# US 10,479,787 B2 · Process for preparation of tetrabenazine and deutetrabenazine

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- Number: US 10,479,787 B2
- Document ID: US10479787B2
- Status: Granted
- Kind: B2
- Application number: 16/095,424
- Filed: 2017-04-12
- Published: 2019-05-09
- Granted: 2019-11-19
- Earliest claimed: 2016-04-22
- Assignees: Lupin Limited
- Applicants: Lupin Limited
- Inventors: Tushar Nandkumar Despande; Dnyaneshwar Tukaram Singare; Yogesh Dadaji Pawar; Yuvraj Atmaram Chavan; Purna Chandra Ray; Girij Pal Singh
- Web page: https://patentgrep.com/patent/US10479787B2

## CPC

- C07D 455/06: containing benzo [a] quinolizine ring systems
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention provides process for preparation of dihydroxy benzoquinoline compound (III) comprising reacting dihydroxy isoquinoline compound (IV) or a salt thereof with (2-acetyl-4-methyl-pentyl)-trimethyl-ammonium iodide (V) and further converting it to tetrabenazine (I) and deutetrabenazine (II).

## Claims

### Claim 1

A process for preparation of deutetrabenazine (II) comprising:
i) obtaining dihydroxy benzoquinoline compound (III)
by reacting dihydroxy isoquinoline compound (IV) or a salt thereof
with (2-acetyl-4-methyl-pentyl)-trimethyl-ammonium iodide (V) or 3-methylene-5-methyl-2-hexanone (VI), and
ii) treating dihydroxy benzoquinoline compound (III) with a source of deuteriated methyl, wherein the source of deuteriated methyl is deuteriated methanol.

### Claim 2 (depends on 1)

The process according to claim 1, wherein the salt thereof of dihydroxy isoquinoline compound (IV) is selected from hydrochloric, hydrobromic, sulfuric or phosphoric.

### Claim 3 (depends on 1)

The process according to claim 1, wherein step (i) is carried out in the presence of a solvent and a base.

### Claim 4 (depends on 3)

The process according to claim 3, wherein the solvent is selected from alcohol, nitrile, acetone, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, glycol, dioxane, propanediol, butanediol, water or mixture thereof.

### Claim 5 (depends on 4)

The process according to claim 4, wherein the solvent is an alcohol selected from methanol, ethanol, propanol or butanol.

### Claim 6 (depends on 4)

The process according to claim 4, wherein the solvent is a nitrile selected from acetonitrile or propionitrile.

### Claim 7 (depends on 3)

The process according to claim 3, wherein the base is selected from an organic or inorganic base.

### Claim 8 (depends on 7)

The process according to claim 7, wherein the base is an organic base selected from alkyl amines.

### Claim 9 (depends on 7)

The process according to claim 7, wherein the base is an inorganic base selected from hydroxide, alkoxides, carbonates or bicarbonates of alkali or alkaline earth metals.

### Claim 10 (depends on 1)

The process according to claim 1, wherein step (ii) is carried out in solvents selected from nitriles, chlorinated hydrocarbon, acetone, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, glycol, dioxane, propanediol or butanediol.

### Claim 11 (depends on 10)

The process according to claim 10, wherein the solvent is a nitrile selected from acetonitrile or propionitrile.

### Claim 12 (depends on 10)

The process according to claim 10, wherein the solvent is a chlorinated hydrocarbon selected from dichloromethane, ethylene dichloride, carbon tetrachloride or chloroform.

### Claim 13 (depends on 1)

The process according to claim 1, wherein step (ii) is optionally carried out in the presence of a catalyst selected from azodicarboxylate and triphenyl phosphine.

### Claim 14 (depends on 13)

The process according to claim 13, wherein the catalyst is an azodicarboxylate selected from diethyl azodicarboxylate or diisopropyl azodicarboxylate.

### Claim 15 (depends on 1)

The process according to claim 1, wherein the dihydroxy benzoquinoline compound (III) is obtained with HPLC purity of greater than 98.5%.

### Claim 16 (depends on 1)

The process according to claim 1, further comprising recrystallization of deutetrabenazine (II) from a solvent.

### Claim 17 (depends on 16)

The process according to claim 16, wherein the solvent is an ester or an alcohol.

### Claim 18 (depends on 17)

The process according to claim 17, wherein the ester is ethyl acetate and the alcohol is isopropanol.

### Claim 19 (depends on 16)

The process according to claim 16, wherein the deutetrabenazine (II) is obtained with HPLC purity of greater than 99.0%.