DESC:Field of the Invention:
The present application relates to an improved and novel process for the preparation
of Deutetrabenazine, which is represented by the following structural formula-I.
5 Formula-I
Background of the Invention:
Deutetrabenazine is a deuterated analog of tetrabenazine which is a benzoquinoline
compound having the chemical name (RR, SS)-1, 3, 4, 6, 7, 11b-hexahydro-9, 10-di
10 (methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one. It and a vesicular
monoamine transporter 2 (VMAT2) inhibitor commonly prescribed for the treatment of
Huntington's disease. Deutetrabenazine has improved pharmacokinetic properties when
compared to the non- deuterated drug. The drug is approved on 03 April 2017 in US for the
treatment of chorea associated with Huntington disease, developed by Teva with the brand
15 name of Austedo .
The patent US8524733B2 first disclosed deutetrabenazine, its analogues and process
for their preparation, the final product was purified by column chromatography.
The US20120003330A1, US20150152099A1 covered various processes for the
preparation of Deutetrabenazine. The processes involve multiple steps, which are not suitable
20 for manufacture of commercial quantities.
The PCT application WO2017182916A1 covered a process for preparation of
Deutetrabenazine. The process involves deuteration in the final stage by using deuterated
methyl source such as CD3I or CD3OH in presence of catalyst. The catalysts are selected
from azodicarboxylate such as diethylazodicarboxylate (DEAD) or diisopropylazodi
25 carboxylate (DIAD) and triphenyl phosphine that are very expensive.
Based on draw backs of the prior art processes , there is a continuous need to develop
a process for the preparation of deutetrabenazine, suitable for commercial manufacturing
with high yields and purity.
3
The present invention provides an improved process for preparation of deutetrabenazine which is efficient, industrially viable and cost effective. The present invention provides a novel process for preparation of deutetrabenazine that does not involve tedious technique of column chromatography.
Brief Description : 5
The first aspect of the present invention is to provide a process for the preparation of the compound of formula-I.
The second aspect of the present invention is to provide a compound of formula-5.
The third aspect of the present invention is to provide a process for the preparation of crystalline form-I of compound of formula-I. 10
Brief description of the drawings:
Figure 1: Illustrates the PXRD pattern of crystalline form-I of compound of formula-I according to example-9
Figure 2: Illustrates the PXRD pattern of crystalline form-I of compound of formula-I according to example-10 15
Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as 20 dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as 25 dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbontetra chloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as 30 methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol,
4
2-fluoro ethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
As used herein the present invention the term “suitable base” refers to inorganic or 5 organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium 10 ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl 15 amino pyridine (DMAP), N-methyl morpholine (NMM), or mixtures thereof.
The term “reducing” agent used in the present invention refers suitable reducing reagents are selected from Lithium aluminium hydride, sodium borohydride, Lithium borohydride, BF3 etherate solution, Pd/C, Ray-nickel;
The term “protecting” agent used in the present invention refers to a suitable protecting 20 reagents that are selected selected from di-tert-butyl dicarbonate, chlorobenzyl formate, benzylbromide, benzylchloride, acetylchloride, fluorenylmethyloxycarbonyl chloride; The term “phase transfer catalyst (PTC)” used in the present invention refers are selected from triethylbenzyl ammonium chloride, tetrabutyl ammoniumbromide, tetrabutyl ammonium chloride, tetrabutyl ammonium acetate, methyl tributyl ammonium chloride, tetrabutyl 25 ammonium hydroxide, tributylbenzylammonium chloride;
The first aspect of the present invention provides a process for the preparation of compound of formula-I,
5
Formula-I
comprising of:
a) Reacting the compound of formula-1
5
Formula-1
with suitable reagent, solvent to provide the compound of formula-2,
Formula-2
10 b) reacting the compound obtained in step-a) with suitable reagent in presence of suitable
solvent to provide the compound of formula-3,
Formula-3
c) reducing the compound obtained in step-b) with suitable reagent in presence of suitable
15 solvent to provide the compound of formula-4,
Formula-4
d) cyclising the compound obtained in step-c) with a suitable reagent, solvent to provide the
compound of formula-5 or salts thereof, optionally purified in suitable solvent,
20
Formula-5
6
e) reacting the compound of formula-5 with compound of formula-6,
Formula-6
in presence of suitable solvent, optionally suitable base, phase transfer catalyst to provide
5 the compound of formula-1.
f) optionally purifying the compound obtained in step-e) in suitable solvents.
