DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of earlier Indian provisional patent application IN 201741047280 filed on December 29, 2017 and Indian provisional patent application IN 201841006981 filed on February 23, 2018, each of which are hereby incorporated by reference in their entireties.
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
The present invention relates generally to the preparation of pharmaceutical active ingredients and more specifically to a process for the preparation of deutetrabenazine and its intermediates.
DESCRIPTION OF RELATED ART
Deutetrabenazine is chemically known as (3R,11bR)-3-(2-methylpropyl)-9,10 bis(trideuterio methoxy)-1,3,4,6,7,11b-hexahydrobenzo[a]quinolizin-2-one or (RR, SS)-1, 3, 4, 6, 7, 11b-hexahydro-9, 10-di(methoxy-d3)-3-(2-methylpropyl)­2H-benzo[a]quinolizin-2-one and is shown below in Formula (I).

Deutetrabenazine is a deuterated analog of tetrabenazine. Deutetrabenazine is marketed in the United States as AUSTEDO® by Teva for the treatment of chorea associated with Huntington’s disease and for the treatment of tardive dyskinesia in adults.
Processes for the preparation of deutetrabenazine are disclosed in U.S. Patent No. 8,524,733.

Disclosed herein are efficient, industrially viable, and cost effective processes for the preparation of a deutetrabenazine intermediates and their conversion to deutetrabenazine.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a process for preparing deutetrabenazine. In one embodiment, deutetrabenazine may be prepared by a process that includes the step of reacting d6-6,7-dimethoxy-3,4-dihydroisoquinoline with a salt of 3-[(dimethylamino)methyl]-5-methylhexan-2-one in the presence of a base in a solvent to produce deutetrabenazine.
In some embodiments, 3-[(dimethylamino)methyl]-5-methylhexan-2-one is a salt of an organic acid. Suitable organic acids include, but are not limited to, oxalic acid, citric acid, formic acid, acetic acid, pyruvic acid, malonic acid, fumaric acid, maleic acid, succinic acid, malic acid, and the like. In some particularly useful embodiments, the organic acid is oxalic acid or citric acid.
The solvent may be a non-polar solvent, a polar aprotic solvent, a polar protic solvent, or mixtures thereof. Examples of non-polar solvents include, but are not limited to, hexanes, heptane, cyclohexane, octane, isooctane, cyclopentane, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, and mixtures thereof. Examples of polar aprotic solvents include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 1,2-dimethoxyethane, and mixtures thereof. Examples of polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof.
The base may be an organic base, inorganic base, or mixtures thereof. Examples of suitable organic bases include, but are not limited to, pyridine, trimethylamine, N,N-diisopropylethylamine, and mixtures thereof. Examples of suitable inorganic bases include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof. Examples of suitable inorganic bases include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof.
Within the context of this embodiment, d6-6,7-dimethoxy-3,4-dihydroisoquinoline may be hydrated, a salt, or a hydrated salt form.
In another embodiment, deutetrabenazine may be prepared by a process that includes the step of reacting a hydrated salt of d6-6,7-dimethoxy-3,4-dihydroisoquinoline with a 2-acetyl-4-methylpentylammonium halide in the presence of a base in a solvent to produce deutetrabenazine. d6-6,7-Dimethoxy-3,4-dihydroisoquinoline may be a salt, for example, of hydrochloric acid, hydrobromic acid, a sulfuric acid, or phosphoric acid.
The solvent may be a non-polar solvent, a polar aprotic solvent, a polar protic solvent, or mixtures thereof. Examples of suitable non-polar solvents include, but are not limited to, hexanes, heptane, cyclohexane, octane, isooctane, cyclopentane, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, and mixtures thereof. Examples of suitable polar aprotic solvents include but are not limited to, acetone, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 1,2-dimethoxyethane, and mixtures thereof. Examples of suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof.
The base may be, for example, an organic base, an inorganic base, or mixtures thereof.
Examples of suitable inorganic bases include, but are not limited to, pyridine, trimethylamine, N,N-diisopropylethylamine, and mixtures thereof. Examples of suitable inorganic bases include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof. Examples of suitable inorganic bases include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof.
In another aspect, the present invention provides a process for the preparation of 2-(d6-3,4-dimethoxyphenyl)ethylamine. In one embodiment, 2-(d6-3,4-dimethoxyphenyl)ethylamine may be prepared by a process that includes the steps of:
a. reacting 2-[2-(3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline of the Formula Va with a deuterated methylating agent in a solvent to produce a 2-[2-(d6-3,4-dimethoxyphenyl)ethyl]-1,3-dioxoisoindoline; and
b. deprotecting the 2-[2-(d6-3,4-dimethoxyphenyl)ethyl]-1,3-dioxoisoindoline with a deprotecting agent to produce 2-(d6-3,4-dimethoxyphenyl)ethylamine,
wherein R is hydrogen, optionally substituted C1 to C10 alkyl, optionally substituted C6 to C14 aryl, or optionally substituted C1 to C16 aralkyl and wherein each substitution is selected from the group consisting of halogens, nitro groups, cyano groups, carboxyl groups, and combinations thereof.
Examples of suitable deuterated methylating agents include, but are not limited to, deuterated iodomethane, deuterated methanol, deuterated dimethyl carbonate, deuterated dimethyl sulfate, deuterated bromomethane, and deuterated methyl trichloroacetate.
The solvent may be a non-polar solvent, a polar aprotic solvent, a polar protic solvent, and mixtures thereof.
Examples of suitable non-polar solvents include, but are not limited to, hexanes, heptane, cyclohexane, octane, isooctane, cyclopentane, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, and mixtures thereof. Examples of suitable polar aprotic solvents include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 1,2-dimethoxyethane, and mixtures thereof. Examples of suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof.
Optionally, 2-[2-(3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline of the Formula Va may be reacted with a deuterated methylating agent in the presence of a base. The base may be an organic base, an inorganic base, or mixtures thereof.
Examples of suitable organic bases include, but are not limited to, pyridine, trimethylamine, N,N-diisopropylethylamine, and mixtures thereof.
Examples of suitable inorganic bases include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof. More specific examples of suitable inorganic bases include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof.
Optionally, 2-[2-(3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline of the Formula Va may be reacted with a deuterated methylating agent in the presence of a catalyst. Examples of suitable catalysts include, but are not limited to, diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, triphenylphosphine, tricyclohexylphosphine, and tributylphosphine.
2-[2-(d6-3,4-dimethoxyphenyl)ethyl]-1,3-dioxoisoindoline may be treated with a deprotecting agent to produce 2-(d6-3,4-dimethoxyphenyl)ethylamine. Examples of suitable deprotecting agents include hydrazine, methylamine, sodium borohydride and acetic acid, pyridine, trimethylamine, and N,N-diisopropylethylamine.
In another aspect, the present invention provides a process for the preparation of 2-[(d6-3,4-dimethoxyphenyl)ethyl]formamide. In one embodiment, 2-[(d6-3,4-dimethoxyphenyl)ethyl]formamide may be prepared by a process that includes the steps of:
a. formylating dopamine with a formylating agent in the presence of a base in a solvent and to produce N-[2-(3,4-dihydroxyphenyl)ethyl]formamide; and
b. reacting N-[2-(3,4-dihydroxyphenyl)ethyl]formamide with a deuterated methylating agent in a solvent to produce 2-[(d6-3,4-dimethoxyphenyl)ethyl]formamide.
The dopamine may optionally be a dopamine salt, for example, dopamine hydrochloride.
Examples of suitable formylating agents include, but are not limited to, formic acid, methyl formate, ethyl formate, propyl formate, and isobutyl formate.
The solvent may be a non-polar solvent, a polar aprotic solvent, a polar protic solvent, or mixtures thereof. Examples of suitable non-polar solvents include, but are not limited to, hexanes, heptane, cyclohexane, octane, isooctane, cyclopentane, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, and mixtures thereof. Examples of suitable polar aprotic solvents include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 1,2-dimethoxyethane, and mixtures thereof. Examples of suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof.
Dopamine hydrochloride may be formylated in the presence of a base. The base may be, for example, an organic base, an inorganic base, or mixtures thereof. Examples of suitable organic bases include, but are not limited to, pyridine, trimethylamine, N,N-diisopropylethylamine, and mixtures thereof. Examples of suitable inorganic bases include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof.
N-[2-(3,4-dihydroxyphenyl)ethyl]formamide may be reacted with a deuterated methylating agent. Examples of suitable deuterated methylating agents include, but are not limited to, deuterated methanol, deuterated dimethyl carbonate, deuterated dimethyl sulfate, deuterated methyl bromide, and deuterated methyl trichloroacetate.
Optionally, N-[2-(3,4-dihydroxyphenyl)ethyl]formamide may be reacted with a deuterated methylating agent in the presence of a catalyst. Examples of suitable catalysts include, but are not limited to, diethyl azodicarboxylate, diisopropyl azodicarboxylate, triphenylphosphine, tricyclohexylphosphine, and a combination of a cobalt salt, a tetradentate phosphine ligand, and a base.
In another embodiment, 2-[(d6-3,4-dimethoxyphenyl)ethyl]formamide may be prepared by a process that includes the steps of :
a. protecting the amine of dopamine with an amine protecting group (e.g., tert-butyloxycarbonyl (BOC) in the presence of a base in a first solvent to produce amine-protected dopamine;
b. reacting the amine-protected dopamine with a deuterated methylating agent in a second solvent to produce a deuterated amine-protected dopamine derivative (e.g., tert-butyl-d6-3,4-dimethoxyphenylethylcarbamate);
c. deprotecting the deuterated amine-protected dopamine derivative to produce 2-(d6-3,4-dimethoxyphenyl)ethylamine; and
d. formylating 2-(d6-3,4-dimethoxyphenyl)ethylamine with a formylating agent to produce 2-[(d6-3,4-dimethoxyphenyl)ethyl]formamide.
Optionally, the dopamine may be a salt, for example dopamine hydrochloride.
The first solvent and the second solvent may be the same or different, and are independently chosen from a non-polar solvent, a polar aprotic solvent, a polar protic solvent, and mixtures thereof. Examples of suitable non-polar solvents include, but are not limited to, hexanes, heptane, cyclohexane, octane, isooctane, cyclopentane, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, and mixtures thereof. Examples of suitable polar aprotic solvents include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 1,2-dimethoxyethane, and mixtures thereof. Examples of suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof.
Dopamine may be protected in the presence of a base. The base may be an organic base, an inorganic base, or mixtures thereof. Examples of suitable organic bases include, but are not limited to, pyridine, trimethylamine, N,N-diisopropylethylamine, and mixtures thereof. Examples of suitable inorganic bases include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof.
The protected dopamine may then be reacted with a deuterated methylating agent. The deuterated methylating agent may be, but is not limited to, deuterated methanol, deuterated dimethyl carbonate, deuterated dimethyl sulfate, deuterated methyl bromide, and deuterated methyl trichloroacetate.
Optionally, N-[2-(3,4-dihydroxyphenyl)ethyl]formamide may be reacted with a deuterated methylating agent reacting step in the presence of a catalyst. Examples of suitable catalysts include, but are not limited to, diethyl azodicarboxylate, diisopropyl azodicarboxylate, triphenylphosphine, tricyclohexylphosphine, and a combination of a cobalt salt, a tetradentate phosphine ligand, and a base.
2-(d6-3,4-Dimethoxyphenyl)ethylamine may then be treated with a formylating agent. Examples of suitable formylating agents include, but are not limited to, formic acid, methyl formate, ethyl formate, propyl formate, isobutyl formate, and mixtures thereof.

