FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
A process for resolution of an intermediate of Valbenazine Tosylate
2. APPLICANT (S)
(a) NAME: Enaltec Labs Pvt. Ltd.
(b) NATIONALITY:
An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS:
Enaltec Labs Pvt. Ltd., 17th Floor, Kesar Solitaire, Plot No. 5, Sector 19, Sanpada, Navi Mumbai- 400705, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION
The present invention relates to a process for resolution of (±) tetrabenazine compound represented by structural formula III to obtain the desired (R,R)-enantiomer of tetrabenazine compound represented by structural formula I which . is an intermediate of Valbenazine Tosylate compound represented by structural . formula II.

Wherein
R is oxo or hydroxy group;
HA is a resolving agent selected from L-(+)-Lactic Acid or L-Aspartic acid.
BACKGROUND OF THE INVENTION
Valbenazine Tosylate is chemically 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, 4-methylbenzenesulfonate (1:2) and was first disclosed in U.S. patent number 8,039,627 and is represented by structural formula II.


Valbenazine Tosylate is well tolerated and effective drug indicated for the treatment of adults with tardive dyskinesia.
U.S. patent number 8,039,627 discloses preparation of valbenzine chromatographic chiral resolution of (±) tetrabenazine compound represented by structural formula V to obtain the desired (R,R)-enantiomer of tetrabenazine compound represented by structural formula VI. However, chiral resolution of (±) tetrabenazine compound represented by structural formula V by column chromatography is not commercially feasible.

PCT publication number 2012000308 discloses chiral resolution of (±) tetrabenazine compound represented by structural formula III by a formation of diastereomeric salts of (+)-Camphorsulfonic acid compound represented by structural formula VII to provide (+) tetrabenazine compound represented by structural formula VI. However, resolution by a formation of diastereomeric salts using (-f-)-Camphorsulfonic acid showed very low yields and inconsistent results which makes it difficult to scale up and hence is not commercially feasible.


PCT publication number 2018067945 discloses chiral resolution of (±)
tetrabenazine compound represented by structural formula V by a formation of
i diastereomeric salts of (-)-0,0'-Di-p-Toluoyl-L-Tartaric acid ((-)-DPTTA)
compound represented by structural formula VIII to provide (+) tetrabenazine
compound represented by structural formula VI.

It further discloses asymmetric reduction of (±) tetrabenazine compound represented by structural formula V using Ruthenium catalyst to obtain (+) hydroxy tetrabenazine compound represented by structural formula IX. Ruthenium catalyst used for the asymmetric reduction is very costly and is not commercially feasible.


US patent application no. 20170183346 also discloses resolution of compound of formula I, wherein R is OH and conversion of Formula I to formula II (Valbenazine Tosylate).

Hence there is need to develop a commercially feasible process for resolution of (±) tetrabenazine compound represented by structural formula III to obtain the desired (R,R)-enantiomer of tetrabenazine compound represented by structural formula I with good yield and chiral purity, which is an intermediate of Valbenazine Tosylate compound represented by structural formula II,

OBJECT OF THE INVENTION
i) The main object of present invention to provide a commercially feasible
process for resolution of (±) tetrabenazine compound represented by structural formula III to obtain the desired (R,R)-enantiomer of tetrabenazine compound represented by structural formula I with good yield and chiral purity.

ii) Another object of present invention is to provide an improved process for the preparation of Valbenazine Tosylate compound represented by structural formula II.
SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide a process for resolution of (±) tetrabenazine compound represented by structural formula III to obtain the desired (R,R)-enantiomer of tetrabenazine compound represented by structural formula I with good yield and chiral purity.
In aspect of the present invention process for preparation of compound of structural formula I:

wherein
R is oxo or hydroxy group;
HA is a resolving agent selected from L-(+)-Lactic Acid or L-Aspartic acid.
In another aspect of the present invention is to provide a process for resolution of (±) tetrabenazine compound represented by structural formula III to obtain the desired (R,R)-enantiomer of tetrabenazine compound represented by structural formula I with good yield and chiral purity, optionally converting (R, R)-