Wherein in step-a) deuterium containing methylating agent and selected from the
group consisting of deuterated methyl iodide, deuterated methyl bromide, deuterated
dimethyl sulfate, deuterated dimethyl carbonate, deuterated methanol optionally in presence
10 of catalyst selected from azodicarboxylate such as diethylazodicarboxylate (DEAD) or diiso
propylazodicarboxylate (DIAD) and triphenylphosphine; the suitable base is selected from
inorgainc base such as sodium carbonate, potassium carbonate, lithium carbonate, sodium
bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium
hydroxide, organic bases such as triethylamine, diisopropylethylamine or mixtures thereof;
15 suitable temperature 0-120°C;
Wherein in step-b) the suitable reagent is nitro methane, the suitable base is selected
from ammonium acetate, sodium acetate, potassium acetate, organic bases such as sodium
methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tertbutoxide,
potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides
20 such as sodium hydride, potassium hydride, lithium hydride triethylamine,
diisopropylethylamine or mixtures thereof; inorgainc base such as sodium carbonate,
potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium
hydroxide, potassium hydroxide, lithium hydroxide and mixtures thereof, suitable
temperature 0-100° C;
25 wherein in step-c) the suitable reagent is selected from sodiumborohydride, borane
(BH3 solution), boron trifluoride solution, lithium aluminium hydride, lithium borohydride,
chloro trimethyl silane, palladium carbon, Raney-Nickel, zinc in acetic acid, zinc, ammonium
chloride or mixture thereof; suitable temperature 0-100° C;
7
Wherein in step-d) the suitable reagent is selected from hexamethylenetetramine,
ethyl formate, methylformate, propyl formate, phosphoryl chloride; suitable temperature 0-
100° C; Wherein in step-e) the suitable base is inorganic base or organic base, the suitable
phase transfer catalyst is selected from triethylbenzyl ammonium chloride, tetrabutyl
5 ammonium bromide, tetrabutyl ammonium chloride, tetrabutyl ammonium acetate, methyl
tributyl ammonium chloride, tetrabutyl ammonium hydroxide, tributyl benzyl ammonium
chloride; Wherein in step-a to f) the suitable solvent is selected from hydrocarbon solvents,
chloro solvents, ether solvents, ketone solvent, nitrile solvent, polar aprotic solvents, polar
protic solvent, alcoholic solvent, ester solvents, water or any mixture thereof;
10
The preferred embodiment of the present invention provides a process for the
preparation of compound of formula-I,
Formula-I
15 comprising of:
a) Reacting the compound of formula-[1]
Formula-1
with deutirated methyl iodide, in presence of potassium carbonate in dimethyl formamide to
20 provide the compound of formula-2,
Formula-2
b) reacting the compound obtained in step-a) with nitromethane, in presence of ammonium
acetate in aceticacid, to provide the compound of formula-3,
25
8
Formula-3
c) reducing the compound obtained in step-b) with sodium borohydride, boron trifluoride
etherate in tetrahydrofuran to provide the compound of formula-4,
5
Formula-4
d) cyclising the compound obtained in step-c) with ethyl formate, phosphorous oxychloride
to provide the compound of formula-5,
10 Formula-5
e) reacting the compound of formula-5 with compound of formula-6,
Formula-6
in presence methanol to provide the compound of formula-1.
15 f) purifying the compound obtained in step-e) in ethyl acetate and isopropanol.
The process of the present invention can be represented schematically as follows:
9
Process for preparation of compound -6
5
The second aspect of the present invention to provide a process for the preparation of
10 compound of formula-5.
Formula-5
comprising of:
15 a)Reacting the compound of formula-[1]
Formula-1
with suitable reagent, solvent to provide the compound of formula-2,
20 Formula-2
10
b)reacting the compound obtained in step-a) with suitable reagent in presence of suitable
solvent to provide the compound of formula-3,
Formula-3
c)reducing the compound obtained in step-b) with suitable reagent 5 in presence of suitable
solvent to provide the compound of formula-4,
Formula-4
d)cyclising the compound obtained in step-c) with a suitable reagent, solvent to provide the
10 compound of formula-5 or salts thereof,
Formula-5
f)optionally purifying the compound obtained in step-e) in suitable solvents.
