Field of the Invention:
The present invention provides an improved process for the preparation of 2-({6-[(3R)-3 -aminopiperidin-1 -yl] -3 -methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl} methyl) benzonitrile represented by the following structural formula-1 and pharmaceutically acceptable salts thereof.
Background of the Invention:
2-( {6- [(3 R)-3 -aminopiperidin-1 -yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl}methyl)benzonitrile monobenzoate, commonly known as Alogliptin benzoate is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Alogliptin benzoate (being marketed under the trade name Nesina in the US and Vipidia in Europe) is an orally administered anti-diabetic drug in the DPP-4 inhibitor class.
US7807689B2 (hereinafter referred as US'689 patent) first discloses Alogliptin, its pharmaceutically acceptable salts and processes for their preparation. The disclosed process is schematically represented as follows.

The disclosed process has several disadvantages to adopt it on commercial scale, few of which are discussed below.
The1 above disclosed process involves the usage of pyrophoric bases such as alkali metal hydrides in almost all the stages of the synthetic process.
• The said process involves the usage of methyl halides for methylation step which are known to be carcinogens and also highly expensive.
• Produces the required product in low yields and also with lesser purity.
• The disclosed process leads to the formation of lot of byproducts along with the required compound out of which major one is dimer impurity which is formed in almost 30-35%.
In view of all the above difficulties there is a significant need in the art to develop an improved process for the preparation of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile and its pharmaceutically acceptable salts which arrests/controls the formation of all the byproducts including dimer impurity in minimal/acceptable levels.
The present inventors has overcome all the above said disadvantages by developing an improved process for the preparation of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile and its pharmaceutically acceptable salts by adopting cost effective reagent for methylation such as dimethyl sulfate, mild and safer reagents for various synthetic conversions and were able to produce the final product in higher yields and better quality.
Brief description of the invention:
The first aspect of the present invention is to provide an improved process for the
preparation of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydro
pyrimidin-l(2H)-yl}methyl)benzonitrile benzoate compound of formula-la.
The second aspect of the present invention is to provide a process for the preparationof 2-((6-chloro-3 -methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)methyl)benzonitrilecompound of formula-5.
The third aspect of the present invention is to provide a process for the preparation of 2-( {6- [(3R)-3 -aminopiperidin-1 -yl] -3 -methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl}methyl)benzonitrile hydrochloride compound of formula-lb.
The fourth aspect of the present invention is to provide a process for the purification of 2-( {6- [(3R)-3 -aminopiperidin-1 -yl] -3 -methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl} methyl)benzonitrile hydrochloride compound of formula-lb.
The fifth aspect of the present invention is to provide a process for the preparation of crystalline form-A of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile benzoate compound of formula-la.
The sixth aspect of the present invention is to provide an alternative process for the preparation of crystalline form-A of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile benzoate compound of formula-la.
Brief Description of the Drawings:
Figure-l: Illustrates the X-Ray powder diffraction (XRPD) pattern of crystalline form-A of
2-( {6- [(3 R)-3 -aminopiperidin-1 -yl] -3 -methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-y 1}
methyl)benzonitrile benzoate (Formula-la).
Figure-2: Illustrates the X-Ray powder diffraction pattern (XRPD) of crystalline 2-({6-
[(3R)-3 -aminopiperidin-1 -yl] -3 -methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl} methyl)
benzonitrile hydrochloride salt (Formula-lb) obtained according to the process disclosed in
US8222411B2.
Detailed Description of the Invention:
The "suitable solvent" used in the present invention can be selected from but not limited to "hydrocarbon solvents" such as n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether (pet ether), benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, dibutyl ether, methyl tert-butyl ether, 2-methoxy ethanol, 1,2-dimethoxy ethane, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, iso-butyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, N,N dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, dimethyl ketone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, t-butanol, ethane-1,2-diol, propane-1,2-diol and the like; "polar solvents" such as water; formic acid, acetic acid, pyridine or their mixtures.
