DESC:FIELD OF THE INVENTION
The invention relates to a process for the preparation of pyridoisoquinoline derivatives having desired purity. Specifically, the invention relates to a process comprising successive intramolecular cyclizations of suitably substituted phenethylamines to give a cyano substituted pyridoisoquinoline intermediate (6) which is further converted to tetrabenazine (1) having desired purity.

BACKGROUND OF THE INVENTION

Pyridoisoquinoline derivatives, which constitutes a sub-group of the broad category of nitrogen heterocycles, represents an important class of active pharmaceutical ingredients covering emetine, dehydroemetine, cephaeline, tetrabenazine which have varied pharmacological activities but structurally belong to the same class of pyridoisoquinolines.

Tetrabenazine of formula (1), chemically known as cis rac-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one, was approved by USFDA on Aug.15, 2008 with the trade name Xenazine for the treatment of chorea associated with Huntington's disease (HD) and symptomatic treatment of hyperkinetic movement disorder.

Tetrabenazine (1)

Tetrabenazine (1), first disclosed in US 2,830,993 was synthesized by reaction of 1-carbethoxymethyl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline with mono isobutyl malonic acid dimethyl ester and paraformaldehyde to give 1-carbethoxymethyl - 2-(2,2-dicarbomethoxy-4-methyl-n-pentyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline. Cyclization of the intermediate under Dieckmann conditions followed by hydrolysis and decarboxylation gave tetrabenazine (1) which was recrystallized from diisopropyl ether.

GB999095 and WO2012081031A1 disclose a process for the preparation of tetrabenazine comprising reaction of 6,7-dimethoxy-3,4-dihydroisoquinoline-hydrochloride with 3-dimethylaminomethyl-5-methylhexan-2-one methiodide in alcohol as a solvent at reflux temperature to give tetrabenazine (1), which is subsequently purified by recrystallization from methanol.

IN 4923/CHE/2012 discloses a process wherein the intermediate 3-dimethyl aminomethyl-5-methylhexan-2-one methiodide is purified by recrystallization in aqueous alcohol, followed by treatment with 6,7-dimethoxy-3,4-dihydroisoquinoline in presence of phase transfer catalyst to give tetrabenazine.

The synthetic methods for benzoquinolizines reported in prior art comprise either reacting isoquinoline derivatives with malonic acid esters or treating dihydroisoquinolines with acid addition salts of Mannich bases derived from formaldehyde, a secondary amine and a ketone with appropriate carbon chain. While the use of malonic esters results in a low-yielding, uneconomical synthetic route, the later route involves the quaternary, acid-addition salts of Mannich base. The alkylated amine free base is converted to the corresponding methyl iodide salt to facilitate isolation, which after purification is converted to the final benzoquinolizine compound.
In addition to the high cost and the problems associated with handling, the mutagenicity of the low boiling reagent methyl iodide necessitates stringent control during operations with refined isolation and purification processes. Also, due to the use of this reagent in the penultimate stage of API synthesis, there are high chances of contamination of the finished product with mutagenic impurities.
Further, it was experimentally observed that when 3-dimethylaminomethyl-5-methylhexan-2-one methiodide prepared by prior art processes was used in preparation of tetrabenazine, the reaction was associated with formation of several impurities during synthesis and storage. This necessitated separation of these impurities, which was time consuming, involved multiple purification steps which were necessary in order to obtain the final compound having desired purity. Thus, in addition to significant contribution to API cost, use of methyl iodide poses several issues ranging from handling problems to mutagenic impurities and imposes stringent requirement of controlling its contamination to ppm level.
Thus, there still exists a need for an economical, industrially viable process for synthesis of tetrabenazine (1), which avoids use of genotoxic reagents and circumvents lengthy, elaborate purification processes for the intermediates and finished product.

The present inventors have developed a convenient, easy-to scale up process for synthesis of tetrabenazine (1), comprising synthesis of the isoquinoline intermediate, ethyl-2-(2-(cyanoethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-acetate (5), followed by cyclization to provide hexahydro pyridoisoquinoline intermediate (6), and subsequent alkylation and decyanation to afford tetrabenazine (1), conforming to regulatory specifications. The final active ingredient is obtained with higher yields as compared to prior art due to the increased output of intermediates and by circumventing purification steps at various stages.