15 Wherein in step-a) deuterium containing methylating agent and selected from the
group consisting of deuterated methyl iodide, deuterated methyl bromide, deuterated
dimethyl sulfate, deuterated dimethyl carbonate, deuterated methanol optionally in presence
of a catalyst selected from azodicarboxylate such as diethylazodicarboxylate (DEAD) or
diiso propylazodicarboxylate (DIAD) and triphenylphosphine; the suitable base is selected
20 from inorgainc base such as sodium carbonate, potassium carbonate, lithium carbonate,
sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium
hydroxide, organic bases such as triethylamine, diisopropylethylamine or mixtures thereof;
suitable temperature 0-120°C; Wherein in step-b) the suitable reagent is nitro methane, the
suitable base is selected from ammonium acetate, sodium acetate, potassium acetate, organic
25 bases such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium
ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide and the like;
11
alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride
triethylamine, diisopropylethylamine or mixtures thereof; inorgainc base such as sodium
carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium
bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide mixtures thereof,
5 suitable temperature 0-100° C; Wherein in step-c) the suitable reagent is selected from
sodiumborohydride, borane (BH3 solution), boron trifluoride solution, lithium aluminium
hydride, lithium borohydride, chloro trimethyl silane, palladium carbon, ray-nickel, zinc in
acetic acid, zinc, ammonium chloride or mixture thereof; suitable temperature 0-100° C;
Wherein in step-d) the suitable reagent is selected from hexamethylenetetramine, ethyl
10 formate, methylformate, propyl formate, phosphoryl chloride ; suitable temperature 0-100°
C; Wherein in step-e) the suitable base is inorganic base or organic base, the suitable phase
transfer catalyst is selected from triethylbenzyl ammonium chloride, tetrabutylammonium
bromide, tetrabutyl ammonium chloride, tetrabutyl ammonium acetate, methyltributyl
ammonium chloride, tetrabutyl ammonium hydroxide, tributyl benzyl ammonium chloride;
15 Wherein in step-a to f) the suitable solvent is selected from hydrocarbon solvents,
chloro solvents, ether solvents, ketone solvent, nitrile solvent, polar aprotic solvents, polar
protic solvent, alcoholic solvent, ester solvents, water or any mixture thereof;
The preferred embodiment of the present invention to provide a process for the
20 preparation of compound of formula-5.
Formula-5
comprising of:
a)Reacting the compound of formula-[1]
25
Formula-1
12
with deutirated methyl iodide, in presence of potassium carbonate in dimethyl formamide to
provide the compound of formula-2,
Formula-2
b) reacting the compound obtained in step-a) 5 with nitromethane, in presence of ammonium
acetate in aceticacid, to provide the compound of formula-3,
Formula-3
c)reducing the compound obtained in step-b) with sodium borohydride, boron trifluoride
10 etherate solution in tetrahydrofuran to provide the compound of formula-4,
Formula-4
d)cyclising the compound obtained in step-c) with ethyl formate, phosphorous oxychloride
to provide the compound of formula-5,
15
Formula-5
The third aspect of the present invention provides process for the preparation of
crystalline form-I of compound of formula-I comprising of;
20 a) Dissolving or suspending the compound of formula-I in a suitable solvent,
b) stirring the reaction mass at 25-100°C,
c) isolating the crystalline form-I of compound of formula-I
wherein in step-a to c) the suitable solvent is selected from hydrocarbon solvents, chloro
solvents, ether solvents, polar, polar aprotic solvents, methanol, isopropanol, ester solvents,
25 ketone solvent, water or any mixture thereof;
13
The preferred embodiment of the present invention provides process for the
preparation of crystalline form-I of compound of formula-I comprising of;
a) suspending the compound of formula-I in a ethyl acetate,
b) stirring the reaction mass at 70-80°C,
5 c) evaporating the reaction mixture obtained in step-b)
d) stirring the compound obtained in step-c) in isopropanol at 75-85°C,
e) isolating the crystalline form-I of compound of formula-I.
The process for the preparation of compound of formula-I developed by the present
10 inventors produces highly pure compound of formula-I with good yield. All the related
substances and residual solvents are controlled well within the limits as suggested by ICH
guidelines and most of the related substances are controlled in non-detectable levels.
The compound of formula-I produced by the process of the present invention is
having purity of greater than 99.5%, preferably greater than 99.7%, more preferably greater
15 than 99.9% by HPLC
The other embodiment of present invention for the preparation of compound of
formula- I can be represented schematically as follows:
20 Deutetrabenazine and its polymorphs produced by the present invention can be
further micronized or milled to get the desired particle size to achieve desired solubility
profile based on different forms of pharmaceutical composition requirements. Techniques
14
that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
PXRD analysis of Deutetrabenazine was carried out using BRUKER D8 ADVANCED/AXS X-Ray diffractometer using Cu Ká radiation of wavelength 1.5406 A° 5 and continuous scan speed of 0.03°/min. IR spectra were recorded on a Perkin-Elmer FTIR spectrometer.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. 10
Examples:
Example-1: Preparation of the compound of formula-3.