The "suitable base" used in the present invention can be selected from but not limited to inorganic bases, organic bases, organosilicon bases, organolithium bases and the like. "Inorganic bases" include but not limited to "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium 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 ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide and the like; ammonia, alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; "organic bases" like dimethylamine, diethylamine, diisopropyl amine, di-n-propylamine, diisopropylethylamine, diisobutylamine, triethylamine, triethanolamine, tributylamine, tert.butylamine, pyridine, 4-dimethylaminopyridine (DMAP), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), N-methyl morpholine (NMM), 1,4-diazabicyclo[2.2.2]octane (DABCO), 2,6-lutidine, imidazole, lithium diisopropylamide (LDA) and the like; organolithium bases such as methyl lithium, n-butyl lithium and the like; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or their mixtures.
The first aspect of the present invention provides an improved process for thepreparation of 2-( {6- [(3 R)-3-aminopiperidin-1 -yl] -3 -methyl-2,4-dipxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile benzoate compound of formula-la, comprising of; a) Reacting the 6-chloropyrimidine-2,4( 1 H,3H)-dione compound of formula-2with 2-(bromomethyl)benzonitrile compound of formula-3 in presence of a suitable base in a suitable solvent to provide 2-((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)benzonitrile compound of formula-4,
b) methylation of compound of formula-4 with a suitable methylating agent in a suitable solvent in presence of a suitable base to provide 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)benzonitrile compound of formula-5,
c) reacting the compound of formula-5 with (R)-piperidin-3-amine free base or its acid-addition salt in presence of a suitable base in a suitable solvent to provide 2-({6-[(3R)-3-aminopiperidin-1 -yl]-3 -methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl} methyl) benzonitrile compound of formula-1,

d) optionally purifying the compound of formula-1,
e) treating the compound of formula-1 obtained in step-c) or step-d) with benzoic acid in a suitable solvent to provide its benzoate salt compound of formula-la,
f) isolating the benzoate salt compound of formula-la from a suitable solvent;
with the proviso that the methylating agent used in step-b) is not methyl halide or methanol/PPh^azodicarboxylate system (Mitsunobu reaction).
Wherein, in step-a) to step-c) the suitable base is selected from organic bases, inorganic bases, organolithium bases, organosilicon bases or their mixtures;
In step-b) the suitable methylating agent is selected from dimethyl sulfate, dimethyl carbonate, trimethyloxoniumtetrafluoroborate (Me30.BF4), trimethylphosphate, methyl alkyl/aryl sulfonates such as methyl methane sulfonate (MeOMs), methyl ethanesulfonate, methyl benzenesulfonate, methyl toluene sulfonate (MeOTs), methyl trifluoromethanesulfonate (MeOTf), tetramethylammonium salts such as tetramethylammonium halides, trimethylsilyldiazomethane (TMSD) and the like;
In step-d) purification of compound of formula-1 involves various techniques that are known to a person skilled in the field of organic chemistry. Such techniques include but not limited to recrystallization from a suitable solvent, solvent-anti solvent technique, salt formation technique, slurrying in a suitable solvent. Preferably compound of formula-1 of the

present invention is purified by salt formation technique which involves the treatment of compound of formula-1 with a suitable acid in a suitable solvent followed by neutralizing the obtained acid-addition salt with a suitable base in a suitable solvent to provide pure compound of formula-1.
Wherein, the suitable acid is selected from inorganic or organic acids. The "inorganic acid" is selected from but not limited to hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid and the like. The "organic acid" is selected from but not limited to formic acid, acetic acid, propionic acid, trifluoroacetic acid, palmitic acid, stearic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, pyruvic acid, salicylic acid, phthalic acid, glycolic acid, lactic acid, malonic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfomc acid, naphthalenesulfonic acid, camphorsulfonic acid, glutamic acid, muconic acid and the like. The suitable base is selected from inorganic bases or organic bases;
In step-a) to step-f) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, ester solvents, polar-aprotic solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents or their mixtures.
