Field of the Invention:

The present invention provides novel process for the preparation of intermediate compounds, which are useful for the preparation of 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione compound represented by the following structural formula-1.

Formula-1 The present invention also provides acid-addition salts of 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione compound of formula-1 in crystalline form.

Background of the Invention:

8-[(3R)-3-Amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione is a dipeptidyl peptidase-IV inhibitor commonly known as Linagliptin developed by Boehringer Ingelheim for the treatment of type-II diabetes. It is approved by USFDA on 2nd May 2011 and is currently marketed under the brand name Tradjenta™ in US and Trajenta in Europe.

Xanthine derivatives which are having the inhibitory effect on the activity of the enzyme dipeptidyl peptidase-IV and process for their preparation has been disclosed in US7407955B2.

Brief Description of the Invention:

The first aspect of the present invention is to provide a novel process for the preparation of (R)-tert-butyl piperidin-3-yl-carbamate compound of formula-8, comprising;

a) Condensing the tert-butyl 3-oxopiperidine-l-carboxylate compound of formula-2 with amine compound of general formula-3 in presence or absence of a suitable acid in a suitable solvent to provide imine compound of general formula-4,

b) reducing the imine compound of general formula-4 with a suitable reducing agent in a suitable solvent to provide compound of general formula-5,

c) treating the compound of general formula-5 with a suitable deprotecting agent in a suitable solvent to provide (R)-tert-butyl 3-aminopiperidine-l-carboxylate compound of formula-6,

d) deprotecting the compound of formula-6 by treating it with a suitable deprotecting agent in a suitable solvent to provide (R)-piperidin-3-amine compound of formula-7,

e) treating the compound of formula-7 with di-tert-butyl dicarbonate in presence of a suitable base in a suitable solvent to provide (R)-tert-butyl piperidin-3-yl-carbamate compound of formula-8.

The second aspect of the present invention is to provide a process for the preparation of imine compound of general formula-4, comprising of condensing the tert-butyl 3-oxopiperidine-1-carboxylate compound of formula-2 with amine compound of general formula-3 in presence or absence of a suitable acid in a suitable solvent to provide imine compound of general formula-4.

The third aspect of the present invention is to provide a process for the preparation of compound of general formula-5, comprising of reducing the imine compound of general formula-4 with a suitable reducing agent in a suitable solvent to provide compound of general formula-5.

The fourth aspect of the present invention is to provide a novel process for the preparation of (R)-tert-butyl 3-aminopiperidine-l-carboxylate compound of formula-6, comprising of deprotecting the compound of general formula-5 by treating it with a suitable deprotecting agent in a suitable solvent to provide (R)-tert-butyl 3-aminopiperidine-l-carboxylate compound of formula-6.

The fifth aspect of the present invention is to provide acetate salt of 8-[(3R)-3-amino-l-piperidinyl] -7-(2-butyn-1 -yl)-3,7-dihydro-3 -methyl-1 - [(4-methyl-2-quinazolinyl)methyl] -1H-purine-2,6-dione compound of formula-1 in crystalline form.

The sixth aspect of the present invention is to provide oxalate salt of 8-[(3R)-3-amino-l-piperidinyl] -7-(2-butyn-1 -yl)-3,7-dihydro-3 -methyl-1 - [(4-methyl-2-quinazolinyl)methyl] -1H-purine-2,6-dione compound of formula-1 in crystalline form.

The seventh aspect of the present invention is to provide phosphate salt of 8-[(3R)-3-amino-1 -piperidinyl]-7-(2-butyn-1 -yl)-3,7-dihydro-3 -methyl-1 -[(4-methyl-2-quinazolinyl) methyl]-lH-purine-2,6-dione compound of formula-1 in crystalline form.

The eighth aspect of the present invention is to provide a novel process for the preparation of 8-[(3R)-3-amino-1 -piperidinyl]-7-(2-butyn-l -yl)-3,7-dihydro-3-methyl-1 -[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione compound of formula-1.

The ninth aspect of the present invention is to provide novel intermediate compounds, which are useful in the synthesis of (R)-tert-butyl piperidin-3-ylcarbamate compound of formula-8.

The tenth aspect of the present invention is to provide a process for the preparation of (R)-piperidin-3-amine compound of formula-7.

The eleventh aspect of the present invention is to provide another process for the preparation of 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione compound of formula-1, comprising of;

a) Condensing the 8-bromo-7-(but-2-ynyl)-3-methyl-l-((4-methylquinazolin-2-yl)methyl)-lH-purine-2,6-(3H,7H)-dione compound of formula-14 with compound of general formula-19 in presence of a suitable base in a suitable solvent to provide compound of general formula-20,

b) deprotecting the compound of general formula-20 by treating it with a suitable deprotecting agent in a suitable solvent to provide 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yi)-3,7-dihydro-3-methyl-1 -[(4-methyl-2-quinazolinyl)methyl]-1 H-purine-2,6-dione compound of formula-1.

Brief Description of the Drawings:

Figure-1: Illustrates the PXRD pattern of crystalline form-M of 8-[(3R)-3-amino-l- piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH- purine-2,6-dione acetate salt.

Figure-2: Illustrates the PXRD pattern of crystalline form-S of 8-[(3R)-3-amino-l-piperidinyl]- 7-(2-butyn-1 -yl)-3,7-dihydro-3-methyl-1 -[(4-methyl-2-quinazolinyl)methyl]-l H-purine-2,6- dione oxalate salt.