A round bottom flask was charged with compound of formula-1(100.0 g), N,N-dimethyl formamide (500 mL) and potassium carbonate (250.14 g) at 25-35°C and stirred for 10 min. Cooled the reaction mixture to 10-20°C, slowly added deuterated methyl iodide (314.85 g) 15 and stirred for 18 hr at 25-35°C. Filtered the unwanted material, washed with ethyl acetate (250 mL). The ethyl acetate layer was charged with water (250 mL) and stirred for 15 min and separated the organic layer. The aqueous layer was extracted with ethyl acetate (2 x 200 mL) and the combined organic layer was washed with brine solution. The organic layer was dried over sodium sulphate, distilled off completely to get the crude compound of formula-2. 20
Other RBF was charged with acetic acid (550 mL), nitromethane (233.93 g) and ammonium acetate (24.61 g) and compound of formula-2 and stirred for 16 hr at 90-100°C. Cooled the reaction mixture to 55-65°C, evaporated the solvent. The reaction mixture was further cooled to 25-35°C, added 1: 1 ratio of ethanol (220 mL) and water (220 mL) and stirred for 90 min at 10-20°C. The precipitated solid was filtered and washed with ethanol (55 mL) and dried to 25 get the title compound.
Yield: 74.43 g
Example-2: Preparation of the compound of formula-5.
A dried round bottom flask was charged with sodium borohydride (168.72 g) and tetrahydro furan (9 L) stirred for 10 min at 25-35°C. Cooled the reaction mixture to 0-5°C, charged BF3 30
15
etharate solution (791 g) slowly over the period of 10-15 min followed by a solution of compound of formula-3 (200 g) in tetrahydrofuran (1.4 L) for about 30 min. The reaction mixture was gradually heated to 60-65°C and stirred for 2 h. Cooled the reaction mixture to 0-10°C, quenched slowly with 1N HCl (2 L) over a period of 30 min and stirred. The reaction mixture was gradually heated to 60-65°C, and stirred for 2 h. Cooled the reaction 5 mixture to 30-35°C, adjusted the pH to 11.5 with 10 % sodium hydroxide solution. The aqueous layer was extracted with MTBE (4 x300 mL), the combined organic layer was dried over sodium sulphate, and evaporated to get the residue of compound of formula-4.
An other RBF was charged with ethylformate (540 mL), compound of formula-4 (150 g) and sodium tert-butoxide (71.43 g) and heated to 50-55°C and stirred for 12 hr. The reaction 10 mixture was cooled to 40-45°C and concentrated to get crude compound. The obtained compound was diluted with dichloromethane (435 mL), water (261 mL) stirred for 10 min and separated the layers. The aqueous layer was extracted with dichloromethane (435 mL), and the combined organic layer was dried over sodium sulphate and evaporated to get the residue compound. The residue compound, phosphorus oxychloride (212 mL) were charged 15 in an other RBF and heated to 90-100°C stirred for 5 hr. Cooled the reaction mixture to 10-20°C, charged with water (600 mL) and adjusted the pH to 8.5 with 20% potassium hydroxide solution and stirred for 10 min. The aqueous layer was charged with dichloro methane (4 x 150 mL) and separated the organic layer. The organic layer was dried over the sodium sulphate and evaporated to get the title compound. 20
Yield: 90.50 g
Example-3: Preparation of the compound of formula-I.
A round bottom flask was charged with methanol (50 mL), compound of formula-5 (10.0 g) compound of formula-6 (17.72 g) and stirred for 10 min. The reaction mixture and heated to 40-45°C and stirred for 35-40 min. Cooled the reaction mixture to 25-35°C, stirred for 60-90 25 min, filtered the isolated solid and washed with methanol (10 mL) and dried to get the title compound.
Yield: 16.39 g; Purity by HPLC: > 97 %
Example-4: Preparation of the compound of formula-8.
16
A round bottom flask was charged with methanol (75 mL), compound of formula-7 (137.5 g) stirred for 10 min. Charged with dimethylamine hydrochloride (25 g), para formaldehyde (137.5 g) to the reaction mixture and heated to 59-65°C and stirred for 14-16 hr. The reaction mixture was cooled to 25-35°C, adjusted the pH to 8.0 with 10% sodium hydroxide solution (10 mL) and charged with ethyl acetate (200 mL) stirred the solution for 10-15 min. The both 5 layers were separated, aqueous layer was extracted with ethyl acetate (2x50 mL), the combined organic layer was washed with water and dried under sodium sulphate. The organic solvent was distilled completely to get the title compound.
