Field of the Invention:
The present invention provides novel crystalline polymorphs of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-pipera2inyl)propoxy]-3-quinoline carbonitrile represented by the following structural formula-1 and processes for their preparation.
C'Ny^CI
Formula-1
Background of the Invention:
4-[(2)4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyt-l-pipera2inyl) propoxyJ-3-quinolinecarbonitrile, commonly known as Bosutinibr is a tyrosine kinase inhibitor. This compound has been described for the first time in US6002008A & USRE42376.
US6002008A & USRE42376 has generically described the synthesis of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile. No physical characteristic details of the said compound were described in the above mentioned patents.
US7767678B2 has described six crystalline polymorphic forms of Bosutinib viz., crystalline monohydrate form-I, monohydrate form-II, IPA solvate form-Ill, hydrate form-lV, anhydrous form-V and methanol solvate form-VI which is incorporated herein as reference.
The present inventors have surprisingly found novel crystalline polymorphs of Bosutinib which can be utilized for the preparation of various pharmaceutical compositions.

Brief description of the invention:
The first aspect of the present invention is to provide novel crystalline polymorph (herein designated as crystalline form-R) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile compound of formula-1.
The second aspect of the present invention is to provide process for the preparation of crystalline form-R of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile compound of formula-].
Brief Description of the Drawings:
Figure-1: Illustrates the PXRD of compound of formula-1 obtained according to example"-6 Figure-2: Illustrates the PXRD of compound of formula-1 obtained according to example-7 Figure-3: Illustrates the PXRD pattern of crystalline form-R of compound of formula-1 Figure-4: Illustrates the PXRD of compound of formula-1 obtained according to example-9 Figure-5: Illustrates the PXRD of compound of formula-1 obtained according to example-10 Figure-6: Illustrates the PXRD of compound of formula-1 obtained according to example-11 Figure-7: Illustrates the PXRD pattern of crystalline form-R3 of compound of formula-1 Figure-8: Illustrates the PXRD pattern of crystalline form-R^ of compound of formula-! Figure-9: Illustrates the PXRD pattern of crystalline form-R| of compound of formula-1 Figure-10: Illustrates the PXRD pattern of crystalline form-R4 of compound of formula-1 Figure-11: Illustrates the PXRD pattern of crystalline form-R5 of compound of formula-! Figure-12: Illustrates the PXRD pattern of crystalline form-R,, of compound of formula-! Figure-13: Illustrates the PXRD pattern of crystalline form-R7 of compound of formula-1 Figure-14: Illustrates the PXRD pattern of crystalline form-R8 of compound of formula-1 Figure-15: Illustrates the PXRD pattern of crystalline form-Rg of compound of formula-1 Figure-16: Illustrates the PXRD pattern of crystalline form-Rio of compound of formula-! Figure-17: Illustrates the PXRD pattern of crystalline form-RM of compound of formula-1 Figure-18: Illustrates the PXRD pattern of crystalline form-R|2 of compound of formula-1 Figure-19: Illustrates the PXRD pattern of crystalline form-R,3 of compound of formula-1 Figure-20: Illustrates the PXRD pattern of crystalline form-R|4 of compound of formula-!

Detailed description of the Invention:
In the present invention the term "hydrocarbon solvents" refers to n-pentane. n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" refers to dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-buiyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" refers to methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents" refers to dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" refers to dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" refers to acetone, methyl ethyl ketone, methyl isobutyl ketone and ihe like; "nitrile solvents" refers to acetonitrile, propionitrile, isobuiyronitrile and ihe like: "alcohol solvents" refers to methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol. iso-butanol, t-butanol, ethane-1,2-diol, propane-1,2-diol and the like; "polar solvents" refers to water.
The first aspect of the present invention provides novel crystalline polymorph of 4-[(2J4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl) propoxy]-3-quinolinecarbonitrile compound of formula-1. The said novel crystalline form is herein designated as crystalline form-R and it is characterized by its PXRD pattern having peaks at 8.5, 18.4 and 23.0 ± 0.2° of 2-theta.
The crystalline form-R of compound of formula-1 of the present invention is further characterized by its PXRD pattern having peaks at 5.7, 8.2, 9.2, 10.1, 10.3, 12.6, 15.6, 16.1, 17.1, 21.2, 22.3, 22.6, 24.0, 25.4, 25.6, 27.3 ± 0.2° of 2-theta.
The crystalline form-R of compound of formula-1 is further characterized by its PXRD pattern as shown in figure-3.
The novel crystalline polymorphs of compound of formula-1 of the present invention are 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-1 is present in the composition in particular polymorphic form mentioned. Such pharmaceutical compositions may comprise compound of formula-1 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 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.
An embodiment of the present invention provides use of crystalline form-R of compound of formula-1 for the preparation of pharmaceutical formulations.
An embodiment of the present invention provides pharmaceutical composition comprising crystalline form-R of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile compound of formula-1 and a! least one pharmaceutically acceptable excipient.
Another embodiment of the present invention provides crystalline form-R of compound of formula-1 having particle size distribution of DQ0 1 ess than 300 JJITI.
A further embodiment of the present invention provides crystalline form-R of compound of formula-1 having particle size distribution of D90 less than 100 urn.
A further embodiment of the present invention provides crystalline form-R of compound of formula-1 having particle size distribution of D90 less than 50 urn.
The second aspect of the present invention provides process for the preparation of crystalline form-R of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile compound of formula-1. comprising of;
a) Dissolving the compound of formula-1 in a suitable first solvent or mixture of solvents.
b) optionally filtering the reaction mixture,
c) combining the solution with a suitable second solvent,
d) filtering the precipitated solid,
e) slurrying the obtained compound in a suitable second solvent as mentioned in step-c),
f) filtering the solid and drying,