enantiomer of tetrabenazine compound represented by structural formula I to Valbenazine Tosylate compound represented by structural formula II. In another aspect of the present invention process for preparation of compound of structural formula II:

wherein
R is oxo or hydroxy group;
HA is a resolving agent selected from L-(+)-Lactic Acid and L-Aspartic acid.
In another aspect of the present invention is to provide a process for resolution of (±) tetrabenazine compound represented by structural formula III to obtain the desired (R,R)-enantiomer of tetrabenazine compound represented by structural formula I with good yield and chiral purity comprising the steps of:
a. treating a solution of (±) tetrabenazine compound represented by structural
formula III in an organic solvent with resolving agent;
b. isolating diastereomeric salt compound represented by structural formula
IV;
c. treating diastereomeric salt compound represented by structural formula
IV with base;

d. isolating (R, R)- enantiomer of tetrabenazine compound represented by
structural formula I,
e. optionally converting (R, R)- enantiomer of tetrabenazine compound
represented by structural formula I to Valbenazine Tosylate compound
represented by structural formula II,

Wherein
R is oxo or hydroxy group;
HA is a resolving agent selected from L-(+)-Lactic Acid and L-Aspartic
acid.
In another aspect of the present invention process for preparation of compound of structural formula II, comprising the steps of:
a. treating a solution of (±) tetrabenazine compound represented by structural
formula III in an organic solvent with resolving agent;
b. isolating diastereomeric salt compound represented by structural formula
IV;
c. treating diastereomeric salt compound represented by structural formula
IV with base;

d. isolating (R, R)- enantiomer of tetrabenazine compound represented by
structural formula I,
e. converting (R, R)- enantiomer of tetrabenazine compound represented by
structural formula I to Valbenazine Tosylate compound represented by
structural formula II,

Wherein
R is oxo or hydroxy group;
HA is a resolving agent selected from L-(+)-Lactic Acid and L-Aspartic
acid.
In another aspect of the present invention is to provide a process for resolution of (±) tetrabenazine compound represented by structural formula III to obtain the desired (R,R)-enantiomer of tetrabenazine compound represented by structural formula I with good yield and chiral purity comprising the steps of:
a. treating a solution of (±) tetrabenazine compound represented by structural
formula III in an organic solvent with L-(+)-Lactic Acid;
b. isolating diastereomeric salt compound represented by structural formula
X;

c. treating diastereomeric salt compound represented by structural formula X
with base;
d. isolating (R, R)- enantiomer of tetrabenazine compound represented by
structural formula I,
e. optionally converting (R, R)- enantiomer of tetrabenazine compound
represented by structural formula I to Valbenazine Tosylate compound
represented by structural formula II,

Wherein,
R is oxo or hydroxy group.
In another aspect of the present invention process for preparation of compound of structural formula II, comprising the steps of:
a. treating a solution of (±) tetrabenazine compound represented by structural
formula III in an organic solvent with L-(+)-Lactic Acid;
b. isolating diastereomeric salt compound represented by structural formula
X;

c. treating diastereomeric salt compound represented by structural formula X
with base;
d. isolating (R, R)- enantiomer of tetrabenazine compound represented by
structural formula I,
e. converting (R, R)- enantiomer of tetrabenazine compound represented by
structural formula I to Valbenazine Tosylate compound represented by
structural formula II,

Wherein,
R is OH. In another aspect of the present invention is to provide a process for resolution of (±) tetrabenazine compound represented by structural formula III to obtain the desired (R,R)-enantiomer of tetrabenazine compound represented by structural formula I with good yield and chiral purity comprising the steps of:
a. treating a solution of (±) tetrabenazine compound represented by structural
formula III in an organic solvent with L-Aspartic acid;
b. isolating diastereomeric salt compound represented by structural formula
XI;
c. treating diastereomeric salt compound represented by structural formula
XI with base;

d. isolating (R, R)- enantiomer of tetrabenazine compound represented by
structural formula I,
e. optionally converting (R, R)- enantiomer of tetrabenazine compound
represented by structural formula I to Valbenazine Tosylate compound
represented by structural formula II,