Yield: 37.5 g
Example-5: Preparation of the compound of formula-6. 10
A round bottom flask was charged with ethyl acetate (350 mL), compound of formula-8 ( 50.0 g) and stirred for 10 min. The reaction was cooled to 0-10°C, methyl iodide (82.8 g) was added and stirred for 16 hr at 25-35°C. The obtained solid was filtered, washed with ethyl acetate and dried to get the title compound.
Yield: 91.5 g 15
Example-6: process for preparation of crystalline Form-I of compound of formula-I.
A round bottom flask was charged with ethyl acetate (50 mL), compound of formula-1 ( 10 g) and stirred for 10 min. The reaction was heated to 70-80°C and stirred for 45 min, charged charcoal and maintained stirring for 30 min. The resulting solution was filtered through hyflow bed, washed with ethyl acetate and stirred at 0-10°C for 30 min. The obtained solid 20 was filtered, washed with ethyl acetate and dried to get the title compound.
The obtained compound PXRD is depicted in figure-1, which is similar to the crystalline form-I of compound of formula-1.
Yield: 10 g; Purity by HPLC: 99.75 %
Example-7: process for preparation of crystalline Form-I of compound of formula-I. 25
A round bottom flask was charged with compound of formula-1 ( 0.7 g) and heated to melting temperature. The molten compound was gradually cooled to 25-35°C and scratched the obtained solid and dried to get the title compound.
The obtained compound PXRD complies with figure -1
Yield: 0.6 g 30
17
Purity by HPLC: > 99.5%
Example-8: Purification of compound of formula-I.
A round bottom flask was charged with compound of formula-1 ( 1.0 g) and acetone (13.0 vol) at 25-35°C stirred for 10 min. The reaction mass cooled to -20°C and stirred for 3-4 hrs, filter the obtained solid and washed with acetone (5 mL) and dried to get the title compound. 5
The obtained compound PXRD complies with figure -1.
Yield: 0.6 g; Purity by HPLC: > 99.5%
Example-9: Purification of compound of formula-I.
A round bottom flask was charged with compound of formula-1 ( 1.0 g) and n-heptane (25.0 mL ) and heated to 55-65°C and stirred for 30 min. The reaction mass cooled to 20-25°C, 10 filter the obtained solid and washed with heptane, dried to get the title compound.
The obtained compound PXRD is depicted in figure -1
Yield: 1.0 g ; Purity by HPLC: > 99.5%
Example-10: Preparation of the compound of formula-I.
A round bottom flask was charged with ethanol (100 mL), compound of formula-5(5.0 g) and 15 stirred for 10 min. A compound of formula-6 (8.0 g) was added to the reaction mass and heated to 75-80°C stirred for 5-6 hr. The reaction mixture was charged with water (200 mL) and extracted with dichloromethane (3x500 mL). The combined organic layer was distilled off completely. The obtained crude compound was purified by silicagel column using a mixture of ethyl acetate and petether (1:4), evaporated 80% of eluted solvents under vacuum 20 below 60°C, the resulting solution was stirred at 25-35°C for 30 min. Filtered the obtained solid, washed with ethyl acetate and dried to get the title compound.
The obtained compound PXRD is depicted in figure -2.
Yield: 3.0 g
Example-11: Preparation of the compound of formula-5. 25
A dried round bottom flask was charged with compound of formula-3 (70 g) , ethanol (1050 mL) stirred for 10 min at 25-35°C. Cooled the reaction mixture to 0-5°C, charged sodium borohydride (33.21 g) and stirred for 2 hr at same temperature. The reaction mixture was quenched with ammonium chloride (28 g in 142 mL ) and evaporated the solvent. The reaction mass was charged with ethyl acetate (350 mL) , ammonium chloride (35 g in 350 30
18
mL) and stirred for 15 min. Separated the both layers, the aqueous layer was extracted with ethyl acetate (350 mL) and the combined organic layer was washed with water (1.4 L) and brine solution (35 g in 350 mL). The organic layer was dried over sodium sulphate and evaporated completely to get the crude compound.
An autoclave vessel was charged with crude compound, methanol (1050 mL) and flushed 5 with nitrogen gas, charged 5 % Pd/C (14 g) and applied 4 kg of hydrogen gas pressure stirred for 8 hr at 25-35°C. Filtered the reaction mixture over hyflow super cell and washed with methanol (280 mL) and evaporated to get the compound of formula-4 as residue.
