compound of Formula I,
,
wherein R1, R2, R3 and X are as defined above; and
vii) optionally purifying compound of Formula I.

In further embodiment, Formula XII used for the preparation of deutetrabenazine is highly pure with purity above 99.0%, preferably 99.5% and above, and most preferably 99.8% and above.

In the process of step (ii), d6-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide compound of Formula IV is isolated by techniques known in art like filtration, evaporation, concentration etc. Isolated tert-butyl (3,4-bis(methoxy-d3)phenethyl)carbamate of Formula IV was obtained in a HPLC purity of greater than 90.0%.

In the process of step (vi) the reaction of 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride of Formula VII with compound of Formula VIII is carried out at a temperature of 30 to 60oC.

In further embodiment, Formula VII is isolated with purity above 99.0%, preferably 99.5% and above, and most preferably 99.8% and above.

In another embodiment the present invention provides a process for the preparation of deutetrabenazine of Formula I, comprising the steps of:
i) formylating dopamine hydrochloride compound of Formula II with formylating agent in presences of base to get N-(3,4-dihydroxyphenethyl)formamide of Formula IX, wherein said formylating agent is selected from formic acid, methyl formate, ethyl formate, isopropyl formate, dimethyl formamide, trimethylorthoformate, and triethylorthoformate,
;
ii) methylating compound of Formula IX to get N-(3,4-bis(methoxy-d3)phenethyl-d6)formamide of Formula VI in presence of deuterating agent selected from deuterated methanol, i.e. CD3OD or CD3OH, and deuterated methyl iodide (CD3I),
;
iii) cyclizing N-(3,4-bis(methoxy-d3)phenethyl-d6)formamide of Formula VI in presence of dehydrating agent to obtain d6-6,7-dimethoxy-3,4-dihydroisoquinoline compound of Formula VII and/or salt thereof, wherein said dehydrating agent is selected from phosphorous oxy chloride, phosphorus pentachloride, and thionyl chloride,
;
(iv) reacting d6-6,7-dimethoxy-3,4-dihydroisoquinoline compound of Formula VII and/or salt thereof, with compound of Formula VIII in presence of solvent to obtain deutetrabenazine compound of Formula I,
,
wherein R1, R2, R3 and X are as defined above; and
v) optionally purifying compound of Formula I.

In another embodiment, the present invention provides a process for the preparation of deutetrabenazine Formula I comprising steps of:
(i) formylating dopamine hydrochloride compound of Formula II with formylating agent in presence of base to get N-(3,4-dihydroxyphenethyl)formamide of Formula IX, wherein said formylating agent is selected from formic acid, methyl formate, isopropyl formate, and dimethyl formamide,
;
(ii) cyclizing N-(3,4-dihydroxyphenethyl)formamide of Formula IX in presence of dehydrating agent to obtain 6,7-dihydroxy-3,4-dihydroisoquinoline compound of Formula XI, wherein said dehydrating agent is selected from phosphorous oxy chloride, phosphorus pentachloride, and thionyl chloride,
;
(iii) methylating 6,7-dihydroxy-3,4-dihydroisoquinoline compound of Formula XI with deuterating agent selected from deuterated methanol (CD3OD or CD3OH) and deuterated methyl iodide (CD3I), to obtain d6-6,7-Dimethoxy-3,4-dihydroisoquinoline compound of Formula VII and/ or salt thereof,
;
(iv) reacting d6-6,7-Dimethoxy-3,4-dihydroisoquinoline compound of Formula VII and/or salt thereof, with compound of Formula VIII in presence of solvent to obtain deutetrabenazine compound of Formula I,
,
wherein R1, R2, R3 and X are as defined above; and
v) optionally purifying compound of Formula I.

In another embodiment, the process of methylation of compound of Formula III, IX or XI with deuterating agent is carried out in presence of reagent selected from diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-p-chlorobenzyl azodicarboxylate (DCAD), 1,1’-(Azodicarbonyl)dipiperidine (ADDA), Tetramethyl azodicarboxamide (TMAD in combination with triphenyl phosphine.

In another embodiment, the process of methylation of compound of Formula III, IX or XI with deuterating agent is carried out at an ambient temperature of -5oC to 30oC.

In another aspect, the present invention further provides a process for the preparation of deutetrabenazine comprising the steps of:
a) nitrating 3,4-dihydroxybenzaldehyde of Formula XIII followed by formylating to obtain (E)-N-(3,4-dihydroxystyryl)formamide of Formula XV, wherein intermediate, (E)-4-(2-nitrovinyl)benzene-1,2-diol of Formula XIV is optionally isolated,
;
b) hydrogenating compound of Formula XV to obtain N-(3,4-dihydroxyphenethyl)formamide of Formula IX,
; and
c) converting compound of Formula IX to deutetrabenazine of Formula I.

