Claims:WE CLAIM:
1. A process for preparation of a compound of formula (1), comprising:
a) N-protection of a compound of formula (2)

with an trityl chloride or fluorenylmethyloxycarbonyl chloride or benzyloxycarbonyl chloride or di-tert-butyl dicarbonate in presence of base and organic solvent to obtain a compound of formula (3);

b) quarternization of nitrogen of compound of formula (3) with benzyl halide or substituted benzyl halide in an organic solvent to obtain a compound of formula (4);

c) partial reduction of the compound of formula (4) in presence of a reducing agent in a organic solvent to obtain a compound of formula (5);

d) hydrolysis of the compound formula (5) in presence of an acid to obtain a compound of formula (6),

e) reductive amination of the compound of formula (6) with methylamine in presence of a lewis acid in an organic solvent, followed by reduction using a reducing agent to obtain a compound of formula (7); and

f) resolution of the compound of formula (7) in presence of a resolving agent in an organic solvent to obtain the compound of formula (1);

wherein R is trityl (Tr) group, fluorenylmethoxycarbonyl (Fmoc) group, benzyloxycarbonyl ( Cbz) group, tert-butoxycarbonyl (Boc) group; R1 is a phenyl or substituted phenyl group; and X represents a halide selected from chloro, bromo, and iodo or any leaving group selected from tosyloxy or mesyloxy.
2. The process as claimed in claim 1, wherein base is triethylamine, pyridine, dimethyl amino pyridine (DMAP), diethyl amino pyridine (DEAP), N-methyl Morpholine, diisopropyl amine, diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, liquid ammonia, sodium carbonate, potassium carbonate, cesium carbonate or sodium bicarbonate.

3. The process as claimed in claim 1, wherein the benzyl or substituted benzyl halide is benzyl chloride, benzyl bromide, substituted benzyl chloride, and substituted benzyl bromide.

4. The process as claimed in claim 1, wherein organic solvent is alcohols such as methanol, ethanol, isopropyl alcohol, and the like or mixture thereof; ketones, such as methyl isobutyl ketone, methyl ethyl ketone, n-butanone, and the like; halogenated solvents, such as dichloromethane, ethylene dichloride, chloroform, and the like; esters, such as ethyl acetate, n-propyl acetate, isopropyl acetate, and the like; hydrocarbon solvents, such as toluene, xylene, cyclohexane, and the like; ethers, such as 1,4-dioxane, tetrahydrofuran, and the like; and amides such as N,N- dimethylformamide, ?,?-dimethylacetamide and the like or dimethylsulfoxide or water mixture of solvents thereof.

5. The process as claimed in claim 1, wherein the reducing agent is sodium borohydride, potassium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride.

6. The process as claimed in claim 1, wherein the acid is hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trichloroacetic acid, acetic acid, hydrobromic acid and mixture(s) thereof.

7. The process as claimed in claim 1, wherein the lewis acid is aluminium trichloride, ferric chloride, zinc chloride, indium chloride, and titanium (IV) tetraisopropoxide.

8. The process as claimed in claim 1, wherein the resoluting agent is di-p-toluoyl-L-tartaric acid, di-p-toluoyl-D-tartaric acid, dibenzoyl tartaric acid, tartaric acid, mandelic acid, and camphor sulphonic acid.

9. A compound of formula (4),

wherein R is trityl (Tr) group, fluorenylmethoxycarbonyl (Fmoc) group, benzyloxycarbonyl (Cbz) group, tert-butoxycarbonyl (Boc) group; R1 is a phenyl or substituted phenyl group; and X represents a halide selected from chloro, bromo, and iodo or any leaving group selected from tosyloxy or mesyloxy.
10. A compound of formula (5),

wherein R is trityl (Tr) group, fluorenylmethoxycarbonyl (Fmoc) group, benzyloxycarbonyl ( Cbz) group, tert-butoxycarbonyl (Boc) group; R1 is a phenyl or substituted phenyl group.
Dated this fifteenth (15th) day of July, 2020,
, Description:“PROCESS FOR THE PREPARATION OF (3R,4R)-(1-BENZYL-4-METHYLPIPERIDIN-3-YL)-METHYLAMINE”

FIELD OF THE INVENTION

The present invention relates to a process for preparation of (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine (1) by employing novel compound of formula (4) and (5). The compound of formula (1) is a key intermediate for the synthesis of Tofacitinib citrate.

