FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"AN IMPROVED PROCESS FOR THE PREPARATION OF (R)-3-BOC AMINO PIPERIDINE, INTERMEDIATE FOR LINAGLIPTIN"
We, CADILA HEALTHCARE LIMITED, an Indian company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Roads, Ahmedabad - 380 015, Gujarat, India,
The following specification particularly describes the invention and the manner in which it is to be performed:

AN IMPROVED PROCESS FOR THE PREPARATION OF (R)-3-BOC AMINO PIPERIDINE, INTERMEDIATE FOR LINAGLIPTIN
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of (R)-3-boc amino piperidine, an intermediate for linagliptin. In particular, the present invention relates to an improved process for the preparation of alkyl piperidine-3-carboxylate and stereoisomers thereof. More particularly, the present invention relates to the use of (R)-3-boc amino piperidine for the preparation of linagliptin.
BACKGROUND OF THE INVENTION
The optically active (R)-(3)-boc amino piperidine of Formula (I) and optically active 3-aminopiperidine are useful as an intermediats for the preparation of a remedy for diabetes mellitus as referred in international (PCT) publication Nos. WO 2005/085246 and WO 2006/112331. The present invention for the preparation of (R)-(3)-boc amino piperidine of Formula (I), an important intermediate for the preparation of various active pharmaceutical ingredients, for example linagliptin can be industrially applied as a method of producing such an intermediate.
U.S. Patent No. 5,051,509 discloses the process for the preparation of (S)-3-aminopiperidine and (R)-3-aminopiperidine starting from L-ornithine hydrochloride and D-ornithine hydrochloride, respectively.
Tetrahedron Letters Vol 42, (2001) Pg, 5645-5649 discloses the process for the preparation of N-benzyl-3-aminopiperidine (racemic) from nipecotate.
International (PCT) Publication No. WO 2007/112368 Al discloses a method for making (R)-3-aminopiperidine dihydrochloride comprising: forming a reaction mixture comprising (R)-3-aminopiperidin-2-one hydrochloride and between 1,0 and 2.5 equivalents of lithium aluminum hydride (relative to (R)-3-aminopiperidin-2-one hydrochloride) in a solvent comprising tetrahydrofuran; maintaining the reaction mixture at a temperature between 45°C and 70°C for a time sufficient to form (R)-3-aminopiperidine; and reacting the (R)-3-aminopiperidine with hydrochloric acid under conditions sufficient to form (R)-3-aminopiperidine dihydrochloride with at least 95%

enantiomeric purity.
International (PCT) Publication No. WO 2007/075630 Al discloses a method for producing 3-aminopiperidine diastereomer by providing a composition containing (R)-3-aminopiperidine and (S)-3-aminopiperidine, combining the composition with a resolving agent in a solvent effective to dissolve racemic 3-aminopiperidine and the resolving agent, and to crystallize the crystalline diasteromeric salt, which is enriched in either the (R)-3-aminopiperidine diastereomer and the (S)-3-aminopiperidine diastereomer.
U.S. Patent No. US 7,820,815 B2 discloses the process for the preparation of (R)-3-(phthalimido)piperidine starting from 3-aminopyridine by hydrogenation. The racemic 3-aminopiperidine was converted to phthalimido derivative by means of phthalic anhydride. The (R) enantiomer was precipitated selectively from racemic crude phthalimide (IV) by means of D-tartaric acid. The (R)-3-(phthalimido)piperidine D-tartrate was condensed with l-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-l-yl)-8-bromoxanthine to obtain phthalimido protected linagliptin and thereby deprotection to obtain Iinagliptin.
U.S. Patent Application Publication No. 2010/0331546 Al discloses a method for optical resolution of an alkylpiperidin-3-yl carbamate, the method including binding an RS mixture of an alkylpiperidin-3-yl carbamate into contact with an optically active tartaric acid in the presence of a solvent.
U.S. Patent Application Publication No. 2011/0021780 Al discloses a manufacturing method for a piperidine-3-ylcarbamate compound in which a pyridine-3-ylcarbamate compound and hydrogen are brought into contact in the presence of a palladium catalyst.
International (PCT) Publication No. WO 2011/160037 A2 discloses process for the preparation of a single enantiomer of 3-aminopiperidine dihydrochloride.
CN 101209990 B discloses a process for the resolution of 3-piperidinecarboxylic acid esters through diastereomeric salts with D- or L-tartaric acids. The racemic methyl 3-piperidinecarboxylate was reacted with L-tartaric acid in methanol to give (S)-methyl 3-piperidinecarboxylate L-tartrate salt. The (S)-methyl 3-piperidinecarboxylate was obtained by adding potassium carbonate solution into

