Field of the invention:
The present invention provides novel polymorphs of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide compound represented by the following structural formula-1 and processes for their preparation.
Formula-1 The present invention also provides novel intermediate compound useful for the preparation of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c] pyridine-3-carboxamide compound of formula-1.

Background of the invention:
1 -(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1 -yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, commonly known as Apixaban (BMS-562247-01) is an anticoagulant for the prevention of venous thromboembolism and venous thromboembolic events. Apixaban is marketed under the trade name "Eliquis" and is being developed in a joint venture by Pfizer and Bristol-Myers squibb.

Lactam containing compounds, their derivatives and process for their preparation was first disclosed in US6967208B2. The disclosed process involves the usage of l-(4-iodophenyl)-3-morpholino-5,6-dihydropyridin-2(lH)-one (herein after referred as "morpholine substituted lactam compound") as an intermediate for the preparation of Apixaban.
Still there is a need in the art to provide a novel process for the preparation of morpholine substituted lactam compound.

Crystalline solvates DMF-5 and FA-2 of Apixaban are disclosed in US2007203178A1; the crystalline forms N-l and H2-2 of Apixaban are disclosed in US7396932B2; and the crystalline forms-I and II of Apixaban are disclosed in IPCOM000216217D.

There is always a need for the crystalline product showing advantageous properties and consistent production of the said polymorph.

The present invention relates to solid state physical properties of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide. These properties may be influenced by controlling the conditions under which this compound is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.

Another important solid state physical property of a pharmaceutical compound is its rate of dissolution in solution which may have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient may reach the patient's bloodstream. The solid state form of a compound may also affect its behavior on compaction and its storage stability.

These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular crystalline or polymorphic form of a substance. The crystalline or polymorphic form may give rise to thermal behavior different from that of the amorphous material or another crystalline or polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and may be used to distinguish some crystalline or polymorphic forms from others. A particular crystalline or polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by X-ray powder diffraction (XRPD), solid state nuclear magnetic resonance (NMR) spectrometry, Raman spectroscopy and infrared (IR) spectrometry.

In deciding which polymorph or crystalline form is preferable, the numerous properties of the polymorphs or crystalline forms must be compared and the preferred polymorph or crystalline form chosen based on the many physical property variables. It is entirely possible that one polymorph or crystalline form can be preferable in some circumstances in which certain aspects, such as ease of preparation, stability, etc., are deemed to be critical. In other situations, a different crystalline form or polymorph may be preferred for greater solubility and/or superior pharmacokinetics.

The discovery of new crystalline or polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. Surprisingly novel crystalline forms of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide have now been observed in the laboratory which showing advantageous properties.

Brief description of the invention:
The first aspect of the present invention is to provide 3-chloro-l-(4-iodophenyl)-5,6-dihydropyridin-2(lH)-one compound of formula-3, which is an useful intermediate in the synthesis of l-(4-iodophenyl)-3-morpholino-5,6-dihydropyridin-2(lH)-one compound of formula-4 and ethyl 6-(4-iodophenyl)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c] pyridine-3-carboxylate compound of formula-6 which in-turn are useful in the synthesis of 1 -(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1 -yl)phenyl]-4,5,6,7-tetrahydro-1 H-pyrazolo [3,4-c]pyridine-3 -carboxamide compound of formula-1.

Further, the first aspect of the present invention also provides process for the preparation of 3-chloro-l-(4-iodophenyl)-5,6-dihydropyridin-2(lH)-one compound of formula-3.
The second aspect of the present invention is to provide a process for the preparation of l-(4-iodophenyl)-3-morpholino-5,6-dihydropyridin-2(lH)-one compound of formula-4, comprising of reacting the 3-chloro-l-(4-iodophenyl)-5,6-dihydropyridin-2(lH)-one compound of formula-3 with morpholine in presence or absence of a suitable solvent to provide l-(4-iodophenyl)-3-morpholino-5,6-dihydropyridin-2( 1 H)-one compound of formula-4.