In another embodiment, the present invention further provides a process for the preparation of deutetrabenazine comprising the steps of:
a) nitrating 3,4-dihydroxybenzaldehyde of Formula XIII to obtain (E)-4-(2-nitrovinyl)benzene-1,2-diol of Formula XIV,
;
b) reducing compound of Formula XIV to obtain dopamine and/ or salt thereof, wherein said reduction is optionally performed in situ without isolation of compound of Formula XIV,
;
c) formylating dopamine and/or salt thereof of step b) with formylating agent in presence of base to get N-(3,4-dihydroxyphenethyl)formamide of Formula IX,
; and
d) converting compound of Formula IX to deutetrabenazine of Formula I.

In another embodiment, the present invention provides amorphous form of deutetrabenazine substantially free from crystalline form. In one another embodiment, the present invention provides crystalline form of deutetrabenazine substantially free from amorphous form wherein amorphous form is less than about 5% of crystalline form, preferably less than about 1% of crystalline form and most preferably less than about 0.5% of crystalline form.

The present invention may further provide amorphous or crystalline form of deutetrabenazine prepared as per the process of the present invention wherein said deutetrabenazine is isolated is anhydrous, hydrates or solvates in nature.

In one another embodiment, the present invention provides substantially pure deutetrabenazine free of impurities of Formula A to I, where each impurity is less than about 1.0% w/w, preferably less than about 0.5% w/w and more preferably 0.3% w/w, and most preferably 0.1% w/w;
, , , , , ,
, , and .

In a preferred embodiment, the deutetrabenazine as prepared by the process of the present invention is substantially pure with each impurity is less than about 0.3% w/w and wherein said deutetrabenazine is isolated with purity of 99.0% and above, and preferably 99.9% above.

In one another embodiment, the present invention provides an amorphous solid dispersion of deutetrabenazine comprising deutetrabenazine along with pharmaceutical acceptable excipient(s).

In one another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of deutetrabenazine comprising the steps of:
a) providing a solution of deutetrabenazine in a suitable solvent;
b) adding atleast one pharmaceutically acceptable excipient to the solution obtained in step a); and
c) isolating the amorphous solid dispersion of deutetrabenazine.

In further embodiment, the deutetrabenazine described herein, for the preparation of various amorphous solid dispersion are amorphous, or crystalline in nature. Even the reaction mixture containing deutetrabenazine can be used for preparing solid dispersions.

In further embodiment, pharmaceutically acceptable excipient may include, but not limited to water soluble and water insoluble polymer.

In another embodiment, the present invention provides the deutetrabenazine of Formula I that is characterized by particle size distribution wherein, d90 is 0.1µm to 200µm, preferably d90 is 2.0 µm to 150µm.

In another embodiment, the present invention provides the amorphous solid dispersion of deutetrabenazine that is characterized by particle size distribution wherein, d90 is not more than 1.0mm.

In another embodiment, the present invention further provides a composition comprising deutetrabenazine as prepared by the process of the present invention, along with atleast one pharmaceutical acceptable excipients.