the diastereomeric salt.
All the prior arts listed herein above and which the inventors are aware of discloses the process for the preparation of (R)-3-boc amino piperidine by reduction of pyridine compound followed by resolution or the corresponding racemic piperidine compound or starting from D-ornithine hydrochloride. In the view of the above citations, it is therefore, desirable to have an improved process for the preparation of (R)-3-boc amino piperidine which is an useful alternative and industrially scale. Further, the improved process provides novel intermediates for the preparation of (R)-3-boc amino piperidine and use thereof for the preparation of linagliptin.
SUMMARY OF THE INVENTION
In one general aspect, there is provided a process for the preparation of (R)-methyl l-benzylpiperidine-3-carboxylate of Formula (V),

the process comprising providing methyl piperidine-3-carboxylate of Formula (VII), optically resolving compound (VII) with optically active mandelic acid to obtain diastereomer salt with (R)-mandelic acid of Formula (VI), and reacting the diastereomer salt of Formula (VI) with benzyl halide in presence of base and phase transfer catalyst to obtain (R)-methyl l-benzylpiperidine-3-carboxylate of Formula

In another general aspect, there is provided a diastereomer salt of (R)-methyl piperidine-3-carboxylate and (R)-mandelic acid of Formula (IV).

In another general aspect, there is provided (R)-methyl l-benzylpiperidine-3-carboxylate of Formula (V).

In another general aspect, there is provided a process for the preparation of methyl piperidine-3-carboxylate of Formula (VII)

the process comprising reacting piperidine 3-carboxylic acid with thionyl chloride in suitable solvent to obtain methyl piperidine-3-carboxylate hydrochloride of Formula (VIII) and reacting the methyl piperidine-3-carboxylate hydrochloride of Formula (VIII) with a base in suitable organic solvent to obtain methyl piperidine-3-carboxylate of Formula (VII).
In another general aspect, there is provided an improved process for the preparation of (R)-3-boc amino piperidine (I),

the process comprising
(a) reacting (R)-methyl l-benzylpiperidine-3-arboxylate of Formula (V),

with hydrazine hydrate in suitable organic solvent to obtain (R)-l-benzylpiperidine-3-carbohydrazide of Formula (IV),

(b) treating compound of Formula (IV) with sodium nitrate in presence of acid to obtain (R)-l-benzylpiperidin-3-amine of Formula (III),

(c) treating compound of Formula (III) with boc anhydride in presence of base to obtain (R)-tert-butyl l-benzylpiperidin-3-ylcarbamate (II);


(d) debenzylating the compound of Formula (II) with Pd/C in presence of catalyst in suitable organic solvent to obtain (R)-3-boc amino piperidine (I); and
(e) isolating (R)-3-boc amino piperidine (I).
In another general aspect, there is provided (R)-l-benzyIpiperidine-3-carbohydrazide of Formula (IV).

In another general aspect, there is provided use of (R)-3-boc amino piperidine (I) prepared by the process of the present invention for the preparation of linagliptin.
DETAILED DESCRIPTION OF THE INVENTION
The above and other objects of the present invention are achieved by the process of the present invention, which leads to preparation of (R)-boc amino piperidine (I) and thereby its use for the preparation of linagliptin.
Optionally, the solution, prior to any solids formation, can be filtered to remove any undissolved solids, solid impurities and the like prior to removal of the solvent. Any filtration system and filtration techniques known in the art can be used.
"Suitable solvent" means a single or a combination of two or more solvents.
As used here in the term "obtaining" or "isolating" may include filtration, filtration under vacuum, centrifugation, and decantation to isolate product. The product obtained may be further or additionally dried to achieve the desired

moisture values. For example, the product may be dried in a hot air oven, tray drier, dried under vacuum and/or in a Fluid Bed Drier.
In one general aspect, there is provided a process for the preparation of (R)-methyl l-benzylpiperidine-3-carboxylate of Formula (V),

the process comprising providing methyl piperidine-3-carboxylate of Formula (VII), optically resolving compound (VII) with optically active mandelic acid to obtain diastereomer salt with (R)-mandelic acid of Formula (VI), and reacting the diastereomer salt of Formula (VI) with benzyl halide in presence of base and phase transfer catalyst to obtain (R)-methyl l-benzylpiperidine-3-carboxyIate of Formula