A preferred embodiment of the present invention provides an improved process for the preparation of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile benzoate compound of formula-la, comprising of;
a) Reacting the 6-chloropyrimidine-2,4(lH,3H)-dione compound of formula-2 with 2-(bromomethyl)benzonitrile compound of formula-3 in presence of triethylamine in toluene to provide 2-((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl) benzonitrile compound of formula-4,
b) methylation of compound of formula-4 with dimethyl sulfate in presence of potassium carbonate in methyl isobutyl ketone to provide 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)methyl)benzonitrile compound of formula-5,

c) reacting the compound of formula-5 with (R)-piperidin-3-amine dihydrochloride in presence of potassium carbonate in acetonitrile to provide 2-({6-[(3R)-3-aminopiperidin-1 -yl] -3 -methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl} methyl)benzonitrile compound of formula-1,
d) treating the compound of formula-1 with isopropyl alcohol-HCl in isopropyl alcohol to provide 2-( { 6- [(3R)-3 -aminopiperidin-1 -yl] -3 -methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile hydrochloride compound of formula-lb
followed by neutralizing the obtained HC1 salt with aqueous sodium carbonate solution in dichloromethane to provide pure compound of formula-1,
e) treating the compound of formula-1 with benzoic acid in dichloromethane to provide its benzoate salt compound of formula-1 a,
f) isolating the compound of formula-la by recrystallizing it from n-propanol to provide pure compound of fomula-1 a.
By developing the above described improved process for the preparation of 2-({6-[(3 R)-3 -aminopiperidin-1 -yl] -3 -methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-y 1} methyl) benzonitrile benzoate compound of formula-la, the present inventors were able to get the final API in excellent yield and quality with all the impurities and residual solvents controlled well within the limits as defined by ICH and some of the impurities in non-detectable level.
The process developed by the present inventors is much efficient in terms of all the parameters like cost-effectiveness, safety, quality and consistently provides the required product with desired quality and impurity profile.
The second aspect of the present invention provides a process for the preparation of 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)benzonitrile compound of formula-5, comprising of methylating the 2-((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)benzonitrile compound of formula-4 by reacting it with a suitable methylating agent in presence of a suitable base in a suitable solvent to provide compound of formula-5.
Wherein, the suitable methylating agent, the suitable base and the suitable solvent are same as defined in step-b) of the first aspect of the present invention.
A preferred embodiment of the present invention provides a process for the preparation of 2-((6-chloro-3 -methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)methyl) benzonitrile compound of formula-5, comprising of methylating the 2-((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)benzonitrile compound of formula-4 by reacting it with dimethyl sulfate in presence of potassium carbonate in methyl isobutyl ketone to provide compound of formula-5.
In an embodiment, the amount of dimethyl sulfate employed in the above methylation step is ranging from 1.0 to 4.0 mole ratio per one mole of compound of formula-4.
In a more preferred embodiment, the amount of dimethyl sulfate employed is ranging from 2.0 to 3.5 mole ratio per one mole of compound of formula-4.
In a most preferable embodiment, dimethyl sulfate is employed in an amount ranging from 2.5 to 3.0 mole ratio per one mole of compound of formula-4.
In the above process, methylation of compound of formula-4 is carried out at a temperature ranging from 20°C to reflux temperature of the solvent employed.
The third aspect of the present invention provides a process for the preparation of 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl}methyi)benzonitrile hydrochloride compound of formula-lb, comprising of treating the 2-({6-[(3R)-3 -aminopiperidin-1 -yl] -3 -methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl} methyl)benzonitrile compound of formula-1 with a suitable HCl source optionally in a suitable solvent to provide its hydrochloride salt compound of formula-lb.
Wherein, the suitable HC1 source is selected from methanol-HCl, ethanol-HCl, isopropyl alcohol-HCl, ethyl acetate-HCl, diethyl ether-HCl, aq.HCl, dry HC1, HC1 gas, NH4CI, acetyl chloride, tri(Ci-C6 alkyl)silyl chloride and the like, wherein acetyl chloride and tri(Ci-C6 alkyl)silyl chloride are used preferably in combination with alcohol solvents; the suitable solvent is same as defined in step-a) of the first aspect of the present invention.