In another embodiment, the present invention further provides method of treating chorea associated with Huntington’s disease and tardive dyskinesia by administering deutetrabenazine prepared as per the process of the present invention.
EXAMPLES
Example 1: Preparation of N-(3,4-dihydroxyphenethyl)formamide of Formula IX:
Triethylamine (789.21 mmol) was added to a suspension of 4-(2-aminoethyl)benzene-1,2-diol hydrochloride of Formula II (100.0 g) in methyl formate (500 mL) at 0oC. Reaction mixture was stirred at 55oC for 15 hours. After completion of reaction (monitored by TLC) excess methyl formate was removed under reduced pressure at 45oC. The resulting residue was diluted with water (500 mL) and stirred at room temperature for 1 hour. The solid separated was filtered off and washed with water (3 x 100 mL). Isolated solid was dried at 65°C for 12 hours yielding 62.0 g pure N-(3,4-dihydroxyphenethyl)formamide.
Example 2: Preparation of N-(3,4-bis(methoxy-d3)phenethyl-d6)formamide of Formula VI:
CD3OH (693.1 mmol) was added to a solution of N-(3,4-dihydroxyphenethyl) formamide (25.0 g) and triphenylphosphine (415.6 mmol) in dry THF (250 mL) at 0oC under nitrogen. DIAD (420.35 mmol) was added to reaction mixture at 0 oC under nitrogen. Reaction mixture stirred at room temperature for 15 h. After completion of reaction (monitored by TLC), reaction mixture concentrated under reduced pressure at 45oC. The resulting crude was purified by column chromatography on silica gel, eluting with 5% MeOH in MDC, yielding 25 g pure N-(3,4-bis(methoxy-d3)phenethyl-d6)formamide of Formula VI.
Example 3: Preparation of d6-6,7-Dimethoxy-3,4-dihydroisoquinoline compound of Formula VII (free base):
A solution of N-(3,4-bis(methoxy-d3)phenethyl-d6)formamide of Formula VI (15 g) in dichloromethane (50 mL) was added to a suspension phosporous pentachloride (63.87 mmol) in dichloromethane (70 mL) at room temperature. Reaction mixture stirred at room temperature for 2 h. After completion of reaction (monitored by TLC), reaction mixture was added to a mixture of crushed ice (55 g) and n-hexane (55 mL). Aqueous layer was kept aside and organic layer was washed with water (55 mL). The combined aqueous layer was acidified with aqueous potassium hydroxide solution. Product was extracted with dichloromethane (5 x 110 mL). The combined organic layer dried over sodium sulphate, filtered and concentrated under reduced pressure at 45oC to furnish 9.5 g crude product. The solid isolated was dried at 40oC for 6 h under reduced pressure, yielding 14.0 g pure d6-6,7-Dimethoxy-3,4-dihydroisoquinoline compound of Formula X.
Example 4: Preparation of Deutetrabenazine of Formula I:
Potassium carbonate (128.36 mmol) was charged slowly to a solution of d6-6,7-Dimethoxy-3,4-dihydroisoquinoline compound of Formula X (30.0 g, 128.36 mmol) and 2-acetyl-N,N,N,4-tetramethylpentan-1-aminium iodide (154.04 mmol) in methanol (135.0 mL) and Water (45.0 mL) at room temperature. Reaction mixture stirred at 45°C for 30 h. After completion of reaction (monitored by TLC), the contents were brought to room temperature and water (90.0 mL) was added into reaction mixture and stirred for 1 hour. The solid separated was filtered off and washed with water (3 x 30 mL), dried at 50oC for 6 h under reduced pressure furnishing 33.0 g crude product. To the crude product obtained was added methanol (130.0 mL) and maintained at 65oC for 1 hour. The temperature was brought down to 0oC and stirring continued for 1 hour. The solid separated was filtered off and washed with chilled methanol (2 x 25.0 mL), dried at 50oC for 6 hours under reduced pressure, yielding 25.0 g pure deutetrabenazine as a White solid (Yield: 85 %).
Example 5: Preparation of N-(3,4-bis(methoxy-d3)phenethyl-d6)formamide of Formula VI:
CD3I (30 g) was added to a solution of N-(3,4-dihydroxyphenethyl)formamide of Formula IX (30 g) and Triphenyl phosphine (461.32 mmol) in anhydrous THF (250.0 mL) at 0oC under nitrogen. DIAD (459.92 mmol) was added into reaction mixture at 0°C and reaction mixture stirred at room temperature for 15 h. After completion of reaction (monitored by TLC), solvent was removed under reduced pressure at 45oC and the resulting crude was purified by column chromatography on silica gel, eluting with CH2Cl2: MeOH (95:5), yielding 28.0g of desired compound.
Example 6: Preparation of tert-butyl (3,4-dihydroxyphenethyl)carbamate of Formula III:
A solution of dopamine hydrochloride (209 g, 1.00 eq.), sodium carbonate (2.50 eq.) and di-tert-butyl dicarbonate (1.10 eq.) in 2.4L tetrahydrofuran / water (5: 1) was stirred at 20°C for 2.5 h. After the starting material was consumed completely, the reaction was diluted with ethyl acetate (2 L) and washed with water (2x600 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure until two volumes of solvent was left. The precipitated solid was isolated by filtration and dried under vacuum to give 260g of desired compound.