In general resolution of methyl piperidine-3-carboxylate of Formula (VII) with (R)-(-)-mandelic acid may be performed in one or more of suitable organic solvent. The suitable organic solvent comprises of methanol, ethanol, isopropanol, 1-butanol, tert-butanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate, acetonirrile, tetrahydrofuran, 1,4-dioxane and the like. In particular, isopropanol may be used.
The embodiments of the process include treating methyl piperidine-3-carboxylate (VII) with (R)-(-)-mandelic acid in isopropanol at 25°C to obtain diastereomer salt of Formula (VI).

In general, the diastereomer salt of Formula (VI) may be further reacted with benzyl halide. The suitable benzyl halide may be benzyl chloride or benzyl bromide in presence of base and phase transfer catalyst in suitable organic solvent.
The base comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like. In particular, sodium carbonate may be used. The phase transfer catalyst comprises of tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium iodide (TBAI), benzyl triethyl ammonium chloride (TEBAC), polyethylene Glycol (PEG-200,400,600,800,1000), crown ethers like 12-crown-4,15-crown-5, 18-crown-6, dibenzo-18-crown-6, diaza-18-crown-6 and the like. In particular, the phase transfer catalyst may be tetrabutyl ammonium bromide (TBAB),
The reaction may be carried out in presence of suitable organic solvent. The suitable organic solvent comprises one or more of toluene, xylene, ethylbenzene, ethyl acetate, isopropyl acetate, butyl acetate, methylene dichloride, ethylene dichloride, chlorobenzene, diisopropyl ether, methyl tert-butyl ether, diethyl ether or mixture thereof with water. In particular, mixture of methylene dichloride and water may be used.
The compound of Formula (V) may be obtained by partitioning the organic and aqueous phases followed by separation of organic phase and removal of organic solvent. The organic solvent may be removed by distillation under vacuum.
The compound of Formula (V) may further be purified to improve the purity. The purification may be performed by treating residue obtained after removal of solvent with suitable acid in a solvent followed by basifying with suitable base in suitable solvent. The pure compound of Formula (V) may be obtained by removal of solvent.
The acid comprises hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, triflouro acetic acid, formic acid, oxalic acid and the like. In particular hydrochloric acid may be used. The suitable base comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like. In particular, sodium

hydroxide may be used.
In general, the suitable solvent for purification comprises one or more of toluene, xylene, ethylbenzene, ethyl acetate, isopropyl acetate, butyl acetate, methylene dichloride, ethylene dichloride, chlorobenzene, diisopropyl ether, methyl tert-butyl ether, diethyl ether. In particular, toluene or methylene dichloride may be used.
In another general aspect, there is provided a diastereomer salt of (R)-methyl piperidine-3-carboxylate and (R)-mandelic acid of Formula (IV).

In another general aspect, there is provided (R)-methyl l-benzylpiperidine-3-carboxylate of Formula (V).

In another general aspect, there is provided a process for the preparation of methyl piperidine-3-carboxylate of Formula (VII)

the process comprising reacting piperidine 3-carboxylic acid with thionyl chloride in suitable solvent to obtain methyl piperidine-3-carboxylate hydrochloride of Formula (VIII) and reacting the methyl piperidine-3-carboxylate hydrochloride of Formula