BRIEF DESCRIPTION OF THE DRAWINGS
Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing therefrom will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying drawing figures wherein:
Figure 1 shows a powder X-ray diffraction (PXRD) pattern of amorphous deutetrabenazine.
DETAILED DESCRIPTION OF THE INVENTION
The present invention now will be described more fully hereinafter with reference to the accompanying examples and experiments in which illustrative embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
The present invention provides processes for the preparation of deutetrabenazine and for intermediates useful in the preparation thereof.
In one aspect, the present invention provides a method for preparing deutetrabenazine.
In one embodiment, deutetrabenazine may be prepared by a process that includes the step of reacting d6-6,7-dimethoxy-3,4-dihydroisoquinoline (Formula II) with a salt of 3-[(dimethylamino)methyl]-5-methylhexan-2-one (Formula III) in the presence of a base to produce deutetrabenazine (Formula I).

Within the context of this step, d6-6,7-dimethoxy-3,4-dihydroisoquinoline may be in free base form, complexed with an acid, hydrated, or any combination thereof. Suitable complexing acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, phosphoric, and the like. d6-6,7-Dimethoxy-3,4-dihydroisoquinoline may be a hemihydrate, monohydrate, dihydrate, trihydrate, sesquihydrate, hemipentahydrate, tetrahydrate, pentahydrate, or any other hydrated form.
Within the context of this step, “XA” may be an organic acid. Suitable organic acids include, but are not limited to, oxalic acid, citric acid, formic acid, acetic acid, pyruvic acid, malonic acid, fumaric acid, maleic acid, succinic acid, malic acid, and the like. In some particularly useful embodiments, “XA” is oxalic acid or citric acid.
The base may be an organic base, an inorganic base, or mixtures thereof. Suitable organic bases include, but are not limited to, pyridine, trimethylamine, N,N-diisopropylethylamine, and mixtures thereof. Suitable inorganic bases include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof. Suitable alkaline metal hydroxides include, but are not limited to, sodium hydroxide, potassium hydroxide, and mixtures thereof. Suitable alkaline metal bicarbonates include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. Suitable alkaline metal carbonates include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof. Suitable alkaline alkoxides include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof. In some particularly useful embodiments, potassium carbonate is used as a base.
The reaction may be carried out in a solvent. The solvent may be a non-polar solvent, a polar aprotic solvent, a polar protic solvent, or mixtures thereof. Suitable non-polar solvents include, but are not limited to, hexanes, heptane, cyclohexane, octane, isooctane, cyclopentane, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, and mixtures thereof. Suitable polar aprotic solvents include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 1,2-dimethoxyethane, and mixtures thereof. Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, methanol, water, or a mixture of methanol and water is used as the solvent.
This reaction may be carried out at an elevated temperature, for example, from about 30 °C to about 110 °C, which includes about 30 °C, about 40 °C, about 50 °C, about 60 °C, about 70 °C, about 80 °C, about 90 °C, about 100 °C, about 110 °C and values therebetween including 30 °C – 100 °C, 30 °C – 90 °C, 30 °C – 80 °C, 30 °C – 70 °C, 30 °C – 60 °C, 30 °C – 50 °C, 30 °C – 40 °C, 40 °C – 110 °C, 40 °C – 100 °C, 40 °C – 90 °C, 40 °C – 80 °C, 40 °C – 70 °C, 40 °C – 60 °C, 40 °C – 50 °C, 50 °C – 110 °C, 50 °C – 100 °C, 50 °C – 90 °C, 50 °C – 80 °C, 50 °C – 70 °C, 50 °C – 60 °C, 60 °C – 110 °C, 60 °C – 100 °C, 60 °C – 90 °C, 60 °C – 80 °C, 60 °C – 70 °C, 70 °C – 110 °C, 70 °C – 100 °C, 70 °C – 90 °C, 70 °C – 80 °C, 80 °C – 110 °C, 80 °C – 110 °C, 80 °C – 100 °C, 80 °C – 90 °C, 90 °C – 110 °C, 90 °C – 100 °C, and 100 °C – 110 °C. Heating may be continued until the reaction completes, as measured by TLC/HPLC.
Deutetrabenazine may be isolated by conventional methods known to those in the art. For example, after the reaction finishes, the reaction mixture may be cooled, for example, to a temperature of about 15 °C to about 30 °C, which includes about 15 °C, about 20 °C, about 25 °C, about 30 °C, and values therebetween, for example, 15 °C – 25 °C, 15 °C – 20 °C, 20 °C – 30 °C, 20 °C – 25 °C, and 25 °C – 30 °C.
Next, water may be added. The reaction mixture may be agitated, (e.g., stirred) for about 2 hours to about 4 hours, after which a solid will have formed. The solid may then be isolated by methods well known in the art. For example, the reaction mixture may be filtered to get deutetrabenazine.
In another embodiment, deutetrabenazine (Formula I) may be prepared by a process that includes the step of reacting a hydrated salt of d6-6,7-dimethoxy-3,4-dihydroisoquinoline with a (2-acetyl-4-methylpentyl)trimethylammonium halide in the presence of a base to produce deutetrabenazine.

Within the context of this reaction, d6-6,7-dimethoxy-3,4-dihydroisoquinoline may be hydrated and complexed with an acid to form a “salt.” Suitable complexing acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, phosphoric, and the like. d6-6,7-Dimethoxy-3,4-dihydroisoquinoline may be a hemihydrate, monohydrate, dihydrate, trihydrate, sesquihydrate, hemipentahydrate, tetrahydrate, pentahydrate, or any other hydrated form. Within the context of this step, “X(-)” is a halide anion. For example, it may be chloride, bromide, or iodide.
The base may be an organic base, an inorganic base, or mixtures thereof. Suitable organic bases include, but are not limited to, pyridine, trimethylamine, N,N-diisopropylethylamine, and mixtures thereof. Suitable inorganic bases include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof. Suitable alkaline metal hydroxides include, but are not limited to, sodium hydroxide, potassium hydroxide, and mixtures thereof. Suitable alkaline metal bicarbonates include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. Suitable alkaline metal carbonates include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof. Suitable alkaline alkoxides include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof. In some particularly useful embodiments, potassium carbonate is used as a base.
The reaction may be carried out in a solvent. The solvent may be, for example, a non-polar solvent, a polar aprotic solvent, a polar protic solvent, or mixtures thereof. Suitable non-polar solvents include, but are not limited to, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, and mixtures thereof. Suitable polar aprotic solvents include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 1,2-dimethoxyethane, and mixtures thereof. Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, methanol, water, or a mixture of methanol and water is used as the solvent.
This reaction may be carried out at an elevated temperature, for example, from about 25 °C to about 110 °C, which includes about 25 °C, about 30 °C, about 40 °C, about 50 °C, about 60 °C, about 70 °C, about 80 °C, about 90 °C, about 100 °C, about 110 °C and values therebetween including 25 °C – 100 °C, 25 °C – 90 °C, 25 °C – 80 °C, 25 °C – 70 °C, 25 °C – 60 °C, 25 °C – 50 °C, 25 °C – 40 °C, 25 °C – 30 °C, 30 °C – 110 °C, 30 °C – 100 °C, 30 °C – 90 °C, 30 °C – 80 °C, 30 °C – 70 °C, 30 °C – 60 °C, 30 °C – 50 °C, 30 °C – 40 °C, 40 °C – 110 °C, 40 °C – 100 °C, 40 °C – 90 °C, 40 °C – 80 °C, 40 °C – 70 °C, 40 °C – 60 °C, 40 °C – 50 °C, 50 °C – 110 °C, 50 °C – 100 °C, 50 °C – 90 °C, 50 °C – 80 °C, 50 °C – 70 °C, 50 °C – 60 °C, 60 °C – 110 °C, 60 °C – 100 °C, 60 °C – 90 °C, 60 °C – 80 °C, 60 °C – 70 °C, 70 °C – 110 °C, 70 °C – 100 °C, 70 °C – 90 °C, 70 °C – 80 °C, 80 °C – 110 °C, 80 °C – 110 °C, 80 °C – 100 °C, 80 °C – 90 °C, 90 °C – 110 °C, 90 °C – 100 °C, and 100 °C – 110 °C.
Heating may be continued until completion of the reaction, which may be monitored, for example, by thin layer chromatography (TLC). Deutetrabenazine then may be isolated, which may be carried out by methods well-known in the art.
For example, after the reaction finishes, the reaction mixture may be cooled to a temperature of about 15 °C to about 30 °C, which includes about 15 °C, about 20 °C, about 25 °C, about 30 °C, and values therebetween, for example, 15 °C – 25 °C, 15 °C – 20 °C, 20 °C – 30 °C, 20 °C – 25 °C, and 25 °C – 30 °C.
Next, water may be added. The reaction mixture may be agitated, (e.g., stirred) for about 2 hours to about 4 hours after which a solid will have formed. The solid then may be isolated by methods well known in the art. For example, the reaction mixture then may be filtered to get deutetrabenazine.
In another aspect, the present invention provides a method for preparing d6-6,7-dimethoxy-3,4-dihydroisoquinoline using 2-[(d6-3,4-dimethoxyphenyl)ethyl]formamide as an intermediate. Thus, in another embodiment, the present invention provides a method for preparing 2-[(d6-3,4-dimethoxyphenyl)ethyl]formamide.
In one embodiment, 2-[(d6-3,4-dimethoxyphenyl)ethyl]formamide may be prepared by a process that includes the steps of:
a) reacting dopamine (Formula VIII) with a formylating agent in the presence of a base to produce N-[2-(3,4-dihydroxyphenyl)ethyl]formamide (Formula IX)
; and
b) reacting N-[2-(3,4-dihydroxyphenyl)ethyl]formamide (Formula IX) with a deuterated methylating agent to produce 2-[(d6-3,4-dimethoxyphenyl)ethyl]formamide (Formula VII).