An other RBF was charged with compound of formula-4, ethyl formate (870 mL), sodium tert-butoxide (71.43 g) and heated to 50-55°C and stirred for 3 hr. The reaction mixture was 10 cooled to 40-45°C, concentrated to get crude compound. The obtained compound was diluted with dichloromethane (435 mL), water (261 mL) stirred for 10 min and separated the layers. The aqueous layer was extracted with dichloromethane (435 mL), and the combined organic layer was dried over sodium sulphate and evaporated to get the residue compound.
The residue compound, phosphorus oxychloride (130.5 mL) were charged in an other RBF 15 and heated to 90-100°C stirred for 5 hr. Cooled the reaction mixture to 10-20°C, charged with water (522 mL) and adjusted the pH to 8.5 with 20% potassium hydroxide solution and stirred for 10 min. The aqueous layer was charged with dichloro methane (2 x 260 mL) and separated the organic layer. The organic layer was dried over the sodium sulphate and evaporated to get the title compound. 20
Yield: 20 g.
Example-12: Preparation of the compound of formula-2.
A round bottom flask was charged with compound of formula-1(50.0 g), N, N-dimethyl formamide (270 mL) and potassium carbonate (130.5 g) at 25-35°C and stirred for 10 min. Cooled the reaction mixture to 10-20°C, added deuterated methyl iodide (160.5 g) slowly and 25 stirred for 18 hr at 25-35°C. Filtered the unwanted material, washed with ethyl acetate (250 mL). The ethyl acetate layer was charged with water (250 mL) and stirred for 15 min and separated the organic layer. The aqueous layer was extracted with ethyl acetate (2 x 200 mL) and the combined organic layer was washed with brine solution. The organic layer was dried over sodium sulphate, distilled off completely to get the crude compound of formula-2. 30
19
Yield: 58 g.
Example-13: Preparation of the compound of formula-3.
A round bottom flask was charged with compound of formula-2 (120 g), acetic acid (660 mL) and stirred for 10 min. Nitromethane (233.93 g) and ammonium acetate (24.61 g) were charged to the reaction mixture simultaneously and stirred for 16 hr at 90-100°C. Cooled the 5 reaction mixture to 55-65°C, evaporated the solvent. The reaction mixture was further cooled to 25-35°C, added 1: 1 ratio of ethanol (264 mL) and water (264 mL) and stirred for 90 min at 10-20°C. The precipitated solid was filtered and washed with ethanol (60 mL) and dried to get the title compound.
Yield: 75 g. 10
Example-14: Preparation of the compound of formula-5.
A round bottom flask was charged with compound of formula-4 (10 g), acetic acid (70 mL) and hexamethylenetetramine (20 g) stirred for 8 hr at 100-110°C. Cooled the reaction mixture to 25-35°C, quenched with water (65 mL) extracted with dichoromethane (3 x 80 mL). The combined organic layer was dried over anhydrous sodium sulfate, concentrated to 15 give the title compound.
Yield: 6.5 g.
Example-15: Preparation of the compound of formula-6.
A round bottom flask was charged with methanol (300 mL), compound of formula-7 (280 g) stirred for 10 min. Dimethylamine hydrochloride (100 g) and para formaldehyde (36.8 g) 20 were added to the reaction mixture and heated to 59-65°C and stirred for 14 hr. The reaction mixture was cooled to 25-35°C, adjusted the pH to 8.0 with 10% sodium hydroxide solution (40 g in 400 mL of water) and charged with water (400 mL) ethyl acetate (800 mL) stirred the solution for 10-15 min. The layers were separated, aqueous layer was extracted with ethyl acetate (3x200 mL). The combined organic layer was washed with water (2x200 mL) 25 and dried under sodium sulphate. The organic solvent was distilled off to get the crude compound.
The obtained crude compound was cooled to 25-35°C, added ethyl acetate (1400 mL) and further cooled to 0-10°C, slowly added iodomethane (349 g) and stirred for 16 hr at 25-35°C. The precipitated solid was filtered, washed with ethyl acetate (100 mL) and dried to 30
20
get the wet compound. The wet compound was stirred in isopropanol (600 mL) at 40-45°C for 3 hr, Filtered the obtained solid and dried to get the title compound.
Yield: 135 g
Example-16: Preparation of the compound of formula-I.