Figure-3: Illustrates the PXRD pattern of crystalline form-N of 8-[(3R)-3-amino-l-piperidinyl]- 7-(2-butyn-1 -yl)-3,7-dihydro-3-methyl-1 -[(4-methyl-2-quinazolinyl)methyl]-1 H-purine-2,6- dione phosphate salt.

Figure-4: Illustrates the PXRD pattern of crystalline 8-[(3R)-3-amino-l-piperidinyl]-7-(2- butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione obtained according to the process described in example-11.

Figure-5: Illustrates the PXRD pattern of crystalline 8-[(3R)-3-amino-l-piperidinyl]-7-(2- butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione obtained according to the process described in example-12.

Detailed Description of the Invention:

The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethylether, diethylether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulphoxide, l-methyl-2-pyrrolidone, acetonitrile and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform and the like; "ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, t-butanol and the like; "polar solvents" such as water; acetic acid or mixtures thereof.

As used herein the present invention the term "suitable base" refers to "alkali metal carbonates" such as sodium carbonate, potassium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium tertbutoxide and the like; and organic bases like diisopropyl amine, diisopropylethylamine, diisobutylamine, triethyl amine, pyridine, 4-dimethylaminopyridine or mixtures thereof.

The first aspect of the present invention provides a novel process for the preparation of (R)-tert-butyl piperidin-3-yl-carbamate compound of formula-8, comprising of;

a) Condensing the tert-butyl 3 -oxopiperidine-1 -carboxylate compound of formula-2 Formula-2 with amine compound of general formula-3 R^NH2 Formula-3 wherein, the group 'R' represents -CH3, -CH2OH. in presence or absence of a suitable acid in a suitable solvent to provide imine compound of general formula-4,

RAVNFomula-4 wherein, the group 'R' represents -CH3, -CH2OH.

b) reducing the compound of general formula-4 with a suitable reducing agent in a suitable solvent to provide compound of general formula-5,

Formula-5 wherein, the group 'R' represents -CH3, -CH2OH.

c) treating the compound of general formula-5 with a suitable deprotecting agent in a suitable solvent to provide (R)-tert-butyl 3-aminopiperidine-l-carboxylate compound of formula-6,

Formula-6

d) deprotecting the compound of formula-6 by treating it with a suitable deprotecting agent in a suitable solvent to provide (R)-piperidin-3 -amine compound of formula-7,

e) treating the compound of formula-7 with di-tert-butyl dicarbonate in presence of a suitable base in a suitable solvent to provide (R)-tert-butyl piperidin-3-ylcarbamate compound of formula-8.

Wherein, in step-a) the suitable acid is selected from p-toluene sulfonic acid, methane sulfonic acid and the like; the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, ether solvent, polar-aprotic solvents, polar solvents or mixtures thereof;

In step-b) the suitable reducing agent is selected from metal hydrides such as sodium borohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminium hydride, lithium triethyl and tri-sec-butyl borohydride (L-selectride), tributyltin hydride; borane-DMS, diborane, diisobutyl aluminium hydride (DIBAL), trichloro silane, triethyl silane, polymethylhydrosiloxane (PMHS), Zn/NaOH, IVPt and the like; the suitable solvent is selected from chloro solvents, alcohol solvents, hydrocarbon solvents, ester solvents, ether solvents, polar-aprotic solvents, polar-solvents or mixtures thereof;

In step-c) the suitable deprotecting agent is selected from Pd/C, Raney Ni, ethyl chloroformate, palladium acetate, platinum oxide and the like; the suitable solvent is selected from alcohol solvents, ether solvents, ester solvents, chloro solvents, hydrocarbon solvents, acetic acid or mixtures thereof;

In step-d) the suitable deprotecting agent is selected from trifluoroacetic acid, hydrochloric acid, methane sulfonic acid, p-toluene sulfonic acid, acetyl chloride, bromotrimethyl silane, iodotrimethyl silane, aq.phosphoric acid, sulfuric acid and the like; the suitable solvent is selected from chloro solvents, ester solvents, ether solvents, alcohol solvents, hydrocarbon solvents or mixtures thereof;

In step-e) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates and organic bases; the suitable solvent is selected from alcohol solvents, ether solvents, chloro solvents, polar-aprotic solvents, polar solvents or mixtures thereof.

The second aspect of the present invention provides a process for the preparation of imine compound of general formula-4, comprising of condensing the tert-butyl 3-oxopiperidine-1-carboxylate compound of formula-2 with amine compound of general formula-3 in presence or absence of a suitable acid in a suitable solvent to provide amine compound of general formula-4.

Wherein the suitable acid and the suitable solvent are same as defined in step-a) of the first aspect of the present invention.

The third aspect of the present invention provides a process for the preparation of compound of general formula-5, comprising of reducing the imine compound of general formula-4 with a suitable reducing agent in a suitable solvent to provide compound of general formula-5.

Wherein, the suitable reducing agent and the suitable solvent are same as defined in step-b) of the first aspect of the present invention.

The fourth aspect of the present invention provides a novel process for the preparation of (R)-tert-butyl 3-aminopiperidine-l-carboxylate compound of formula-6, comprising of deprotecting the compound of general formula-5 by treating it with a suitable deprotecting agent in a suitable solvent to provide (R)-tert-butyl 3-aminopiperidine-l-carboxylate compound of formula-6.

Wherein, the suitable deprotecting agent and the suitable solvent are same as defined in step-c) of the first aspect of the present invention.