BACKGROUND OF THE INVENTION
Tofacitinib citrate chemically known as 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxo-propanenitrile, 2-hydroxypropane-1,2,3-tricarboxylate described as FORMULA I below and as disclosed in WO 02/096909, U.S. Pat. No.7,301,023. US FDA approved it for rheumatoid arthritis.

The key step for the preparation of 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxo-propanenitrile as depicted in (Scheme-1) WO 02/096909 includes:
(i) resolution of racemic (1-Benzyl-4-methylpiperidin-3-yl)-methylamine to (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine using Di-p-toluoyl-L-tartarate;
(ii) condensation of 4-Chlropyrrolo[2,3-d]pyrimidine with (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine to get (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine; and
(iii) debenzylation of (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine followed by condensation with cyano acetic acid derivative to get 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxo-propanenitrile (Tofacitinib citrate), (Scheme-1).

The most important part for the preparation of Tofacitinib citrate is the synthesis of (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine as it is very tedious synthesis and also requires very expensive reagent. There are several processes reported in literature for the synthesis and resolution of racemic (1-Benzyl-4-methylpiperidin-3yl)-methylamine to (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine.
WO 2007/012953 discloses preparation of 1-Benzyl-3-methoxycarbonylamino-4-methyl-pyridinium bromide and it's asymmetric reduction using mixture of Ruthenium and Iridium based chiral catalysts under hydrogenation condition to provide (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine with 84% cis isomer, having 68% ee.
The patent further discloses the preparation of same intermediate by applying partial reduction followed by asymmetric reduction approach to obtain highly enriched Piperidine derivative as depicted in Scheme-2.

Both the approaches make use of very high chiral catalyst loading and render their commercial use expensive and difficult. Further, the process requires very high pressure which makes it risky, costlier and unfavorable for scale up.
WO 2010/123919 provides an additional process for preparation of (1-Benzyl-4-methylpiperidin-3-yl)-methylamine, which includes:
(i) protection of amino group of 3-Amino-4-methyl pyridine with Dimethyl carbonate in presence of Potassium tert-butoxide in Tetrahydrofuran;
(ii) quaternization of Nitrogen of Pyridine system using Benzyl bromide in Toluene;
(iii) partial reduction of the quaternized Pyridine system to produce 1,2,5,6-Tetrahydropyridine in presence of Sodium borohydride in Methanol;
(iv) reduction with Platinum oxide in Methanol provides Piperidine derivative. Followed by the purification by column chromatography; and
(v) further reaction with Lithium aluminium hydride and purification by column chromatography to get (1-Benzyl-4-methyl-piperidin-3-yl)-methylamine.
The process has several drawbacks. Overall process yield is very poor i.e. approximately 40%. The process uses column chromatography at two stages. Lithium aluminum hydride, a known pyrophoric reagent, account for the safety risk during its manufacturing. Lastly Platinum oxide is very explosive in presence of hydrogen. It is very costly reagent which discourages its use on plant scale. Overall the process is costlier, not so safe to work on commercial scale and demands stringent skill of art.
WO 2010/123919 further reveals an additional procedure for the preparation of (1-Benzyl-4-methylpiperidin-3-yl)-methylamine and the synthetic procedure is summarized in Scheme-3.

