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 VALBENAZINE”

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 valbenazine and salts thereof.

BACKGROUND OF THE INVENTION
Valbenazine, also known as L-valine (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester, is represented by the structure of formula II.
II
Valbenazine acid addition salts are represented by the structure of formula I.
I
Valbenazine tosylate, a compound of formula Ia, is a vesicular monoamine transporter 2 (VMAT2) inhibitor indicated for the treatment of adults with tardive dyskinesia.
Ia

SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of valbenazine, a compound of formula II or salts thereof,
II
the process comprising:
(a) reacting tetrabenazine, a compound of formula V,
V
with a chiral resolving agent (HA) to give (3R,11bR)-tetrabenazine, a compound of formula Va;
Va
(b) reducing the compound of formula Va, to give (2R,3R,11bR)-dihydrotetrabenazine, a compound of formula IVa, as the major diastereomer and (2S,3R,11bR)-dihydrotetrabenazine, a compound of formula IVb, as the minor diastereomer;
IVa IVb
(c) reacting the compound of formula IVa, with N-protected-L-valine to give N-protected valbenazine, the compound of formula III,
III
wherein R is selected from the group consisting of Boc, Cbz, Fmoc, acetyl, trifluoroacetyl, benzyl, trityl, tosyl and mesyl;
(d) deprotecting the compound of formula III to give valbenazine, the compound of formula II;
(e) optionally, reacting the compound of formula II with an acid to give valbenazine acid addition salt.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic XRPD of valbenazine dihydrobromide as obtained in Example 6.
Figure 2 is a characteristic XRPD of valbenazine disulphate as obtained in Example 7.
Figure 3 is a characteristic XRPD of valbenazine ditosylate as obtained in Example 9.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of valbenazine, a compound of formula II or salts thereof,
II
the process comprising:
(a) reacting tetrabenazine, a compound of formula V,
V
with a chiral resolving agent (HA) to give (3R,11bR)-tetrabenazine, a compound of formula Va;
Va
(b) reducing the compound of formula Va, to give (2R,3R,11bR)-dihydrotetrabenazine, a compound of formula IVa, as the major diastereomer and (2S,3R,11bR)-dihydrotetrabenazine, a compound of formula IVb, as the minor diastereomer;
IVa IVb
(c) reacting the compound of formula IVa, with N-protected-L-valine to give N-protected valbenazine, the compound of formula III,
III
wherein R is selected from the group consisting of Boc, Cbz, Fmoc, acetyl, trifluoroacetyl, benzyl, trityl, tosyl and mesyl;
(d) deprotecting the compound of formula III to give valbenazine, the compound of formula II;
(e) optionally, reacting the compound of formula II with an acid to give valbenazine acid addition salt.
In the present application, the term “room temperature” means a temperature of about 25°C to about 30°C.
In (a) of the process for the preparation of valbenazine, tetrabenazine is reacted with chiral resolving agent (HA) to give (3R,11bR)-tetrabenazine.
A suitable chiral resolving agent (HA) includes but is not limited to acids such as camphorsulfonic acid, bromocamphorsulfonic acid, camphanic acid, camphoric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, dibenzyl tartaric acid, diethyl tartrate, diisopropyl tartrate, tartaric acid, ditolyl tartaric acid, quinic acid, pyroglutamic acid, phenylpropionic acid, naphthyl ethylsuccinamic acid, malic acid, mandelic acid, glutamic acid, or mixtures thereof.
The reaction may be carried out in the presence of a solvent. A suitable solvent includes, but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; 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; water or mixtures thereof.
The reaction may be carried out at a temperature of about 10°C to about reflux temperature of the solvent.
In one embodiment, step (a) of the above process comprises:
(ai) reacting tetrabenazine, a compound of formula V, with a chiral resolving agent (HA) to form an isomeric mixture of the compound of formula VI;
VI
(aii) separating the desired (R,R)-isomer, a compound of formula VIa, and the undesired (S,S)-isomer, a compound of formula VIb, from the isomeric mixture of the compound of formula VI;
VIa VIb
(aiii) optionally, recycling the undesired (S,S)-isomer, the compound of formula VIb, to generate an isomeric mixture of the compound of formula VI;
(aiv) optionally, repeating steps (aii) and (aiii); and
(av) converting the (R,R)-isomer, the compound of formula VIa, obtained in step (aii) to (3R,11bR)-tetrabenazine, the compound of formula Va.
In step (ai) of the above process, tetrabenazine is reacted with a chiral resolving agent to form an isomeric mixture of the compound of formula VI.
In one embodiment, the chiral resolving agent selected is di-p-tolyl-L-tartaric acid.
In one embodiment, step (ai) of the above process is carried out in solvent selected from the group consisting of methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and mixtures thereof.
In one embodiment, step (ai) of the above process is carried out in ethyl acetate.
In one embodiment, step (ai) is carried out at a temperature of about 10°C to about reflux temperature of the solvent.
In one embodiment, step (ai) is carried out at about room temperature.
In one embodiment, step (ai) is carried out at a temperature of about 75°C to about 80°C.
In one embodiment, step (ai) is carried out in ethyl acetate at about room temperature.
In one embodiment, step (ai) is carried out in ethyl acetate at a temperature of about 75°C to about 80°C.
In step (aii) of the above process, the desired (R,R)-isomer, a compound of formula VIa, and the undesired (S,S)-isomer, a compound of formula VIb, are separated from the isomeric mixture of the compound of formula VI, by any of the following:
(x) by carrying out step (ai) in a solvent in which one of the isomers, or salt thereof is soluble and the other isomer, or salt thereof is insoluble and precipitated out; or
(y) by carrying out step (ai) in a solvent and by adding an anti-solvent to it wherein one of the isomers, or salt thereof is precipitated out; or