The fifth aspect of the present invention provides acetate salt of 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione compound of formula-1 in crystalline form herein designated as crystalline form-M, which is characterized by its PXRD pattern having peaks at about 4.1, 8.3, 9.6, 11.4, 11.6, 12.3, 12.8, 14.9, 15.9, 16.6, 17.2, 18.5, 19.9, 22.1, 23.3, 23.8, 24.8 and 31.8 ± 0.2 degrees of 20 values. The crystalline form-M is further characterized by its PXRD pattern as illustrated in figure-1.

The sixth aspect of the present invention provides oxalate salt of 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione compound of formula-1 in crystalline form herein designated as crystalline form-S, which is characterized by its PXRD pattern having peaks at about 3.1, 5.4, 6.1, 8.1, 9.1, 11.0,15.3 and 19.2 ± 0.2 degrees of 20 values. The crystalline form-S is further characterized by its PXRD pattern as illustrated in figure-2.

The seventh aspect of the present invention provides phosphate salt of 8-[(3R)-3-amino-1 -piperidinyl]-7-(2-butyn-1 -yl)-3,7-dihydro-3-methyl-1 -[(4-methyl-2-quinazolinyl) methyl]-1H-purine-2,6-dione compound of formula-1 in crystalline form herein designated as crystalline form-N, which is characterized by its PXRD pattern having peaks at about 3.4, 4.9, 7.8, 9.9, 12.6, 14.4, 17.5, 17.9, 22.4, 24.6, 25.0, 27.5, 29.7 and 32.6 ± 0.2 degrees of 29 values. The crystalline form-N is further characterized by its PXRD pattern as illustrated in figure-3.

The eighth aspect of the present invention provides a novel process for the preparation of 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione compound of formula-1, comprising of;

a) Treating the 1 -(2-aminophenyl)ethanone compound of formula-9 o Formula-9 with hydroxylamine hydrochloride in presence of a suitable base in a suitable solvent to provide (E)-l-(2-aminophenyl)ethanone oxime compound of formula-10,

Formula-10

b) condensing the compound of formula-10 with 2-chloroacetyl chloride in presence of a suitable acid in a suitable solvent to provide 2-(chloromethyl)-4-methylquinazoline 3-oxide compound of formula-11,

Formula-11

c) deoxygenation of compound of formula-11 by treating it with a suitable deoxygenating agent optionally in presence of a suitable base in a suitable solvent to provide 2- (chloromethyl)-4-methylquinazoline compound of formula-12,

Formula-12

d) condensing the compound of formula-12 with 8-bromo-7-(but-2-ynyl)-3-methyl-lH-purine- 2,6-(3H,7H)-dione compound of formula-13

I Formula-13 in presence of a suitable base in a suitable solvent to provide 8-bromo-7-(but-2-ynyl)-3-methyl-1 -((4-methylquinazolin-2-yl)methyl)-1 H-purine-2,6-(3H,7H)-dione compound of formula-14,

Formula-14

e) condensing the compound of formula-14 with (R)-tert-butyl piperidin-3-ylcarbamate compound of formula-8 obtained by the process disclosed in the first aspect of the present invention in presence of a suitable base in a suitable solvent to provide (R)-tert-butyl l-(7- (but-2-ynyl)-3 -methyl-1 -((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro- lH-purin-8-yl) piperidin-3-ylcarbamate compound of formula-15,
O Formula-15

f) deprotecting the compound of formula-15 by treating it with a suitable deprotecting agent in a suitable solvent to provide 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3- methyl-1 -[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione compound of formula-1.

Wherein, in step-a) the suitable base is selected from hydroxides, alkoxides, carbonates and bicarbonates of alkali metals and organic bases; the suitable solvent is selected from alcohol solvents, polar-aprotic solvents, chloro solvents, hydrocarbon solvents, ester solvents, ether solvents, ketone solvents, polar solvents or mixtures thereof;

In step-b) the suitable acid is acetic acid and the suitable solvent is selected from alcohol solvents, polar-aprotic solvents, chloro solvents, hydrocarbon solvents, ester solvents, ether solvents, ketone solvents, polar solvents or mixtures thereof;

In step-c) the suitable deoxygenating agent is selected from low-valent titanium, phosphorous and sulfur compounds such as phosphorous trichloride, phosphorous oxychloride; Pd/C, palladium acetate, Raney Ni, tributyltin hydride, trifiuoroacetic anhydride, Z11/NH4CI, aluminium iodide and the like; the suitable base wherever necessary is selected from hydroxides, alkoxides and carbonates of alkali metals; and the suitable solvent is selected from chloro solvents, polar-aprotic solvents, alcohol solvents, ether solvents, ester solvents, hydrocarbon solvents, polar solvents or mixtures thereof;

In step-d) the suitable base is selected from hydroxides, carbonates and bicarbonates of alkali metals and organic bases; the suitable solvent is selected from polar-aprotic solvents, chloro solvents, alcohol solvents, ether solvents, ester solvents, hydrocarbon solvents or mixtures thereof;

In step-e) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates and organic bases; the suitable solvent wherever necessary is selected from alcohol solvents, ether solvents, polar-aprotic solvents or mixtures thereof;

In step-f) the suitable deprotecting agent and the suitable solvents are same as defined for step-d) of the first aspect of the present invention.

The 8-bromo-7-(but-2-ynyl)-3 -methyl- lH-purine-2,6(3H,7H)-dione compound of formula-13 utilized in step-d) of the eighth aspect of the present invention can be synthesized by any of the processes known in the art, for example it can be synthesized by condensing the 8-bromo-3 -methyl- lH-purine-2,6(3H,7H)-dione compound of formula-16

Formula-16 with l-bromo-but-2-yne in presence of a suitable base such as diisopropylethyl amine in a suitable solvent.