Example 7: Preparation of tert-butyl (3,4-bis(methoxy-d3)phenethyl)carbamate of Formula IV:
A solution of tert-butyl (3,4-dihydroxyphenethyl)carbamate of Formula III (130 g, 1.00 equiv), potassium carbonate (3.00 equiv) and 18-crown-6(1,4,7,10,13,16- hexaoxacyclooctadecane) (0.03 equiv) in acetone (800 mL) was stirred at 38°C. After 30 min., CD3OD (3.00 equiv) was added to the reaction, and the mixture was stirred at 38°C for 12 h. Then an additional CD3OD (1.00 equiv) was added to the solution and the solution was stirred for 5 h. Then the mixture was cooled to room temperature and the solid was filtered. The filtrate was concentrated under vacuum. The resultant solid was dissolved in water (300 mL) and extracted with ethyl acetate (3x300 mL), the organic layers was combined and concentrated under vacuum to give 120g of desired compound.
Example 8: Preparation of 2-(3,4-bis(methoxy-d3)phenyl)ethan-1-amine of Formula V:
A solution of tert-butyl (3,4-bis(methoxy-d3)phenethyl)carbamate of Formula IV (100 g, 1.00 eq.) in ethyl acetate (1.5 L) was stirred at room temperature. Then HCl gas was introduced into the reaction mixture for 2h. The precipitated solid was isolated by filtration. The solid was dissolved in 300 mL of water. The pH value of the solution was adjusted to 12 with sodium hydroxide (solid). The resulting solution was stirred for 1 h at 5- 10°C. The resulting solution was extracted with 6x800 mL of ethyl acetate and the organic layers combined, dried over sodium sulfate, and concentrated under vacuum to give 80g of desired compound.
Example 9: Preparation of d6-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide of Formula VI:
A solution of 2-(3,4-bis(methoxy-d3)phenyl)ethan-1-amine of Formula V (69 g, 1.00 equiv) in methyl formate (220 mL) was heated under reflux overnight. The solution was concentrated under vacuum to give 70 g of d6-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide.
Example 10: Preparation of 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride of Formula VII (HCl salt):
A solution of d6-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide of Formula VI (70 g, 1.00 equiv) in phosphorus oxychloride (100 mL) was stirred at 105°C for 1 h. Then the solution was concentrated under vacuum to remove phosphorus oxychloride. The residual oil was dissolved in ice / water. The solution was made basic with potassium carbonate with cooling. The basic aqueous solution was extracted with dichloromethane. The collected organic phase was dried using sodium sulfate and then filtered. The dichloromethane was removed by concentration under vacuum to give an orange oil.
Example 11: Preparation of Deutetrabenazine:
Potassium carbonate (128.36 mmol) was charged slowly to a solution of d6-6,7-Dimethoxy-3,4-dihydroisoquinoline hydrochloride compound of Formula VII (30.0 g) and 2-acetyl-N,N,N,4-tetramethylpentan-1-aminium iodide (154.04 mmol) in methanol (135.0 mL) and water (45.0 mL) at room temperature. Reaction mixture stirred at 45°C for 30 h. After completion of reaction (monitored by TLC), the contents were brought to room temperature and water (90.0 mL) was added into reaction mixture and stirred for 1 hour. The solid separated was filtered off and washed with water (3 x 30 mL), dried at 50oC for 6 h under reduced pressure furnishing 33.0 g crude product. To the crude product obtained was added methanol (130.0 mL) and maintained at 65oC for 1 hour. The temperature was brought down to 0oC and stirring continued for 1 hour. The solid separated was filtered off and washed with chilled methanol (2 x 25.0 mL), dried at 50oC for 6 hours under reduced pressure, yielding 25.0 g pure deutetrabenazine as a white solid (Yield: 88 %).
Example 12: Preparation of amorphous amorphous solid dispersion of Deutetrabenazine with povidone K 30
Deutetrabenazine (500 mg), povidone K 30 (500 mg) and methanol (50 ml) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 15 minutes at 50°C. The reaction mass temperature cooled to 25°C. The reaction mass was filtered to remove any insoluble particles. The reaction mass was evaporated under vacuum at 55°C for over 20 minutes.
Example 13: Preparation of amorphous amorphous solid dispersion of Deutetrabenazine with hydroxypropyl cellulose
Deutetrabenazine (500 mg), hydroxypropyl cellulose (500 mg) and methanol (50 ml) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 15 minutes at 50°C. The reaction mass temperature cooled to 25°C. The reaction mass was filtered to remove any insoluble particles. The reaction mass was evaporated under vacuum at 55°C for over 20 minutes.