(z) by removing the solvent of step (ai) and adding a second solvent to it in which one of the isomers, or salt thereof is soluble and the other isomer, or salt thereof is insoluble and precipitated out.
In one embodiment, the RR-isomer, the compound of formula VIa is selectively separated from the SS-isomer, the compound of formula VIb by being insoluble and precipitated out in the solvent and the SS-isomer, or salt thereof being soluble in the solvent.
In one embodiment, the RR-isomer, the compound of formula VIa is selectively separated from the SS-isomer, the compound of formula VIb by being insoluble and precipitated out in ethyl acetate and the SS-isomer being soluble in ethyl acetate.
In one embodiment, the RR-isomer, the compound of formula VIa is selectively separated from the SS-isomer, the compound of formula VIb by being soluble in the solvent and the SS-isomer, or salt thereof being insoluble and precipitated out in the solvent.
In one embodiment, the RR-isomer, the compound of formula VIa is selectively separated from the SS-isomer, the compound of formula VIb by addition of a suitable anti-solvent wherein one of the isomers, or salt thereof is precipitated out.
A suitable anti-solvent includes but is not limited to ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; dimethyl formamide, dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.
In one embodiment, the RR-isomer, the compound of formula VIa is selectively separated from the SS-isomer, the compound of formula VIb by completely removing the solvent of step (ai) and addition of a second solvent to obtain a slurry.
In one embodiment, in the obtained slurry the RR-isomer, the compound of formula VIa remains insoluble and the SS-isomer, the compound of formula VIb remains in solution.
In one embodiment, in the obtained slurry the SS-isomer, the compound of formula VIb remains insoluble and the RR-isomer, the compound of formula VIa remains in solution.
In one embodiment, the RR-isomer, the compound of formula VIa, or salt thereof is selectively separated from the above slurry by methods known in the art such as filtration, centrifugation and the like.
In one embodiment, the SS-isomer, the compound of formula VIb is selectively separated from the above slurry by methods known in the art such as filtration, centrifugation and the like.
The second solvent includes but is not limited to ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; dimethyl formamide, dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.
In step (aiii) of the above process, the undesired (S,S)-isomer, the compound of formula VIb, is optionally recycled to generate an isomeric mixture of the compound of formula VI.
In one embodiment, the undesired (S,S)-isomer, the compound of formula VIb, is recycled to generate an isomeric mixture of the compound of formula VI by stirring and/or heating the solution containing the compound of formula VIb.
In one embodiment, the solution containing the compound of formula VIb is the reaction mixture of step (ai) wherein the compound of formula VIb is soluble in the solvent and remains in the solution.
In one embodiment, the undesired (S,S)-isomer, the compound of formula VIb, which is soluble in solvent of step (ai), is recycled by stirring and/or heating the reaction mixture obtained in step (ai) to generate an isomeric mixture of the compound of formula VI.
In one embodiment, the undesired (S,S)-isomer, the compound of formula VIb, which is soluble in solvent of step (ai), is recycled by stirring and/or heating the reaction mixture obtained in step (ai) to generate an isomeric mixture of the compound of formula VI, wherein the solvent of step (ai) is ethyl acetate.
In step (aiv) of the above process, the steps of isomeric separation of RR-isomer, the compound of formula VIa and SS-isomer, the compound of formula VIb, and recycling of SS-isomer, the compound of formula VIb, to give isomeric mixture of isomeric mixture of the compound of formula VI are optionally repeated to increase the productivity of RR-isomer, the compound of formula VIa.
In step (av) of the above process, the (R,R)-isomer, the compound of formula VIa, is treated with a base to give (3R,11bR)-tetrabenazine, the compound of formula Va.
A suitable base includes, but is not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, ammonia; or mixtures thereof.
In one embodiment, step (av) of the above process is carried out in the presence ammonia.
In one embodiment, step (av) of the above process is carried out in the presence of a solvent selected from esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; 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; water or mixtures thereof.
In one embodiment, step (av) of the above process is carried out in methanol.
In one embodiment, step (av) of the above process is carried out at about room temperature.
In one embodiment, the compound of formula Va is obtained in a yield of >50%.
In one embodiment, the present invention provides (3R,11bR)-tetrabenazine, the compound of formula Va in a yield of >50%, the process comprising:
(ai) reacting tetrabenazine, a compound of formula V, with a chiral resolving agent (HA) to form an isomeric mixture of the compound of formula VI;
(aii) separating the desired (R,R)-isomer, a compound of formula VIa, and the undesired (S,S)-isomer, a compound of formula VIb, from the isomeric mixture of the compound of formula VI;
(aiii) recycling the undesired (S,S)-isomer, the compound of formula VIb, to generate an isomeric mixture of the compound of formula VI;
(aiv) optionally, repeating steps (aii) and (aiii); and
(av) converting the (R,R)-isomer, the compound of formula VIa, obtained in step (aii) to (3R,11bR)-tetrabenazine, the compound of formula Va.
In one embodiment, the present invention provides (3R,11bR)-tetrabenazine, the compound of formula Va in a yield of >50%, the process comprising:
(ai) reacting tetrabenazine, a compound of formula V, with di-p-tolyl-L-tartaric acid to form an isomeric mixture of the compound of formula VI in ethyl acetate at about reflux temperature;
(aii) separating the desired (R,R)-isomer, a compound of formula VIa, and the undesired (S,S)-isomer, a compound of formula VIb, from the isomeric mixture of the compound of formula VI;