wherein, R is oxo or hydroxyl group .
In another aspect of the present invention process for preparation of compound of structural formula II, comprising the steps of:
a. treating a solution of (±) tetrabenazine compound represented by structural
formula III in an organic solvent with L-Aspartic acid;
b. isolating diastereomeric salt compound represented by structural formula
XI;
c. treating diastereomeric salt compound represented by structural formula
XI with base;
d. isolating (R, R)- enantiomer of tetrabenazine compound represented by
structural formula I,

e. converting (R, R)- enantiomer of tetrabenazine compound represented by structural formula I to Valbenazine Tosylate compound represented by structural formula II,

wherein,
R is OH.
In an embodiment present invention is to provide a process for resolution of (±)
tetrabenazine compound represented by structural formula III to obtain the desired
(R,R)-enantiomer of tetrabenazine compound represented by structural formula I.
In an embodiment, the examples of resolving agent includes but not limited to L-
(+)-Lactic Acid; L-Aspartic acid.
In an embodiment, the examples of organic solvent can include but not limited to
alcohol solvent selected from C1 to C4 alcohol such as methanol, ethanol,
isopropanol, butanol or mixture thereof and chlorinated solvent selected from
dichloromethane, chloroform or the mixture thereof.
In a preferred embodiment, organic solvent is C1 to C4 alcohol, more preferably such as methanol, ethanol, isopropanol, butanol.
In an embodiment present invention is to provide a process for resolution of (±) tetrabenazine compound represented by structural formula III to obtain the desired

(R,R)-enantiomer of tetrabenazine compound represented by structural formula I and conversion of formula I to formula II,

Wherein in Formula I is 0= or -OH.
In an embodiment, compound of formula V is converted to compound of formula IIIB in the presence of reducing agent in the presence of a reducing agent in suitable solvent. The R oxo (0=) group in Formula V is converted to -OH (Formula IIIB)

In another embodiment, compound of formula IX is converted to compound of
formula VI in the presence of reducing agent in the presence of a reducing agent
in suitable solvent. The R oxo (O=) group in Formula I (VI) is converted to -OH
(Formula IX) !

In another embodiment the reducing agent is a borohydride.
In another embodiments the reducing agent is lithium borohydride, calcium borohydride, sodium borohydride, magnesium borohydride, potassium borohydride, 9-BBN, cyano borohydride, bis-triphenylphosphine borohydride,

sodium triethyl borohydride, tetrabutylammonium borohydride,
tetramethylammonium borohydride, tetraethylammonium borohydride, or lithium
triethyl borohydride. In yet other embodiments the reducing agent is sodium
borohydride.
In another embodiments, the solvent comprises dichloromethane and an alcohol.
In certain embodiments, the alcohol is a C1-4 alcohol. In yet other embodiments,
the solvent mixture comprises dichloromethane and ethanol. In certain
embodiments, the solvent mixture comprises dichloromethane and ethanol.
In an embodiments, conversion of compound of formula (I) wherein R is OH to
compound of formula II:
Step i) Esterification by reacting compound of Formula (IA) with amine-protected
Valine amino acid (P-Valine) to give compound of Formula XII,
Step ii) conversion of compound of Formula to compound of Formula II
(Valbenazine tosylate):

wherein P is amino protecting group.
In an embodiment, Step i) Esterification by reacting compound of Formula (IX)
with amine-protected Valine amino acid (P-Valine) to give compound of Formula
XII, using coupling reagents such as, but not limited to, DCC (N,N'-
dicyclohexylcarbodiimide), EDC (l-Ethyl-3-(3-