Process involves debenzylation and quaternization of ethyl 1-Benzyl-3-oxopiperidine-4-carboxylate followed by protection of the resulted Ethyl 3-oxopiperidine-4-carboxylate derivative using di-tert-butyl dicarbonate. Protected Piperidine derivative was methylated by abstracting the Methylenic proton using Sodium hydride and further reaction with Iodomethane. In the next stage deprotection of N-tert-butoxycarbonyl group was carried out in acidic media, and the resulting 4-Methylpiperidin-3-one was benzylated followed by reductive amination with Methylamine and Sodium triacetoxyborohydride provide the desired product (1-Benzyl-4-methylpiperidin-3-yl)-methylamine.
The overall conversion involves five stages from quite a complex starting material. The process involves protection and deprotection in different stages. Use of costly, non safe reagents such as Sodium hydride and lacrimatic Benzyl bromide and Sodium triacetoxyborohydride limit its commercial scale production. The process has major drawback with respect to the use of column chromatography at three stages. Moreover disclosure of process is silent about the purity of intermediates and of the target molecule produced. The overall yield mentioned for the process is also very low i.e. 13.6 molar percent.
U.S. Pat. No. 6,627,754 provides a similar reductive amination route as discussed in WO 2010/123919 for the synthesis of (1-Benzyl-4-methyl piperidin-3-yl)-methylamine from 1-Benzyl-4-methylpiperidin-3-one in a sealed tube using Sodium triacetoxyborohydride as a reducing agent. Sodium triacetoxyborohydride is extremely moisture sensitive pyrophoric reagent. Sealed tube reaction is difficult to execute on large scale.

US 9,951,012 discloses process for preparation of (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine, comprising: (i) N-acylation of 3-Amino-4-methyl pyridine (Formula III) with alkyl, aryl or substituted aryl acid anhydride or acid chloride to get Formula IVa; (ii) quaternization of Nitrogen of Pyridine system having Formula IVa, using Benzyl or substituted Benzyl halide in an organic solvent or aqueous solvent or mixture(s) thereof to get Formula Va; (iii) partial reduction of the optionally isolated quarternized pyridine system having Formula Va to produce 1,2,5,6-Tetrahydropyridine system of Formula VIa in the presence of a reducing agent or any Borohydride agent in an organic solvent or aqueous solvent or mixture(s) thereof, at an ambient temperature; (iv) hydrolysis of 1,2,5,6-Tetrahydropyridine system of Formula VIa in presence of an acid or mixture of acids to get Formula VIIa, at an ambient temperature; (v) reductive amination of Formula VIIa using Methylamine in presence of any Lewis acids in an organic solvent or aqueous solvent or mixture(s) thereof followed by reduction using any reducing agent or any alkali metal Borohydride derivatives produce compound of Formula VIIIa, at an ambient temperature; and (vi) further resolution of compound VIIIa in presence of any resoluting agent in an organic solvent or aqueous solvent or mixture(s) thereof produce compound of Formula IIa. and the synthetic procedure is summarized in Scheme-4.

Above the approaches make use of very high risk and difficult. Further, the process obtain very low yield and unfavorable for scale up.
The processes taught by prior art have several drawbacks namely expensive, not suitable for scale up at plant level, energy intensive, difficult, giving lower yields, forcing use of corrosive acids, longer duration of corrosive reactions and less user friendly. Considering the drawbacks of prior art and very complex methodologies applied, for the preparation of the (1-Benzyl-4-methyl piperidin-3-yl)-methylamine, there is a urgent and pressing need for simple, energy economical, financially cheaper plant friendly process, environment friendly process for the preparation of (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine to synthesize Tofacitinib citrate that does not use hygroscopic and pyrophoric chemicals and yet provides better yields.
Hence, there is consequently a need development for new methods to sort out prior art existing methods. So, our inventors have developed a novel method for the preparation of (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine. The present invention is providing a simple, cost effective with high purity and good yield on industrial applicable process
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of (1-Benzyl-4-methylpiperidin-3-yl)-methylamine.
The one embodiment of the present invention provides process for preparation of a compound of formula (1), comprising:
a) N-protection of a compound of formula (2)

with an trityl chloride or fluorenylmethyloxycarbonyl chloride or benzyloxycarbonyl chloride or di-tert-butyl dicarbonate in presence of base and organic solvent to obtain a compound of formula (3);

b) quarternization of nitrogen of compound of formula (3) with benzyl halide or substituted benzyl halide in an organic solvent to obtain a compound of formula (4);

c) partial reduction of the compound of formula (4) in presence of a reducing agent in a organic solvent to obtain a compound of formula (5);

d) hydrolysis of the compound formula (5) in presence of an acid to obtain a compound of formula (6),