(aiii) recycling the undesired (S,S)-isomer, the compound of formula VIb, to generate an isomeric mixture of the compound of formula VI;
(aiv) optionally, repeating steps (aii) and (aiii); and
(av) converting the (R,R)-isomer, the compound of formula VIa, obtained in step (aii) to (3R,11bR)-tetrabenazine, the compound of formula Va.
In (b) of the process for the preparation of valbenazine, the compound of formula Va is reduced to give (2R,3R,11bR)-dihydrotetrabenazine, a compound of formula IVa, as the major diastereomer and (2S,3R,11bR)-dihydrotetrabenazine, a compound of formula IVb, as the minor diastereomer.
The term “major diastereomer” means the compound of formula IVa is obtained in a chiral purity of =50%.
In one embodiment, the term “major diastereomer” means the compound of formula IVa is obtained in a chiral purity of =80%.
The term “minor diastereomer” means the compound of formula IVb is obtained in a chiral purity of =50%.
In one embodiment, the term “minor diastereomer” means the compound of formula IVb is obtained in a chiral purity of =20%.
In one embodiment, the compound of formula Va is reduced to give the compound of formula IVa, as major diastereomer and the compound of formula IVb, as minor diastereomer with the ratio of major to minor diastereomers of =4:1.
The reaction may be carried out in the presence of a reducing agent selected from the group consisting of hydrides such as sodium borohydride, lithium borohydride, lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxyborohydride; borane complexes such as borane-tetrahydrofuran, borane-dimethylsulfide, and mixtures thereof. Preferably, the reducing agent selected is sodium borohydride.
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 and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; dimethyl formamide; dimethyl sulfoxide; dimethyl acetamide; water or mixtures thereof. Preferably, the solvent selected is methanol, ethanol, tetrahydrofuran or mixtures thereof.
In one embodiment, the compound of formula IVa is purified using solvents selected from the group consisting of alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane; water and mixtures thereof.
In one embodiment, the compound of formula IVa is purified using cyclohexane.
In one embodiment, the compound of formula IVa is purified using methanol-water mixture.
In one embodiment, the compound of formula IVa prepared by the process described herein, is obtained in a chiral purity of =80%.
In one embodiment, the compound of formula IVa prepared by the process described herein, is obtained in a chiral purity of =99%.
In one embodiment, the present invention provides the compound of formula IVa as the major diastereomer with a chiral purity of =99%, the process comprising:
(i) reducing the compound of formula Va using sodium borohydride to give compound of formula IVa; and
(ii) purifying the compound of formula IVa using cyclohexane.
In one embodiment, the present invention provides the compound of formula IVa as major diastereomer with a chiral purity of =99%, the process comprising:
(i) reducing the compound of formula Va using sodium borohydride to give compound of formula IVa; and
(ii) purifying the compound of formula IVa using methanol-water mixture.
In (c) of the process for the preparation of valbenazine, the compound of formula IVa is reacted with N-protected-L-valine to give N-protected valbenazine, the compound of formula III.
The reaction may be carried out in the presence of a coupling reagent selected from the group consisting of 1,1'-carbonyldiimidazole (CDI), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), 1,3-dicyclohexylcarbodiimide (DCC) and mixtures thereof. Preferably, the coupling reagent selected is DCC.
The reaction may be carried out in the presence of a base selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, 4-dimethylaminopyridine and mixtures thereof. Preferable the base selected is 4-dimethylaminopyridine.
In (d) of the process for the preparation of valbenazine, the compound of formula III is deprotected to give valbenazine.
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.
The metal catalyst used for deprotection in hydrogenation reaction includes but is not limited to platinum oxide, palladium oxide, palladium on carbon. Preferably the hydrogenation catalyst selected is palladium on carbon.
In (e) of the above process, valbenazine is reacted with an acid to give valbenazine acid addition salt.
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 or malic acid.
The reaction is 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 present invention provides valbenazine dihydrobromide as depicted in Figure 1.
In one embodiment, the present invention provides valbenazine disulphate characterized by Figure 2.
In one embodiment, the present invention provides pharmaceutical compositions comprising valbenazine or salt 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 valbenazine or salt 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 valbenazine or salt 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 (3R,11bR)-tetrabenazine
To a mixture of tetrabenazine (9g) in ethyl acetate (270mL), was added di-p-tolyl-L-tartaric acid (5.48g) at about room temperature and the reaction mixture was maintained for about 3h at about room temperature. The reaction mixture was filtered and washed with ethyl acetate. The solid obtained was again slurry washed with ethyl acetate at about 40°C to about 45°C. The slurry mass was filtered and washed with ethyl acetate. The solid obtained was dried at about 50°C to about 55°C under reduced pressure for about 1h. The solid obtained was dissolved in methanol (25mL) and the reaction mixture was stirred for about 15min to about 25min at about room temperature. The reaction mass was neutralized by adding ammonia solution (1.25mL) and water (165mL) was added to the mass for complete precipitation and stirred for about 1h. The solid product was filtered, suction dried followed by vacuum drying to give (3R,11bR)- tetrabenazine as white solid.
Yield: 2.8g
[a]D22= +68.38° (c 1.04, MeOH)