Compound of formula-16 used in the above process can be synthesized by any of the processes known in the art such as US7879864B2.

The ninth aspect of the present invention provides novel intermediate compounds represented by the following structural formulae, which are useful in the synthesis of (R)-tert-butyl piperidin-3-ylcarbamate compound of formula-8.

wherein, the group 'R' represents -CH3, -CH2OH.

The tenth aspect of the present invention provides a process for the preparation of (R)-piperidin-3-amine compound of formula-7, comprising of; a) Treating the pyridin-3 -amine compound of formula-17

N Formula-17
with a suitable chiral auxiliary in a suitable solvent to provide compound of general

wherein, R" represents , , H*C and the like;

b) reducing the compound of general formula-18 with a suitable reducing agent in a suitable solvent to provide compound of general formula-19, H Formula-19 wherein, R" is same as defined above;

c) hydrolyzing the compound of general formula-19 to provide (R)-piperidin-3 –amine compound of formula-7.

Wherein, in step-a) the suitable chiral auxiliary is selected from aliphatic and aromatic chiral acids such as mandelic acid, naproxen, ibuprofen and the like; the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents, alcohol solvents, polar-aprotic solvents or mixtures thereof;

In step-b) the suitable reducing agent is selected from Raney Ni, Pd/C, Pt/C, Rh/C and the like; the suitable solvent is selected from alcohol solvents, chloro solvents, hydrocarbon solvents, ester solvents, ether solvents, polar-aprotic solvents, polar solvents or mixtures thereof;

The eleventh aspect of the present invention provides another process for the preparation of 8-[(3R)-3-amino-l -piperidinyl]-7-(2-butyn-l -yl)-3,7-dihydro-3-methyl-1 -[(4-methyl-2- quinazolinyl)methyl]-lH-purine-2,6-dione compound of formula-1, comprising of;

a) Condensing the 8-bromo-7-(but-2-ynyl)-3-methyl-l-((4-methylquinazolin-2-yl)methyl)-lH-purine-2,6-(3H,7H)-dione compound of formula-14 with compound of general formula-19 in presence of a suitable base in a suitable solvent to provide compound of general formula-20,

b) deprotecting the compound of general formula-20 by treating it with a suitable deprotecting agent in a suitable solvent to provide 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7- dihydro-3-methyl-1 -[(4-methyl-2-quinazolinyl)methyl]-1 H-purine-2,6-dione compound of formula-1.

Wherein, in step-a) the suitable base and the suitable solvent are same as defined in step-e) of the eighth aspect of the present invention;

In step-b) the suitable deprotecting agent and the suitable solvent are same as defined in step-f) of the eighth aspect of the present invention.

An embodiment of the present invention provides a process for the preparation of (R)-tert-butyl piperidin-3-yl-carbamate compound of formula-8, comprising of;

a) reducing the tert-butyl pyridin-3 -ylcarbamate compound of formula-21

Formula-21 with a suitable reducing agent in a suitable solvent to provide tert-butyl piperidin-3-yl carbamate compound of formula-22,

b) resolution of compound of formula-22 with (R)-(-)-acetoxy(phenyl)acetic acid in a suitable solvent or mixture of solvents to provide (R)-tert-butyl piperidin-3-yl-carbamate compound of formula-8.

Wherein, in step-a) the suitable reducing agent is selected from Rh, Pd, Pt, PtC>2, Raney Ni and the like; the suitable solvent is selected from alcoholic solvents, ether solvents, ester solvents, hydrocarbon solvents, polar solvents, chloro solvents, acetic acid or their mixture;

in step-b) the suitable solvent is selected from alcoholic solvents, ester solvents, ether solvents, hydrocarbon solvents, nitrile solvents, chloro solvents, polar-aprotic solvents, polar solvents or their mixtures; the amount of solvent used is in the range of 2-8 volumes, preferably 4-6 volumes with respect to tert-butyl piperidin-3-ylcarbamate compound of formula-22 and the amount of (R)-(-)-acetoxy(phenyl)acetic acid used is in the range of 0.7-2 mole ratio, preferable 0.9-1.5 mole ratio per one mole ratio of tert-butyl piperidin-3-ylcarbamate compound of formula-22.

The resolution of compound of formula-22 as mentioned in step-b) above comprises of reacting the compound of formula-22 with (R)-(-)-acetoxy(phenyl)acetic acid in a suitable solvent or mixture of solvents to provide corresponding optically active acetoxy(phenyl) acetic acid salt of (R)-tert-butyl piperidin-3-yl-carbamate, followed by neutralization of the obtained salt with a suitable inorganic or organic base in a suitable solvent to provide compound of formula-8.

Resolution of compound of formula-22 of the present invention can also be carried out using optically active di-benzoyltartaric acid (DBTTA), di-p-toluoyltartaric acid (DPTTA), di-p-anisoyltartaric Acid (DATA), 3-chloro mandelic acid, camphor sulfonic acid, bromocamphor-10-sulfonic acid, malic acid and the like.

The tert-butyl pyridin-3-ylcarbamate compound of formula-21 utilized in step-a) of the above embodiment is prepared by reacting the pyridin-3 -amine compound of fomula-17 with di-tert.butyl dicarbonate in presence of a suitable organic or inorganic base in a suitable solvent.