A dried round bottom flask was charged with sodium borohydride (210.8 g) and tetrahydro 5 furan (5 L) stirred for 10 min at 25-35°C. Cooled the reaction mixture to 0-5°C, charged BF3 etharate solution (988.4 g) slowly over the period of 15-30 min. A solution of compound of formula-3 (250 g) in tetrahydrofuran (3.75 L) was added about 60 min to the above reaction mixture at 0-5°C, and gradually heated to 55-65°C stirred for 2 hr. Cooled the reaction mixture to 0-10°C, quenched slowly with 1N HCl (5 L) over a period of 30 min and stirred. 10 The reaction mixture was gradually heated to 60-65°C, and stirred for 12 h. Cooled the reaction mixture to 25-35°C, adjusted the pH to 11.5 with 10 % sodium hydroxide solution (250 g in 2.5 L of water). The aqueous layer was successively extracted with MTBE (4x750 mL) and sodium chloride (125 g in 1.25 L), the combined organic layer was dried over sodium sulphate, and evaporated and stripped off with n-heptane to get the compound of 15 formula-4.
An other RBF was charged with ethylformate (716.39 mL), compound of formula-4 and heated to 45-55°C and stirred for 5 hr. The reaction mixture was evaporated to get crude residue compound. The obtained compound was cooled to 25-35°C, charged with phosphorous oxychloride (384 g) and heated to 90-100°C stirred for 12 hr. Cooled the 20 reaction mixture to 25-35°C, charged with water (585 mL) further cooled and adjusted the pH to 9.5 with 20% sodium carbonate solution (350 g in 1 L of water) and stirred for 10 min. The aqueous layer was charged with dichloromethane (300 mL) and separated the organic layer. The resulting aqueous layer was extracted with dichloromethane (300 mL). The combined organic layer was dried over the sodium sulphate and evaporated, co distilled with 25 methanol (62.5 mL) to get the compound-5 as residue.
A round bottom flask was charged with methanol (470 mL), compound of formula-5 compound of formula-6 (166.3 g) and stirred for 10 min. The reaction mixture and heated to 40-45°C and stirred for 40 hr. Cooled the reaction mixture to 25-35°C, charged with water (188 mL) and further cooled to 0-10°C stirred for 2 hr. Filtered the obtained solid and washed 30
21
with acetone (12.5 mL) and water (188 mL) and dried to get the title compound.
Yield: 81.4 g
Example-17: Purification of compound of formula-I.
A round bottom flask was charged with compound of formula-1 ( 100 g) and ethyl acetate (800 mL) and heated to 70-80°C and stirred for 45 min. The reaction mass charged with 5 carbon (5 g) and stirred for 30 min, filtered the mass through hyflow bed and washed with ethyl acetate (100 mL) at 70-75°C. The filtrate solution was distilled off completely, charged with isopropanol (200 mL) and heated to 75-85°C stirred for 45 min. Cooled the reaction mixture to 5-10°C and stirred for 90 min. The obtained solid was filtered and washed with isopropanol (50 mL), dried to get the title compound. 10
The obtained compound PXRD is complies with figure -1
Yield: 80 g
Purity by HPLC: > 99.6% ,CLAIMS:1. A process for the preparation of compound of formula-I,
Formula-I
5 comprising of:
a)Reacting the compound of formula-1
Formula-1
with suitable reagent, solvent to provide the compound of formula-2,
10
Formula-2
b) reacting the compound obtained in step-a) with suitable reagent in presence of suitable
solvent to provide the compound of formula-3,
15 Formula-3
c) reducing the compound obtained in step-b) with suitable reagent in presence of suitable
solvent to provide the compound of formula-4,
Formula-4
20 d) cyclising the compound obtained in step-c) with a suitable reagent, solvent to provide the
compound of formula-5 or salts thereof, optionally purified in suitable solvent,
23
Formula-5
e) reacting the compound of formula-5 with compound of formula-6,
5 Formula-6
in presence of suitable solvent, optionally suitable base, phase transfer catalyst to provide
the compound of formula-1,
f) optionally purifying the compound obtained in step-e) in suitable solvents.