EXAMPLE 2: Preparation of (3R,11bR)-tetrabenazine
To a mixture of tetrabenazine (1g) in ethyl acetate (15mL), was added di-p-tolyl-L-tartaric acid (2.4g) at about room temperature and the reaction mixture was heated to about reflux temperature for about 3h and cooled to about room temperature. The reaction mixture was then stirred for about 15h, filtered and washed with ethyl acetate. The solid obtained was again slurry washed with ethyl acetate at about 50ºC to about 55ºC. The solid obtained was dried at about 50ºC to about 55ºC under reduced pressure for about 1h. The solid obtained was dissolved in methanol (9mL) and the reaction mixture was stirred for about 15min to about 25min at about room temperature. The reaction mass was neutralized by adding ammonia solution (5mL) and water (18mL) was added to the mass for complete precipitation and stirred for about 1h. The solid product was filtered and dried.
Yield: 0.75g
[a]D22= +66.01° (c 1.04, MeOH)

EXAMPLE 3: Preparation of 2R,3R,11bR- dihydrotetrabenazine
To a mixture of 3R,11bR-tetrabenazine (2g) in tetrahydrofuran (10mL) and methanol (4mL) cooled to about 0ºC to 5ºC, was added sodium borohydride (0.24g) and the reaction mixture was maintained at about the same temperature for about 2h. The reaction mixture was quenched with aqueous ammonium chloride solution and water. The reaction mixture was stirred for about 10min to about 15min at about 0ºC to about 5ºC. The temperature of the reaction mixture was raised to about room temperature and ethyl acetate was added to it. The reaction mixture was stirred for about 10min to about 15min at about room temperature and the two layers were separated. The organic layer was concentrated under reduced pressure to give a residue. Cyclohexane was added to the residue and the mixture was maintained at about room temperature for about 2h. The solid obtained was filtered and dried.
Yield: 1.8g
[a]D25= + 55.38° (c 0.6, MeOH)

