DESC:A PROCESS FOR THE PREPARATION OF (3R,4R)-1-BENZYL-N,4-DIMETHYL PIPERIDIN-3-AMINE DIHYDROCHLORIDE”

FIELD OF THE INVENTION
The present invention relates to a process for preparation of (3R,4R)-1-Benzyl-N,4-dimethyl piperidin-3-amine dihydrochloride (VI) a key intermediate for the preparation of Tofacitinib citrate with high yield and purity.

BACKGROUND OF THE INVENTION
Tofacitinib citrate, developed by Pfizer (United States), was approved by the FDA in November 2012 for the treatment of moderately to severely active rheumatoid arthritis in adults with inadequate response or intolerance to methotrexate. Chemical name is (3R,4R)-4­methyl-3-(methyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamino)-ß-oxo-1-piperidinepropane nitrile, 2­hydroxy-1,2,3-propanetri carboxylate, its chemical structural formula is as follows:

WO2002096909 discloses a process for the preparation of a Tofacitinib intermediate, namely, bis[(1-benzyl-4-methylpiperidin-3-yl)-methylamine] di p toluyl L tartrate (V). In this process, a compound of formula (IIIa) is first treated with HCl in the presence of toluene and ethanol to obtain a compound of formula (IV). Subsequently, the compound (IV) is reacted with di p toluyl L tartaric acid in the presence of NaOH, isopropanol (IPA), and methanol (MeOH) to produce the compound of formula (V). The process is schematically illustrated below.:

HU231015 discloses a process for the preparation of 1 benzyl 4 methyl 3 (methylamino)pyridin 1 ium bromide. In this process, a compound of formula (I) is first treated with a 40% aqueous methylamine solution and copper powder in the presence of dichloromethane (DCM) to yield a compound of formula (II). Thereafter, the compound of formula (II) is reacted with benzyl bromide in the presence of acetone to furnish the compound of formula (III). The process is schematically illustrated below.

WO2014097150 discloses a process for the preparation of (1 benzyl 4 methylpiperidin-3-yl)-methylamine. In this process, a compound of formula (I) is reacted with benzyl bromide in the presence of toluene to yield a compound of formula (Ia). Subsequently, the compound of formula (Ia) is treated with methylamine and cuprous oxide to afford a compound of formula (III). Finally, the compound of formula (III) is reduced with sodium borohydride to produce a compound of formula (IIIa). The process is schematically illustrated below.

The above-described processes suffer from several disadvantages, including the use of copper in the preparation of the compound of formula (III), which lengthens reaction times and leads to the formation of unwanted impurities, rendering the processes commercially unviable.

The present invention describes an improved process for efficiently preparing 1 Benzyl N,3 dimethylpiperidin 4 amine dihydrochloride (IV).

This improved process offers several advantages, including shorter reaction times, reduced impurities, lower costs, ease of scale-up, enhanced commercial viability, higher yields, and better product purity.

OBJECT OF THE INVENTION

The present invention relates to a process for the preparation of (3R,4R)-1 Benzyl N,4 dimethylpiperidin 3 amine dihydrochloride (VI), a key intermediate used in the synthesis of Tofacitinib citrate, which is produced with high yield and purity.

SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of (3R,4R)-1 Benzyl N,4 dimethylpiperidin 3 amine dihydrochloride (VI), a key intermediate used in the synthesis of Tofacitinib citrate, which is produced with high yield and purity.

One aspect of the present invention provides, a process for the preparation of (3R,4R)-1-Benzyl-N,4-dimethylpiperidin-3-amine dihydrochloride (VI) comprising the steps of:

a) treating the compound of formula (I)

with monomethylamine in presence of a base and one or more catalysts to produce the compound of formula (II);

b) reacting the compound of formula (II) with benzyl bromide in a suitable solvent to produce the compound of formula (III);

c) reducing the compound of formula (III) in presence of a one or more catalysts in a suitable solvent to produce the compound of formula (IV);

d) resolving the compound of the formula (IV) with (-)-Di-p-toluoyl-L-tartaric acid in a suitable solvent to produce the compound of formula (V); and

e) basifying the compound of the formula (V) with a base in presence of a suitable solvent to produce the compound of the formula (VI).