The third aspect of the present invention is to provide a novel process for the preparation of ethyl 6-(4-iodophenyl)-1 -(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]
pyridine-3-carboxylate compound of formula-6, comprising of reacting the 3-chloro-l-(4-iodophenyl)-5,6-dihydropyridin-2(lH)-one compound of formula-3 with (Z)-ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate compound of formula-5 in presence of a suitable base in a suitable solvent to provide ethyl 6-(4-iodophenyl)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c] pyridine-3-carboxylate compound of formula-6.
The fourth aspect of the present invention is to provide a novel crystalline form of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1 -yl)phenyl]-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c] pyridine-3-carboxamide compound of formula-1 (herein designated as crystalline form-M) and process for its preparation.

The fifth aspect of the present invention is to provide a novel crystalline form of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1 -yl)phenyl]-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c] pyridine-3-carboxamide compound of formula-1 (herein designated as crystalline form-S) and process for its preparation.
The sixth aspect of the present invention is to provide a novel crystalline form of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1 -yl)phenyl]-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c] pyridine-3-carboxamide compound of formula-1 (herein designated as crystalline form-N) and process for its preparation.

Brief description of the drawings:
Figure-1: Illustrates the powder X-Ray diffraction pattern of crystalline form-M of l-(4-
methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1 -yl)phenyl]-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]
pyridine-3-carboxamide compound of formula-1.

Figure-2: Illustrates the DSC thermogram of crystalline form-M of l-(4-methoxyphenyl)-7-oxo-
6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide
compound of formula-1.

Figure-3: Illustrates the powder X-Ray diffraction pattern of crystalline form-S of l-(4-
methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1 -yl)phenyl]-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]
pyridine-3-carboxamide compound of formula-1.

Figure-4: Illustrates the DSC thermogram of crystalline form-S of l-(4-methoxyphenyl)-7-oxo-
6-[4-(2-oxopiperidin-1 -yl)phenyl]-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1.

Figure-5: Illustrates the powder X-Ray diffraction pattern of crystalline form-N of l-(4-
methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]
pyridine-3-carboxamide compound of formula-1.

Figure-6: Illustrates the DSC thermogram of crystalline form-N of l-(4-methoxyphenyl)-7-oxo-
6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide
compound of formula-1.

Detailed description of the invention:
As used herein the present invention the term "suitable solvent" refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet.ether, benzene, toluene, xylene and the like; "chloro solvents" such as dichloromethane, dichloroethane, carbon tetrachloride, chloroform and the like; "ester solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and the like; "polar aprotic solvents" such as dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, acetonitrile, propionitrile and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, dioxane and the like; "alcoholic solvents" such as methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol and the like; "ketone solvents" such as acetone, propanone, methyl ethyl ketone, methylisobutyl ketone, methylisopropyl ketone and the like; and "polar solvents" such as water; and/or their mixtures thereof.

The term "suitable base" used herein the present invention refers, but not limited to "inorganic bases" selected from alkali and alkaline earth metal hydroxides, alkoxides, carbonates and bicarbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium tert-butoxide, lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali meta amides such as sodium amide, potassium amide, lithium
amide and the like, ammonia; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and/or their mixtures thereof.

The first aspect of the present invention provides 3-chloro-l-(4-iodophenyl)-5,6-dihydropyridin-2(lH)-one compound of formula-3, which is an useful intermediate in the synthesis of l-(4-iodophenyl)-3-morpholino-5,6-dihydropyridin-2(lH)-one compound of formula-4 and ethyl 6-(4-iodophenyl)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c] pyridine-3-carboxylate compound of formula-6 which in-turn are useful in the synthesis of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1 -yl)phenyl]-4,5,6,7-tetrahydro-1 -H-pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1.

Further, the first aspect of the present invention also provides a process for the preparation of 3-chloro-l-(4-iodophenyl)-5,6-dihydropyridin-2(lH)-one compound of formula-3, comprising of treating the 3,3-dichloro-l-(4-iodophenyl)piperidin-2-one compound of formula-2
Formula-2 with lithium carbonate in presence of alkali metal halides such as lithium chloride, sodium chloride in a suitable solvent at a suitable temperature to provide 3-chloro-l-(4-iodophenyl)-5,6-dihydropyridin-2(lH)-one compound of formula-3.