EXAMPLE 4: Preparation of 2R,3R,11bR-dihydrotetrabenazine
A mixture of 3R,11bR-tetrabenazine (10g) in ethanol (200mL) was cooled to about -3ºC to 3ºC. Sodium borohydride (1.01g) was added to the reaction mixture by maintaining the temperature between about 0ºC to about 5ºC. The reaction mixture was stirred for about 2h at about 0°C to about 5°C. The reaction mixture was quenched with water (5mL) followed by addition of methylene chloride. The reaction mixture was stirred for about 10min to about 15min at about 0ºC to about 5ºC and ammonium hydroxide was added. The temperature was raised to about room temperature and the two layers were separated. The organic layer was concentrated under reduced pressure to give a residue. Methanol and water were added dropwise to the residue and the solid obtained was filtered and vacuum dried.
Yield: 9g
M.P. 99.0 to 99.2°C,
[a]D25= +59.33°, (c 1.04, MeOH)

EXAMPLE 5: Preparation of valbenazine
To a mixture of 2R,3R,11bR-dihydrotetrabenazine (15g) in methylene chloride (225mL) was added 4-dimethylaminopyridine (4.6g) and Cbz-L-valine (14g). The reaction mixture was cooled to about 0ºC to about 5ºC, stirred for about 5min and N,N'-dicyclohexylcarbodiimide (12.1g) was added to it. The reaction mixture was stirred for about 4h, filtered and washed with dilute hydrochloric acid. To the filtrate, aqueous sodium bicarbonate solution was added and the reaction mixture was stirred. The two layers were separated and the organic layer was concentrated under reduced pressure to give a residue. To the residue, methanol was added followed by wet palladium on carbon (2.4g) and the reaction mixture was stirred under hydrogen pressure. The reaction mixture was filtered, concentrated and degassed. Cyclohexane was added to the obtained solid and the mixture was stirred for about 30min. The solid was filtered, dried under reduced pressure to give valbenazine.
Yield: 65%