A preferred embodiment of the present invention provides a process for the preparation of 2-( {6- [(3R)-3 -aminopiperidin-1 -yl] -3 -methyl-2,4-dioxo-3,4-dihydro pyrimidin-l(2H)-yl}methyl)benzonitrile hydrochloride compound of formula-lb, comprising of treating the 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile compound of formula-1 with isopropyl alcohol-HCl to provide its hydrochloride salt compound of formula-lb.
The fourth aspect of the present invention provides a process for the purification of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl} methyl)benzonitrile hydrochloride compound of formula-lb, comprising of recrystallizing the compound of formula-lb from a suitable solvent or mixture of solvents to provide pure compound of formula-lb.
Wherein, the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, ester solvents, polar-aprotic solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents or their mixtures.
A preferred embodiment of the present invention provides a process for the purification of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile hydrochloride compound of formula-lb, comprising of recrystallizing the compound of formula-lb from acetonitrile to provide pure compound of formula-lb.
US8222411B2 (herein after referred as US'411 patent) assigned to Takeda pharmaceuticals discloses a process for the preparation of Alogliptin hydrochloride salt in column-41 under experimental methods section. The present inventors has in-toto repeated the process disclosed in the above said US'411 patent in duplicate experiments and ended up with crystalline solid of Alogliptin HCl. The present inventors have analyzed the obtained crystalline solid by PXRD and the PXRD pattern of the same has been provided in figure-2.
WO2007035372A2 discloses two solid state forms of 2-({6-[(3R)-3-aminopiperidin-1 -yl] -3 -methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl} methyl)benzonitrile benzoate compound of formula-la and processes for their preparation. Out of the two forms, one is crystalline form therein designated as form-A and the other one is amorphous form designated as form-I. The said patent also discloses the pharmaceutical composition and method of treatment comprising the said solid state forms.
The fifth aspect of the present invention provides a process for the preparation of crystalline form-A of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile benzoate compound of formula-la, comprising of;
a) Treating 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile compound of formula-1 with benzoic acid in a suitable solvent,
b) removing the solvent from the reaction mixture,
c) isolating the compound of formula-la from a suitable solvent to provide crystalline form-A of compound of formula-1 a.
Wherein, in step-a) & step-c) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, ester solvents, polar-aprotic solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents or their mixtures.
An embodiment of the present invention provides a process for the preparation of crystalline form-A of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydro pyrimidin-l(2H)-yl}methyl)benzonitrile benzoate compound of formula-la, comprising of;
a) Treating the 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydro pyrimidin-l(2H)-yl}methyl)benzonitrile compound of formula-1 with benzoic acid in dichloromethane,
b) distilling off dichloromethane from the reaction mixture,
c) slurrying the obtained solid in methyl tert-butyl ether,
d) filtering the solid and drying to provide crystalline form-A of compound of formula-1 a.
Another embodiment of the present invention provides a process for the preparation of crystalline form-A of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydro pyrimidin-l(2H)-yl}methyl)benzonitrile benzoate compound of formula-la, comprising of;
a) Treating the 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydro pyrimidin-l(2H)-yl}methyl)benzonitrile compound of formula-1 with benzoic acid in dichloromethane,
b) distilling off dichloromethane from the reaction mixture to obtain a solid,
c) slurrying the obtained solid in cyclohexane,
d) filtering the solid and drying to provide crystalline form-A of compound of formula-1 a.
Another embodiment of the present invention provides a process for the preparation of crystalline form-A of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile benzoate compound of formula-la, comprising of;
a) Treating the 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydro pyrimidin-l(2H)-yl}methyl)benzonitrile compound of formula-1 with benzoic acid in dichloromethane,
b) distilling off dichloromethane from the reaction mixture to obtain a solid,
c) dissolving the obtained solid in n-propanol by heating the reaction mixture to reflux temperature,
d) cooling the reaction mixture to 25-30°C, preferably to 0-5°C,
e) filtering the precipitated solid and drying to provide crystalline form-A of compound of formula-la.