10 2. The process according to claim 1 wherein in step-a) deuterium containing methylating
agent and selected from the group consisting of deuterated methyl iodide, deuterated methyl
bromide, deuterated dimethyl sulfate, deuterated dimethyl carbonate, deuterated methanol
optionally in presence of catalyst selected from azodicarboxylate such as
diethylazodicarboxylate (DEAD) or diiso propylazodicarboxylate (DIAD) and triphenyl
15 phosphine; the suitable base is selected from inorgainc base such as sodium carbonate,
potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium
hydroxide, potassium hydroxide, lithium hydroxide, organic bases such as triethylamine,
diisopropylethylamine or mixtures thereof; suitable temperature 0-120°C;
wherein in step-b) the suitable reagent is nitro methane, the suitable base is selected from
20 ammonium acetate, sodium acetate, potassium acetate, organic bases such as sodium
methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tertbutoxide,
potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides
such as sodium hydride, potassium hydride, lithium hydride triethylamine,
diisopropylethylamine or mixtures thereof; inorgainc base such as sodium carbonate,
25 potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium
hydroxide, potassium hydroxide, lithium hydroxide mixtures thereof, suitable temperature 0-
100° C;
24
wherein in step-c) the suitable reagent is selected from sodiumborohydride, borane (BH3
solution), boron trifluoride solution, lithium aluminium hydride, lithium borohydride, chloro
trimethyl silane, palladium carbon, ray-nickel, zinc in acetic acid, zinc, ammonium chloride
or mixture thereof; suitable temperature 0-100° C;
5 wherein in step-d) the suitable reagent is selected from hexamethylenetetramine, ethyl
formate, methylformate, propyl formate, phosphoryl chloride suitable temperature 0-100° C;
wherein in step-e) the suitable base is inorganic base or organic base, the suitable phase
transfer catalyst is selected from triethylbenzyl ammonium chloride, tetrabutylammonium
bromide, tetrabutyl ammonium chloride, tetrabutyl ammonium acetate, methyltributyl
10 ammonium chloride, tetrabutyl ammonium hydroxide, tributyl benzyl ammonium chloride;
wherein in step-a to f) the suitable solvent is selected from hydrocarbon solvents, chloro
solvents, ether solvents, ketone solvent, nitrile solvent, polar aprotic solvents, polar protic
solvent, alcoholic solvent, ester solvents, water or any mixture thereof;
15 3. A process for the preparation of compound of formula-I,
Formula-I
comprising of:
a) Reacting the compound of formula-1
20
Formula-1
with deutirated methyl iodide, in presence of potassium carbonate in dimethyl formamide to
provide the compound of formula-2,
25 Formula-2
25
b) reacting the compound obtained in step-a) with nitromethane, in presence of ammonium
acetate in aceticacid, to provide the compound of formula-3,
Formula-3
c) reducing the compound obtained 5 in step-b) with sodium borohydride, boron trifluoride
etherate in tetrahydrofuran to provide the compound of formula-4,
Formula-4
d)cyclising the compound obtained in step-c) with ethyl formate, phosphorous oxychloride
10 to provide the compound of formula-5,
Formula-5
e) reacting the compound of formula-5 with compound of formula-6,
15 Formula-6
in presence methanol to provide the compound of formula-1.
f) purifying the compound obtained in step-e) in ethyl acetate and isopropanol to get the
compound of formula-I.
4. A process for the preparation of compound of formula-5.
20
Formula-5
comprising of:
26
a)Reacting the compound of formula-1
Formula-1
with deutirated methyl iodide, in presence of potassium carbonate in dimethyl formamide to
5 provide the compound of formula-2,
Formula-2
b) reacting the compound obtained in step-a) with nitromethane, in presence of ammonium
acetate in aceticacid, to provide the compound of formula-3,
10
Formula-3
c)reducing the compound obtained in step-b) with sodium borohydride, boron trifluoride
etherate in tetrahydrofuran to provide the compound of formula-4,
15 Formula-4
d)cyclising the compound obtained in step-c) with ethyl formate, phosphorous oxychloride
to provide the compound of formula-5,
Formula-5
20 5. A process for the preparation of crystalline form-I of compound of formula-I comprising
of;
a)Dissolving or suspending the compound of formula-I in a suitable solvent,
b)stirring the reaction mass at 25-100°C,
c) isolating the crystalline form-I of compound of formula-I
27
wherein in step-a) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, polar, polar aprotic solvents, methanol, isopropanol, ester solvents, ketone solvent, water or any mixture thereof;
6. A process for the preparation of crystalline form-I of compound of formula-I comprising of; 5
a) suspending the compound of formula-I in a ethyl acetate,
b) stirring the reaction mass at 70-80°C,
c) evaporating the step-b) reaction mixture,
d) stirring the compound obtained in step-c) in isopropanol at75-85°C,
e) isolating the crystalline form-I of compound of formula-I. 10
7. The compound of formula-I produced by any of the proceeding claims having purity of greater than 99.5%, preferably greater than 99.7%, more preferably greater than 99.9% by HPLC.
8. Crystalline form of compound of formula-I obtained according to any preceding claims having particle size of D(0.9) < 100 ìm, preferably D(0.9) < 50 ìm and most preferably 15 D(0.9) <10 ìm.