EXAMPLE 6: Preparation of valbenazine dihydrobromide
A solution of valbenazine (0.5g) in acetonitrile (5mL) was stirred for about 10min. The reaction mixture was cooled to about 0ºC to about 5ºC and aqueous hydrogen bromide (48%w/w, 0.4gm) was added to it. The temperature of the reaction mixture was raised to about room temperature. The reaction mixture was stirred for about 1h at about the same temperature and concentrated under reduced pressure to give a residue. Ethyl acetate was added to the reaction mixture and the solid obtained was filtered, washed with ethyl acetate and dried at about 50ºC to give valbenazine dihydrobromide.
Yield: 0.67g
1H NMR (400MHz, DMSO): d 10.5 (bs,1H), 8.5 (bs,3H), 6.8 (s,2H), 5.1 (s,1H), 4.6 (s,1H), 4.0 (s,1H), 3.75 (s,3H), 3.74 (s,3H), 3.61-3.59 (m,1H), 3.18-2.93 (m,6H), 2.21-2.19 (m,2H), 1.9 (d,1H), 1.60 (d,1H), 1.31 (t,1H), 1.12-1.08 (m,1H), 1.02 (d,6H), 0.89 (d,6H)

EXAMPLE 7: Preparation of valbenazine disulphate
Sulphuric acid (0.23g) was added to a solution of valbenazine (0.5g) in acetonitrile (5mL) and the reaction mixture was stirred for about 10min at about room temperature. Diisopropyl ether (50mL) was added and the reaction mixture was stirred for about 50min at about the same temperature. The solid obtained was filtered, washed with diisopropyl ether and dried under reduced pressure to give valbenazine disulphate.
Yield: 0.40g
[a]D20= +7.10° (c 0.2, MeOH).
1H NMR (400MHz, DMSO): d 8.20 (bs,6H), 6.7 (s,1H), 6.68 (s,1H), 5.23 (s,1H), 4.76 (d,1H), 3.93-3.88 (m,1H), 3.75 (s,3H), 3.71 (s,3H), 3.33-3.30 (m,1H), 3.15-2.89 (m,3H), 2.69-2.45 (m,3H), 2.22-2.13 (m,2H), 1.89 (d,1H), 1.73-1.45 (m,1H), 1.44 (t,1H), 1.1-1.06 (m,1H), 1.02 (d,6H), 0.85 (d,6H)

EXAMPLE 8: Preparation of valbenazine ditosylate
p-Toluene sulfonic acid (0.3g) was added to a solution of valbenazine (12g) in acetonitrile (36mL). The solution was heated to about 45ºC to about 50ºC and was stirred for about 15h. Acetonitrile (12mL) was added to the reaction mixture which was stirred for about 20min at about 50ºC. The reaction mixture was cooled to about 25ºC, stirred for about 20min, filtered and vacuum dried to give valbenazine ditosylate.
Yield: 13g

EXAMPLE 9: Preparation of valbenazine ditosylate
Valbenazine tosylate (1g) was dissolved in methanol (2mL) and methyl tert-butyl ether (20mL) was added slowly to the mixture. To the mixture, methanol (4mL) was added dropwise which was stirred overnight and filtered. The solid was washed with methyl tert-butyl ether (2mL), vacuum dried at about 50°C.
Yield: 0.56g
XRPD peaks of valbenazine ditosylate:
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
5.32 16.58 6.37 19.91 4.45 11.51
6.27 14.09 58.01 20.50 4.33 6.75
8.43 10.47 0.67 20.87 4.25 1.50
9.74 9.07 1.59 21.28 4.17 0.75
10.65 8.30 5.07 22.07 4.02 4.76
11.45 7.72 1.55 22.58 3.93 9.15
12.07 7.33 0.95 22.96 3.87 4.94
12.52 7.06 2.05 23.34 3.81 1.57
12.78 6.92 1.71 24.26 3.66 6.02
13.76 6.43 1.82 24.53 3.62 8.47
15.55 5.69 9.13 25.20 3.53 6.59
16.01 5.53 5.09 25.57 3.48 3.93
16.52 5.36 7.80 26.18 3.40 1.51
16.81 5.27 4.50 27.46 3.24 3.72
16.97 5.22 5.54 28.41 3.14 1.42
17.83 4.97 7.56 28.97 3.08 1.30
18.31 4.84 4.83 29.48 3.02 2.09
19.68 4.50 100.00 30.34 2.94 1.99
,CLAIMS:WE CLAIM