In another aspect of the present invention, the compound of Formula (VI) is further converted into Tofacitinib or a pharmaceutically acceptable salt thereof. In yet another aspect, the compound of Formula (VI) is further converted into Tofacitinib citrate.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of (3R,4R)-1 Benzyl N,4 dimethylpiperidin 3 amine dihydrochloride (VI), a key intermediate used in the synthesis of Tofacitinib citrate, which is produced with high yield and purity.

One embodiment of the present invention provides a process for the preparation of (3R,4R)-1-Benzyl-N,4-dimethylpiperidin-3-amine dihydrochloride (VI), which comprises the steps of:
a) treating the compound of formula (I) with monomethyl amine in presence of a base and one or more catalysts to produce the compound of formula (II);
b) reacting the compound of formula (II) with benzyl bromide in a suitable solvent to produce the compound of formula (III);
c) reducing the compound of formula (III) in presence of one or more catalysts in a suitable solvent to produce the compound of formula (IV);
d) resolving the compound of the formula (IV) with (-)-Di-p-toluoyl-L-tartaric acid in a suitable solvent to produce the compound of formula (V); and
e) basifying the compound of the formula (V) with a base in presence of a suitable solvent to produce the compound of the formula (VI).

In another aspect of the present invention, the compound of Formula (VI) is further converted into Tofacitinib or a pharmaceutically acceptable salt thereof. In yet another aspect, the compound of Formula (VI) is further converted into Tofacitinib citrate.

In an embodiment of the present invention, wherein the catalyst, which is used in the step (a) and/or step (b) are selected from palladium, platinum, rhodium, Raney nickel, copper(I) oxide, copper powder, cuprous iodide, cuprous bromide or a mixture thereof.

In another embodiment of the present invention, the reducing agent, which is used in the step (b) is selected from sodium borohydride, sodium cyanoborohydride, lithium borohydride, or lithium triethylborohydride.

In another embodiment of the present invention, the base used in the step (a) and/or step (d)are selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, caesium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, or potassium bicarbonate.

In another embodiment of the present invention, the suitable solvent, which are used in any of the above steps are selected from sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutanol, tert-butanol; nitriles such as acetonitrile and propionitrile; ether solvent such as tetrahydrofuran, diisopropylether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and aromatic hydrocarbons such as toluene, anisole, heptane and xylene; esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone; halogenated hydrocarbons such as chloroform, dichloromethane; water; cyclohexane and N-methyl-2-pyrrolidone or mixtures thereof.

The advantages of the present invention:

1. Faster reaction time: The invention significantly reduces the reaction time required to prepare compound (formula II) from 40 hours to 20-24 hours. This is achieved by utilizing one or more catalysts, specifically copper(I) oxide and Pd/C. This translates to reduction in production time, leading to cost savings.
2. Improved product purity: The invention utilizes a catalyst (Raney Ni) in the process for preparing compound (formula IV). This results in a product free from unwanted impurities. This ensures the final product meets the required quality standards and enhances its effectiveness.

The following examples illustrate the present invention but should not be construed as limiting the scope of the invention.

EXAMPLES:
EXAMPLE 1: Preparation of 1-benzyl-4-methyl-3-(methylamino)pyridin-1-ium Bromide.

Bromo-4-methylpyridine (100 g, 0.588 mol), aqueous monomethylamine (5 mL), potassium carbonate (40.2 g, 0.29 mol), copper(I) oxide (128 g, 0.034 mol), and palladium on carbon were added to a flask at 25–30?°C. The reaction mixture was stirred at 95–100?°C for 20–24 hours. After completion, the mixture was cooled to 25–35?°C and filtered. The filtrate was extracted with dichloromethane, and the solvent was distilled off to obtain a residue. This residue was dissolved in acetone, and benzyl bromide was added at 25–35?°C. The reaction mixture was then heated to 45–50?°C for 4–6 hours. After completion, the mixture was cooled to 25–35?°C, and the resulting solid was filtered off, washed with acetone, and dried at 55–60?°C to yield 1 benzyl 4 methyl 3 (methylamino)pyridin-1 ium bromide.