A preferred embodiment of the present invention provides a process for the preparation of (R)-tert-butyl piperidin-3-yl-carbamate compound of formula-8, comprising;

a) reducing the tert-butyl pyridin-3 -ylcarbamate compound of formula-21 with Rh/C in a mixture of isopropyl alcohol and acetic acid to provide tert-butyl piperidin-3-ylcarbamate compound of formula-22,

b) reacting the compound of formula-22 with (R)-(-)-acetoxy(phenyl)acetic acid in a mixture of n-butanol and ethyl acetate to provide(R)-(-)-acetoxy (phenyl)acetic acid salt of (R)-tert-butyl piperidin-3-yl-carbamate,

c) neutralizing the salt obtained in step-b) by treating it with aq. sodium hydroxide solution to provide compound of formula-8.

An embodiment of the present invention provides diastereomer salt of optically active tert-butyl piperidin-3-ylcarbamate with optically active acetoxy(phenyl)acetic acid.

A preferred embodiment of the present invention provides (R)-(-)-acetoxy(phenyl) acetic acid salt of (R)-tert-butyl piperidin-3-ylcarbamate represented by the following structural formula;

An embodiment of the present invention provides a process for the preparation of 8-[(3R)-3-amino-1 -piperidinyl]-7-(2-butyn-1 -yl)-3,7-dihydro-3-methyl-l -[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione compound of formula-1, comprising of;

a) reducing the tert-butyl pyridin-3-yl carbamate compound of formula-21 with Rh/C in a suitable solvent to provide tert-butyl piperidin-3-yl carbamate compound of formula-22,

b) resolution of compound of formula-22 with (R)-(-)-acetoxy(phenyl)acetic acid to provide (R)-tert-butyl piperidin-3-yl-carbamate compound of formula-8,

c) condensing the (R)-tert-butyl piperidin-3-ylcarbamate compound of formula-8 with 8-bromo-7-(but-2-ynyl)-3 -methyl-1 -((4-methylquinazolin-2-yl)methyl)-1 H-purine-2,6-(3H,7H)-dione compound of formula-14 in presence of a suitable base in a suitable solvent to provide (R)-tert-butyl l-(7-(but-2-ynyl)-3-methyl-l-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tefrahydro-lH-purin-8-yl)piperidin-3-ylcarbamate compound of formula-15,

d) deprotecting the compound of formula-15 by treating it with a suitable deprotecting agent in a suitable solvent to provide 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione compound of formula-1.

Wherein, in step-a) the suitable reducing agent is selected from Rh, Pd, Pt, Pt02, Raney Ni and the like; the suitable solvent is selected from alcoholic solvents, ether solvents, ester solvents, hydrocarbon solvents, polar solvents, chloro solvents, acetic acid or their mixture;

in step-b) the suitable solvent is selected from alcoholic solvents, ester solvents, ether solvents, hydrocarbon solvents, nitrile solvents, chloro solvents, polar-aprotic solvents, polar solvents or their mixtures;

In step-c) the suitable base and the suitable solvent are same as defined for step-e) of the eighth aspect of the present invention;

In step-d) the suitable deprotecting agent and the suitable solvent are same as defined for step-f) of the eighth aspect of the present invention;

US7407955B2 patent discloses Linagliptin as a solid with melting range 198-202°C. The applicant in his later patent application US2007259900A1 describes the said form as a mixture of crystalline form-A & form-B. The PXRD pattern of MSNL produced Linagliptin is similar to the PXRD pattern of mixture of crystalline form-A & form-B, which is illustrated in figure-4 and figure-5.

The PXRD analysis of the crystalline compounds of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using CuKa radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.

The 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4- methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione compound of formula-1 produced by the present invention was analyzed by HPLC under the following conditions; Apparatus: A liquid chromatographic system equipped with variable wavelength UV-detector and integrator; Column: Cosmicsil Agate, C8, 150x4.6 mm, 3.0 urn or equivalent; Flow rate: 1.0 mL/min; Wavelength: 225 nm; Column temperature: 35°C; Injection volume: 5 uL; Run time: 50 min; Diluent: acetonitrile:buffer (80:20, v/v); Elution: gradient; Buffer: Transfer 1 ml of H3PO4 and 2 gm of 1-octane sulfonic acid in 1000 ml of milli-Q-water. Mix well and filter this solution through 0.22 urn Nylon membrane filter paper; Mobile phase-A: Buffer:acetonitrile (95:5 v/v); Mobile phase-B: acetonitrile:water: Buffer (80:10:10 v/v/v).

The particle size distribution of 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione of the present invention is measured using Malvern Mastersizer 2000 instrument.

The 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4- methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione compound of formula-1 produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball mills, roller and hammer mills and jet mills. Milling or micronization may be performed before drying or after drying of the product.

The present invention is schematically represented as follows. Scheme-1:

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.

Examples:

Example-1: Preparation of 8-bromo-7-(but-2-ynyl)-3-methyl-lH-purine-2,6-(3H,7H)-dione (Formula-13)

l-bromo-but-2-yne (149.2 gm) was added to a mixture of 8-bromo-3-methyl-lH-purine-2,6(3H,7H)-dione (250 gm), N,N-dimethyl formamide (2500 ml) and N,N-diisopropylethyl amine (197.4 gm) at 30-35°C. Heated the reaction mixture to 65-70°C and stirred for 4 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 30-35°C. Water (5000 ml) was added to the reaction mixture at 30-35°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 284.0 gm.