(VIII) with a base in suitable organic solvent to obtain methyl piperidine-3-carboxylate of Formula (VII).
In general, the reaction of piperidine 3-carboxylic acid with thionyl chloride may be performed in suitable solvent. The suitable solvent comprises one or more of methanol/ ethanol, isopropanol, 1-butanol, tert-butanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane and the like. In particular, methanol may be used.
The base comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like. In particular, sodium hydroxide may be used. The suitable solvent for reacting methyl piperidine-3-carboxylate hydrochloride of Formula (VIII) with sodium hydroxide comprises one or more of water, methanol, ethanol, isopropanol, 1-butanol, tert-butanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, tetrahydrofuran. In particular water may be used.
In another general aspect, there is provided an improved process for the preparation of (R)-3-boc amino piperidine (I),

the process comprising
(a) reacting (R)-methyl l-benzylpiperidine-3-carboxylate of Formula (V),

with hydrazine hydrate in suitable organic solvent to obtain (R)-l-benzylpiperidine-3-carbohydrazide of Formula (IV),

(b) treating compound of Formula (IV) with sodium nitrate in presence of acid to obtain (R)-l-benzylpiperidin-3-amine of Formula (III),

(c) treating compound of Formula (III) with boc anhydride in presence of base to obtain (R)-tert-butyl l-benzylpiperidin-3-ylcarbamate (II);

(d) debenzylating the compound of Formula (II) with Pd/C in presence of catalyst in suitable organic solvent to obtain (R)-3-boc amino piperidine (I); and
(e) isolating (R)-3-boc amino piperidine (I).
In general, the suitable solvent for reacting (R)-methyl l-benzylpiperidine-3-carboxylate of Formula (V) with hydrazine hydrate comprises one or more of water, methanol, ethanol, isopropanol, 1-butanol, tert-butanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, tetrahydrofuran. In particular methanol may be used.
The acid comprises one or more of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, triflouro acetic acid, formic acid, oxalic acid and the like. In particular triflouro acetic acid may be used.

The base comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like. In particular, sodium carbonate may be used.
The catalyst for debenzylation reaction comprises of ammonium formate. The suitable solvent comprises one or more of water, methanol, ethanol, isopropanol, 1-butanol, tert-butanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, tetrahydrofuran. In particular methanol may be used.
The embodiments of the process include debenzylating (R)-tert-butyl 1-benzylpiperidin-3-ylcarbamate with Pd/C in presence of ammonium formate in methanol solvent. The (R)-boc amino piperidine of Formula (I) may be isolated distilling methanol after completion of the reaction followed by treating the residue with methylene dichloride and then by cyclohexane. The isolated (R)-boc amino piperidine compound of Formula (I) was having melting range 115-120°C and specific optical rotation (SOR) +3.31 (C = 0.5 in DMF) with chiral purity of atleast 98%.
In another general aspect, there is provided (R)-l-benzylpiperidine-3-carbohydrazide of Formula (IV).

In another general aspect, there is provided use of (R)-3-boc amino piperidine (I) prepared by the process of the present invention for the preparation of linagliptin.
In another general aspect, (R)-3-boc amino piperidine (I) can be prepared by the reaction scheme-1 as shown below, which is also the scope of the present invention.


Scheme-1
The present invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. Example-l:-Preparation of methyl piperidine-3-carboxylate hydrochloride (VIII)

Piperidine-3-carboxyIic acid (20 g) in methanol (160 mL) was cooled to 0-5°C and thionyl chloride (16.8 g) was added. The reaction mixture was stirred at 25°C for 30 min and heated to 40°C to 45°C for 4 hrs. After completion of reaction as monitored by TLC, the reaction mixture was distilled and treated with toluene. Toluene (20 mL) was added at 25°C and stirred for 30 min. The reaction mixture was filtered and washed with toluene. The product was dried to obtain 97% methyl piperidine-3-carboxylate hydrochloride. Example-2: - Preparation of methyl piperidine-3-carboxylate (VII)


Methyl piperidine-3-carboxylate hydrochloride (15 g) in water (15 mL) was added NaOH (3.6 g) and stirred for 1 hour at 25°C. The product was extracted with methylene dichloride (125 mL) followed by removal of methylene dichloride by distillation to obtain 86% methyl piperidine-3-carboxylate as an oil. Example-3: Preparation of Mandelate salt of (R)-methyl piperidine-3-carboxylate (VI)