Wherein, the "suitable solvent" employed is selected from hydrocarbon solvents, chloro solvents, ester solvents, ether solvents, alcoholic solvents, ketone solvents, polar aprotic solvents, polar solvents and/or mixtures thereof; preferably polar aprotic solvents; the "lithium carbonate" and the "alkali metal halide" are employed in molar proportions ranging from 0.2 to 1 equivalents per one mole of compound of formula-2; the "suitable solvent" is employed in an amount ranging from 2 to 10 volumes per lg of compound of formula-2; and the suitable temperature is 0-130°C.

The 3,3-dichloro-l-(4-iodophenyl)piperidin-2-one compound of formula-2 which is used as a starting material in the first aspect of the present invention is commercially available or it can be synthesized by any of the methods known in the art.

The second aspect of the present invention provides a process for the preparation of l-(4-iodophenyl)-3-morpholino-5,6-dihydropyridin-2( 1 H)-one compound of formula-4
Formula-4 comprising of reacting the 3-chloro-l-(4-iodophenyl)-5,6-dihydropyridin-2(lH)-one compound of formula-3 with morpholine in presence or absence of a suitable solvent at a suitable temperature to provide l-(4-iodophenyl)-3-morpholino-5,6-dihydropyridin-2(lH)-one compound of formula-4.

Wherein, the "suitable solvent" employed is selected from hydrocarbon solvents, chloro solvents, ester solvents, ether solvents, alcoholic solvents, ketone solvents, polar aprotic solvents, polar solvents and/or mixtures thereof; preferably hydrocarbon solvents and ester solvents;
the "morpholine" is employed in molar proportions ranging from 1 to 10 equivalents per one mole of compound of formula-3; the "suitable solvent" is employed in an amount ranging from 2 to 10 volumes per lg of compound of formula-3; and the suitable temperature is 0-140°C.
The l-(4-iodophenyl)-3-morpholino-5,6-dihydropyridin-2(lH)-one compound of formula-4 obtained in the second aspect of the present invention can be further utilized in the

synthesis of 1 -(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1 -yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1 by the conventional methods known from US6967208B2 and US6919451B2.

The third aspect of the present invention provides a novel process for the preparation of
ethyl 6-(4-iodophenyl)-1 -(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]
pyridine-3-carboxylate compound of formula-6,

Formula-6 comprising of reacting the 3-chloro-l-(4-iodophenyl)-5,6-dihydropyridin-2(lH)-one compound of formula-3 with (Z)-ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate compound of formula-5

Formula-5 in presence of a suitable base in a suitable solvent at a suitable temperature to provide ethyl 6-(4-iodophenyl)-1 -(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine-3 -carboxylate compound of formula-6.

Wherein, the "suitable solvent" employed is selected from hydrocarbon solvents, chloro solvents, ester solvents, ether solvents, alcoholic solvents, ketone solvents, polar aprotic solvents, polar solvents and/or mixtures thereof, preferably hydrocarbon solvents and ester solvents; the "suitable base" is inorganic base or organic base, preferably organic base such as triethyl amine;
The "suitable base" is employed in molar proportions ranging from 1 to 2 equivalents per one mole of compound of formula-3; the "suitable solvent" employed is in an amount ranging from 2 to 10 volumes per lg of compound of formula-3; and the suitable temperature is 0-100°C.

The (Z)-ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate compound of formula-5, which is used as a starting material in the third aspect of the present invention is commercially available or it can be prepared by any of the prior known methods.
The ethyl 6-(4-iodophenyl)-1 -(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate compound of formula-6 obtained by the process disclosed in the third aspect of the present invention can be further converted to l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1 by the conventional methods known in the art.