g) slurrying the obtained compound in water,
h) filtering the solid and drying the material to provide crystalline form-R of compound of formula-1.
Wherein, in step-a) the suitable first solvent is selected from but not limited to chloro solvents, alcohol solvents, ketone solvents, ester solvents, nitrile solvents, polar-aprotic solvents and/or their mixtures; and the dissolution of compound of formula-1 in a suitable first solvent or mixture of solvents can be carried out at a suitable temperature ranges from 0°C to reflux temperature of the solvent used;
In step-c) the suitable second solvent is selected from but not limited 10 ether solvents; and combining the solution with a suitable second solvent can be carried out ai a suitable temperature ranges from -40°C to reflux temperature of the solvent used;
In step-e) slurrying the compound in a suitable second solvent can be carried out at a • suitable temperature ranges from -40°C to reflux temperature of the solvent used;
In step-g) slurrying the compound in water can be carried out at a suitable temperature ranges from 0°C to 60°C.
A preferred embodiment of the present invention provides a process for the preparation of crystalline form-R of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitri!e, comprising of;
a) Dissolving the compound of formula-1 in a mixture of methanol and dichloromeihane.
b) optionally filtering the reaction mixture,
c) combining the solution with methyl tert.butyl ether,
d) filtering the precipitated solid,
e) slurrying the obtained compound in methyl tert.butyl ether,
f) filtering the solid and drying,
g) slurrying the obtained compound in water,
h) filtering the solid and drying the material to provide crystalline form-R of compound of formula-1.

Any physical form of compound of formula-1 can be utilized as input for the preparation of novel crystalline polymorphs of the present invention.
On the other hand, the novel crystalline polymorphs of compound of formula-1 of the present invention can be utilized as input for the preparation of amorphous form or other crystalline polymorphs of compound of formula-1.
Our co-pending application, IN4144/CHE/2015 has described two crystalline polymorphs viz., form-M and form-S of compound of formula-1 which is cited herein as reference.
The PXRD analysis of crystalline solids of the present invention was carried out using BRUKER/D8 ADVANCE diffractometer using CuKa radiation of wavelength 1.5406A0 and at a continuous scan speed of 0.03°/min.
The compound of formula-1 obtained by the processes of the present invention was analyzed by HPLC under the following conditions:
Apparatus: A liquid chromatograph equipped with variable wavelength UV-detector; Column: YMC Triart CI8, 250x4.6 mm, S-5um, 12 nm or equivalent; Wavelength: 265 nm; Column temperature: 40°C; Auto sampler temperature: 5°C; Diluent: Acetonitrile: water (50:50 v/v); Elution: gradient; Buffer preparation: Weigh accurately 3.08 gm of ammonium acetate and dissolve in 1000 mL of Milli-Q-water. Filter the solution through 0.22 Nylon membrane filter paper and sonicate to degas it; Mobile phase-A: Buffer: Acetonitrile (95:5 v/v); Mobile phase-B: Acetonitrile: Water (90:10 v/v).
The novel crystalline polymorphs of compound of formula-1 of the present invention can be further micronized or milled to get 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 includes but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling or micronization may be performed before drying or after drying of the product.

The best mode of carrying out the present invention is illustrated by the below mentioned example. This example is provided as illustration only and hence should not be construed as limitation to the scope of the invention.
Examples:
Example-1: Preparation of methyl 4-(3-chloropropoxy)-3-methoxy benzoate
Thionyl chloride (85 gm) was slowly added to a mixture of 4-hydroxy-3-methoxy benzoic acid (100 gm) and methanol (500 ml) at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 90 min at the same temperature. Distilled off the solvent completely from the reaction mixture. Cooled the reaction mixture to 25-30°C. Dimethyl formamide (300 ml), potassium carbonate (164 gm) followed by l-bromo-3-chloro propane (140 gm) were added to the obtained compound at 25-30°C and stirred the reaction mixture for 5 hrs at the same temperature. Water was added to the reaction mixture at 25-30°C and stirred for 3 hrs at the same temperature. Filtered the solid, washed with water and dried the material to get the title compound. Yield: 141.0 gm; M.R: 105-107°C.
Example-2: Preparation of methyl 2-amino-4-(3-chloropropoxy)-5-methoxy benzoate
A mixture of methyl 4-(3-chloropropoxy)-3-methoxy benzoate (100 gm) and acetic acid (150 ml) was heated to 45-50°C. Nitric acid (100 gm) was slowly added to the reaction mixture at 45-50°C and stirred the reaction mixture for 6 hrs at the same temperature. Cooled the reaction mixture to 25-30°C, water was slowly added and stirred the reaction mixture for 4 hrs at the same temperature. Filtered the solid and washed with water. The obtained solid. Iron powder (64.8 gm) and methanol (750 ml) were added to aqueous ammonium chloride solution (91.6 gm of ammonium chloride in 300 ml of water) at 25-30°C. Heated the reaction mixture to 65-70°C and stirred for 5 hrs at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with methanol. Distilled off the solvent from the filtrate. Water and dichloromethane were added to the obtained compound at 25-30°C and stirred for 5 min. Both the organic and aqueous layers were separated. Distilled off the solvent completely from the organic layer and then co-distilled with cyclohexane. Toluene (150 ml) was added to the obtained compound and heated the reaction