Methyl piperidine-3-carboxylate (8 g) was taken in isopropanol (24 mL) and stirred for 15 minutes at 25°C. R-(-)-mandelic acid (9.2 g) was added to the reaction mixture and heated at 75°C-80°C for 1 hour. The reaction mixture was cooled and filtered. The wet-cake was washed with isopropanol and dried to obtain 47% (R)-(-)-mandelate salt of (R)-methyl piperidine-3-carboxyIate. Example-4:-Preparation of (R)-methyl l-benzylpiperidine-3-carboxylate (V)

Sodium carbonate (3.2 g) in water (17.5 mL) was stirred for 15 min and (R)-(-)-mandelate salt of (R)-methyl piperidine-3-carboxylate (7 g), TBAB (0.7 g) and methylene dichloride (35 mL) were added to it. The reaction mixture was stirred for 15 min and diluted with benzyl chloride (4 g) in methylene dichloride (7 mL). The reaction mixture was heated at 40°C to 45°C for 7 hours. After completion of the reaction as monitored by TLC, water (35 mL) and methylene dichloride (20 mL) were added. The reaction mixture was stirred for 30 min and settled. The separated organic layer was distilled under vacuum to obtain 7 g (-R)-methyl 1-benzylpiperidine-3-carboxylate as an oil.
Purification: The obtained oil was treated with 20% hydrochloric acid (21 mL) and stirred for 30 min. The product was washed with toluene (30 mL). The aqueous

phase was basified with sodium hydroxide (4.5 g) to adjust the pH 9. The product thus obtained was extracted with methylene dichloride (42 mL) followed by removal of methylene dichloride by distillation under vacuum to obtain 82% (R)-methyl 1-benzylpiperidine-3-carboxylate as an oil. Bxample-5: - Preparation of (R)-l-benzylpiperidine-3-carbohydrazide (IV)

(R)-methyl l-benzylpiperidine-3-carboxylate (5 g) in methanol (12.5 mL) was added 80% hydrazine hydrate (6.7 g) in 30 min at 25°C. The reaction mixture was heated to 80°C for 4 hours. After the complete of the reaction as monitored by TLC, the reaction mixture was distilled to remove methanol under vacuum at 45°C. Water (25 mL) was added to the residue and extracted with methylene dichloride (50 mL) to obtain 94% (R)-l-benzylpiperidine-3-carbohydrazide as viscous oil. Example-6: Preparation of (R)-l-benzylpiperidin-3-amine (III)

(R)-l-benzylpiperidine-3-carbohydrazide (4.5 g) was taken in water (23 mL) at 25°C and cooled to 0°C. Sodium nitrate (2 g) and triflouro acetic acid (6.6) were added to the reaction mixture and stirred for. 1 hour. The reaction mixture was heated to 80°C for 1 hour. After complete of the reaction as monitored by TLC, the reaction mixture was cooled and diluted with 6N sodium hydroxide (4.5 mL). The product was extracted with methylene dichloride followed by distillation to remove methylene dichloride under vacuum to obtain 85% (R)-l-benzylpiperidin-3-amine as an oil.

Example-7: Preparation of (R)-tert-butyl l-benzylpiperidin-3-ylcarbamate (II)

(R)-l-benzylpiperidin-3-amine (2.5 g) was taken in methanol (6.5 mL) and cooled to 0°C 20% sodium carbonate (7.5 mL) solution and Boc-anhydride (7.9 g) were added to the reaction mixture and stirred for 2 hours at 10°C After completion of the reaction as monitored by TLC, the reaction mixture was filtered and washed with water (15 mL) and hexane (10 mL). The product was dried at 55°C for 4 hours to obtain 81%. After TLC complies, filter the reaction mass, wash with water (15ml, 6Vol) and hexane (10ml, 4Vol) Dry the product at 50-550C for 4-5 hr (R)-tert-butyl 1-benzylpiperidin-3-ylcarbamate. Example - 8: - Preparation of (R)-3-boc amino piperidine (I)

(R)-tert-butyl l-benzylpiperidin-3-ylcarbamate (2 g) in methanol (16 mL) was added ammonium format (1.07 g) and Pd/C 10% (0.5 g). The reaction mixture was heated at 60-65°C for 1 hour. After the completion of the reaction as monitored by TLC, the reaction mixture was cooled to 25°C, filtered and washed with methanol. Methanol was distilled under vacuum at 45°C to obtain residue. The residue was treated with methylene dichloride (20 mL) followed by removal of methylene dichloride. The residue was treated with cyclohexane and stirred for 30 min and filtered. The wet-cake was washed with cyclohexane and dried at 50-55°C for 5 hours to obtain 80% yellow to off-white (R)-3-boc amino piperidine. Melting range - 115-120°C SOR = +3.31; C= 0.5 in DMF, Chiral HPLC > 98%.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