The fourth aspect of the present invention provides a novel crystalline form-M of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c] pyridine-3-carboxamide compound of formula-1, characterized by;

a) its PXRD pattern substantially in accordance with figure-1,

b) its powder X-Ray diffractogram having peaks at 12.7, 13.8, 16.9, 18.4, 22.0, 26.9, 29.0 and 32.7±0.2 degrees of two-theta, and

c) its DSC thermogram substantially in accordance with figure-2.
The fourth aspect of the present invention also provides a process for the preparation of crystalline form-M of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1, comprising the following steps of:

a) Adding isopropanol to l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1,

b) heating the reaction mixture,

c) cooling the reaction mixture,

d) filtering the solid and drying to get crystalline form-M of compound of formula-1.

The fourth aspect of the present invention also provides another process for the preparation of crystalline form-M of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1, comprising the following steps of:

a) Adding aqueous isopropanol to l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-
yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide compound of
formula-1,

b) heating the reaction mixture,

c) cooling the reaction mixture,

d) filtering the solid and drying to get crystalline form-M of compound of formula-1.
The fifth aspect of the present invention provides a novel crystalline form-S of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1 -yl)phenyl]-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c] pyridine-3-carboxamide compound of formula-1, characterized by;

a) its PXRD pattern substantially in accordance with figure-3,

b) its powder X-ray diffractogram having peaks at 5.7, 7.3, 11.5, 13.4, 15.9, 17.5, 17.8, 20.0, 22.1, 23.4 and 25.1±0.2 degrees of two-theta, and

c) its DSC thermogram substantially in accordance with figure-4.

The fifth aspect of the present invention also provides a process for the preparation of crystalline form-S of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1, comprising the following steps of:

a) Dissolving the l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1 in a mixture of dichloromethane and methanol by heating,

b) filtering the reaction mixture,

c) cooling the filtrate,

d) filtering the solid and drying to get crystalline form-S of compound of formula-1.

The sixth aspect of the present invention provides a novel crystalline form-N of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c] pyridine-3-carboxamide compound of formula-1, characterized by; a) its PXRD pattern substantially in accordance with figure-5,

b) its powder X-ray diffractogram having peaks at 6.0, 7.1, 12.8, 13.6, 15.1, 15.6, 16.1, 16.4, 17.5, 19.1, 21.3, 21.6, 22.7 and 24.4±0.2 degrees of two-theta,

c) its DSC thermogram substantially in accordance with figure-6.

The sixth aspect of the present invention also provides a process for the preparation of crystalline form-N of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1, comprising the following steps of:

a) Adding a mixture of dichloromethane and ethyl acetate to l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1,

b) heating the reaction mixture,

c) cooling the reaction mixture,

d) filtering the solid and drying to get crystalline form-N of compound of formula-1.

The l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1 used in the present invention can be prepared by any one of the prior art processes disclosed in US6919451 B2 or US7396932 B2.
The l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1 as 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 crystalline form-M, form-S and form-N of compound of formula-1 of the present invention are useful in the manufacture of pharmaceutical composition for the prevention of venous thromboembolism and venous thromboembolic events.

PXRD analysis of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1 of the present invention was carried out using BRUKER/AXS X-ray diffractometer using Cu Ka radiation of wavelength 1.5406 A0 at a continuous scan speed of 0.03 7min.

Differential scanning calorimetric (DSC) analysis was performed on a Q10 V9.6 Build 290 calorimeter with closed aluminium pans, heating the samples from 40 to 300°C in a dry nitrogen atmosphere at a rate of 10°C/min.

The present invention is schematically represented as follows. Scheme:

The process described in the present invention was demonstrated in examples illustrated below.

These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:
Example-1: Preparation of 3-chloro-l-(4-iodophenyl)-5,6-dihydropyridin-2(lH)-one
(Formula-3)
Lithium carbonate (4.08 gm) followed by lithium chloride (2.28 gm) were added to a mixture of 3,3-dichloro-l-(4-iodophenyl)piperidin-2-one compound of formula-2 (30 gm) and dimethylformamide (60 ml) at 25-30°C and stirred for 5 min at the same temperature. Heated the reaction mixture to 110-115°C and stirred for 4 hrs at the same temperature. After completion of the reaction, the reaction mixture was cooled to 30-35°C. Water was added to the reaction mixture at 30-35°C and stirred for 1 hr at the same temperature. Filtered the precipitated solid and then dried to get the title compound. Yield: 25.0 gm; MR: 120-130°C.