Example-2: Preparation of 8-bromo-7-(but-2-ynyl)-3-methyl-l-((4-methylquinazolin-2-yl)methyl)-lH-purine-2,6-(3H,7H)-dione(Formula-14)

A mixture of 2-(chloromethyl)-4-methylquinazoline (77 gm), 8-bromo-7-(but-2-ynyl)-3-methyl-lH-purine-2,6-(3H,7H)-dione (100 gm), sodium carbonate (46.3 gm) and 1-methyl-2-pyrrolidone (500 ml) was heated to 125-130°C and stirred for 5-6 hrs at the same temperature. After completion of the reaction, the reaction mixture was heated to 30-35°C. Water (500 ml) and methanol (600 ml) were added to the reaction mixture at 30-35°C and stirred for 10 min at the same temperature. Slowly added aq.acetic acid (40 ml of acetic acid in 50 ml of water) to the reaction mixture at 30-35°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with aq.methanol and dried to get the title compound. Yield: 120.0 gm.

Example-3: Preparation of tert-butyl pyridin-3-ylcarbamate (Formula-21)

Pyridin-3-amme compound of formula-17 (100 gm) was added to a mixture of sodium bicarbonate (6.5 gm), isopropyl alcohol (150 ml) and water (50 ml) at 25-30°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 5-10°C and aq.sodium carbonate solution (57.5 gm of sodium carbonate in 150 ml water) followed by a solution of di-tert.butyl dicarbonate (267 gm) in isopropanol (50 ml) were slowly added to the reaction mixture. Raised the temperature of the reaction mixture to 25-30°C and stirred for 15 hrs at the same temperature. After completion of the reaction, water was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound; Yield: 178.0 gm; M.R: 116-122°C.

Example-4: Preparation of tert-butyl piperidin-3-ylcarbamate (Formula-22)

Tert-butyl pyridin-3-ylcarbamate compound of formula-21 (50 gm) and Rh/C (18.5 gm) were added to a mixture of isopropyl alcohol (200 ml) and acetic acid (50 ml) in an autoclave vessel at 25-30°C and stirred for 10 min at the same temperature. 5-6 Kg/cm2 pressure of hydrogen gas was applied to the reaction mixture at 25-3 0°C and stirred for 15 min at the same temperature. Heated the reaction mixture to 60-65°C and stirred for 30 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C. Filtered the reaction mixture through hyflow bed and washed with isopropyl alcohol. Distilled off the solvent completely from the filtrate under reduced pressure. Water was added to the obtained compound at 25-30°C and stirred for 15 min at the same temperature. Basified the reaction mixture using 10% sodium hydroxide solution at 10-15°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 36.0 gm; M.R: 101-109°C.

Example-5: Preparation of (R)-tert-butyl piperidin-3-ylcarbamate (R)-(-)-acetoxy (phenyl)acetic acid salt

Tert-butyl piperidin-3-ylcarbamate compound of formula-22 (35 gm) was added to a mixture of n-butanol (90 ml) and ethyl acetate (35 ml) at 25-30°C and stirred for 15 min at the same temperature. (R)-(-)-acetoxy (phenyl)acetic acid (35 gm) was added to the reaction mixture at 25-30°C and stirred for 45 min at the same temperature. Heated the reaction mixture to 60-65°C and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 45-50°C and stirred for 3 hrs at the same temperature. Further cooled the reaction mixture to 10-15°C and stirred for 5 hrs at the same temperature. Filtered the solid, washed with ethyl acetate and dried to get the title compound; Yield: 23.0 gm.

Example-6: Purification of (R)-tert-butyl piperidin-3-ylcarbamate (R)-(-)-acetoxy (phenyl)acetic acid salt (R)-tert-butyl piperidin-3-ylcarbamate (R)-(-)-acetoxy (phenyl)acetic acid salt (23 gm) was added to a mixture of n-butanol (35 ml) and ethyl acetate (35 ml) at 25-30°C and stirred for 10 min at the same temperature. Heated the reaction mixture to 75-80°C and stirred for 3 hrs at the same temperature. Cooled the reaction mixture to 10-15 °C and stirred for 3 hrs at the same temperature. Filtered the solid, washed with ethyl acetate and dried to get the title compound. Yield: 17.0 gm; MR: 158-160°C.

Example-7: Preparation of (R)-tert-butyl piperidin-3-ylcarbamate (Formula-8)

(R)-tert-butyl piperidin-3-ylcarbamate (R)-(-)-acetoxy (phenyl)acetic acid salt (15 gm) and water (45 ml) were charged into a clean and dry RBF at 25-30°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 10-15°C. Basified the reaction mixture with 10% sodium hydroxide solution at 10-15°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with water and dried to get the title compound;Yield: 4.6 gm.

ExampIe-8: Preparation of (R)-tert-butyl l-(7-(but-2-ynyl)-3-methyI-l-((4-methylqninazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl) piperidin-3-ylcarbamate (Formula-15)

A mixture of 8-bromo-7-(but-2-ynyl)-3 -methyl- l-((4-methylquinazolin-2-yl)methyl)-lH-purine-2,6-(3H,7H)-dione (100 gm), (R)-tert-butyl piperidin-3-yl-carbamate (48.6 gm), potassium carbonate (45.6 gm) and N,N-dimethyl formamide (800 ml) was heated to 75-80°C and stirred for 9 hrs at the same temperature. After completion of the reaction, water (2000 ml) was slowly added to the reaction mixture at 30-35°C. Dichloromethane (1000 ml) was added to the reaction mixture and stirred for 15 min. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with methyl tert.butyl ether. Cooled the obtained residue to 30-35°C, methyl tert.butyl ether (300 ml) was added and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with methyl tert. butyl ether and dried to get the title compound. Yield: 95.0 gm.