We claim:
1. An improved process for the preparation of (R)-3-boc amino piperidine (I),

the process comprising
(a) reacting (R)-methyl l-benzylpiperidine-3-carboxylate of Formula (V),

with hydrazine hydrate in suitable organic solvent to obtain (R)-l-benzylpiperidine-3-carbohydrazide of Formula (IV),

(b) treating compound of Formula (IV) with sodium nitrate in presence of acid to obtain (R)-l-benzylpiperidin-3-amine of Formula (III),

(c) treating compound of Formula (III) with boc anhydride in presence of base to obtain (R)-tert-butyl l-benzylpiperidin-3-ykarbamate (II);


(d) debenzylating the compound of Formula (II) with Pd/C in presence of catalyst in suitable organic solvent to obtain (R)-3-boc amino piperidine (I); and
(e) isolating (R)-3-boc amino piperidine (I).
2. The process as claimed in claim 1 (a), wherein the suitable solvent comprises
one or more of water, methanol, ethanol, isopropanol, 1-butanol, tert-butanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, tetrahydrofuran.
3. The process as claimed in claim 1 (b), wherein the acid comprises one or more
of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, triflouro acetic acid, formic acid, oxalic acid.
4. The process as claimed in claim 1 (c), wherein the base comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate.
5. The process as claimed in claim 1 (d), wherein the suitable solvent comprises water, methanol, ethanol, isopropanol, 1-butanol, tert-butanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, tetrahydrofuran.
6. The process as claimed in claim 1 (e), wherein (R)-3-boc amino piperidine (I) is isolated by treating residue obtained by removal of solvent with methylene dichloride and then by cyclohexane.

7. A process for the preparation of (R)-methyl l-benzylpiperidine-3-carboxylate of Formula (V),

the process comprising providing methyl piperidine-3-carboxylate of Formula (VII), optically resolving compound (VII) with optically active mandelic acid to obtain diastereomer salt with (R)-mandelic acid of Formula (VI), and reacting the diastereomer salt of Formula (VI) with benzyl halide in presence of base and phase transfer catalyst to obtain (K)-methyl l-benzyIpiperidine-3-carboxylate of Formula (V).

8. The process as claimed in claim 7, wherein the resolution is performed in one or more of suitable organic solvent comprises methanol, ethanol, isopropanol, 1-butanol, tert-butanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane.
9. The process as claimed in claim 7, wherein the base comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate.
10. The process as claimed in claim 7, wherein the phase transfer catalyst comprises of tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium

iodide (TBAI), benzyl triethyl ammonium chloride (TEBAC), polyethylene Glycol (PEG-200, 400, 600, 800, 1000), crown ethers like 12-crown-4, 15-crown-5, 18-crown-6, dibenzo-18-crown-6, diaza-18-crown-6.
11. A diastereomer salt of (R)-methyl piperidine-3-carboxyIate and (R)-mandelic acid of Formula (IV).

12. (R)-methyl l-benzylpiperidine-3-carboxyIate of Formula (V).

13. A process for the preparation of methyl piperidine-3-carboxylate of Formula (VII)

the process comprising reacting piperidine 3-carboxylic acid with thionyl chloride in suitable solvent to obtain methyl piperidine-3-carboxylate hydrochloride of Formula (VIII) and reacting the methyl piperidine-3-carboxylate hydrochloride of Formula (VIII) with a base in suitable organic solvent to obtain methyl piperidine-3-carboxylate of Formula (VII).

14. The process as claimed in claim 13, wherein suitable solvent comprises one or more of methanol, ethanol, isopropanol, 1-butanol, tert-butanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane.
15. The process as claimed in claim 13, wherein the base comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate.
16. (R)-l-benzylpiperidine-3-arbohydrazide of Formula (IV).

17. The process according to claim 1, wherein (R)-3-boc amino piperidine (I) is used for the preparation of linagliptin.