Example-2: Preparation of 3-chloro-l-(4-iodophenyl)-5,6-dihydropyridin-2(lH)-one (Formula-3)

Lithium carbonate (2.99 gm) followed by sodium chloride (2.76 gm) were added to a mixture of 3,3-dichloro-l-(4-iodophenyl)piperidin-2-one compound of formula-2 (50 gm) and dimethylformamide (150 ml) at 25-30°C and stirred for 10 min at the same temperature. Heated the reaction mixture to 110-115°C and stirred for 6 hrs at the same temperature. After completion of the reaction, the reaction mixture was cooled to 30-35°C. Water was added to the reaction mixture at 30-35°C and stirred for 1 hr at the same temperature. Filtered the precipitated crystalline solid and then dried to get the title compound. Yield: 42.0 gm; M.R: 120-130°C.

Example-3: Preparation of l-(4-iodophenyI)-3-morpholino-5,6-dihydropyridin-2(lH)-one (Formula-4)

Toluene (5 ml) was added to a mixture of 3-chloro-l-(4-iodophenyl)-5,6-dihydropyridin-2(1H)-one compound of formula-3 (5 gm) and morpholine (5.09 gm) at 25-30°C and stirred for 5 min at the same temperature. Heated the reaction mixture to 115-120°C and stirred for 3 hrs at the same temperature. After completion of the reaction, the temperature of the reaction mixture was reduced to 30-35°C. Water was added to the reaction mixture at 30-35°C and stirred for 15
hrs at the same temperature. Filtered the precipitated solid and then dried to get the title
compound.

Yield: 3.8 gm.

Example-4: Preparation of ethyl 6-(4-iodophenyl)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate(Formula-6)

A mixture of 3-chloro-l-(4-iodophenyl)-5,6-dihydropyridin-2(lH)-one compound of formula-3 (79.2 gm), (Z)-ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate compound of formula-5 (65 gm) and toluene (450 ml) was heated to 90-100°C and stirred for 5 min at the same temperature. Triethyl amine (72 gm) was slowly added to the reaction mixture at 90-100°C and stirred for 21/2 hrs at the same temperature. After completion of the reaction, the temperature of the reaction mixture was reduced to 25-35°C. Water (110 ml) was added to the reaction mixture at 25-35°C and stirred for 8 hrs at the same temperature. Filtered the solid, washed with water and then dried to get the title compound. Yield: 78.5 gm.

Example-5: Preparation of crystalline form-M of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-
oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide
(Formula-1)
1 -(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1 -yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1 (6.25 gm) was added to isopropanol (400 ml) 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 0-5°C and stirred for 60 min the same temperature. Filtered the solid, washed with isopropanol and then dried to get the title compound.

Yield: 4.5 gm; Water content: 0.30% w/w.

The PXRD and DSC of the obtained compound are illustrated in figure-1 and figure-2 respectively.

Example-6: Preparation of crystalline form-M of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

(Formula-1)
l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-
pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1 (6.25 gm) was added to 50%
aqueous isopropanol (60 ml) at 25-30°C. Heated the reaction mixture to 50-60°C and stirred for
4 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 60 min at
the same temperature. Filtered the solid and then dried to get the title compound.
Yield: 4.1 gm; Water content: 0.35% w/w.

The PXRD and DSC of the obtained compound are illustrated in figure-1 and figure-2
respectively.

Example-7: Preparation of crystalline form-S of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-
oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide
(Formula-1)

1 -(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1 -yl)phenyl]-4,5,6,7-tetrahydro- 1H-pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1 (34 gm) was added to a mixture of dichloromethane and methanol (1020 ml, in 3:7 ratio) at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 15 min at the same temperature. Filtered the reaction mixture and washed with a mixture of dichloromethane and methanol. Cooled the filtrate to 0-5°C and stirred for 60 min at the same temperature. Filtered the precipitated solid and then dried to get the title compound.

Yield: 24.0 gm; M.R: 235-245°C; Water content: 7.38% w/w.