e) reductive amination of the compound of formula (6) with methylamine in presence of a lewis acid in an organic solvent, followed by reduction using a reducing agent to obtain a compound of formula (7); and

f) resolution of the compound of formula (7) in presence of a resolving agent in an organic solvent to obtain the compound of formula (1);

wherein R is trityl (Tr) group, fluorenylmethoxycarbonyl (Fmoc) group, benzyloxycarbonyl ( Cbz) group, tert-butoxycarbonyl (Boc) group; R1 is a phenyl or substituted phenyl group; and X represents a halide selected from chloro, bromo, and iodo or any leaving group selected from tosyloxy or mesyloxy.

The second embodiment of the present invention provides a novel compound of formula (4),

wherein R is trityl (Tr) group, fluorenylmethoxycarbonyl (Fmoc) group, benzyloxycarbonyl (Cbz) group, tert-butoxycarbonyl (Boc) group; R1 is a phenyl or substituted phenyl group; and X represents a halide selected from chloro, bromo, and iodo or any leaving group selected from tosyloxy or mesyloxy.
The third embodiment of the present invention provides a novel compound of formula (5),

wherein R is trityl (Tr) group, fluorenylmethoxycarbonyl (Fmoc) group, benzyloxycarbonyl (Cbz) group, tert-butoxycarbonyl (Boc) group; R1 is a phenyl or substituted phenyl group.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of (1-Benzyl-4-methylpiperidin-3-yl)-methylamine.
The one embodiment of the present invention provides process for preparation of a compound of formula (1), comprising:
a) N-protection of a compound of formula (2)

with an trityl chloride or fluorenylmethyloxycarbonyl chloride or benzyloxycarbonyl chloride or di-tert-butyl dicarbonate in presence of base and organic solvent to obtain a compound of formula (3);

b) quarternization of nitrogen of compound of formula (3) with benzyl halide or substituted benzyl halide in an organic solvent to obtain a compound of formula (4);

c) partial reduction of the compound of formula (4) in presence of a reducing agent in a organic solvent to obtain a compound of formula (5);

d) hydrolysis of the compound formula (5) in presence of an acid to obtain a compound of formula (6),

e) reductive amination of the compound of formula (6) with methylamine in presence of a lewis acid in an organic solvent, followed by reduction using a reducing agent to obtain a compound of formula (7); and

f) resolution of the compound of formula (7) in presence of a resolving agent in an organic solvent to obtain the compound of formula (1);

wherein R is trityl (Tr) group, fluorenylmethoxycarbonyl (Fmoc) group, benzyloxycarbonyl ( Cbz) group, tert-butoxycarbonyl (Boc) group; R1 is a phenyl or substituted phenyl group; and X represents a halide selected from chloro, bromo, and iodo or any leaving group selected from tosyloxy or mesyloxy.

The second embodiment of the present invention provides a novel compound of formula (4),

wherein R is trityl (Tr) group, fluorenylmethoxycarbonyl (Fmoc) group, benzyloxycarbonyl (Cbz) group, tert-butoxycarbonyl (Boc) group; R1 is a phenyl or substituted phenyl group; and X represents a halide selected from chloro, bromo, and iodo or any leaving group selected from tosyloxy or mesyloxy.
The third embodiment of the present invention provides a novel compound of formula (5),

wherein R is trityl (Tr) group, fluorenylmethoxycarbonyl (Fmoc) group, benzyloxycarbonyl (Cbz) group, tert-butoxycarbonyl (Boc) group; R1 is a phenyl or substituted phenyl group.
The process according to the embodiment of the present invention enables the preparation of 3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine (1) with significantly high purity, yield and therefore is suitable for mass production and economical.
The process according to the embodiment of the present invention, Step a) involves N-protection of a compound of formula (2) with an trityl chloride or fluorenylmethyloxycarbonyl chloride or benzyloxycarbonyl chloride or di-tert-butyl dicarbonate in presence of base and organic solvent to obtain a compound of formula (3) and optionally isolating it. The reaction may be carried out at temperatures ranging from about 0° C to about 40°C., or from about 25°C to about 30°C.