The sixth aspect of the present invention provides an alternative process for the preparation of crystalline form-A of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile benzoate compound of formula-la, comprising of;
a) Treating the 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydro pyrimidin-l(2H)-yl}methyl)benzonitrile compound of formula-1 with benzoic acid in dichloromethane,
b) distilling off the solvent completely from the reaction mixture to provide crystalline form-A of compound of formula-1 a.
The formation of the following impurities has been observed during the synthesis of Alogliptin benzoate by the process of the present invention. All these impurities were identified, characterized and well controlled within the limits as required by ICH guidelines. The observed impurities are;
The crystalline 2-({6-[(3R)-3-aminopiperidin-1 -yl]-3-methyl-2,4-dioxo-3,4-dihydro pyrimidin-l(2H)-yl}methyl)benzonitrile benzoate compound of formula-la obtained by the present invention is useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula-la is present in the composition in particular polymorphic form mentioned. Such pharmaceutical compositions may comprise compound of formula-la present in the composition in a range of between 0.005% and 100% (wt/wt), with the balance of the pharmaceutical composition comprising additional substances such as conventional pharmaceutical excipients, diluents, lubricants, binders, wetting agents, disintegrating agents, glidants, sweetening agents, flavoring agents, emulsifying agents, solubilizing agents, pH buffering agents, perfuming agents, surface stabilizing agents, suspending agents and other conventional pharmaceutically inactive agents.
The PXRD analysis of the crystalline compounds of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and at a continuous scan speed of 0.037min.
The 2-( {6- [(3R)-3 -aminopiperidin-1 -yl]-3 -methyl -2,4-dioxo-3,4-dihy dropyrimidin-l(2H)-yl}methyi)benzonitrile benzoate compound of formula-la of the present invention was analyzed by HPLC under the following conditions;
Apparatus: A liquid chromatograph equipped with variable wavelength UV detector; Column: Zorbax SB-C8, 250x4.6 mm, 5um or equivalent; Wavelength: 225 nm; Column temperature: 60°C; Auto sampler temperature: 5°C; Injection volume: 5 uL; Elution: gradient; Diluent: Acetonitrile:water (50:50 v/v); Buffer: Weigh accurately about 7.0 gm of sodium perchlorate monohydrate into 1000 mL of milli-Q-water and adjust its pH to 2.0 with dil.perchloric acid and filter this solution through 0.22um Nylon membrane filter paper. Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile: Buffer (70:30 v/v).
The enantiomeric purity of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-rnethyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile benzoate compound of formula-la of the present invention was analyzed by HPLC under the following conditions; Apparatus: A liquid chromatograph equipped with variable wavelength UV detector; Column: CHIRAL PAK IC-3, 250><4.6 mm, 3 urn or equivalent; Wavelength: 270 nm; Column temperature: 25°C; Auto sampler temperature: 5°C; Injection volume: 10 uL; Elution: Isocratic; Diluent: Methanol; Mobile phase: Ethanol:Dichloromethane:Ethanolamine (800:200:2 v/v/v); S-isomer stock solution preparation: Weigh accurately about 8 mg of S-isomer into a 10 mL volumetric flask, add about 5-7 mL of diluent and sonicate to dissolve. Make up to the mark with diluent and mix well.
The 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile benzoate 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, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
The present invention is schematically represented as follows. Synthetic scheme:
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-l: Preparation of 2-((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)
methyl)benzonitrile (Formula-4)
Triethylamine (82.3 gm) was added to a mixture of 6-chloropyrimidine-2,4(lH,3H)-dione compound of formula-2 (100 gm) and toluene (750 ml) at 25-30°C and stirred the reaction mixture for 40 min at the same temperature. A solution of 2-(bromomethyl)benzonitrile compound of formula-3 (133.8 gm) in toluene (750 ml) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 105-110°C and stirred for 2 hrs at the same temperature. Reduced the temperature of the reaction mixture to 70-75°C and water was added to it. Cooled the reaction mixture to 25-30°C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with water followed by with toluene and suck dried the material. N,N-dimethylformamide (50 ml) and toluene (400 ml) were added to the obtained solid at 25-30°C. Heated the reaction mixture to 95-100°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with toluene and dried the material to get the title compound. Yield: 124.0 gm; M.R: 240-245°C.