Dopamine first may be reacted with a formylating agent in a solvent in the presence of a base. Within the context of this embodiment, dopamine may be in free base form or present as a salt, for example, a hydrochloride salt. Examples of suitable formylating agents include, but are not limited to, formic acid and alkylformates such as (but not limited to) methyl formate, ethyl formate, propyl formate, and isobutyl formate. In some particularly useful embodiments, formic acid is used as the formylating agent.
The base may be an organic base, an inorganic base, or mixtures thereof. Suitable organic bases include, but are not limited to pyridine, trimethylamine, N,N-diisopropylethylamine, and mixtures thereof. Suitable inorganic bases include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof. Suitable alkaline metal hydroxides include, but are not limited to, sodium hydroxide, potassium hydroxide, and mixtures thereof. Suitable alkaline metal bicarbonates include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. Suitable alkaline metal carbonates include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof. Suitable alkaline alkoxides include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof. In some particularly useful embodiments, potassium carbonate is used as the base.
Dopamine may be reacted with a formylating agent in a solvent. Examples of suitable solvents include non-polar solvents, polar aprotic solvents, polar protic solvents, and mixtures thereof. Suitable non-polar solvents include, but are not limited to, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, and mixtures thereof. Suitable polar aprotic solvents include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 1,2-dimethoxyethane, and mixtures thereof. Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, the solvent is toluene.
Dopamine may be reacted with a formylating agent at an elevated temperature, for example, at a temperature of about 40 °C to about 110 °C, which includes about 40 °C, about 50 °C, about 60 °C, about 70 °C, about 80 °C, about 90 °C, about 100 °C, about 110 °C and values therebetween including 40 °C – 100 °C, 40 °C – 90 °C, 40 °C – 80 °C, 40 °C – 70 °C, 40 °C – 60 °C, 40 °C – 50 °C, 50 °C – 110 °C, 50 °C – 100 °C, 50 °C – 90 °C, 50 °C – 80 °C, 50 °C – 70 °C, 50 °C – 60 °C, 60 °C – 110 °C, 60 °C – 100 °C, 60 °C – 90 °C, 60 °C – 80 °C, 60 °C – 70 °C, 70 °C – 110 °C, 70 °C – 100 °C, 70 °C – 90 °C, 70 °C – 80 °C, 80 °C – 110 °C, 80 °C – 110 °C, 80 °C – 100 °C, 80 °C – 90 °C, 90 °C – 110 °C, 90 °C – 100 °C, and 100 °C – 110 °C. Heating may be continued until reaction completion, monitored by TLC/HPLC. N-[2-(3,4-dihydroxyphenyl)ethyl]formamide may be isolated by methods well known in the art. For example, isolation may be carried out by concentrating the reaction mixture under reduced pressure (e.g., vacuum).
Next, N-[2-(3,4-dihydroxyphenyl)ethyl]formamide may be reacted with a deuterated methylating agent to form 2-[(d6-3,4-dimethoxyphenyl)ethyl]formamide. Suitable deuterated methylating agents include, but are not limited to, deuterated methanol, deuterated dimethyl carbonate, deuterated dimethyl sulfate, deuterated methyl bromide, deuterated methyl trichloroacetate, and the like.
A catalyst optionally may be employed at this step. The catalyst may be, for example, an azodicarboxylate such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, triphenylphosphine, tricyclohexylphosphine, or a combination of cobalt, a tetradentate phosphine ligand (e.g., P(CH2CH2PPh2)3 (PP3)), and a base (“[Co]/PP3/base”). A catalyst maybe particularly useful when the deuterated methylating agent is deuterated methanol.
This reaction may be carried out in a solvent. The solvent may be a non-polar solvent, a polar aprotic solvent, a polar protic solvent, or mixtures thereof. Examples of suitable non-polar solvents include, but are not limited to, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, and mixtures thereof. Suitable polar aprotic solvents include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 1,2-dimethoxyethane, and mixtures thereof. Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, dichloromethane is used as the solvent.
The reaction may be facilitated by agitation (e.g., stirring) at a temperature of about 0 °C to about 40 °C, which includes 0 °C, 5 °C, 10 °C, 15 °C, 20 °C, 25 °C, 30 °C, 35 °C, 40 °C and any value therebetween, including 0 °C – 35 °C, 0 °C – 30 °C, 0 °C – 25 °C, 0 °C – 20 °C, 0 °C – 15 °C, 0 °C – 10 °C, 0 °C – 5 °C, 5 °C – 40 °C, 5 °C – 35 °C, 5 °C – 30 °C, 5 °C – 25 °C, 5 °C – 20 °C, 5 °C – 15 °C, 5 °C – 10 °C, 10 °C – 40 °C, 10 °C – 35 °C, 10 °C – 30 °C, 10 °C – 25 °C, 10 °C – 20 °C, 10 °C – 15 °C, 15 °C – 40 °C, 15 °C – 35 °C, 15 °C – 30 °C, 15 °C – 25 °C, 15 °C – 20 °C,, 20 °C – 40 °C, 20 °C – 35 °C, 20 °C – 30 °C, 20 °C – 25 °C, 25 °C – 40 °C, 25 °C – 35 °C, 25 °C – 30 °C, 30 °C – 40 °C, 30 °C – 35 °C, and 35 °C – 40 °C. Agitation may continue until the completion of reaction, which may be monitored by TLC/HPLC.
2-[(d6-3,4-Dimethoxyphenyl)ethyl]formamide may be isolated by conventional methods, for example, by liquid-liquid extraction and concentration of the organic fraction to isolate a solid.
In another embodiment, 2-[(d6-3,4-dimethoxyphenyl)ethyl]formamide may be prepared by a process that includes the formation of 2-(d6-3,4-dimethoxyphenyl)ethylamine.
In one embodiment, 2-(d6-3,4-dimethoxyphenyl)ethylamine may be prepared by a process that includes the steps of:
a) protecting the amine moiety of dopamine (Formula VIII) to form protected dopamine (Formula V);

b) reacting the protected dopamine (Formula V) with a deuterated methylating agent to produce a protected 2-(d6-3,4-dimethoxyphenyl)ethylamine (Formula VI); and

c) deprotecting to get 2-(d6-3,4-dimethoxyphenyl)ethylamine (Formula IV).