dimethylaminopropyl)carbodiimide) or DIC (N,N'-Diisopropylcarbodiimide),
preferably with the addition additive such as, but not limited to, HOBt
(Hydroxybenzotriazole), NHS (N-hydroxysuccinimide), or DMAP (4-
Dimethylaminopyridine). The amino group of valine can be protected by
protecting group PGs such as, but not limited to, Boc (tert-butyloxycarbonyl) or
Cbz (carboxybenzyl) protecting groups (Boc-Valineor Cbz-valine). The reaction
can be conducted in organic solvents such as, but not limited to, THF, DCM,
EtOAc or DMF in a range of temperatures from 0 °C to 100 °C, preferably from
10°Cto70°C.
Step ii) Compound of Formula XII (amino-protected Valbenazine compound) can
be deprotected to obtain compound of Formula XIII (Valbenazine) . This reaction
may be performed using a suitable deprotecting agent in a suitable solvent
depending on the nature of the protecting group itself
In a preferred embodiment, the conversion of compound of Formula XII to
Formula XIII is optional.
In a preferred embodiment, compound of Formula XII (amino-protected
Valbenazine is Boc-Valbenazine or Cbz Boc-Valbenazine), which is converted to
Valbenazine tosylate (compound of formula II) by reaction with p-toluenesulfonic
acid.
In a preferred embodiment, compound of Formula XII (wherein P- is Boc) is
treated with p-toluenesulfonic acid to give compound of formula II (Valbenazine
tosylate).
In certain embodiments, compound of Formula XII (wherein P- is Boc) is
converted to compound of formula II (Valbenazine tosylate) via compound of
formula XIII (Valbenazine).
In a preferred embodiment, the compound of formula XIII is isolated or not
isolated.
In a preferred embodiment, Compound of Formula XII (wherein P- is Boc) is
treated with p-toluenesulfonic acid to give compound of formula II (Valbenazine
tosylate) , predicated, solid was separated and dried to give solid form of
compound of formula II (Valbenazine tosylate).

In an embodiment, compound of Formula XII (wherein P- is Cbz) is treated with
H2 Pd/C in methanol to give compound of formula XIII (Valbenazine).
In a preferred embodiment, compound of Formula XIII (Valbenazine) treated
with p-toluenesulfonic acid to give compound of formula II (Valbenazine
tosylate).
Example:
In the following example, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1:
Preparation of Valbenazine tosylate (compound of formula II)
Synthesis of (2S,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-
hexahydro-lH-pyrido[2,l-a]isoquinolin-2-one (the compound of formula VI)
A 500 ml 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser. The reaction vessel was charged with (3R,11bR)-1,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one, (3 g, 0.0094 mol,) and methanol (15 ml). The mixture was refluxed for 1 hour, and L-lactic Acid was charged (0.85 g, 0.0094 mol,). The mixture was refluxed for another 30 minutes; cool to 0-5°C. The solid was isolated by filtration and the cake was wash with (30 ml) methanol. The solid was dry in tray dryer to give 1.5 g L-lactic acid salt of (3R,11bR)-l,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one (the compound of formula X, wherein R is =0). The reaction vessel was charged with L-lactic acid salt with methylene chloride (15 ml), the pH was adjusted by 7.5 by using 10% sodium carbonate aqueous solution. The reaction mixture was extracted with methylene chloride (5 ml X 2). The resulting organic layer was washed with water (5 ml). The solvent was evaporated to give the compound of formula VI as off white product. (Yield: 0.9 g; (30%); (Purity by TLC; 95%). SOR + 66 (C=1 in methanol).

Synthesis of (2S,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-
hexahydro-1H-pyrido[2,1-a]isoquinoIin-2-o1 (the compound of formula IX)
A 2000 ml 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser. The reaction vessel was charged with (2S,3R,11bR)-1,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one (1 g, 0.0031 mol,) the compound of formula VI, Sodium borohydride (0.07 g, 0.0018 mol,), methanol (6 ml). The mixture was stirred for 2 hrs at ambient temperature. The solvent was removed in vacuum, degas the material and the residue was dissolved in (5 ml water). The reaction mixture was extracted with methylene chloride (5 ml, 2.5 ml, and 1.5 ml). The resulting organic layer was washed with water (2 mix2). The solvent was evaporated to give 0.8 g of the compound of formula IX. (Yield: 0.9 g; (98%); (Purity by TLC: 80 %)). SOR + 66 (C=l in methanol).
Synthesis of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-lH-pyrido[2,1-a]isoquinolin-2-yl 2-(((benzyloxy)carbonyl)amino)-3-methylbutanoate (the compound of formula XII, wherein P is Cbz)
A 500 ml 3-necked round bottom flask was equipped with a mechanical stirrer,
thermometer, and condenser. The reaction vessel was charged with (2S,3R,11bR)-
3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-lH-pyrido[2,l-a]isoquinolin-
2-ol (2 g, 0.0062 mol,) (the compound of formula IX), 4-Dimethyl amino pyridine
(0.375 g, 0.003 mol,), methylene chloride (30 ml), N-Carbobenzyloxy-L-Valine
(1.9 g, 0.0075 mol). Added Dicyclohexylcarbodiimide (1.55 g, 0.0075 mol). The
reaction mixture was stirred for 12 hr at ambient temperature. Filter the byproduct
and methylene chloride filtrate treated with dil HC1 solution followed by water.
The solvent was evaporated to give 3.3 g (S)-(2R,3R,llbR)-3-isobutyl-9,10-
dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,l-a]isoquinolin-2-yl 2-
(((benzyloxy)carbonyl)amino)-3-methylbutanoate (the compound of formula XII, wherein P is Cbz) as light yellow product (Yield: 95%); (Purity by TLC: 90 %)).