OBJECT OF THE INVENTION

An objective of the present invention is to provide a convenient and efficient process for the preparation of pyridoisoquinoline derivatives which does not involve mutagenic reagents.
Yet another object of the present invention is to provide an industrially viable, convenient, cost-effective process for preparation of tetrabenazine (1) having desired purity with a significant control on the formation of impurities.

SUMMARY OF THE INVENTION

The present invention relates to a novel method for synthesis of tetrabenazine (1) having desired purity.
An aspect of the invention relates to a process for preparation of tetrabenazine (1) comprising synthesis of ethyl-3-[(2-cyanoethyl)-(3,4-dimethoxyphenethyl)amino)-3-oxopropanoate (4), conversion to give ethyl-2-(2-(cyanoethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl) acetate (5), further treatment with a base to provide 9,10-dimethoxy-2-oxo-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a] isoquinoli- ne-3-carbonitrile (6), followed by alkylation to give 3-isobutyl-9,10-dimethoxy-2-oxo-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carbonitrile (7) and subsequent decyanation to yield tetrabenazine (1) having desired purity.

The objectives of the present invention will become more apparent from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors, while developing a convenient and industrially applicable process for tetrabenazine aimed at a process which would be free from mutagenic reagents and the associated genotoxic impurities. Further, the process was required to provide the final compound having desired purity in good yield, yet avoiding the cumbersome separation procedures to get rid of the associated impurities generated during the synthetic sequence.

It was observed that most of the prior art methods resorted to use of the known mutagen, methyl iodide for preparing the salt of amine intermediate for ease of handling and purification prior to further use. This imposed stringent requirement of controlling its contamination to ppm level. The inventors, in order to avoid using methyl iodide, attempted conversion of 3-dimethylaminomethyl-5-methylhexan-2-one to the hydrochloride salt and its use in further synthetic sequence. This however, was not possible as the said salt could not be isolated as a free flowing solid which hampered its purification and further use in tetrabenazine synthesis.

While carrying out the exhaustive experimental work aimed at synthesis of pyridoisoquinolines such as tetrabenazine, the present inventors unexpectedly found that the intramolecular cyclization of suitably substituted phenethylamines provided isoquinoline derivatives. Further cyclization of the alkylcyano substituted intermediates gave cyano-substituted pyrido-isoquinolines, which after decyanation resulted in the corresponding pyridoisoquinoline derivatives. In case of tetrabenazine, a facile alkylation at the desired position in the pyridoisoquinoline derivative followed by decyanation provided the final compound.

Synthesis of substituted isoquinoline derivatives from homoveratrylamine following an easy synthetic sequence, clubbed with the serendipitous observation of the benefits of controlling impurities resulted in a concise, economical process for tetrabenazine without using mutagenic reagents, along with a substantial control on impurity formation.

Thus, the present synthetic strategy not only avoids the mutagenic reagents in prior art processes but also provides a novel, industrially feasible, and convenient route for quinolizine derivatives such as tetrabenazine, wherein the final product is obtained in good yield with purity conforming to specifications.



Scheme 1: Method embodied in present invention for preparation of Tetrabenazine (1)

In an embodiment, 2-(3,4-dimethoxyphenyl)ethylamine, also known as homoveratrylamine (2), was treated with acrylonitrile in an organic solvent to give N-2-cyanoethyl homoveratrylamine (3). The organic solvent was selected from the group of alcohols such as ethanol, methanol, isopropyl alcohol etc. and mixtures thereof. The reaction was carried out in the temperature range of 100C to 350C. After completion, as monitored by HPLC, concentration of reaction mass, extraction with an organic solvent such as ethyl acetate and separation and concentration of the organic layer provided N-2-cyanoethyl homoveratrylamine (3).
In a further embodiment, compound (3) was treated with ethyl malonyl chloride in presence of a base in a solvent to give the N-substituted phenethylamine derivative (4). The base was selected from a group of alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, alkaline earth metal bicarbonates such as lithium carbonate, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate etc.
The solvent used for the reaction was an organic solvent selected from the group of aromatic hydrocarbons such as toluene, xylenes etc. along with water. The proportion of water was varied over a range of 10 to 70% with respect to the volume of solvent and it was observed that better yields were obtained when the amount of water was between 25% and 45% of the solvent mixture.
The reaction was carried out in the temperature range of 0°C to 10°C. After completion, as monitored by TLC, extraction of the reaction mixture with toluene and concentration of the organic layer afforded ethyl 3-[(2-cyanoethyl)-(3,4-dimethoxyphenethyl)amino)-3-oxopropanoate (4).
Intramolecular cyclization of (4) using phosphorous oxychloride in an organic solvent, in the temperature range of 600C to 800C followed by reduction using borohydrides gave the bicyclic isoquinoline intermediate, ethyl 2-(2-(cyanoethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (5). The organic solvent for cyclization was selected from the group of aprotic solvents such as acetonitrile, tetrahydrofuran etc., while the reduction was carried out in presence of alcoholic solvents such as ethanol, methanol, isopropyl alcohol etc., in the temperature range of 00C to 350C. After completion, as monitored by HPLC, neutralization of the reaction mixture, extraction with an organic solvent selected from esters such as ethyl acetate, separation and concentration of the organic layer provided (5).
Further treatment of (5) with a base selected from alkali metal hydroxides, alkali metal alkoxides such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tertiary butoxide, potassium tertiary butoxide etc., using aprotic solvent selected from the group of solvents such as acetonitrile (ACN), tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMAc) etc., and mixtures thereof, gave the tricyclic pyrido-isoquinoline intermediate (6). After completion, quenching the reaction mass with ammonium chloride solution, followed by extraction with toluene and concentration of the organic layer provided (6). Optionally, (6) was treated with alcoholic solvents such as methanol, ethanol, isopropanol etc. and used for further reactions.