Within the context of the reaction schemes depicted above, “P” is an amine protecting group. According to the present embodiment, the amine group of dopamine may be protected. Amine protecting groups (“P”) are well known to those skilled in the art. Examples of suitable amine protecting groups, as well as suitable conditions for protecting and deprotecting can be found in prior art, such as J.F.W. McOmie’s Protecting Groups on Organic Chemistry and Greene's Protective Groups in Organic Synthesis, 5th Edition, Peter G. M. Wuts, John Wiley & Sons, Inc., Hoboken, New Jersey (2014), which are incorporated herein by reference in their entirety. Examples of suitable amine protecting groups include, but are not limited to, carbonyls (e.g., methyl carbamate, 9-fluorenylmethyoxycarbonyl (Fmoc), trichloroethoxycarbonyl (Troc), p-chlorobenzyloxycarbonyl, tert-butyloxycarbonyl (BOC), 2-trimethylsilylethyloxycarbonyl (Teoc), allyloxycarbonyl (Alloc), p-methoxybenzyl carbonyl (Moz), and carboxybenzyl (Cbz)), sulfonyls (e.g., p-toluenesufonyl (Ts), trimethylsilylethanesulfoyl (Ses), tert-butylsulfonyl (Bus), benzenesulfonyl, 4-methoxyphenylsulfonyl, 4-nitrobenzenesulfonyl (nosyl)), trityl (trt), benzyl (Bn), 3,4-dimethyoxybenzyl (Dmpm), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP), acetyl (Ac), formyl, trifluoroacetyl (Tfa), trichloroacetyl, benzoyl (Bz), 4-chlorobenzoyl, tert- butylacetyl, 4-nitrobenzoyl, 2-bromoacetyl, 2-chloroacetyl, 4-bromobenzoyl, o-nitrophenoxyacetyl, phthalyl, pivaloyl, propionyl, a-chlorobutyryl, carboxaldehyde, 2-nitrophenylsulfenyl (Nps), phthalimides, benzoyl, substituted benzoyl, benzyl, substituted benzyl, and benzhydryl. In some embodiments, tert-butyloxycarbonyl (BOC) is used as a protecting group.
Methods for protecting and deprotecting are well known in the art. For example, a base may be used. Suitable bases include organic bases, inorganic bases, or mixtures thereof. Suitable organic bases include, but are not limited to pyridine, trimethylamine, N,N-diisopropylethylamine, and mixtures thereof. Suitable inorganic bases include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof. Suitable alkaline metal hydroxides include, but are not limited to, sodium hydroxide, potassium hydroxide, and mixtures thereof. Suitable alkaline metal bicarbonates include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. Suitable alkaline metal carbonates include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof. Suitable alkaline alkoxides include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof. In some particularly useful embodiments, sodium carbonate was used as a base.
The protecting step may be carried out in a solvent. The solvent may be a non-polar solvent, a polar aprotic solvent, a polar protic solvent, or mixtures thereof. Suitable non-polar solvents include, but are not limited to, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, tetrahydrofuran, dichloromethane, and mixtures thereof. Suitable polar aprotic solvents include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 1,2-dimethoxyethane, and mixtures thereof. Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, a mixture of tetrahydrofuran and water is used as the solvent.
Within the context of this embodiment, dopamine may be in free base form or salt form, for example, a hydrochloride salt.
The protected dopamine may be isolated by methods well-known in the art. For example, a liquid-liquid extraction may be performed using ethyl acetate as the extracting solvent. The target compound may be isolated from said fraction, for example, by concentrating the solvent, cooling the solvent, or carrying out both, to facilitate formation of a solid. The solid may be isolated by methods well known in the art, for example by filtration. The solid may also be dried.
Next, the protected dopamine may be reacted with a deuterated methylating agent to form protected 2-(d6-3,4-dimethoxyphenyl)ethylamine. Agitation (e.g., stirring) may facilitate the reaction, which may be carried out at a temperature of about 25 °C to about 35 °C.
Suitable deuterated methylating agents include, but are not limited to, deuterated methanol, deuterated dimethyl carbonate, deuterated dimethyl sulfate, deuterated methyl bromide, deuterated methyl trichloroacetate, and the like.
This reaction may be carried out in a solvent. The solvent may be a non-polar solvent, a polar aprotic solvent, a polar protic solvent, or mixtures thereof. Suitable non-polar solvents for this step include, but are not limited to, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, and mixtures thereof. Suitable polar aprotic solvents include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 1,2-dimethoxyethane, and mixtures thereof. Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, dichloromethane is used as the solvent.
A catalyst may optionally be employed at this step. The catalyst may be, for example, an azodicarboxylate such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, triphenylphosphine, tricyclohexylphosphine, or a combination of cobalt, a tetradentate phosphine ligand (e.g., P(CH2CH2PPh2)3 (PP3)), and a base (“[Co]/PP3/base”). A catalyst may be particularly useful when the deuterated methylating agent is deuterated methanol.
After completion of the reaction, which may be monitored, e.g., by TLC or HPLC, the protected 2-(d6-3,4-dimethoxyphenyl)ethylamine may be isolated. This may be carried out by methods conventionally used in the art. For example, liquid-liquid extraction may be used to extract the protected 2-(d6-3,4-dimethoxyphenyl)ethylamine into an organic layer and the solvent may be removed from the extraction fraction, for example, by concentrating the fraction under vacuum to obtain a residue which may be further processed to isolate the protected 2-(d6-3,4-dimethoxyphenyl)ethylamine.
Next, the 2-(d6-3,4-dimethoxyphenyl)ethylamine may be deprotected. The reaction may be carried out, for example, at a temperature of about 25 °C to about 30 °C.
Methods for deprotection are well known in the art. For example, an acid may be used. The acid may be hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, or mixtures thereof. In some particularly useful embodiments, hydrochloric acid is used to deprotect 2-(d6-3,4-dimethoxyphenyl)ethylamine. In some embodiments, hydrogen chloride is bubbled through the solution to deprotect 2-(d6-3,4-dimethoxyphenyl)ethylamine.
Deprotection may be carried out in a solvent. The solvent may be a non-polar solvent, a polar aprotic solvent, a polar protic solvent, or mixtures thereof. Suitable non-polar solvents include, but are not limited to, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, and mixtures thereof. Suitable polar aprotic solvents include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 1,2-dimethoxyethane, and mixtures thereof. Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, ethyl acetate, and mixtures thereof. In some particularly useful embodiments, ethyl acetate is used as the solvent.
The reaction mixture may be agitated (e.g., stirred) to facilitate formation of a solid. The precipitated solid may be isolated, for example, by filtration.
2-(d6-3,4-Dimethoxyphenyl)ethylamine may be converted to 2-[(d6-3,4-dimethoxyphenyl)ethyl]formamide by reacting 2-(d6-3,4-dimethoxyphenyl)ethylamine with a formylating agent. Examples of suitable formylating agents include, but are not limited to, ethyl formate, methyl formate, isobutyl formate, propyl formate, formic acid, and the like. The reaction may be facilitated by heating, for example, by heating the reaction mixture to reflux.
In one embodiment, 2-(d6-3,4-dimethoxyphenyl)ethylamine may be prepared by a process that uses a 2-[2-(3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline and a 2-[2-(d6-3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline as intermediates. For example, 2-(d6-3,4-dimethoxyphenyl)ethylamine may be prepared by a process that includes the steps of:
a) reacting dopamine (Formula VIII) with an optionally substituted phthalic anhydride to form an optionally substituted 2-[2-(3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline (Formula Va);

b) reacting the optionally substituted 2-[2-(3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline (Formula Va) with a deuterated methylating agent to produce an optionally substituted 2-[2-(d6-3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline (Formula VIa); and

c) reacting the optionally substituted 2-[2-(d6-3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline (Formula VIa) with a suitable reagent to produce 2-(d6-3,4-dimethoxyphenyl)ethylamine (Formula IV).

Within the context of this reaction, “R” is hydrogen, an optionally substituted C1 to C10 alkyl, an optionally substituted C6 to C14 aryl, or an optionally substituted C1 to C16 aralkyl. Suitable substitution moieties include halogens, nitro groups, cyano groups, carboxyl groups, and combinations thereof.
According to this embodiment, dopamine may be reacted with an optionally substituted phthalic anhydride to form an optionally substituted 2-[2-(3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline. Within the context of this embodiment, dopamine may be in free base form or present as a salt, for example, a hydrochloride salt.
This reaction may be carried out in a solvent. The solvent may be a non-polar solvent, a polar aprotic solvent, a polar protic solvent, or mixtures thereof. Suitable non-polar solvents include, but are not limited to, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, and mixtures thereof. Suitable polar aprotic solvents include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 1,2-dimethoxyethane, and mixtures thereof. Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, the reaction is carried out in dimethylformamide or dimethylsulfoxide.
The reaction may be facilitated by agitating (e.g., stirring) the reaction mixture at an elevated temperature. For example, the reaction mixture may be held at a temperature of about 80 °C to about 140 °C, which includes about 80 °C, about 90 °C, about 100 °C, about 110 °C, about 120 °C, about 130 °C, about 140 °C and values therebetween including 80 °C – 130 °C, 80 °C – 120 °C, 80 °C – 110 °C, 80 °C – 100 °C, 80 °C – 90 °C, 90 °C – 140 °C, 90 °C – 130 °C, 90 °C – 120 °C, 90 °C – 110 °C, 90 °C – 100 °C, 100 °C – 140 °C, 100 °C – 130 °C, 100 °C – 120 °C, 100 °C – 110 °C, 110 °C – 140 °C, 110 °C – 130 °C, 110 °C – 120 °C, 120 °C – 140 °C, 120 °C – 130 °C, and 130 °C – 140 °C.
Agitation may continue until the completion of reaction, which may be monitored by TLC/HPLC.
The optionally substituted 2-[2-(3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline may be isolated by conventional methods. For example, the reaction mixture may be cooled, for example, to about 25 °C to about 30 °C and water may be added. The solid may be isolated, for example, by filtration, to get the optionally substituted 2-[2-(3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline.
Next, the optionally substituted 2-[2-(3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline may be reacted with deuterated methylating agent to produce optionally substituted 2-[2-(d6-3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline. Within the context of this embodiment, suitable deuterated methylating agents include, but are not limited to, deuterated iodomethane, deuterated methanol, deuterated dimethyl carbonate, deuterated dimethyl sulfate, deuterated methyl bromide, deuterated methyl trichloroacetate, and the like.
This reaction may be carried out in a solvent. The solvent may be a non-polar solvent, a polar aprotic solvent, a polar protic solvent, or mixtures thereof. Suitable non-polar solvents include, but are not limited to, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, and mixtures thereof. Suitable polar aprotic solvents include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 1,2-dimethoxyethane, and mixtures thereof. Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof.
The reaction may be facilitated by agitation (e.g., stirring) at a temperature of about 0 °C to about 40 °C, which includes 0 °C, 5 °C, 10 °C, 15 °C, 20 °C, 25 °C, 30 °C, 35 °C, 40 °C and any value therebetween, including 0 °C – 35 °C, 0 °C – 30 °C, 0 °C – 25 °C, 0 °C – 20 °C, 0 °C – 15 °C, 0 °C – 10 °C, 0 °C – 5 °C, 5 °C – 40 °C, 5 °C – 35 °C, 5 °C – 30 °C, 5 °C – 25 °C, 5 °C – 20 °C, 5 °C – 15 °C, 5 °C – 10 °C, 10 °C – 40 °C, 10 °C – 35 °C, 10 °C – 30 °C, 10 °C – 25 °C, 10 °C – 20 °C, 10 °C – 15 °C, 15 °C – 40 °C, 15 °C – 35 °C, 15 °C – 30 °C, 15 °C – 25 °C, 15 °C – 20 °C, 20 °C – 40 °C, 20 °C – 35 °C, 20 °C – 30 °C, 20 °C – 25 °C, 25 °C – 40 °C, 25 °C – 35 °C, 25 °C – 30 °C, 30 °C – 40 °C, 30 °C – 35 °C, and 35 °C – 40 °C. Agitation may continue until the completion of reaction, which may be monitored by TLC/HPLC.
The optionally substituted 2-[2-(d6-3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline may be isolated by conventional methods, for example, by liquid-liquid extraction and removing the solvent in the organic fraction, e.g., by concentration under vacuum.
Optionally, the step of reacting 2-[2-(3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline with a deuterated methylating agent may be performed in the presence of a base. The base may be an organic base, an inorganic base, or mixtures thereof. Suitable organic bases include, but are not limited to pyridine, trimethylamine, N,N-diisopropylethylamine, and mixtures thereof. Suitable inorganic bases include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof. Suitable alkaline metal hydroxides include, but are not limited to, sodium hydroxide, potassium hydroxide, and mixtures thereof. Suitable alkaline metal bicarbonates include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. Suitable alkaline metal carbonates include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof. Suitable alkaline alkoxides include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof. In some particularly useful embodiments, potassium carbonate is used as a base.
In instances where deuterated iodomethane is used as the deuterated methylating agent, it has been found particularly useful to use potassium carbonate as a base and carry out the reaction in dimethylformamide or dimethyl sulfoxide.
Optionally 2-[2-(3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline may be reacted with a deuterated methylating agent in the presence of a catalyst.
Suitable catalysts include, but are not limited to, diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butylazodicarboxylate, triphenylphosphine, tricyclohexylphosphine, tributylphosphine, or the like.
In instances where deuterated methanol is used as the deuterated methylating agent, it has been found particularly useful to carry out the reaction using a catalyst.
Next, the 2-[2-(d6-3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline may be reacted with a suitable reagent to produce 2-(d6-3,4-dimethoxyphenyl)ethylamine. Examples of suitable reagents include, but are not limited to, hydrazine (including hydrates thereof), methylamine, sodium borohydride/acetic acid, pyridine, trimethylamine, N,N-diisopropylethylamine, and the like. In some particularly useful embodiments, hydrazine is used as the suitable reagent.
This reaction may be carried out in a solvent. Suitable solvents include non-polar solvents, polar aprotic solvents, polar protic solvents, or mixtures thereof. Suitable non-polar solvents include, but are not limited to, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, and mixtures thereof. Suitable polar aprotic solvents include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 1,2-dimethoxyethane, and mixtures thereof. Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, ethyl acetate, and mixtures thereof.
This reaction may be facilitated by agitating (e.g., stirring) the reaction mixture at an elevated temperature. For example, the reaction mixture may be held at a temperature of about 50 °C to about 70 °C. This may be continued until the reaction is complete, which may be from about 3 hours to about 6 hours. 2-(d6-3,4-Dimethoxyphenyl)ethylamine then may be isolated by methods conventionally used in the art. For example, the solvent may be removed, e.g., by concentration, to form a residue. In some embodiments, a precipitate may be formed by cooling the reaction mixture to about 25 °C to about 30 °C and adjusting the pH of the mixture to 0-1, for example, with hydrochloric acid. The obtained reaction mixture may be agitated (e.g., stirred) at an elevated temperature, for example, at a temperature of about 50 °C to about 70 °C. This may be continued for a desired length of time, e.g., for about 1 hour to about 2 hours. The reaction mixture may be cooled, e.g., to about 25 °C to about 30 °C, and the mixture may be filtered and the filtrate collected. The filtrate may then be concentrated to form a residue.
Next, the residue may be suspended in water and the pH may be adjusted to about 11-12, e.g., with a sodium hydroxide solution. 2-(d6-3,4-Dimethoxyphenyl)ethylamine may be extracted from the mixture using dichloromethane. After separation from the aqueous layer, the dichloromethane may be removed from the organic layer by methods well known in the art, for example, by concentrating under vacuum or rotary evaporation.
Next, 2-(d6-3,4-dimethoxyphenyl)ethylamine may be reacted with a formylating agent to produce 2-[(d6-3,4-dimethoxyphenyl)ethyl]formamide. Formylating agents include, but are not limited to, formic acid, ethyl formate, methyl formate, isopropyl formate, propyl formate, and the like. The reaction may be facilitated by heating, for example, by heating the reaction mixture to reflux.
d6-2-[(d6-3,4-Dimethoxyphenyl)ethyl]formamide (Formula VII) may be converted to d6-6,7-dimethoxy-3,4-dihydroisoquinoline (Formula II) by a process known in the prior art that includes the step of reacting d6-2-[(d6-3,4-dimethoxyphenyl)ethyl]formamide (Formula VII) with phosphoryl oxychloride.