Example-2: Preparation of 2-((6-chIoro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) methyl)benzonitrile (FormuIa-5) Dimethyl sulfate (68 gm) and potassium carbonate (67 gm) were added to a mixture of 2-((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)benzonitrile compound of formula-4 (50 gm) and methyl isobutyl ketone (250 ml) at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 28 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture. Dichloromethane and water were added to the obtained solid at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under atmospheric pressure and co-distilled with cyclohexane. 150 ml of cyclohexane was added to the obtained solid at 25-30°C and stirred for 45 min at the same temperature. Filtered the solid, washed with cyclohexane and dried the material to get the title compound. Yield: 45.0 gm; M.R: 150-164°C.
Example-3: Preparation of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyI-2,4-dioxq-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitriIe (Formula-1)
Potassium carbonate (110 gm) and 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)benzonitrile compound of formula-5 (55 gm) were added to a mixture of (R)-piperidin-3-amine dihydrochloride (38 gm) and acetonitrile (275 ml) at 25-30°C. Heated the reaction mixture to 70-75°C and stirred for 10 hrs at the same temperature. Reduced the temperature of the reaction mixture to 40-45°C and potassium carbonate (33 gm) was added. Heated the reaction mixture to 70-75°C and stirred for 10 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and filtered. Distilled off the solvent from the filtrate under reduced pressure to get the title compound. Yield: 70.0 gm.
Example-4: Preparation of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yI}methyl)benzonitriIe hydrochloride (Formula-lb)
Isopropyl alcohol (220 ml) was added to 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile compound of formula-1 (70 gm) at 25-30°C and cool the reaction mixture to 10-15°C. Isopropyl alcohol-HCl (220 ml) was slowly added to the reaction mixture at 10-15°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol. Acetonitrile (275 ml) was added to the obtained solid at 25-30°C. Heated the reaction mixture to 60-65°C 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 acetonitrile and dried the material to get the title compound. The PXRD of the obtained compound is similar to fig-2. Yield: 53.0 gm.
Example-5: Preparation of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yI}methyl)benzonitrile benzoate (Formula-la)
Aqueous sodium carbonate solution (dissolve 12.7 gm of sodium carbonate in 120 ml of water) was added to a mixture of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile hydrochloride compound of formula-lb (30 gm) and dichloromethane (150 ml) at 25-30°C and stirred for 20 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Washed the combined organic layer with water and filtered through Whatmann filter paper. Benzoic acid (9.3 gm) was added to the filtered organic layer at 25-30°C and stirred for 10 min at the same temperature. Distilled off the solvent completely from the reaction mixture provided the title compound as a crystalline solid. The PXRD pattern of the obtained compound is similar to figure-1. Yield: 33.0 gm.
Example-6: Preparation of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrilebenzoate (Formula-la)
Aqueous sodium carbonate solution (dissolve 12.7 gm of sodium carbonate in 120 ml of water) was added to a mixture of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile hydrochloride compound of formula-lb (30 gm) and dichloromethane (150 ml) at 25-30°C and stirred for 20 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Washed the combined organic layer with water and filtered through Whatmann filter paper. Benzoic acid (9.3 gm) was added to the filtered organic layer at 25-30°C and stirred for 10 min at the same temperature. Distilled off the solvent completely from the reaction mixture and co-distilled with methyl tert-butyl ether under reduced pressure. Methyl tert-butyl ether (150 ml) was added to the obtained compound at 25-30°C and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the solid, washed with methyl tert-butyl ether and dried the material to get the title compound. The PXRD pattern of the obtained compound is similar to figure-1. Yield: 32.0 gm; Purity by HPLC: 99.9%.
Particle size distribution: D(0.1) is 0.72 urn; D(0.5) is 8.34 um; D(0.9) is 34.23 urn; D(4,3) is 13.46 um.