In a further embodiment, compound (6) was decyanated using a mineral acid at reflux temperatures to give the pyrido-isoquinoline derivative (6A), which was then converted to either tetrabenazine derivatives or other active pharmaceutical ingredients (APIs) employing suitable synthetic sequences. The mineral acid was selected from hydrochloric acid, sulfuric acid etc. and mixtures thereof.

In yet another embodiment, compound (6) was treated with isobutyl bromide in presence of a base, selected from alkali metal hydroxides, alkoxides like potassium tertiary butoxide using polar aprotic solvent selected from DMF, DMSO, DMAc etc. to give (7). The reaction was carried out in the temperature range of 400C to 600C.

Refluxing (7) in presence of a mineral acid selected from hydrochloric acid, sulfuric acid etc. and mixtures thereof provided the desired compound, tetrabenazine (1). After completion, as monitored by HPLC, neutralization of the reaction mixture, extraction with a halogenated hydrocarbon solvent like dichloromethane, separation and concentration of the organic layer provided (1) which did not require further purification before formulation.
The following examples are meant to be illustrative of the present invention. These examples exemplify the invention and are not to be construed as limiting the scope of the invention.

EXAMPLES

Example 1: Preparation of 3-(3,4-dimethoxyphenethyl)amino)propanenitrile (3)
Acrylonitrile (2.9 g) was gradually added to a stirred solution of homoveratrylamine (2, 10 g) in methanol (50 ml) at room temperature. The reaction was continued at the same temperature till completion, as monitored by TLC, HPLC. After completion, the reaction mixture was concentrated and water was added to the residue. Extraction with ethyl acetate, followed by separation and concentration of the organic layer provided compound 3 as light yellow oil.
Yield: (12.1 g; 93%).
1H NMR (CDCl3, 400 MHz) d: 2.49 (t, 2H, J = 6.68 Hz), 2.75 (t, 2H, J = 6.84 Hz,), 2.87-2.95 (m, 4H), 3.86 (s, 3H), 3.87 (s, 3H), 6.73-6.75 (m, 2H), 6.81 (d, 1H, J = 8 Hz);
13C NMR: (CDCl3, 100 MHz) d: 18.71, 35.85, 45.01, 50.51, 55.84, 55.90, 111.37, 111.92, 118.61, 120.52, 132.03, 147.57 and 148.98.
Mass: 235.3 (M+1).