Example-9: Preparation of (R)-tert-butyl l-(7-(but-2-ynyl)-3-methyl-l-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl) piperidin-3-ylcarbamate (Formula-15)

(R)-tert-butyl piperidin-3-yl-carbamate (49 gm) was added to a mixture of 8-bromo-7-(but-2-ynyl)-3-methyl-l-((4-methylquinazolin-2-yl)methyl)-lH-purine-2,6-(3H,7H)-dione (100 gm), potassium carbonate (46 gm) and N,N-dimethyl formamide (400 ml) at 25-30°C and stirred for 15 min at the same temperature. Heated the reaction mixture to 70-75°C and stirred for 16 hrs at the same temperature. After completion of the reaction, water and toluene were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with water followed by 10% sodium chloride solution. Dried the organic layer over sodium sulfate and distilled off the solvent completely form the organic layer under reduced pressure and co-distilled with ethyl acetate. 1000 ml of ethyl acetate was added to the obtained compound, heated the reaction mixture to reflux temperature and stirred for 45 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound; Yield: 94.0 gm; Purity by HPLC: 95.85%.

Example-10: Preparation of 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione (Formula-1)

Trifluoroacetic acid (500 ml) was slowly added to a mixture of (R)-tert-butyl l-(7-(but-2-ynyl)-3-methyl-l-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl) piperidin-3-ylcarbamate (100 gm) and dichloromethane (1500 ml) at 30-35°C and stirred for 6 hrs at the same temperature. Quenched the reaction mixture with chilled water at 0-5°C. Both the organic and aqueous layers were separated, washed the organic layer with sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with ethyl acetate. Added ethyl acetate (300 ml) to the obtained residue at 30-35°C and stirred for 30 min at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound; Yield: 62.0 gm.

Example-11: Preparation of 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione (Formula-1)

Trifluoroacetic acid (250 ml) was slowly added to a mixture of (R)-tert-butyl l-(7-(but-2-ynyl)-3 -methyl-1 -((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1 H-purin-8-yl) piperidin-3-ylcarbamate (100 gm) and toluene (500 ml) at 25-30°C and stirred for 7 hrs at the same temperature. After completion of the reaction, the reaction mixture was added to ice cooled water and stirred for 1 hr at 0-5°C. Both the organic and aqueous layers were separated and the pH of the reaction mixture was adjusted to 10 with 50% potassium carbonate solution. Toluene and methanol were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with water followed by 10% sodium chloride solution. Dried the organic layer over sodium sulfate, carbon (10 gm) was added and stirred for 45 min at 50-55°C. Filtered the reaction mixture through hyfiow bed, distilled off the solvent completely form the filtrate and co-distilled with methanol followed by ethyl acetate. 500 ml of ethyl acetate was added to the obtained compound, heated the reaction mixture to reflux temperature and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with ethyl acetate and dried to get the title compound. Yield: 60.0 gm; Melting Point: 199°-203°C; Purity by HPLC: 98.85%; The PXRD pattern of the obtained compound is shown in figure-4.

Example-12: Purification of 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyI-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione (Formula-1) Method-1: A mixture of 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione (5.0 gm) and methanol (10 ml) was heated to 65-70°C and stirred for 60 min at the same temperature. Cooled the reaction mixture to 45-50°C and methyl tert.butyl ether (15 ml) was added. Cooled the reaction mixture to 30-35°C, 25 ml of methyl tert.butyl ether was added and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with methyl tert.butyl ether and dried to get pure title compound. Yield: 3.4 gm.

Method-2: A mixture of methanol (400 ml) and 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione (100 gm) was heated to reflux temperature and stirred for 20 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. Methanol (70 ml) was added to the obtained solid, heated the reaction mixture to reflux temperature and stirred for 20 min at the same temperature. Filtered the reaction mixture through hyfiow bed and washed with methanol. Distilled off the solvent completely under reduced pressure and co-distilled with ethyl acetate. 350 ml of ethyl acetate was added to the obtained compound, heated the reaction mixture to reflux temperature and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 25-3 0°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with ethyl acetate and dried to get the pure title compound. Yield: 55.0 gm; Melting Point: 199°-203°C; Purity by HPLC: 99.85%. The PXRD of the obtained compound is shown in figure-5. Particle size distribution: D(0.1) is 3.62 urn; D(0.5) is 20.89 um; D(0.9) is 51.38 um.

Example-13: Preparation of crystalline form-M of 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dmydro-3-methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6- dione acetate salt

Acetic acid (0.67 gm) was added to a mixture of 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-1 -yl)-3,7-dihydro-3 -methyl-1 -[(4-methyl-2-quinazolinyl)methyl]-1 H-purine-2,6-dione (5.0 gm) and ethanol (40 ml) at 70-75°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with ethanol and dried to get the title compound. The PXRD of the obtained compound is shown in figure-1. Yield: 4.2 gm.

Example-14: Preparation of crystalline form-S of 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione oxalate salt

Oxalic acid (0.95 gm) was added to a mixture of 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione (5.0 gm) and ethanol (40 ml) at 70-75°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with ethanol and dried to get the title compound. The PXRD of the obtained compound is shown in figure-2; Yield: 4.1 gm.