The process according to the embodiment of the present invention, Step b) involves the quarternization of nitrogen of compound of formula (3) with benzyl halide or substituted benzyl halide in an organic solvent to obtain a compound of formula (4) and optionally isolating it. The reaction may be carried out at temperatures ranging from about 75°C to about 130°C or from about 100° C to about 110°C.

The process according to the embodiment of the present invention, Step c) involves the partial reduction of the compound of formula (4) in presence of a reducing agent in a organic solvent to obtain a compound of formula (5). The reaction may be carried out at temperatures ranging from about 20°C to about 40°C., or from about 25°C to about 30°C.

The process according to the embodiment of the present invention, Step d) involves the hydrolysis of the compound formula (5) in presence of an acid to obtain a compound of formula (6). The reaction may be carried out at temperatures ranging from about 55°C to about 85°C or from about 60°C to about 80°C.

The process according to the embodiment of the present invention, Step e) involves the reductive amination of the compound of formula (6) with methylamine in presence of a lewis acid in an organic solvent, followed by reduction using a reducing agent to obtain a compound of formula (7). The reaction may be carried out at temperatures ranging from about 0°C to about 30°C., or from about 10°C to about 15°C.

The process according to the embodiment of the present invention, Step f) involves the resolution of the compound of formula (7) in presence of a resolving agent in an organic solvent to obtain the compound of formula (1). The reaction may be carried out at temperatures ranging from about 30°C to about 60°C., or from about 40°C to about 50°C.

The process according to the embodiment of the present invention, wherein base is triethylamine, pyridine, dimethyl amino pyridine (DMAP), diethyl amino pyridine (DEAP), N-methyl Morpholine, diisopropyl amine, diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, liquid ammonia, sodium carbonate, potassium carbonate, cesium carbonate or sodium bicarbonate.

The process according to the embodiment of the present invention, wherein the benzyl or substituted benzyl halide is benzyl chloride, benzyl bromide, substituted benzyl chloride, and substituted benzyl bromide.

The process according to the embodiment of the present invention, wherein organic solvent is alcohols such as methanol, ethanol, isopropyl alcohol, and the like or mixture thereof; ketones, such as methyl isobutyl ketone, methyl ethyl ketone, n-butanone, and the like; halogenated solvents, such as dichloromethane, ethylene dichloride, chloroform, and the like; esters, such as ethyl acetate, n-propyl acetate, isopropyl acetate, and the like; hydrocarbon solvents, such as toluene, xylene, cyclohexane, and the like; ethers, such as 1,4-dioxane, tetrahydrofuran, and the like; and amides such as N,N- dimethylformamide, ?,?-dimethylacetamide and the like or dimethylsulfoxide or water mixture of solvents thereof.

The process according to the embodiment of the present invention, wherein the reducing agent is sodium borohydride, potassium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride.

The process according to the embodiment of the present invention, wherein the acid is hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trichloroacetic acid, acetic acid, hydrobromic acid and mixture(s) thereof.

The process according to the embodiment of the present invention, wherein the lewis acid is aluminium trichloride, ferric chloride, zinc chloride, indium chloride, and titanium (IV) tetraisopropoxide.

The process according to the embodiment of the present invention, wherein the resoluting agent is di-p-toluoyl-L-tartaric acid, di-p-toluoyl-D-tartaric acid, dibenzoyl tartaric acid, tartaric acid, mandelic acid, and camphor sulphonic acid.

The process according to the embodiment of the present invention provides (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine (1) with high purity and good yield.

According to the present invention, the aforesaid methods should in particular be more industrially scalable, allow the desired compounds to be obtained with high yields, and use cheaper reagents which are simpler to handle and industrial applicable.
The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES

Example-1: 4-Methyl-N-tritylpyridin-3-amine (3)
To a Suspension of 4-methylpyridine-3-amine (10 gm, 0.092 mol) in dichloromethane (100 ml) and Triethylamine (18.7gm,0.184mol), Trityl chloride (30.9gm,0.110 mol) were added lot wise at about 0-10° C. The reaction mixture was stir for about 10 hr at about 25-30°C, the progress of the reaction was monitored by TLC, after completion of the reaction. The resultant reaction mass was add with water (100 ml) at about 10-15° C and then temperature of the mass was raised to about 20-25°C. The resultant reaction mass was stir for about 30 min at same temperature and layers were separated. The dichloromethane layer was washed with hexanes (50 ml) and concentrated under vacuum at about 50-55°C to afford a Solid. The obtained solid was filtered and washed with toluene to afford the title product as a light brown solid (31 g; Yield=95%).