Example-7: Preparation of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile benzoate (Formula-la)
Aqueous sodium carbonate solution (dissolve 12.7 gm of sodium carbonate in 120 ml of water) was added to a mixture of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo- 3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile hydrochloride compound of formula-lb (30 gm) and dichloromethane (150 ml) at 25-30°C and stirred for 20 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Washed the combined organic layer with water and filtered through Whatmann filter paper. Benzoic acid (9.3 gm) was added to the filtered organic layer at 25-30°C and stirred for 10 min at the same temperature. Distilled off the solvent completely from the reaction mixture and co-distilled with n-propanol. n-Propanol (270 ml) was added to the obtained solid at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 15 min at the same temperature. Cooled the reaction mixture to 25-30°C, further cooled to 0-5°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with n-propanol and dried the material to get the title compound as a crystalline solid. The PXRD pattern of the obtained compound is similar to figure-1. Yield: 31.0 gm; M.R: 178-183°C; Water content: 0.24% w/w. Purity by HPLC: 99.92%; Enantiomeric purity by chiral HPLC: 99.99%. Alcohol impurity: Not detected; Chloro impurity: 0.02%; Dimer impurity: 0.03%; 3-aminopiperidine impurity: Not detected; Highest individual unspecified impurity: 0.02%; Particle size distribution: D(0.1) is 1.26 urn; D(0.5) is 9.33 urn; D(0.9) is 58.45 um; D(4,3) is 21.19 um.

We Claim:
1. A process for the preparation of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile benzoate compound of formula-la, comprising of; a) Reacting the 6-chloropyrimidine-2,4(lH,3H)-dione compound of formula-2
with 2-(brornomethyl)benzonitrile compound of formula-3
in presence of a suitable base in a suitable solvent to provide 2-((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-l (2H)-yl)methyl)benzonitrile compound of formula-4,
b) methylation of compound of formula-4 with a suitable methylating agent in a suitable solvent in presence of a suitable base to provide 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)methyl)benzonitrile compound of formula-5,
c) reacting the compound of formula-5 with (R)-piperidin-3-amine free base or its acid-addition salt in presence of a suitable base in a suitable solvent to provide 2-({6- [(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-y 1} methyl)benzonitrile compound of formula-1,
d) optionally purifying the compound of formula-1,
e) treating the compound of formula-1 obtained in step-c) or step-d) with benzoic acid in a suitable solvent to provide its benzoate salt compound of formula-la,
f) isolating the compound of formula-1 a from a suitable solvent or mixture of solvents, with the proviso that the suitable methylating agent used in step-b) is not methyl halide or methanol/PPh^/azodicarboxylate system (Mitsunobu reaction).
2. A process according to claim 1, wherein,
in step-a) to step-c) the suitable base is selected from organic bases, inorganic bases, organolithium bases, organosilicon bases or their mixtures;
in step-b) the suitable methylating agent is selected from dimethyl sulfate, dimethyl carbonate, trimethyloxonium tetrafluoroborate (Me30.BF4), trimethylphosphate, methyl alkyl/aryl sulfonates such as methyl methane sulfonate (MeOMs), methyl ethanesulfonate, methyl benzenesulfonate, methyl toluene sulfonate (MeOTs), methyl trifiuoromethanesulfonate (MeOTf), tetramethylammonium salts such as tetramethylammonium halides, trimethylsilyldiazomethane (TMSD);
in step-d) purification of compound of formula-1 involves the salt formation technique by treatment of compound of formula-1 with a suitable acid in a suitable solvent followed by neutralizing the obtained acid-addition salt with a suitable base to provide pure compound of formula-1;
in step-a) to step-f) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, ester solvents, polar-aprotic solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents or their mixtures.