Synthesis of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,l-a]isoquinolin-2-yI ester (the compound of formula XIII)
A mixture of 10% Pd/C (0.45 g, 15 % w/w), (the compound of formula XII) (3 g, 0.0054 mol) and Methanol (120 ml) was charged to a 1.0 L Autoclave, under a nitrogen atmosphere. Hydrogen was charged to the reaction vessel for up to 5 kg pressure. The mixture was shaken for 7-8 hours, maintaining hydrogen pressure between 3-5 kg pressure. Hydrogen was released and the mixture was purged with nitrogen 3 times. The suspension was filtered through a hyflo bed and rinsed with methanol. The filtrate was concentrated in vacuum affording the compound of formula XIII (Yield: 2.2 g; 95%); (Purity by TLC: 97 %)).
Synthesis of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,llb-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate Valbenazine Tosylate (the compound of formula II)
A 500 ml 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser. The reaction vessel was charged with (2 g, 0.0047 mol) (the compound of formula XIII) with acetone (10 ml). The mixture was stirred for hour at ambient temperature. The suspension was filtered through celite bed. Clear filtrate treated with p-Toluene sulfonic acid monohydrate (1.9 g, 0.010 mol). The mixture was stirred for 2 hrs at ambient temperature. The solid was isolated by filtration and wash the cake with (2 ml) acetone. Dry the solid in tray dryer to give 2.2 g Valbenazine Tosylate; the compound of formula II as a white solid. (Yield: 60%); (Purity by TLC: 98 %).
Example 2:
Preparation of Valbenazine tosylate (compound of formula II)
Synthesis of (3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-
lH-pyrido[2,1-a]isoquinolin-2-ol (Formula XIV, wherein R is OH)
A 2000 ml 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser. The reaction vessel was charged with (3R,11bR)-

1,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one (50 g, 0.157 mol,), Sodium borohydride (3.5 g, 0.092 mol), methanol (30 ml). The mixture was stirred for 2hrs at ambient temperature. The solvent was removed in vacuum, degas the material and the residue was dissolved in (250 ml water). The reaction mixture was extracted with methylene chloride (250 ml, 125 ml, and 75 ml). The resulting organic layer was washed with water (100 ml><2). The solvent was evaporated to give 47.5 g of compound of formula la with 98% purity by TLC (95 % yield) as off white product.
Synthesis of (2S,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (the compound of formula IX)
A 500 ml 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser. The reaction vessel was charged with (3R,11bR)-1,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-3 -(2-methylpropyl)-2H-benzo[a]quinolizin-2-ol (3 g, 0.0093 mol,), methanol (18 ml). The mixture was refluxed for 1 hr, charged L-Aspartic acid (1.23 g, 0.0093 mol,), The mixture was refluxed for another 30 minutes and cool to ambient temperature. The solid was isolated by filtration and wash the cake with (3 ml) methanol. Dry the solid in tray dryer to give 1.65 g L-Aspartic Acid salt of (3R,11bR)-l,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-ol. The reaction vessel was charged with solid of L-Aspartate salt with methanol (18 ml), adjust pH 8 by using aqueous ammonia solution. The reaction mixture was extracted with methylene chloride (30 ml X 2). The resulting organic layer was washed with water (30 ml). The solvent was evaporated to give 0.8 g of the compound of formula IX with 95% purity by TLC (yield: 26.6 %) as off white product. SOR + 67 (C=l in methanol).
Synthesis of (S)-(2R,3R,11bR)-3-isobutyl-940-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-(((benzyloxy)carbonyl)amino)-3-methylbutanoate (the compound of formula XII, wherein P is Cbz)