Example -2: 1-benzyl-4-methyl-3-(tritylamino) pyridin-1-ium bromide (4)
Benzyl bromide (3.73gm, 0.021mol.) was added to a solution of 4-Methyl-N-tritylpyridin-3-amine (10 gm, 0.028mol) in toluene (150 ml) and stir for 3 hours at about 100-110°C to complies the reaction, monitored by TLC, after completion of the reaction. The resultant reaction mass was allow to cool at ambient temperature. The obtained solid was filtered and washed with toluene to afford the title product as a light brown solid (13 g; Yield=87.8%).

Example -3: 1-benzyl-4-Methyl-N-trityl-1,2,5,6-tetrahydropyridin-3-amine (5)
Sodium cyan borohydride (5g, 0.079mol) was added lot-wise to a solution of 1-benzyl-4-methyl-3-(tritylamino) pyridin-1-ium bromide (10g, 0.022mol) in methanol (100 ml). The resulting solution was stirred at ambient temperature for about 16 hours, the progress of the reaction was monitored by TLC, after completion of the reaction and then reaction mass was allow cool to10-15°C. The obtained solid was filtered and washed with methanol to afford the title product as off-white solid (6g; Yield=70%).

Example-4: 1-benzyl-4-methylpiperidin-3-one (6)
Concentrated HCl 32% (20 ml, 2 volume) and 1-benzyl-4-Methyl-N-trityl-1,2,5,6-tetrahydropyridin-3-amine (10 gm, 0.022mol) were charged in a round-bottom flask with an overhead stirrer and stirred for 10 min at room temperature. The resultant reaction mixture was heated to 65-70°C and stir for 3-4 hrs at same temperature, the progress of the reaction was monitored by TLC, after completion the reaction and then reaction mixture was cooled to 25-30 °C. The resultant mass was adjusted pH to 10 -12 by using 30% sodium hydroxide solution. The resultant reaction mass was extracted with ethyl acetate/hexanes (100 ml). The resultant ethyl acetate layer was concentrated. The obtained residue was filtered to afford the title product as a light reddish brown liquid (5 gm; Yield=71%).

Example -5: 1-Benzyl-N,4-dimethylpiperidin-3-amine (7)
Titanium (IV) tetraisopropoxide (18.17 gm, 0.063 mol) solution was added to a solution of 1-benzyl-4-methylpiperidin-3-one (10g, 0.027mol) in Methanol (30ml) at 5-10°C and stirred for 40-45mints at 5-10°C, followed by added with methanolic mono methylamine solution (33%, 10 mL, 0.5volumes). The resultant reaction mixture was stirred at 5-10 °C for 1 hour, followed by added with sodium borohydride (2 g, 0.052 mol) at same temperature and stir for 1 hour as the progress of the reaction was monitored by TLC, after completion the reaction. The resultant reaction mass was filtered off followed by distillation to obtain the title product (racemic crude amine) as off-white solid (5 gm; Yield=71%).

Example -6: (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine (1)
The crude 1-Benzyl-N,4-dimethylpiperidin-3-amine (10gm,0.045mol) was resolved by using L-ditoluoyl tartaric acid (17.5gm, 0.045mol) in 1:1 mixture of methanol and water (100 L). The reaction mixture was stirred for an hour at 40-45 °C, and the precipitated product was filtered off to obtain the title product as off-white solid (3.5 gm; Yield=35%)