EXAMPLE 2: Preparation of 1-benzyl-N,4-dimethyl piperidin-3-amine dihydrochloride
Benzyl 4 methyl 3 (methylamino)pyridin 1 ium bromide (100 g, 0.34 mol), sodium borohydride (56 g, 1.48 mol), and a mixture of ethanol and water were added to a flask at 25–35?°C. The reaction mixture was maintained at this temperature for 4–6 hours. Upon completion, the reaction was quenched with purified water, and the product was extracted into dichloromethane. The dichloromethane extract was distilled to obtain a residue, which was then dissolved in alcohol, and Raney nickel was added. The mixture was subsequently heated in an autoclave at 60–65?°C for 1–2 hours. After filtering off the metal catalyst, a solution of isopropanol and HCl was added to the reaction mass at 25–35?°C. The reaction mixture was then cooled, and the precipitated solid was filtered off at 0–5?°C, yielding pure 1 benzyl N,4 dimethylpiperidin 3 amine dihydrochloride.

Yield: 85% ; Chiral purity: 94%

Preparation of (3R,4R)-1-benzyl-N,4-dimethyl piperidin-3-amine((2R,3R)- 2,3-bis ((4-methylbenzoyl) oxy) succinate) (2:1)
Benzyl N,4 dimethylpiperidin 3 amine dihydrochloride (100 g, 0.34 mol), methanol, sodium hydroxide solution (30 mL), and ((2R,3R)-2,3 bis((4 methylbenzoyl)oxy)succinate) (100 g, 0.25 mol) were added to a flask maintained at 60–65?°C. The reaction mixture was stirred at 60–65?°C for 4–5 hours. After completion, the mixture was cooled to 0–5?°C, and the precipitated compound was filtered off to yield pure (3R,4R)-1 benzyl N,4 dimethylpiperidin 3 amine ((2R,3R)-2,3 bis((4 methylbenzoyl)oxy)succinate).

Yield: 45% ; Chiral purity: 99%

Preparation of (3R,4R)-1-benzyl-N,4-dimethyl piperidin-3-amine dihydrochloride
(3R,4R)-1 benzyl N,4 dimethylpiperidin 3 amine ((2R,3R)-2,3 bis((4 methylbenzoyl)oxy)succinate) (2:1) (or 200 g [100 g; 0.12 mol]), methanol, and a sodium hydroxide solution (30 mL) were added to a flask. A clear solution was obtained by extracting with dichloromethane, and the dichloromethane residue was distilled. The residue was then taken up in an alcohol solvent, and Raney nickel was added. The reaction mixture was heated in an autoclave and maintained at 60–65?°C for 1–2 hours. After filtering off the metal catalyst, a solution of IPA and HCl was added to the reaction mixture at 25–35?°C. The mixture was then cooled to 0–5?°C, and the precipitated solid was filtered off to yield pure (3R,4R)-1 benzyl N,4 dimethylpiperidin 3 amine dihydrochloride.

Yield: 85%; Chiral purity: 99%
,CLAIMS:WE CLAIM,
1. A process for the preparation of (3R,4R)-1-Benzyl-N,4-dimethylpiperidin-3-amine dihydrochloride (VI) comprising the steps of:
a) treating the compound of formula (I)

with monomethylamine in presence of a base and one or more catalysts to produce the compound of formula (II);

b) reacting the compound of formula (II) with benzyl bromide in a suitable solvent to produce the compound of formula (III);

c) reducing the compound of formula (III) in presence of one or more catalyst in a suitable solvent to produce compound of formula (IV);

d) resolving the compound of the formula (IV) with (-)-Di-p-toluoyl-L-tartaric acid in a suitable solvent to produce compound of formula (V); and

e) basifying the compound of the formula (V) with a base in presence of a suitable solvent to produce the compound of the formula (VI).

2. The process according to the claim 1, wherein the compound of Formula (VI) is further converted to Tofacitinib or a pharmaceutically acceptable salt thereof.

3. The process according to the claim 1, wherein the one or more catalysts are selected from the group consisting of palladium, platinum, rhodium, Raney nickel, copper(I) oxide, copper powder, cuprous iodide, and cuprous bromide and a mixture thereof.

4. The process according to the claim 1, wherein the reducing agent is selected from sodium borohydride, sodium cyanoborohydride, lithium borohydride, and or lithium triethyl borohydride.

5. The process according to the claim 1, wherein the base is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, caesium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, or potassium bicarbonate.

6. The process according to the claim 1, wherein the suitable solvent(s) which are selected from sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutanol, tert-butanol; nitriles such as acetonitrile and propionitrile; ether solvent such as tetrahydrofuran, diisopropylether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and aromatic hydrocarbons such as toluene, anisole, heptane and xylene; esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone; halogenated hydrocarbons such as chloroform, dichloromethane; water; cyclohexane and N-methyl-2-pyrrolidone or mixtures thereof.