WE CLAIM

1. A process for the preparation of deutetrabenazine of Formula I

comprising the steps of:
a) methylating compound of Formula A to get deuterated compound of Formula B in presence of deuterated agent,

wherein R is selected from Boc and -CHO, or
methylating compound of Formula XI to get d6-6,7-Dimethoxy-3,4-dihydroisoquinoline compound of Formula VII and/ or salt thereof, in presence of deuterating agent,
,
wherein said deuterating agent is represented as compound of Formula XIII,
,
wherein Y2 is selected from the group consisting of hydroxyl, halogen, alkyl sulfate, alkyl sulfonate, halosulfonate, perhaloalkyl sulfonate, aryl sulfonate, alkylaryl sulfonate, dialkyloxonium, alkylphosphate, and alkylcarbonate, any of which may be optionally substituted; and
b) converting compound of Formula B or VII to deutetrabenazine of Formula I.

2. The process as claimed in claim 1, wherein said compound of Formula A is represented as compound of Formula III and IX,
, and .

3. The process as claimed in claim 1, wherein said compound of Formula B is represented as compound of Formula IV and VI,
, and .

4. The process as claimed in claim 1, wherein said deuterating agent is selected from deuterated methanol (CD3OD or CD3OH) and deuterated methyl iodide (CD3I).

5. A process for the preparation of deutetrabenazine compound of Formula I,

comprising the steps of:
a) adding 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline of Formula VII and/or salt thereof, with compound of Formula VIII in presence of solvent to obtain deutetrabenazine compound of Formula I,
,
wherein R1, R2, R3 are independently selected from (un)substituted C1-C6 alkyl, (un)substituted cycloalkyl, (un)substituted cycloheteroalkyl, (un)substituted aryl, (un)substituted alkaryl, (un)substituted heteroaryl; X is selected from halogen, alkyl sulfate, alkyl sulfonate, halosulfonate, perhaloalkyl sulfonate, aryl sulfonate, alkylaryl sulfonate, dialkyloxonium, alkylphosphate, and alkylcarbonate, any of which may be optionally substituted; and
vii) optionally purifying compound of Formula I.

6. A process for the preparation of deutetrabenazine compound of Formula I, comprising the steps of:
a) formylating 2-(3,4-bis(methoxy-d3)phenyl)ethan-1-amine of Formula V in presence of formylaing agent to get d6-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide of Formula VI,
, or
formylating dopamine hydrochloride compound of Formula II with formylating agent to get N-(3,4-dihydroxyphenethyl)formamide of Formula IX,
,
wherein said formylating agent is represented by Formula XII or C1-C6 alkyl orthoformate,

wherein Y represents group consisting of hydroxyl, acetoxy, alkoxy, halogen, haloalkoxy, perhaloalkoxy, heteroalkoxy, and aryloxy, any of which may be optionally substituted, NR4R5, wherein R4 and R5 are independently selected from hydrogen, (un)substituted alkyl and the like;
and R is selected from the group consisting of hydrogen and deuterium; and
b) converting compound of Formula VI or Formula IX to deutetrabenzine of Formula I.

7. The process as claimed in claim 6, wherein said formylating agent is selected from formic acid, methyl formate, isopropyl formate, trimethylorthoformate, triethylorthoformate and dimethyl formamide.

8. The process as claimed in any of the preceding claim, wherein said process further comprises the steps of:
(i) cyclizing N-(3,4-dihydroxyphenethyl)formamide of Formula IX in presence of dehydrating agent to obtain 6,7-dihydroxy-3,4-dihydroisoquinoline compound of Formula XI,
; or
cyclizing N-(3,4-bis(methoxy-d3)phenethyl-d6)formamide of Formula VI in presence of dehydrating agent to obtain d6-6,7-dimethoxy-3,4-dihydroisoquinoline compound of Formula VII and/or salt thereof,
;
wherein said dehydrating agent is selected from phosphorous oxy chloride, phosphorus pentachloride, and thionyl chloride,
(ii) methylating 6,7-dihydroxy-3,4-dihydroisoquinoline compound of Formula XI with deuterating agent to obtain d6-6,7-Dimethoxy-3,4-dihydroisoquinoline compound of Formula VII and/ or salt thereof,
;
(iii) reacting d6-6,7-Dimethoxy-3,4-dihydroisoquinoline compound of Formula VII and/or salt thereof obtained from step (i) or (ii), with compound of Formula VIII in presence of solvent to obtain deutetrabenazine compound of Formula I,
,
wherein R1, R2, R3 and X are as defined above; and
(iv) optionally purifying compound of Formula I.

9. Substantially pure deutetrabenazine obtained by the process of any of the preceding claim wherein said deutetrabenazine is characterized by purity of 99.0% and above with each impurity less than about 0.3% w/w.

10. A process for the preparation of an amorphous solid dispersion of deutetrabenazine comprising the steps of:
a) providing a solution of deutetrabenazine in a suitable solvent;
b) adding atleast one pharmaceutically acceptable excipient to the solution obtained in step a); and
c) isolating the amorphous solid dispersion of deutetrabenazine.