Example-7: Preparation of tert-butyl (4-methylpyridin-3-yl)carbamate (3).
To a Suspension of 4-methylpyridine-3-amine (10 gm, 0.092 mol) in 100 ml dichloromethane and Triethylamine (18.7gm,0.184mol), BoC anhydride/di-tert-butyl dicarbonate (22.2gm,0.101 mol) was added dropwise at about 0-10°C. The reaction mixture was stirred for about 5-6 hr at about 25-30°C, the progress of the reaction was monitored by TLC, after completion of the reaction. The resultant reaction mass was added with water (100 ml) at about 10-15°C and then temperature of the mass was raised to about 20-25°C. The resultant reaction mass was stir for about 30 min at same temperature and layers were separated. The dichloromethane layer was washed with hexanes (50 ml) and concentrated under vacuum at about 50-55°C to afford a Solid. The obtained solid was filtered and washed with hexanes to afford the title product as a light yellow brown solid (18 g; Yield=93%).

Example-8: Preparation of 1-benzyl-3-((tert-butoxycarbonyl) amino)-4-methylpyridin-1-ium bromide (4)
Benzyl bromide (9gm,0.052mol.) was added to a solution of tert-butyl (4-methylpyridin-3-yl) carbamate (10 gm, 0.048mol) in toluene (150 ml) and stir for 3 hours at about 100-110°C, the progress of the reaction was monitored by TLC, after completion of the reaction. The resultant reaction mass was allow to cool at ambient temperature. The obtained solid was filtered and washed with toluene to afford the title product as a light brown solid (15g; Yield=82%).

Example-9: Preparation of tert-butyl (1-benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl) carbamate (5)
Sodium borohydride (5g, 0.132mol) was added lot-wise to a solution of 1-benzyl-3-((tert-butoxycarbonyl) amino)-4-methylpyridin-1-ium bromide (10g, 0.026mol) in methanol (100 ml). The resulting solution was stirred at ambient temperature for about 16 hours, the progress of the reaction was monitored by TLC, after completion of the reaction and then reaction mass allow to cool to10-15°C. The obtained Solid was filtered and washed with methanol to afford the title product as off-white solid (6 g; Yield=76%).

Example-10: Preparation of 1-benzyl-4-methylpiperidin-3-one (6)
Concentrated Hydrochloric acid, ~32% (20 ml, 2 volume) and tert-butyl (1-benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl) carbamate (10 gm, 0.033mol) were charged in a round-bottom flask with an overhead stirrer and stirred for 10 min at room temperature. The resultant reaction mixture was heated to 65-70 °C and stirred for 3-4 hrs, the progress of the reaction was monitored by TLC, after completion the reaction and then the mixture was allow to cool at 25-30 °C. The resultant mass was adjusted pH to 10 -12 by using 30% sodium hydroxide Solution. The resultant reaction mass was extracted with ethyl acetate/hexane (100 mL). The obtained ethyl acetate layer was concentrated to afford a residue. The obtained residue was filtered to afford the title product as a light reddish brown liquid (5 gm; Yield=71%).

Example -11: Preparation of 1-Benzyl-N-4-dimethylpiperidin-3-amine (7)
Titanium (IV) tetraisopropoxide (18.17 gm, 0.063 mol) solution was added in to a solution of 1-benzyl-4-methylpiperidin-3-one (10g, 0.027mol) in Methanol (30ml) at 5-10°C and stirred for 40-45 min at 5-10°C, followed by added with methanolic monomethylamine solution (33%, 10 mL, 0.5volumes). The resultant mixture was stirred at 5-10 °C for 1 hour, followed by added with sodium borohydride (2 g, 0.052 mol) at same temperature and stir for 1 hour as the progress of the reaction was monitored by TLC, after completion the reaction. The resultant reaction mass was filtered off followed by distillation to obtain titled product (racemic crude amine) as off-white solid (5 gm; Yield=71%).

Example-12: Preparation of (3R,4R)-1-Benzyl-N-4-dimethylpiperidin-3-amine (1)
The crude 1-Benzyl-N,4-dimethylpiperidin-3-amine (10gm,0.045mol) was resolved by using L-dipara toulyl tartaric acid (17.5gm, 0.045mol) in 1:1 mixture of methanol and water (100 L). The reaction mixture was stirred for an hour at 40 - 45 °C, and the precipitated product was filtered off to obtain the title product as off-white solid (3.5 gm; Yield=35%).