Example 2: Preparation of ethyl 3-[(2-cyanoethyl)-(3,4-dimethoxyphenethyl) amino)-3-oxopropanoate (4)
Potassium carbonate (6.5 g) and water (30 ml) were added to a stirred solution of compound 3 (10 g) in toluene (50 ml) at room temperature and the reaction mixture was cooled to 5 to 10 °C. Ethyl malonyl chloride (6.7g) was gradually added to the reaction mixture and the reaction was continued at 5 to 10 °C, till completion as monitored by TLC & HPLC. After completion of the reaction, the resulting mass was extracted with toluene. Separation and concentration of the organic layer provided compound 4 as a light yellow oil.
Yield: (14.1 g); (95%).
1H NMR (CDCl3, 400 MHz) d: 1.28 (t, 3H, J = 7.16 Hz), 2.67 (t, 2H, J = 6.48 Hz), 2.82 (t, 2H, J = 7 Hz), 3.20 (s, 2H), 3.51 (t, 2H, J = 6.52 Hz), 3.63 (t, 2H, J = 7 Hz), 3.86 (s, 3H), 3.87 (s, 3H), 4.19- 4.23 (m, 2H), 6.66-6.71 (m, 2H), 6.81 (d, 1H, J = 8.08 Hz);
13C NMR: (CDCl3, 100 MHz) d: 13.97, 15.84, 34.84, 40.76, 43.11, 51.58, 55.84, 55.87, 61.54, 111.56, 111.85, 118.16, 120.74, 129.69, 148.08, 149.23, 166.68 and 167.06.
Mass: 349.3 (M+1).

Example 3: Preparation of ethyl 2-(2-(cyanoethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (5)
Phosphorous oxychloride (6.6 g) was gradually added to a stirred solution of 4 (10.0 g.) in acetonitrile (50 ml) at room temperature and the reaction mixture was heated between 70 and 75°C. After completion of reaction, as monitored by HPLC, the reaction mixture was concentrated and quenched with water (100 ml). Sodium borohydride (1.6 g) was added gradually, in small portions, to the resulting mixture with continued stirring at 25 to 30 °C, till completion of the reaction, as monitored by HPLC. After completion, the reaction mixture was neutralized and extracted with ethyl acetate. Separation and concentration of the organic layer provided (5) as light brown oil.
Yield: (8.6 g); (90%).
1H NMR (CDCl3, 400 MHz) d: 1.29 (t, 3H J = 7.16 Hz), 2.44 (m, 1H), 2.50-2.58 (m, 3H), 2.73-2.90 (m, 5H), 3.21-3.29 (m, 1H), 3.83 (s, 3H), 3.84 (s, 3H), 4.09-4.13 (dd, 1H, J = 4.4 Hz, 10.16 Hz), 4.16-4.26 (m, 2H), 6.55 (s, 1H), 6.56 (s, 1H).
13C NMR: (CDCl3, 100 MHz) d: 14.23, 17.55, 22.88, 42.19, 43.91, 49.40, 55.84, 55.93, 57.29, 60.72, 110.16, 111.61, 118.94, 125.95, 127.56, 147.65, 147.93 and 171.97.
Mass: 333.3 (M+1).

Example 4: Preparation of 9,10-dimethoxy-2-oxo-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carbonitrile (6)
Potassium tertiary butoxide (3.2 g) was gradually added to a stirred solution of compound 5 (8.5g) in THF (50 ml) at room temperature. The mixture was stirred at same temperature till completion, as monitored by HPLC. After completion, the reaction mixture was concentrated and saturated ammonium chloride solution was added to the residue. Extraction with toluene, separation and concentration of the organic layer, optionally followed by treatment with methanol provided (6) as an off-white solid.
Yield: (5.12 g); (70%)
1H NMR (CDCl3, 400 MHz) d: 2.50-2.58 (m, 1H), 2.71-2.81 (m, 2H), 2.9-3.17 (m, 4.6H), 3.47-3.54 (m, 0.4H), 3.62 (dd, 1H, J = 6.4, 12 Hz), 3.74 (br. dd, 1H, J = 1.6, 7.6 Hz), 3.83 (s, 2.4H), 3.84 (s, 0.6H), 3.86 (s, 2.4H), 3.87 (s, 0.6H), 6.49 (s, 0.8H), 6.51 (s, 0.2H), 6.62 (s, 0.8H), 6.63 (s, 0.2H).
Mass: 287.3 (M+1).