A 500 ml 3-necked round bottom flask was equipped with a mechanical stirrer,
thermometer, and condenser. The reaction vessel was charged with (2S,3R,11bR)-
3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,l-a]isoquinolin-
2-ol (2 g, 0.0062 mol,), 4-Dimethyl amino pyridine (0.375 g, 0.003 mol,),
methylene chloride (30 ml), N-Carbobenzyloxy-L-Valine (1.9 g, 0.0075 mol).
Added Dicyclohexylcarbodiimide (1.55 g, 0.0075 mol). The reaction mixture was
stirred for 12 hr at ambient temperature. Filter the byproduct and methylene
chloride filtrate treated with dil HC1 solution followed by water. The solvent was
evaporated to give 3.3 g (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-
2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-
(((benzyloxy)carbonyl)amino)-3-methylbutanoate with 90% purity by TLC (yield: 95 % ) as light yellow product.
Synthesis of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyI-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester (the compound of formula XIII)
A mixture of 10% Pd/C (0.45 g, 15 % w/w), the compound of formula XII, wherein P is Cbz (3 g, 0.0054 mol) and Methanol (120 ml) was charged to a 1.0 L Autoclave, under a nitrogen atmosphere. Hydrogen was charged to the reaction vessel for up to 5 kg pressure. The mixture was shaken for 7-8 hours, maintaining hydrogen pressure between 3-5 kg pressure. Hydrogen was released and the mixture was purged with nitrogen 3 times. The suspension was filtered through a hyflo bed and rinsed with methanol. The filtrate was concentrated in vacuum affording product 2.2 g with 95% purity by TLC (yield: 97%).
Synthesis of (S)-2-amino-3-methyI-butyric acid (2R,3R41bR)~3-isobutyI-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester ditosylate (Valbenazine Tosylate)
A 500 ml 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser. The reaction vessel was charged with (2 g, 0.0047 mol) Valbenazine (compound of formula XIII) with acetone (10 ml). The mixture

was stirred for hour at ambient temperature. The suspension was filtered through celite bed. Clear filtrate treated with p-Toluene sulfonic acid monohydrate (1.9 g, 0.010 mol). The mixture was stirred for 2 hrs at ambient temperature. The solid was isolated by filtration and wash the cake with (2 ml) acetone. Dry the solid in tray dryer to give 2.2 g Valbenazine Tosylate as a white solid with 98% purity by TLC (yield: 60%).

We Claim:
1. A process for preparation of Valbenazine Tosylate compound of structural
formula II, comprising the steps of:
a. treating a solution of (±) tetrabenazine compound represented by structural
formula III in an organic solvent with resolving agent;
b. isolating diastereomeric salt compound represented by structural formula
IV;
c. treating diastereomeric salt compound represented by structural formula
IV with base;
d. isolating (R, R)- enantiomer of tetrabenazine compound represented by
structural formula I,
e. converting (R, R)- enantiomer of tetrabenazine compound represented by
structural formula I to Valbenazine Tosylate compound represented by
structural formula II,

wherein,
R is oxo or hydroxy group;
HA is a resolving agent selected from L-(+)-Lactic Acid and L-Aspartic
acid.