3. A process for the preparation of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-
3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile benzoate compound of formula-la,
comprising of;
a) Reacting the 6-chloropyrimidine-2,4(lH,3H)-dione compound of formula-2 with 2-(bromomethyl)benzonitrile compound of formula-3 in presence of triethylamine in toluene to provide 2-((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)methyl) benzonitrile compound of formula-4,
b) methylation of compound of formula-4 with dimethyl sulfate in presence of potassium carbonate in methyl isobutyl ketone to provide 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)benzonitrile compound of formula-5,
c) reacting the compound of formula-5 with (R)-piperidin-3-amine dihydrochloride in presence of potassium carbonate in acetonitrile to provide 2-({6-[(3R)-3-aminopiperidin-1 -yl] -3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl} methyl) benzonitrile compound of formula-1,
d) treating the compound of formula-1 with isopropyl alcohol-HCl in isopropyl alcohol to provide 2-( {6- [(3R)-3 -aminopiperidin-1 -yl]-3 -methyl-2,4-dioxo-3,4-dihydro pyrimidin-l(2H)-yl}methyl)benzonitrile hydrochloride compound of formula-lb followed by neutralizing the obtained HC1 salt with aqueous sodium carbonate solution in dichloromethane to provide pure compound of formula-1,
e) treating the compound of formula-1 with benzoic acid in dichloromethane to provide its benzoate salt compound of formula-la,
f) isolating the compound of formula-la by recrystallizing it from n-propanol to provide pure compound of formula-la.
4. A process for the preparation of 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-
l(2H)-yl)methyl)benzonitrile compound of formula-5, comprising of methylating the 2-
((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)methyl)benzonitrile compound of
formula-4 by reacting it with a suitable methylating agent in a suitable solvent in
presence of a suitable base to provide compound of formula-5, with the proviso that the
methylating agent is not methyl halide or methanol/PPhj/azodicarboxylate system
(Mitsunobu reaction).

5. A process according to claim 4, wherein
the suitable methylating agent is selected from dimethyl sulfate, dimethyl carbonate, trimethyloxoniumtetrafluoroborate (Me30.BF4), trimethylphosphate, methyl alkyl/aryl sulfonates such as methyl methane sulfonate (MeOMs), methyl ethanesulfonate, methyl benzenesulfonate, methyl toluene sulfonate (MeOTs), methyl trifiuoromethanesulfonate (MeOTf), tetramethylammonium salts such as tetramethylammonium halides, trimethylsilyldiazomethane (TMSD);
the suitable base is selected from inorganic bases, organic bases, organolithium bases, organosilicon bases or their mixtures;
the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, ester solvents, polar-aprotic solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents or their mixtures.
6. A process for the preparation of 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)benzonitrile compound of formula-5, comprising of methylating the 2-((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-l (2H)-yl)methyl)benzonitrile compound of formula-4 with dimethyl sulfate to provide compound of formula-5.
7. The process according to claim 6, wherein the amount of dimethyl sulfate employed is ranging from 1.0 to 4.0 mole ratio, preferably 2.0 to 3.5 mole ratio, more preferably 2.5 to 3.0 mole ratio per one mole of compound of formula-4 and the methylation reaction is carried out at a temperature ranging from 20°C to reflux temperature of the solvent employed.
8. A process for the preparation of 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile hydrochloride compound of formula-lb, comprising of treating the 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile compound of formula-1 with a suitable HC1 source selected from methanol-HCl, ethanol-HCl, isopropyl alcohol-HCl, ethyl acetate-HCl, diethyl ether-HCl optionally in presence of a solvent to provide compound of formula-1 b.

9. A process for the preparation of crystalline form-A of 2-({6-[(3R)-3-aminopiperidin-l-
yl]-3 -methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl} methyl)benzonitrile benzoate
compound of formula-la, comprising of;
a) Treating the 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile compound of formula-1 with benzoic acid in dichloromethane,
b) distilling off dichloromethane from the reaction mixture to obtain crystalline solid,
c) dissolving the obtained solid in n-propanol by heating,
d) cooling the reaction mixture,
e) filtering the precipitated solid and drying to provide crystalline form-A of compound of formula-la.
10. A process for the preparation of crystalline form-A of 2-({6-[(3R)-3-aminopiperidin-l-
yl] -3 -methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl} methyl)benzonitrile benzoate
compound of formula-la, comprising of;
a) Treating the 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)benzonitrile compound of formula-1 with benzoic acid in dichloromethane,
b) distilling off dichloromethane completely from the reaction mixture to obtain crystalline form-A of compound of formula-1 a.