Example 5: Preparation of 3-isobutyl-9,10-dimethoxy-2-oxo-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carbonitrile (7)
Potassium tertiary butoxide (0.86 g) was added to a solution of 6 (2.0 g) in DMF (8 ml) stirred at room temperature, followed by gradual addition of isobutyl bromide (1.0g). The reaction was continued at 50 to 55 °C, till completion, as monitored by TLC. After completion, water was added to the reaction mass, followed by extraction with ethyl acetate. Concentration of the organic layer provided (7) as a light brown oil, which was passed through an alumina column to give the desired compound (7) as an off- white solid.
Yield: (1.4 g); (59%)
1H NMR (CDCl3, 400 MHz) d (ppm): 0.90 (d, 3H, J = 6.56 Hz), 1.04 (d, 3H, J = 6.52 Hz), 1.77 (m, 1H), 1.86 (dd, 1H J = 7.36, 14.28 Hz), 2.4 (dd, 1H, J = 6.04, 14.24 Hz), 2.59-2.63 (m, 3H), 2.97-3.041 (m, 3H), 3.09-3.17 (m, 1H) 3.27 (d, 1H, J = 11.2 Hz), 3.54 (d, 1H, J = 11.2 Hz), 3.83 (s, 3H), 3.86 (s, 3H), 6.51 (s, 1H), 6.62 (s, 1H);
13C NMR: (CDCl3, 100 MHz) d: 23.03, 23.19, 25.73, 29.21, 43.08, 44.71, 50.74, 53.07, 55.87, 55.99, 61.87, 63.32, 107.53, 111.44, 118.71, 126.18, 127.20, 147.66, 148.02, and 201.79
Mass: 343.3 (M+1).

Example 6: Preparation of tetrabenazine (1)
A stirred reaction mixture of 7 (0.2 g), and hydrochloric acid (6N, 20 ml) was heated at 80 to 100°C till completion of the reaction, as monitored by TLC. After completion, the reaction mixture was neutralized using aqueous sodium hydroxide solution and extracted with dichloromethane. Separation and concentration of the organic layer, followed by optional purification using isopropyl alcohol gave tetrabenazine (1) as a white solid.
Yield: (0.065 g), (35 %)
1H NMR (CDCl3, 400 MHz) d (ppm): 0.91 (d, 3H, 6.52 Hz), 0.92 (d, 3H, J = 6.4 Hz), 1.01-1.06 (m, 1H), 1.60-1.69 (m, 1H), 1.77-1.84 (m, 1H), 2.35 (t, 1H, 11.6 Hz), 2.50-2.62 (m, 2H), 2.72-2.76 (m, 2H), 2.9 (dd, 1H, J = 3.04, 13.56 Hz), 3.07-3.16 (m, 2H), 3.29 (dd, 1H, J = 6.28, 11.56 Hz), 3.5 (d, 1H, J = 11.96 Hz), 3.83 (s, 3H), 3.86 (s, 3H), 6.55 (s, 1H), 6.61 (s, 1H).
Mass: 318.44 (M+1).
,CLAIMS:1) A process for the preparation of tetrabenazine (1) comprising,
a) reaction of 3-(3,4-dimethoxyphenethyl)amino)propanenitrile (3) with ethyl malonyl chloride in presence of a base and a solvent to give ethyl 3-[(2-cyanoethyl)-(3,4-dimethoxyphenethyl) amino)-3-oxopropanoate (4),
b) reaction of compound (4) with phosphorous oxychloride in an organic solvent followed by reduction with sodium borohydride to provide ethyl-2-(2-(cyanoethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl) acetate (5),
c) treatment of compound (5) with a base in a solvent to give 9,10-dimethoxy-2-oxo-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carbonitrile (6),
d) alkylation of compound (6) with isobutyl bromide in presence of a base in an organic solvent to give 3-isobutyl-9,10-dimethoxy-2-oxo-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carbonitrile (7), followed by treatment with an acid to yield tetrabenazine (1).

2) The process as claimed in claim 1(a), wherein the base is selected from alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates.

3) The process as claimed in claim 1(a), wherein the solvent is selected from the group of aromatic hydrocarbons consisting of toluene, ortho xylene, meta xylene, para xylene and mixtures thereof, along with water.

4) The process as claimed in claim 1(b), wherein the organic solvent is selected from the group of aprotic solvents consisting of acetonitrile and tetrahydrofuran.

5) The process as claimed in claim 1(c), wherein the base is selected from the group of alkali metal hydroxides, alkali metal alkoxides consisting of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tertiary butoxide and potassium tertiary butoxide.

6) The process as claimed in claim 1(c), wherein the solvent is selected from the group of aprotic solvents consisting of acetonitrile, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide and dimethylacetamide.

7) The process as claimed in claim 1(d), wherein the base is selected from the group of alkali metal alkoxides consisting of sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tertiary butoxide and potassium tertiary butoxide.
8) The process as claimed in claim 1(d), wherein the solvent is selected from the group of aprotic solvents consisting of dimethylformamide, dimethyl sulfoxide and dimethylacetamide.
9) The process as claimed in claim 1(d), wherein the acid is selected from the group of mineral acids consisting of hydrochloric acid, sulfuric acid.