The PXRD and DSC of the obtained compound are illustrated in figure-3 and figure-4 respectively.

Example-8: Preparation of crystalline form-N of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-
oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide
(Formula-1)

A mixture of dichloromethane and ethyl acetate (625 ml, in 3:7 ratio) was added to l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1 -yl)phenyl]-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c] pyridine-3-carboxamide compound of formula-1 (6.25 gm) 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 0-5°C and stirred for 60 min at the same temperature. Filtered the solid and then dried
to get title compound.

Yield: 3.9 g; Water content: 5.21% w/w.

The PXRD and DSC of the obtained compound are illustrated in figure-5 and figure-6
respectively.

Example-9: Preparation of crystalline form-M of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-
oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide
(Formula-1)

1 -(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1 -yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1 (34 gm) was added to a mixture of dichloromethane and methanol (1020 ml, in 3:7 ratio) at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 15 min at the same temperature. Filtered the reaction mixture and washed with a mixture of dichloromethane and methanol. Cooled the filtrate to 0-5°C and stirred for 60 min at the same temperature. Filtered the precipitated solid and added to isopropanol (510 ml). Heated the reaction mixture to reflux temperature and stirred for 15 minutes at the same temperature. The reaction mixture was cooled to 0-5°C and stirred for 60 minutes at the same temperature. Filtered the solid and then dried to get crystalline form-M of compound of formula-1. Yield: 23 g; Water content: 0.30%w/w.

The PXRD and DSC of the obtained compound are illustrated in figure-1 and figure-2 respectively.

Example-10: Preparation of crystalline form-M of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-
oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide
(Formula-1)

1 -(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1 -yl)phenyl]-4,5,6,7-tetrahydro- 1H-pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1 (34 gm) was added to a mixture of dichloromethane and methanol (1020 ml, in 3:7 ratio) at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 15 min at the same temperature. Filtered the reaction
mixture and washed with a mixture of dichloromethane and methanol. Cooled the filtrate to
0-5 °C and stirred for 60 min at the same temperature. Filtered the precipitated solid and added to
aq.isopropanol (340 ml). Heated the reaction mixture to 50-60°C and stirred for 15 minutes at the
same temperature. The reaction mixture was cooled to 25-35°C and stirred for 60 minutes at the
same temperature. Filtered the solid and then dried to get crystalline form-M of compound of
formula-1.

Yield: 23 g; Water content: 0.35%w/w.

The PXRD and DSC of the obtained compound are illustrated in figure-1 and figure-2
respectively.

We Claim:

1. 3-chloro-l-(4-iodophenyl)-5,6-dihydropyridin-2(lH)-one represented by the structural formula
2. A process for the preparation of 3-chloro-l-(4-iodophenyl)-5,6-dihydropyridin-2(lH)-one compound of formula-3,

Formula-3 comprising of treating the 3,3-dichloro-l-(4-iodophenyl)piperidin-2-one compound of formula-2

Formula-2 with lithium carbonate in presence of alkali metal halide such as lithium chloride and sodium chloride in a suitable solvent selected from hydrocarbon solvents, chloro solvents, ester solvents, ether solvents, alcoholic solvents, ketone solvents, polar aprotic solvents, polar solvents and/or mixtures thereof, preferably polar aprotic solvents at a suitable temperature to provide 3-chloro-l-(4-iodophenyl)-5,6-dihydropyridin-2(lH)-one compound of formula-3.

3. The process according to claim 2, wherein:

the lithium carbonate and alkali metal halide are employed in molar proportions ranging from 0.2 to 1 equivalents per one mole of compound of formula-2; the suitable solvent is employed in an amount ranging from 2 to 10 volumes per lg of compound of formula-2; and the suitable temperature is 0-130°C.