Alternatively, d6-6,7-dimethoxy-3,4-dihydroisoquinoline (Formula II) may be prepared by the methods disclosed in U.S. Patent No. 8,524,733 (which is hereby incorporated by reference), for example, by reacting 2-(d6-3,4-dimethoxyphenyl)ethylamine (Formula IV) with hexamethylenetetramine in the presence of acetic acid/trifluoroacetic acid to produce d6-6,7-dimethoxy-3,4-dihydroisoquinoline (Formula II).

As disclosed above, d6-6,7-dimethoxy-3,4-dihydroisoquinoline may be reacted with either 3 [(dimethylamino)methyl]-5-methylhexan-2-one or a (2-acetyl-4-methylpentyl)trimethylammonium halide to form deutetrabenazine.
In another aspect, the present invention provides amorphous deutetrabenazine.
Samples of amorphous deutetrabenazine, prepared by methods disclosed herein, were analyzed by powder X-ray diffraction (PXRD) to determine crystallinity. An exemplary PXRD pattern is shown in Figure 1.
PXRD analyses were performed on a BRUKER® D-8 Discover powder diffractometer equipped with a goniometer of ?/2? configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40 kV and 30 mA. The experiments were conducted over the 2? range of 2.0°-50.0°, 0.030° step size, and 0.4 seconds step time.
In another aspect, the present invention provides a process for the preparation of amorphous deutetrabenazine.
In one embodiment, amorphous deutetrabenazine may be prepared by a process that includes the steps of:
a) dissolving deutetrabenazine in a solvent; and
b) removing the solvent to isolate amorphous deutetrabenazine.
According to this embodiment, deutetrabenazine may be dissolved in a solvent. Within the context of this embodiment, the starting deutetrabenazine material may be any polymorphic form.
The solvent may be, for example, an alcohol solvent, a ketone solvent, a halogenated solvent, or any mixture thereof. Specific examples of alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, isobutyl alcohol, tertiary-butanol, isopentyl alcohol, 1-pentanol, 2-pentanol, and mixtures thereof. Examples of suitable ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, or mixtures thereof. Examples of suitable chlorinated solvent include, but are not limited to dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, and mixtures thereof.
In particularly useful embodiments, deutetrabenazine is dissolved in methanol or dichloromethane. Dissolution may be facilitated by carrying out this step at an elevated temperature, for example, at reflux. The resulting clear solution may optionally be filtered, for example through diatomaceous earth, e.g., HYFLO®, to remove any undissolved particulate.
Next, according to this embodiment, the solvent may be removed to isolate amorphous deutetrabenazine. This may be carried out by well-known techniques such as, for example, evaporation, distillation, spray drying, lyophilization, agitated thin film drying, or combinations thereof. In certain embodiments, spray drying or distillation is used to remove the solvent.
Deutetrabenazine may be useful in the treatment of chorea associated with Huntington’s Disease. Thus, it may be incorporated into a pharmaceutical dosage form for administration to patients in need of such treatment.
Deutetrabenazine, prepared by methods disclosed herein, including the amorphous form, may be incorporated into a pharmaceutical dosage form, for example, an oral dosage form such as a capsule or tablet. In addition to deutetrabenazine, the capsule or tablet may also include other excipients, such as, but not limited to, ammonium hydroxide, black iron oxide, n-butyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, polyethylene oxide, polysorbate 80, polyvinyl alcohol, povidone, propylene glycol, shellac, talc, titanium dioxide, and artificial colorings, such as FD&C blue #2 lake, FD&C red #40 lake, and yellow #6 lake.
Dosage forms may contain a pharmaceutically effective amount of deutetrabenazine. In particularly useful embodiments, the dosage form is a tablet and contains 6 mg, 9 mg, or 12 mg of deutetrabenazine.
In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.
EXAMPLES
Example 1: Preparation of 2-[2-(3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline
Dopamine hydrochloride (50.0 g) and phthalic anhydride (41 g) were added to dimethylformamide (150 mL) and the reaction mixture was stirred overnight at 95 °C – 105 °C. Water (1000 mL) was added to the reaction mixture and stirred for 1 – 2 hours at 25 °C – 30 °C, then filtered to isolate a solid. The solid was washed with water and dried in an air oven at 55 °C – 60 °C to get 2-[2-(3,4-dihyroxyphenyl)ethyl]-1,3-dioxoisoindoline (60.0 g, 80.5% yield, purity = 99.72%).
Example 2: Preparation of 2-[d6-2-(3,4-dimethoxyphenyl)ethyl]-1,3-dioxoisoindoline
Diisopropyl azodicarboxylate (DIAD) (53.50 g) was slowly added to a mixture of 2-[2-(3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline (25 g), deuterated methanol (22.26 g), and triphenylphosphine (69.38 g) in dichloromethane (200 mL) while stirring at 25 °C. The reaction mixture was stirred for 2 hours. Water was slowly added into the reaction mixture and stirred at 30 °C – 35 °C for 15 – 20 minutes and the layers were separated. The organic layer was concentrated under vacuum. Methanol was added to the residue and the mixture was stirred then filtered to obtain a solid which was washed with methanol and dried under vacuum at 50 °C – 55 °C to produce 2-[d6-2-(3,4-dimethoxyphenyl)ethyl]-1,3-dioxoisoindoline (20 g, 71.5% yield, purity = 98.36%).
Example 3: Preparation of 2-[d6-2-(3,4-dimethoxyphenyl)ethyl]-1,3-dioxoisoindoline
Deuterated iodomethane (11.24 g) was slowly added to a mixture of 2-[2-(3,4-dimethoxyphenyl)ethyl]-1,3-dioxoisoindoline (10 g) and potassium carbonate (14.63 g) in dimethylformamide (20 mL) and stirred at 25 °C. The reaction mixture was stirred for 2 – 4 hours, maintaining the temperature at 25 °C – 35 °C. Water was slowly added into the reaction mixture and stirred at 25 °C – 30 °C for 2 hours. The reaction mixture was filtered to obtain a solid which was washed with water and dried in an oven at 50-55 °C to get 2-[d6-2-(3,4-dimethoxyphenyl)ethyl]-1,3-dioxoisoindoline. (10.5 g, 93.75% yield).
Example 4: Preparation of 2-(d6-3,4-dimethoxyphenyl)ethylamine
Hydrazine hydrate (2.36 g) was added to a mixture of 2-[2-(d6-3,4-dimethoxy-phenyl)ethyl]-1,3-dioxoisoindoline (15 g) at 25 °C – 30 °C in methanol (75 mL). The reaction mixture was stirred for 4 – 5 hours at 60 °C – 65 °C then cooled to 25 °C – 30 °C. The pH of the mixture was adjusted to 0 – 1 with hydrochloric acid. The reaction mixture was then heated to 60 °C – 65 °C and maintained for 1 hour at 60 °C – 65 °C. The reaction mixture was then cooled to 25 °C – 30 °C and filtered. The filtrate was concentrated under vacuum to obtain a residue. Water (90 mL) was added to the residue and the pH of the mixture was adjusted to 11 – 12 with sodium hydroxide. Dichloromethane was then added. The mixture was agitated and then layers were allowed to separate. The dichloromethane layer was concentrated under vacuum to get 2-(d6-3,4-dimethoxyphenyl)ethylamine (8.5 g, 96% yield).
Example 5: Preparation of d6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride hydrate
A mixture of hexamethylenetetramine (6.24 g) and 2-(d6-3,4-dimethoxyphenyl)ethylamine (4.0 g) in trifluoroacetic acid (20 mL) was prepared. The reaction mixture was stirred overnight at 72 °C – 75 °C then cooled to 25 °C – 30 °C. Water was slowly added and the pH of the reaction mixture was adjusted to 8.0 – 9.0 with potassium carbonate. Ethylene acetate was then added. After agitation and allowing the layers to separate, the organic layer was washed with water and concentrated under vacuum to form a residue. Isopropyl alcohol (20 mL) was added to the residue and the mixture was stirred for 10 – 15 minutes. The pH of the reaction mixture was adjusted to 0.5 – 2.0 with concentrated hydrochloric acid, maintaining the reaction mixture temperature at 25 °C – 35 °C. The reaction mixture was stirred at 25 °C – 35 °C for 3 – 4 hours then further cooled to 8 °C – 13 °C. The reaction mixture was filtered to isolate a solid, which was washed with chilled isopropyl alcohol and dried at 50 °C – 55 °C to give d6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride hydrate (3.0 g, purity = 98.85%).
Example 6: Preparation of deutetrabenazine
A solution of 20% potassium carbonate in water was added to a mixture of d6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride hydrate (3 g) in water (6 mL) while stirring the mixture at 25 °C. The pH was adjusted to 8.0 – 9.0, maintaining the temperature at 25 °C – 30 °C. Dichloromethane was charged to the mixture which was stirred for 20 – 30 minutes. The layers were allowed to separate, and the organic layer was washed with water. Water (4.5 mL), benzyl triethylammonium chloride (0.686 g,0.003mol) and (2-acetyl-4-methylpentyl)trimethylammonium iodide (3.25 g, 0.0104 mol) were then charged to the organic layer. The reaction mass was heated to 90 °C – 95 °C and distilled at 90 °C – 95 °C for 16 hours. The reaction mixture was cooled to 25 °C – 30 °C after which ethyl acetate was added. The reaction mixture stirred for 20 – 30 minutes. The organic and aqueous layers were separated and the organic layer was washed with water and concentrated under vacuum to form a residue. Isopropyl alcohol was charged to the residue and the reaction mixture was heated to 70 °C – 75 °C and stirred for 30 minutes. The reaction mixture was then cooled to 25 °C – 30 °C, stirred for 2 – 3 hours, then filtered. The obtained solid was washed with isopropyl alcohol then purified with isopropyl alcohol to get Deutetrabenazine (1.8 g, HPLC purity 99.85%).