2. A process for preparation of compound of structural formula I, comprising the steps of:
a. treating a solution of (±) tetrabenazine compound represented by structural
formula III in an organic solvent with resolving agent;
b. isolating diastereomeric salt compound represented by structural formula
IV;
c. treating diastereomeric salt compound represented by structural formula
IV with base;
d. isolating (R, R)-enantiomer of tetrabenazine compound represented by
structural formula I,
e. optionally converting (R, R)- enantiomer of tetrabenazine compound
represented by structural formula I to Valbenazine Tosylate compound
represented by structural formula II,

wherein
R is oxo or hydroxy group;
HA is a resolving agent selected from L-(+)-Lactic Acid and L-Aspartic
acid. 3. A process for preparation of compound of structural formula I, comprising the steps of:

a. treating a solution of (±) tetrabenazine compound represented by structural
formula III in an organic solvent with L-(+)-Lactic Acid;
b. isolating diastereomeric salt compound represented by structural formula
X;
c. treating diastereomeric salt compound represented by structural formula X
with base;
d. isolating (R, R)- enantiomer of tetrabenazine compound represented by
structural formula I,
e. optionally converting (R, R)- enantiomer of tetrabenazine compound
represented by structural formula I to Valbenazine Tosylate compound
represented by structural formula II,

Wherein,
R is oxo or hydroxy group.
4. A process for preparation of Valbenazine Tosylate compound of structural formula II, comprising the steps of:

a. treating a solution of (±) tetrabenazine compound represented by structural
formula III in an organic solvent with L-(+)-Lactic Acid;
b. isolating diastereomeric salt compound represented by structural formula
X;
c. treating diastereomeric salt compound represented by structural formula X
with base;
d. isolating (R, R)- enantiomer of tetrabenazine compound represented by
structural formula I,
e. converting (R, R)- enantiomer of tetrabenazine compound represented by
structural formula I to Valbenazine Tosylate compound represented by
structural formula II,

wherein, R is OH.
5. A process for preparation of compound of structural formula I, comprising the steps of:

a. treating a solution of (±) tetrabenazine compound represented by structural
formula III in an organic solvent with L-Aspartic acid;
b. isolating diastereomeric salt compound represented by structural formula
XI;
c. treating diastereomeric salt compound represented by structural formula
XI with base;
d. isolating (R, R)- enantiomer of tetrabenazine compound represented by
structural formula I,
e. optionally converting (R, R)- enantiomer of tetrabenazine compound
represented by structural formula I to Valbenazine Tosylate compound
represented by structural formula II,

wherein, R is oxo or hydroxyl group.
6. A process for preparation of Valbenazine Tosylate compound of structural formula II, comprising the steps of:
a. treating a solution of (±) tetrabenazine compound represented by structural formula III in an organic solvent with L-Aspartic acid;

b. isolating diastereomeric salt compound represented by structural formula
XI;
c. treating diastereomeric salt compound represented by structural formula
XI with base;
d. isolating (R, R)- enantiomer of tetrabenazine compound represented by
structural formula I,
e. converting (R, R)- enantiomer of tetrabenazine compound represented by
structural formula I to Valbenazine Tosylate compound represented by
structural formula II,

wherein, R is OH.
7. The process as claimed in any of claims 1 to 5, wherein organic solvent is methanol, ethanol, isopropanol or butanol.
8. The process as claimed in any of claims 1 to 5, wherein Valbenazine Tosylate compound of structural formula II, comprising the steps of:


wherein P is amino protecting group,
Step i) Esterification by reacting compound of Formula (IX) with amine-protected
Valine amino acid (P-Valine) to give compound of Formula XII,
Step ii) conversion of compound of Formula to compound of Formula II
(Valbenazine tosylate).
9. The process as claimed in claim 8, wherein step i) is carried using coupling
reagents selected from DCC (N,N'- dicyclohexylcarbodiimide), EDC (l-Ethyl-3-
(3-dimethylaminopropyl)carbodiimide) or DIC (N,N'-Diisopropylcarbodiimide),
optionally in presence of HOBt (Hydroxybenzotriazole), NHS (N-
hydroxysuccinimide), or DMAP (4-Dimethylaminopyridine).
10. The process as claimed in claim 8, wherein step ii) wherein compound of
Formula XII is treated with H2, Pd/C to give compound of formula XIII
(Valbenazine) and treating with p-toluenesulfonic acid to give compound of
formula II.