4. A process for the preparation of l-(4-iodophenyl)-3-morpholino-5,6-dihydropyridin-2(lH)-one compound of formula-4

comprising of reacting the 3-chloro-l-(4-iodophenyl)-5,6-dihydropyridin-2(lH)-one compound of formula-3 with morpholine in presence or absence of a suitable solvent selected from hydrocarbon solvents, chloro solvents, ester solvents, ether solvents, alcoholic solvents, ketone solvents, polar aprotic solvents, polar solvents and/or mixtures thereof, preferably hydrocarbon solvents and ester solvents at a suitable temperature to provide l-(4-iodophenyl)-3-morpholino-5,6-dihydropyridin-2( 1 H)-one compound of formula-4.

5. The process according to claim-4, wherein:

the morpholine is employed in molar proportions from 1 to 10 equivalent per one mole of compound of formula-3; the suitable solvent is employed in an amount ranging from 2 to 10 volumes per lg of compound of formula-3; and the suitable temperature is 0-140°C.

5. A process for the preparation of ethyl 6-(4-iodophenyl)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine-3 -carboxylate compound of formula-6,
Formula-6 comprising of reacting the chloro-l-(4-iodophenyl)-5,6-dihydropyridin-2(lH)-one compound of formula-3 with (Z)-ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate compound of formula-5

Formula-5 in presence of a suitable organic base in a suitable solvent selected from hydrocarbon solvents, chloro solvents, ester solvents, ether solvents, alcoholic solvents, ketone solvents, polar aprotic solvents, polar solvents and/or mixtures thereof, preferably hydrocarbon solvents and ester solvents at a suitable temperature to provide ethyl 6-(4-iodophenyl)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate compound of formula-6.

7. The process according to claim 6, wherein:

the suitable base is employed in molar proportions ranging from 1 to 2 equivalents per one mole of compound of formula-3; the suitable solvent is used in an amount ranging from 2 to 10 volumes per lg of compound of formula-3; the suitable temperature is 0-100°C.

8. A novel crystalline form of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-
4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1,
wherein:

a) Crystalline form-M is characterized by,

i) its PXRD pattern substantially in accordance with figure-1,

ii) its powder X-ray diffractogram having peaks at 12.7, 13.8, 16.9, 18.4, 22.0, 26.9, 29.0
and 32.7±0.2 degrees of two-theta, and iii) its DSC thermogram substantially in accordance with figure-2,

b) crystalline form-S is characterized by;

i) its PXRD pattern substantially in accordance with figure-3,

ii) its powder X-ray diffractogram having peaks at 5.7, 7.3, 11.5, 13.4, 15.9, 17.5, 17.8,
20.0, 22.1, 23.4 and 25.1±0.2 degrees of two-theta, and iii) its DSC thermogram substantially in accordance with figure-4,

c) crystalline form-N is characterized by;

i) its PXRD pattern substantially in accordance with figure-5,
ii) its powder X-ray diffractogram having peaks at 6.0, 7.1, 12.8, 13.6, 15.1, 15.6, 16.1,
16.4, 17.5, 19.1, 21.3, 21.6, 22.7 and 24.4±0.2 degrees of two-theta, and iii) its DSC thermogram substantially in accordance with figure-6,

9. A process for the preparation of crystalline form-M of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1 -yl)phenyl]-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine-3 -carboxamide compound of formula-1 as defined in claim-8, comprising of:

a) Adding isopropanol or aqueous isopropanol to l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1,

b) heating the reaction mixture,
c) cooling the reaction mixture,
d) filtering the solid and drying to get crystalline form-M of compound of formula-1.
or a process for the preparation of crystalline form-S of compound of formula-1 as defined in claim-8, comprising of;

a) Dissolving the l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1 in a mixture of dichloromethane and methanol by heating,

b) filtering the reaction mixture,
c) cooling the filtrate,

d) filtering the solid and drying to get crystalline form-S of compound of formula-1.
or a process for the preparation of crystalline form-N of compound of formula-1 as defined in claim-8, comprising of;

a) Adding a mixture of dichloromethane and ethyl acetate to l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide compound of formula-1,

b) heating the reaction mixture,

c) cooling the reaction mixture,

d) filtering the solid and drying to get crystalline form-N of compound of formula-1.

10. Use of novel crystalline forms of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl) phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide as defined in claim-8 for the preparation of pharmaceutical composition.