Example 7: Preparation of deutetrabenazine
Potassium carbonate (0.793 g) was slowly added to a mixture of (2-acetyl-4-methylpentyl)trimethylammonium iodide (5.44 g) and d6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride hydrate (5 g) in ethanol (25 mL) while stirring the reaction mixture at 25 °C – 30 °C. The reaction mixture was heated to 40 °C – 45 °C and maintained at 40 °C – 45 °C until a sufficient percent of the starting material was consumed. The reaction mixture was then cooled to 25 °C – 30 °C, water was added, and the reaction mixture was stirred for 2 – 3 hours. The reaction mixture was filtered and the solid was washed with water and dried at 55 °C for 8 hours in an oven to yield deutetrabenazine (3.0 g).
Example 8: Preparation of deutetrabenazine
Potassium carbonate (2.6 g) was slowly added to a mixture of d6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride hydrate (4.0 g) and 3-[(dimethylamino)methyl]-5-methylhexan-2-one oxalate (4.23 g) in a mixture of methanol (6 mL) and water (18 mL) at 25 °C – 30 °C. The reaction mixture was heated to 40 °C – 45 °C and maintained at 40 °C – 45 °C until a sufficient percent of the starting material had been consumed (72 hours). The reaction mixture was cooled to 25 °C – 30 °C, water was added, and the reaction mixture was stirred for 2 – 3 hours. The reaction mixture was filtered and the solid was washed with water and dried vacuum oven at 55 °C for 12 hours to give deutetrabenazine (2.0 g, 94.48%).
Example 9: Preparation of deutetrabenazine
A solution of potassium carbonate was added to a suspension of 3-[(dimethylamino)methyl]-5-methylhexan-2-one oxalate in a mixture of water (24 mL) and n-heptane (6 mL) while stirring the reaction mixture at 25 °C. The pH was adjusted to 8.0 – 9.0, and the reaction mixture was stirred for 30 minutes at 25 °C – 30 °C. The organic and aqueous layers were separated. The heptane fraction containing 3-[(dimethylamino)methyl]-5-methylhexan-2-one was added to a solution of d6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride hydrate ( 4.0 g) in water (8 mL) and the mixture was stirred until less than 10% of the d6-6,7-dimethoxy-3,4-dihydroisoquinoline remained. The reaction mixture was cooled to 15 °C – 20 °C and the reaction mixture was filtered to obtain a solid which was washed with water and n-heptane to get Deutetrabenazine (1.5 g, 66.47%).
Example 10: Preparation of 2-[2-(3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline
Dopamine hydrochloride (300.0 g) and phthalic anhydride (284.4 g) were added to dimethylformamide (900 mL) and the reaction mixture was stirred for 12 – 15 hours at 115 °C – 120 °C. Water (3000 mL) was added to the reaction mixture and stirred for 1 – 2 hours at 25 °C – 30 °C. The reaction mixture was filtered and the solid was washed with water. Water (1500 mL) was charged to the wet solid and the pH of the mixture was adjusted to 7.0 – 7.5 with 5% aqueous sodium bicarbonate. The mixture was stirred for 2 hours at 25 °C – 30 °C then filtered to obtain a solid which was washed with water then dried in an air oven at 55 °C – 60 °C to get 2-[2-(3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline (yield: 412.0 g, HPLC purity = 99.71%).
Example 11: Preparation of 2- [2-( d6-3,4-dimethoxyphenyl)ethyl]-1,3-dioxoisoindoline
Diisopropyl azodicarboxylate (53.50 g) was slowly added to a mixture of 2-[2-(3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline (25 g), deuterated methanol (22.26 g), and triphenylphosphine (69.38 g) in dichloromethane (200 mL) while stirring the mixture at 25 °C. The reaction mixture was stirred for 2 hours. Water was slowly added into the reaction mixture and stirred at 30 °C – 35 °C for 15 – 20 minutes after which the organic and aqueous layers were separated. The organic layer was concentrated under vacuum to form a residue. Acetonitrile (100 mL) was charged to the residue and the mixture was stirred at 75 °C – 80 °C for 2 hours. The mixture was cooled to 25 °C – 30 °C then stirred for 2 – 3 hours. Methanol was added, and the mixture was filtered. The solid was washed with methanol and dried under vacuum at 50 °C – 55 °C to produce 2-[2-(d6-3,4-dimethoxyphenyl)ethyl]-1,3-dioxoisoindoline (Yield: 20 g, HPLC Purity = 99.26%).
Example 12: Preparation of 2-[2-(d6-3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline
Deuterated iodomethane (460.6 g) was slowly added to a mixture of 2-[2-(3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline (300 g) and potassium carbonate (731.8 g) in dimethylformamide (1200 mL) while stirring the mixture at 25 °C. The reaction mixture was stirred for 8 – 12 hours at 25 °C – 35 °C. Water (6000 mL) was slowly added into the reaction mixture which was stirred at 25 °C – 30 °C for 2 hours then filtered. The solid was washed with water. Acetonitrile (1200 mL) was added to the solid and the mixture was stirred at 75 °C – 80 °C for 2 hours then cooled to 25 °C – 30 °C and stirred again for 3 hours at 25 °C – 30 °C. This mixture was then further cooled to 0 °C – 5 °C and stirred for 2 hours after which it was filtered. The solid was washed with acetonitrile and dried under vacuum at 50 °C – 55 °C to produce 2-[2-(d6-3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline (Yield: 282 g, HPLC Purity = 99.69%).
Example 13: Preparation of 2-(d6-3,4-dimethoxyphenyl)ethylamine
An aqueous solution of hydrazine hydrate (80%, 125 mL) was added to a mixture of 2-[2-(d6-3,4-dihydroxyphenyl)ethyl]-1,3-dioxoisoindoline (225 g) in methanol (1125 mL). The reaction mixture was maintained at a temperature of 25 °C – 30 °C, then stirred for 4 – 6 hours at 60 – 65 °C. The reaction mixture was cooled to 25 °C – 30 °C and concentrated hydrochloric acid (~35%, 135 mL) was added. The reaction mixture was heated to 60 °C – 65 °C and maintained at that temperature for 4 hours. The reaction mixture was cooled to 25 °C – 30 °C and filtered. The filtrate was concentrated under vacuum. Water (225 mL) was added to the residue and the mixture was twice washed with dichloromethane (2 x 225 mL) after which the pH was adjusted to 12 – 13 with a sodium hydroxide solution. Dichloromethane was then added to extract the title compound. After separating, the dichloromethane layer was washed with a sodium chloride solution then concentrated under vacuum to give 2-(d6-3,4-dimethoxyphenyl)ethylamine (Yield:122 g, HPLC purity = 99.91%).
Example 14: Preparation of d6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride hydrate
A mixture of 2-(d6-3,4-dimethoxyphenyl)ethylamine (125.0 g) in ethyl formate (375 mL) was heated to reflux for 5 – 7 hours. The reaction progress was monitored by measuring presence of the starting material with TLC/HPLC. After the reaction progressed sufficiently, the reaction mixture was concentrated under vacuum to form a residue. Acetonitrile (625 mL) was charged to the residue and the mass was stirred for 15 minutes at 25 °C – 30 °C. The reaction mixture was cooled to 10 °C and phosphoryl chloride (118.72 g) was slowly added at 10 °C – 20 °C. The reaction mixture was heated to 70 °C – 75 °C and maintained at that temperature for 2 – 4 hours. Reaction progress was checked by monitoring presence of starting material by TLC/HPLC. The reaction mixture was cooled to 35 °C – 40 °C, then concentrated under vacuum maintaining the temperature below 70 °C. Water was slowly added to the reaction mixture and the pH was adjusted to 8.0 – 9.0 with an ammonium hydroxide. Ethyl acetate was then added to extract the title compound. The aqueous and organic layers were separated, and the organic layer as washed with water and concentrated under vacuum. Isopropyl alcohol (375 mL) was added to the residue and the reaction mixture was stirred for 10-15 minutes. The pH of the reaction mixture was adjusted to 0.5 – 2.0 with concentrated hydrochloric acid (~100 mL), maintaining the temperature of the reaction mixture at 25 °C – 35 °C. The reaction mixture was stirred at 25 °C – 35 °C for 3 – 4 hours then cooled to 8 °C – 13 °C. The reaction mixture was filtered and the solid was washed with chilled isopropyl alcohol then dried at 50 °C – 55 °C to give d6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride hydrate. (Yield: 105 g, HPLC purity = 99.28%).
Example 15: Preparation of deutetrabenazine
A solution of 20% potassium carbonate in water (267 mL) was added to a mixture of d6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride hydrate (89 g) in water (180 mL) while stirring the mixture at 25 °C. The pH was adjusted to 8.0 – 9.0 at 25 °C – 30 °C, dichloromethane was added, and the mixture was stirred for 20 – 30 minutes. The organic layer was separated from the aqueous layer then washed with water. Water (66 mL) was added to the organic layer along with benzyltriethylammonium chloride (25.15 g) and (2-acetyl-4-methylpentyl)trimethylammonium iodide (119.28 g). The reaction mass was heated to 90 °C – 95 °C and distilled at 90 °C – 95 °C for 5 – 8 hours. The reaction mixture was cooled to 25 °C – 30 °C. Ethyl acetate (800 mL) was charged to the mixture, which was stirred for 20 – 30 minutes. The aqueous and organic layers were separated. The organic layer was washed with water and concentrated under vacuum to form a residue. Isopropyl alcohol was charged to the residue and the reaction mixture was heated to 70 °C – 75 °C and stirred for 30 minutes. The reaction mixture was cooled to 25 °C – 30 °C, stirred for 2 – 3 hours, and then filtered. The solid was washed with isopropyl alcohol then purified with isopropyl alcohol to get deutetrabenazine (Yield: 60.5 g, HPLC purity = 99.84%).