1. A process for the preparation of valbenazine, a compound of formula II or salts thereof,
II
the process comprising:
(a) reacting tetrabenazine, a compound of formula V,
V
with a chiral resolving agent (HA) to give (3R,11bR)-tetrabenazine, a compound of formula Va;
Va
(b) reducing the compound of formula Va, to give (2R,3R,11bR)-dihydrotetrabenazine, a compound of formula IVa, as the major diastereomer and (2S,3R,11bR)-dihydrotetrabenazine, a compound of formula IVb, as the minor diastereomer;
IVa IVb
(c) reacting the compound of formula IVa, with N-protected-L-valine to give N-protected valbenazine, the compound of formula III,
III
wherein R is selected from the group consisting of Boc, Cbz, Fmoc, acetyl, trifluoroacetyl, benzyl, trityl, tosyl and mesyl;
(d) deprotecting the compound of formula III to give valbenazine, the compound of formula II;
(e) optionally, reacting the compound of formula II with an acid to give valbenazine acid addition salt.

2. The process as claimed in claim 1, wherein step (a) comprises:
(ai) reacting tetrabenazine, a compound of formula V, with a chiral resolving agent (HA) to form an isomeric mixture of the compound of formula VI;
VI
(aii) separating the desired (R,R)-isomer, a compound of formula VIa, and the undesired (S,S)-isomer, a compound of formula VIb, from the isomeric mixture of the compound of formula VI;
VIa VIb
(aiii) optionally, recycling the undesired (S,S)-isomer, the compound of formula VIb, to generate an isomeric mixture of the compound of formula VI;
(aiv) optionally, repeating steps (aii) and (aiii); and
(av) converting the (R,R)-isomer, the compound of formula VIa, obtained in step (aii) to (3R,11bR)-tetrabenazine, the compound of formula Va.

3. The process as claimed in claim 1, wherein the chiral resolving agent (HA) comprises an acid selected from the group consisting of camphorsulfonic acid, bromocamphorsulfonic acid, camphanic acid, camphoric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, dibenzyl tartaric acid, diethyl tartrate, diisopropyl tartrate, tartaric acid, ditolyl tartaric acid, quinic acid, pyroglutamic acid, phenylpropionic acid, naphthyl ethylsuccinamic acid, malic acid, mandelic acid, glutamic acid, and mixtures thereof.

4. The process as claimed in claim 1, wherein step (a) is carried out in the presence of solvent selected from esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate; 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; water or mixtures thereof.

5. The process as claimed in claim 1, wherein step (a) is carried out at a temperature of 25°C to 100°C.

6. The process as claimed in claim 1 or claim 2, wherein in step (a), the compound of formula Va is obtained in a yield of >50%.

7. The process as claimed in claim 1, wherein step (b) is carried out in the presence of a reducing agent selected from the group consisting of sodium borohydride, lithium borohydride, lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, borane-tetrahydrofuran, borane-dimethylsulfide.

8. The process as claimed in claim 1, wherein in step (d), 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.

9. The process as claimed in claim 1, wherein in step (e), the acid is selected from the group consisting 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 and malic acid.

Dated this 12th day of December, 2018

(Signed)____________________
DR. MADHAVI KARNIK
SENIOR GENERAL MANAGER-IPM
GLENMARK PHARMACEUTICALS LIMITED