Example-15: Preparation of crystalline form-N of 8-[(3R)-3-amino-l-piperidinyl]-7-(2-buryn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione phosphate salt

Phosphoric acid (1.0 gm) was added to a mixture of 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione (5.0 gm) and ethanol (40 ml) at 70-75°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with ethanol and dried to get the title compound. The PXRD of the obtained compound is shown in figure-3. Yield: 4.3 gm.

We Claim:

1. Crystalline form-M of 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3- methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione acetate salt, characterized by;

a) its X-Ray powder diffraction pattern having peaks at 4.1, 8.3, 9.6, 11.4, 11.6, 12.3, 12.8, 14.9,15.9,16.6,17.2,18.5,19.9, 22.1,23.3,23.8,24.8, 31.8± 0.2 degrees of 20;

b) its PXRD pattern substantially in accordance with figure-1.

2. Crystalline form-S of 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3- methyl-l-[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione oxalate salt, characterized by;

a) its X-Ray powder diffraction pattern having peaks at 3.1, 5.4, 6.1, 8.1, 9.1, 11.0, 15.3 and 19.2 ± 0.2 degrees of 29,

b) its PXRD pattern substantially in accordance with figure-2.

3. Crystalline form-N of 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3- methyl-1 -[(4-methyl-2-quinazolinyl)methyl]-lH-purine-2,6-dione phosphate salt, characterized by;

a) its X-ray powder diffraction pattern having peaks at 3.4, 4.9, 7.8, 9.9, 12.6, 14.4, 17.5, 17.9,22.4,24.6,25.0,27.5,29.7 and 32.6 ± 0.2 degrees of 20,

b) its PXRD pattern substantially in accordance with figure-3.

4. A process for the preparation of (R)-tert-butyl piperidin-3-yl-carbamate compound of formula-8,

H Formula-8
comprising of resolution of tert-butyl piperidin-3-ylcarbamate compound of formula-22

with (R)-(-)-acetoxy(phenyl)acetic acid in a suitable solvent or mixture of solvents to provide (R)-tert-butyl piperidin-3-yl-carbamate compound of formula-8.

5. A process according to claim 4, wherein the suitable solvent is selected from alcoholic solvents, ester solvents, ether solvents, hydrocarbon solvents, nitrile solvents, chloro solvents, polar-aprotic solvents, polar solvents or their mixtures;

the amount of (R)-(-)-acetoxy(phenyl)acetic acid used is in the range of 0.7-2 mole ratio, preferable 0.9-1.5 mole ratio per one mole ratio of tert-butyl piperidin-3-ylcarbamate compound of formula-22.

6. A process for the preparation of (R)-tert-butyl piperidin-3-yl-carbamate compound of formula-8, comprising of;

a) reducing the tert-butyl pyridin-3-ylcarbamate compound of formula-21

Formula-21 with a suitable reducing agent in a suitable solvent to provide tert-butyl piperidin-3-yl carbamate compound of formula-22,

b) resolution of compound of formula-22 with (R)-(-)-acetoxy(phenyl)acetic acid in a suitable solvent or mixture of solvents to provide compound of formula-8.

7. A process according to claim 5, wherein,

in step-a) the suitable reducing agent is selected from Rh, Pd, Pt, Pt02, Raney Ni; the suitable solvent is selected from alcoholic solvents, ether solvents, ester solvents, hydrocarbon solvents, polar solvents, chloro solvents, acetic acid or their mixture;

in step-b) the suitable solvent is selected from alcoholic solvents, ester solvents, ether solvents, hydrocarbon solvents, nitrile solvents, chloro solvents, polar-aprotic solvents, polar solvents or their mixtures;

8. A process for the preparation of (R)-tert-butyl piperidin-3-yl-carbamate compound of formula-8, comprising of;

a) reducing the tert-butyl pyridin-3-ylcarbamate compound of formula-21 with Rh/C in a mixture of isopropyl alcohol and acetic acid to provide tert-butyl piperidin-3-yl carbamate compound of formula-22,

b) resolution of compound of formula-22 with (R)-(-)-acetoxy(phenyl)acetic acid in a mixture of n-butanol and ethyl acetate to provide compound of formula-8.

9. A diastereomer salt of optically active tert-butyl piperidin-3-ylcarbamate with optically active acetoxy(phenyl)acetic acid.

10. A process for the preparation of 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-1 -[(4-methyl-2-quinazolinyl)methyl]-1 H-purine-2,6-dione compound of formula-1, comprising of;

a) reducing the tert-butyl pyridin-3-ylcarbamate compound of formula-21 with Rh/C in a suitable solvent to provide tert-butyl piperidin-3-yl carbamate compound of formula-22,

b) resolution of compound of formula-22 with (R)-(-)-acetoxy(phenyl)acetic acid to provide (R)-tert-butyl piperidin-3-yl-carbamate compound of formula-8,

c) condensing the (R)-tert-butyl piperidin-3-ylcarbamate compound of formula-8 with 8-bromo-7-(but-2-ynyl)-3 -methyl-1 -((4-methylquinazolin-2-yl)methyl)-1 H-purine-2,6-(3H,7H)-dione compound of formula-14

Formula-14 in presence of a suitable base in a suitable solvent to provide (R)-tert-butyl l-(7-(but-2-ynyl)-3-methyl-l-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl) piperidin-3-ylcarbamate compound of formula-15,

Formula-15
d) deprotecting the compound of formula-15 by treating it with a suitable deprotecting agent in a suitable solvent to provide compound of formula-1.