Example 16: Preparation of Deutetrabenazine
Potassium carbonate (0.793 g) was slowly added to a mixture of d6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride hydrate (5.0 g) and (2-acetyl-4-methylpentyl)trimethylammonium iodide (5.44 g) in ethanol (25 mL) while stirring the mixture at 25 °C – 30 °C. The reaction mixture was heated to 40 °C – 45 °C and maintained at that temperature until a sufficient percent of the starting material had been consumed. The reaction mixture was cooled to 25 °C – 30 °C after which water was added and the mixture was stirred for 2 – 3 hours. The reaction mixture was filtered and the solid was washed with water and dried in an oven at 55 °C for 8 hours to yield deutetrabenazine (3.0 g).
Example 17: Preparation of Deutetrabenazine
3-[(Dimethylamino)methyl]-5-methylhexan-2-one oxalate was suspended in a mixture of water (24 mL) and n-heptane (24 mL) while stirring the mixture at 25 °C. A solution of potassium carbonate was added, the pH was adjusted to 8.0 – 9.0, and the reaction mixture was stirred for 30 minutes at 25 °C – 30 °C. The aqueous and organic layers were separated. The heptane fraction containing 3-[(dimethylamino)methyl]-5-methylhexan-2-one was added to a solution of d6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride hydrate ( 4.0 g) in water (8 mL) and the mixture was stirred until less than 10% of the d6-6,7-dimethoxy-3,4-dihydroisoquinoline remained. The reaction mixture was cooled to 15 °C – 20 °C, filtered, and the obtained solid was washed with water and n-heptane to get deutetrabenazine (1.5 g, 66.47%).
Example 18: Preparation of N-[2-(3,4-dihydroxyphenyl)ethyl]formamide
Potassium carbonate (7.7 g, 0.055 moles) was slowly added to a mixture of dopamine hydrochloride (10.0 g, 0.053 moles) in toluene (60 mL) while stirring the reaction mixture at 25 °C – 35 °C. Stirring was continued for 45-60 minutes, then formic acid (5.7 g, 0.124 mol) was slowly added at 25 °C – 35 °C. The reaction suspension was heated to 95 °C – 100 °C and maintained at that temperature for 17 hours. Reaction progress was checked by measuring presence of the starting material by TLC/HPLC. The reaction mixture was concentrated under reduced pressure at 45 °C – 50 °C. Water (20 mL) was added to the residue and the mixture was stirred for 1 – 2 hours at room temperature. The reaction mixture was filtered and the solid was washed with water and dried in vacuum oven at 55 °C for 15 hours to get N-[2-(3,4-dihydroxyphenyl)ethyl]formamide.
Example 19: Preparation of N- [2-(d6 -3,4-dimethoxyphenyl)ethyl]formamide
Diisopropyl azodicarboxylate (16.62 g, 0.0822 mol) was slowly added to a mixture of N-[2-(3,4-dihydroxyphenyl)ethyl]formamide (5 g, 0.0274 mol), deuterated methanol (3.56 g, 0.098 mol) and triphenylphosphine (16.62 g, 0.0822 mol) in dichloromethane (40 mL) while stirring at 25 °C. The reaction mixture was stirred at 25 °C – 35 °C until a sufficient percent of the starting material had been consumed, measured by TLC/HPLC. Water was slowly added into the reaction mixture and stirred at 30 °C – 35 °C for 15 – 20 minutes and the organic and aqueous layers were separated. The organic layer was concentrated under vacuum to form a residue. Toluene (50 mL) was charged to the residue and the mixture was stirred. The reaction mixture was filtered, and the filtrate was washed three times with 5% aqueous sodium hydrogen sulfate (15 mL x 3). The aqueous layers were combined, and the pH of the combined aqueous layers was adjusted to 8 – 10 with an ammonia solution. Dichloromethane was then added, the organic and aqueous layers were separated, and the dichloromethane fraction was concentrated under vacuum to get N- [2-(d6 -3,4-dimethoxyphenyl)ethyl]formamide.
Example 20: Preparation of d6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride hydrate
Phosphoryl oxychloride (4.08 g, 0.0267 mol) was slowly added to a mixture of N-[2-(d6-3,4-dimethoxyphenyl)ethyl]formamide (3.2 g, 0.0148 mol) in acetonitrile (7 mL) while stirring the mixture at 10 °C – 25 °C. The reaction mixture was heated to 70 °C – 75 °C and maintained at that temperature for 2 – 3 hours until a sufficient percent of the starting material had been consumed, measured by TLC/HPLC. The reaction mixture was cooled to 35 °C – 40 °C. The reaction mixture was concentrated under vacuum. Water was slowly added to the residue and the reaction mixture was adjusted pH 8.0 – 9.0 with ammonium hydroxide. Ethyl acetate was added, and the organic and aqueous layers were separated. The organic layer was washed with water and concentrated under vacuum. Isopropyl alcohol (16 mL) was added to the obtained residue and the mixture was stirred for 10 – 15 minutes. The pH of the reaction mixture was adjusted to 1.0 – 2.0 with concentrated hydrochloric acid, maintaining the temperature at 25 °C – 35 °C. The reaction mixture was then stirred at 25 °C – 35 °C for 3 – 4 hours then filtered. The solid was washed with chilled isopropyl alcohol and dried at 50 °C – 55 °C to give d6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride hydrate (1.2 g).
Example 21: Preparation of deutetrabenazine
A solution of 20% potassium carbonate solution in water (3 mL) was added to a mixture of d6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride hydrate (1 g, 0.0034) in water (5 mL)while stirring the mixture at 25 °C. The pH was adjusted 8.0-9.0 at 25 °C – 30 °C. Dichloromethane was charged to the reaction mixture, which was then stirred for 20 – 30 minutes. The organic layer and aqueous layer were separated, and the organic layer was washed with water. Water (4.5 mL) was added to the organic layer along with benzyltriethylammonium chloride (0.224 g, 0.001 mol) and (2-acetyl-4-4methylpentyl)trimethylammonium iodide (1.08 g, 0.0034). The reaction mass was heated to 90 °C – 95 °C and distilled at 90 °C – 95 °C for 15 hours. The reaction mixture was cooled to 25 °C – 30 °C, ethyl acetate was added, and the mixture was stirred for 20 – 30 minutes. The organic and aqueous layers were separated. The organic layer was washed with water and concentrated under vacuum to form a residue. Isopropyl alcohol was charged to the residue and the reaction mixture was heated to 70 °C – 75 °C and stirred for 30 minutes. The reaction mixture was cooled to 25 °C – 30 °C, stirred for 1 – 2 hours, and then filtered. The solid was washed with isopropyl alcohol and dried in an oven for 10 hours to yield Deutetrabenazine (250 mg).
Example 22: Preparation of deutetrabenazine
Potassium carbonate(0.793 g) was slowly added to a mixture of d6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride hydrate (5.0 g) and 2-acetyl-4-methylpentyl)trimethylammonium iodide(5.44g) in methanol (25 mL) while stirring the mixture at 25 °C – 30 °C. The reaction mixture was heated to 40 °C – 45 °C and maintained at 40 °C – 45 °C until sufficient disappearance of the starting material, measured by TLC/HPLC. The reaction mixture was cooled to 25 °C – 30 °C, water was added, and the mixture was stirred for 2 – 3 hours. The reaction mixture was filtered and the solid was washed with water and dried at 55 °C for 8 hours in an oven ( 3.2 g).
Example 23: Preparation of tert-butyl [2-(3,4-dihydroxyphenyl)ethyl]carbamate
Di-tert-butyl-dicarbonate (31.6 g, 0.145 mol) was slowly added to a mixture of dopamine hydrochloride (25.0 g, 0.132 mol) and sodium carbonate (34.9 g, 0.329 mol) in a mixture of tetrahydrofuran (240 mL) and water (48 mL). The mixture was stirred at about 25 °C for 2.5 hours until a sufficient percent of the starting material had been consumed, measured by TLC/HPLC. The reaction mixture was diluted with ethyl acetate, the organic layer was separated, then washed with water. The organic layer was concentrated under reduced pressure at 45 °C – 50 °C until 2-2.5 volume of solvent was left The reaction mixture was cooled to 25 °C – 30 °C and stirred for two hours to yield a solid. The solid was isolated by filtration and dried under vacuum to get tert-butyl [2-(3,4-dihydroxyphenyl)ethyl]carbamate (22.3 g).
Example 24: Preparation of 2-[d6-3,4-dimethoxyphenyl]ethylamine
Diisopropyl azodicarboxylate (47.9 g, 0.237 mol) was slowly added to a mixture of tert-butyl [2-(3,4-dihydroxyphenyl)ethyl]carbamate (20 g, 0.079 mol), deuterated methanol (25.3 g, 0.79 mol) and triphenylphosphine (62.1 g, 0.237 mol) in dichloromethane (160 mL) while stirring the reaction mixture at 25 °C. The reaction mixture was stirred at 25 °C – 35 °C until sufficient disappearance of the starting material, measured by TLC/HPLC. Water (100 mL)was slowly added into the reaction mixture which was stirred at 30 °C – 35 °C for 15 – 20 minutes. The organic and aqueous layers were separated and trifluoroacetic acid was added to the organic layer at 25 °C – 30 °C, which was then stirred for 2 – 3 hours. Water was slowly added into the reaction mixture, which was stirred at 30 °C – 35 °C for 15 – 20 minutes, after which the layers were separated. The pH of the aqueous layer was adjusted to 8 – 10 using aqueous ammonia. Dichloromethane was added, the aqueous and organic layers were separated, and the organic layer was concentrated by vacuum to get 2-[d6-3,4-dimethoxyphenyl]ethylamine.

Example 25: Preparation of N-[2-(d6-3,4-dimethoxyphenyl)ethyl]formamide
A mixture of 2-(d6-3,4-dimethoxyphenyl)ethylamine (100 g) in ethyl formate (300 mL) was heated to reflux and maintained at reflux for 7 – 12 hours. The solution was concentrated under vacuum to get N-[2-(d6-3,4-dimethoxyphenyl)ethyl]formamide.
Example 26: Preparation of N-[2-(d6-3,4-dimethoxyphenyl)ethyl]formamide
A mixture of 2-(d6-3,4-dimethoxyphenyl)ethylamine in formic acid was heated to reflux and maintained at reflux until a sufficient percent of the starting material had been consumed, measured by TLC/HPLC. The solution was concentrated under vacuum to get N-[2-(d6-3,4-dimethoxyphenyl)ethyl]formamide.
Example 27: Preparation of amorphous deutetrabenazine
Deutetrabenazine (2 g) was dissolved in methanol (25 mL) at 65 ± 5 °C. The resulting clear solution was filtered through diatomaceous earth (e.g., HYFLO®) to remove any undissolved particulate. The solvent was removed by rotary evaporation at 30 °C – 35 °C to get amorphous deutetrabenazine.
Example 28: Preparation of amorphous form of deutetrabenazine
Deutetrabenazine (1.0 g) was dissolved in dichloromethane (10 mL) at 35 ± 5 °C. The resulting clear solution was filtered through diatomaceous earth (e.g., HYFLO®) to remove any undissolved particulate. The solution was washed with dichloromethane and the solvent was removed by rotary evaporation at 30 °C – 35 °C to get amorphous deutetrabenazine.
Example 29: Preparation of amorphous form of deutetrabenazine
Deutetrabenazine (2.0 g) was dissolved in methanol (25 mL) at 65 ± 5 °C. The resulting clear solution was filtered through diatomaceous earth (e.g., HYFLO®) to remove any undissolved particulate. The solution was subjected to spray drying in a BÜCHI-290 laboratory spray dryer to get amorphous deutetrabenazine.
Example 30: Preparation of deutetrabenazine (we included this example)
A solution of 20% potassium carbonate solution in water (315 mL) was added to a mixture of d6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride hydrate (115 g) in water (230 mL) while stirring the mixture at 25 °C. Dichloromethane (575 mL) was charged to the reaction mixture, which was then stirred for 20 – 30 minutes. The organic layer and aqueous layer were separated, and the organic layer was washed with water (57.5 mL). The solvent was distilled out completely at 35 °C – 40 °C. Water (518 mL), benzyltriethylammonium chloride (27.26 g) and (2-acetyl-4-methylpentyl)trimethylammonium iodide (125.19 g) was charged to the resulting residue. The reaction mass was heated to 35 °C – 45 °C and maintained at 35 °C – 45 °C for 45 – 60 hours. The reaction mixture was cooled to 25 °C – 30 °C, ethyl acetate (1150 mL) was added, and the mixture was stirred for 20 – 30 minutes. The organic and aqueous layers were separated. The organic layer was washed with water (230 mL) and concentrated under vacuum to form a residue. Isopropyl alcohol (230 mL) was charged to the residue and the reaction mixture was heated to 70°C – 75 °C and stirred for 30 minutes. The reaction mixture was cooled to 25 °C – 30 °C, stirred for 1 – 2 hours, and then filtered. The solid was washed with isopropyl alcohol (115mL) and dried at 55 °C in vacuum oven for 10 hours to get deutetrabenazine (120 g, HPLC purity 99.85%).

,CLAIMS:1. A process for preparing deutetrabenazine of formula (I),

comprising the step of reacting d6-6,7-dimethoxy-3,4 dihydro isoquinoline or its salt of formula (II)

with salt of 3-(dimethylamino)methyl)-5methylhexan-2-one formula (III)

in the presence of a solvent and a base to produce deutetrabenazine of formula (I)

2. The process according to claim 1, wherein the solvent is selected from the group comprising of hexanes, heptane, cyclohexane, octane, isooctane, cyclopentane, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, acetone, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 1,2-dimethoxyethane, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof and base is selected from the group comprising of pyridine, trimethylamine, N,N-diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof.
3. The process according to claim 1, wherein the organic acid is selected from the group consisting of oxalic acid, citric acid, formic acid, acetic acid, pyruvic acid, malonic acid, fumaric acid, maleic acid, succinic acid, and malic acid.
4. A process for preparation of a deutetrabenazine intermediate 2-(d6-3,4-dimethoxyphenyl) ethanamine of formula (IV)

comprising the steps of :
a) reacting 2-[2-(3,4-dihydroxyphenyl)ethyl]-isoindole-1,3-dione of formula (Va)

with a source of deuterated methyl in a solvent and optionally in the presence of base and catalyst to produce 2-[ d6-2-(3,4-dihydroxyphenyl)ethyl]-isoindole-1,3-dione of formula (VIa)

b) deprotection of compound of formula (VIa) to produce 2-(d6-3,4-dimethoxyphenyl) ethanamine of formula (IV), wherein R in the compound of formulae (VIa) and (Va) may be selected from hydrogen, C1 to C10 alkyl, C6 to C14 aryl and C1 to C16 aralkyl and wherein the alkyl, aryl and aralkyl are optionally substituted with halogens, nitro groups, cyano groups and carboxylic groups.

5. The process according to claim 4, wherein the deuterated methylating agent is selected from the group consisting of deuterated iodomethane, deuterated methanol, deuterated dimethyl carbonate, deuterated dimethyl sulfate, deuterated bromomethane, and deuterated methyl trichloroacetate.
6. The process according to claim 4, wherein the solvent is selected from the group comprising of hexanes, heptane, cyclohexane, octane, isooctane, cyclopentane, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, acetone, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 1,2-dimethoxyethane, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof and the base is selected from the group comprising of pyridine, trimethylamine, N,N-diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof.
7. The process according to claim 4, wherein the deprotecting agent is selected from the group consisting of hydrazine, methylamine, sodium borohydride and acetic acid, pyridine, trimethylamine, and N,N-diisopropylethylamine.
8. The process according to claim 4, wherein the reacting step is carried out in the presence of a catalyst selected from the group comprising of diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, triphenylphosphine, tricyclohexylphosphine, and tributylphosphine.
9. A process for preparation of deutetrabenazine (I)

comprising the step of reacting a hydrated salt of d6-6,7-dimethoxy-3,4 dihydro isoquinoline of formula (IIa)

with 2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium halide of formula (IIIa)

in the presence of a solvent and a base to produce deutetrebenazine.

10. The process according to claim 9, wherein the salt is selected from the group consisting of a hydrochloric acid salt, a hydrobromic acid salt, a sulfuric acid salt, and a phosphoric acid salt.
11. The process according to claim 9, wherein the solvent is selected from the group comprising of hexanes, heptane, cyclohexane, octane, isooctane, cyclopentane, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, acetone, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 1,2-dimethoxyethane, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof and base is selected from the group comprising of pyridine, trimethylamine, N,N-diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof.
12. A process for preparation of deutetrebenazine intermediate d6-6,7-dimethoxy-phenyl)-ethyl-formamide of formula (IV)

comprising the reaction of N-(2-(3,4-dihydroxy-phenyl)-ethyl-formamide of formula (VI)

with a source of deuterated methanol in a solvent and optionally in the presence of catalyst to produce of d6 -6,7-dimethoxy-phenyl)-ethyl-formamide of formula (IV).

13. The process according to claim 12, wherein the deuterated methylating agent is selected from the group consisting of deuterated methanol, deuterated dimethyl carbonate, deuterated dimethyl sulfate, deuterated methyl bromide, and deuterated methyl trichloroacetate.
14. The process according to claim 12, wherein the reaction is carried out in the presence of a catalyst selected from the group comprising of diethyl azodicarboxylate, diisopropyl azodicarboxylate, triphenylphosphine, tricyclohexylphosphine, and a combination of a cobalt salt, a tetradentate phosphine ligand, and a base.
15. A process for preparation of deutetrabenazine intermediate d6-6,7-dimethoxy-phenyl)-ethyl-formamide of formula (IV)

comprising the steps of :
a) reacting dopamine hydrochloride of formula (V)

with an amine protecting group in the presence of a solvent and a base to produce amine protected 3,4-dihydroxyphenylethylcarbamate of formula (VII)

b) reacting the compound of formula (VII) with a source of deuterated methyl in a solvent and optionally in the presence of catalyst to produce of tert-butyl- d6 -3,4-dimethoxyphenylethylcarbamate formula (VIII)

c) deprotection of compound of formula (VIII) to produce 2-(d6-3,4-dimethoxyphenyl) ethanamine of formula (IX)

reacting compound of formula (IX) with formylating agent to produce d6-6,7-dimethoxy-phenyl)-ethyl-formamide of formula (IV).
16. The process according to claim 15, wherein the first solvent and the second solvent are independently selected from the group comprising of hexanes, heptane, cyclohexane, octane, isooctane, cyclopentane, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, acetone, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, 1,2-dimethoxyethane, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof
17. The process according to claim 15, wherein the base is selected from the group comprising of of pyridine, trimethylamine, N,N-diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof.
18. The process according to claim 15, wherein the deuterated methylating agent is selected from the group consisting of deuterated methanol, deuterated dimethyl carbonate, deuterated dimethyl sulfate, deuterated methyl bromide, and deuterated methyl trichloroacetate.
19. The process according to claim 15, wherein the reacting step is carried out in the presence of a catalyst selected from the group comprising of diethyl azodicarboxylate, diisopropyl azodicarboxylate, triphenylphosphine, tricyclohexylphosphine, and a combination of a cobalt salt, a tetradentate phosphine ligand, and a base.
20. The process according to claim 15, wherein the formylating agent is selected from the group consisting of formic acid, methyl formate, ethyl formate, propyl formate, and isobutyl formate.