mixture to 55-60°C. Cyclohexane (250 ml) was slowly added to the reaction mixture at 55-60°C and stirred the reaction mixture for 30 min 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 cyclohexane and then dried the material to provide the title compound. Yield: 82.0 gm; M.R: 95-100°C.
Example-3: Preparation of 7-(3-chloropropoxy)-6-methoxy-4-oxo-3,4-dihydroquinolinc-3-carbonitrile
A mixture of methyl 2-amino-4-(3-chloropropoxy)-5-methoxy benzoate (100 gm) and dimethylformamide-dimethyl acetal (200 gm) was heated to 75-80°C and stirred the reaction mixture for 8 hrs at the same temperature. Distilled off the reaction mixture under reduced pressure and cooled the obtained compound to 25-30°C and kept aside. Acetonitrile (150 ml) was slowly added to a pre-cooled mixture of tetrahydrofuran (600 ml) and sodium hexamethyldisilazane (600 ml; 40% solution in tetrahydrofuran) at -70°C to -75°C under nitrogen atmosphere and stirred the reaction mixture for 90 min at the same temperature. A solution of above obtained compound in tetrahydrofuran (200 ml) was slowly added to the reaction mixture at -70°C to -75°C and stirred for 3 hrs at the same temperature. Acetic acid (200 ml) was slowly added to the reaction mixture at -70°C to -75°C. Raise the temperature of the reaction mixture to 25-30°C and water was added. Distilled off the solvent completely from the reaction mixture under reduced pressure. Water (1000 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 water and then dried the material. Isopropyl alcohol (500 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. Filtered the solid, washed with isopropyl alcohol and then dried the material to provide the title compound. Yield: 88.0 gm; M.R: 250-260°C (decomposition).
Example-4: Preparation of 4-chloro-7-(3-chloropropoxy)-6-methoxyquinolinc-3-carbonitrile

Phosphorous oxychloride (131.1 gm) was slowly added to a mixture of 7-(3-chloropropoxy)-6-methoxy-4-oxo-3,4-dihydroquinoline-3-carbonitrile (100 gm) and toluene (500 ml) at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 5 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Cooled the reaction mixture to 25-30°C, water was added and stirred for 1 hr at the same temperature. Filtered the solid and washed with water. Aqueous sodium bicarbonate solution was slowly added to the obtained compound at 25-30°C and stirred the reaction mixture for 1 hr at the same temperature. Filtered the compound, washed with water and then dried the material. Isopropyl alcohol (500 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 90 min at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol and then dried the material to provide the title compound. Yield: 86.0 gm; MR: 165-172°C.
Example-5: Preparation of 7-(3-chloropropoxy)-4-((2,4-dichIoro-5-methoxyphenyl) amino)-6-methoxyquinoline-3-carbonitriIe hydrochloride
Isopropyl alcohol-HCl (50 ml) was slowly added to a mixture of 4-chloro-7-(3-chloropropoxy)-6-methoxyquinoline-3-carbonitrile (100 gm), acetonitrile (800 m!) and 2.4-dichloro-5-methoxyaniline (71 gm) at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 15 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the compound, washed with acetonitrile and suck dried the material. Methanol (700 ml) was added to the obtained solid at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 45 min 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 methanol and then dried the material to provide the title compound. Yield: 134.0 gm; M.R: 255-258°C; Purity by HPLC: 96.49%.
Example-6: Preparation of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-|3-(4-methyl-l-piperazinyl)propoxy|-3-quinolinecarbonitrile methanol solvate

Potassium carbonate (29.5 gm), triethylamine (21.6 gm), potassium iodide (3.55 gm) and tetrabutyl ammonium bromide (6.85 gm) were added to a mixture of 7-(3-ch1oro propoxyJ^-^^-dichloro-S-methoxyphenyOaminoJ^-methoxyquinolineO-carbonitrile hydrochloride (100 gm), N-methyl piperazine (107.1 gm) and acetonitrile (700 ml) at 25-30°C. Heated the reaction mixture to 70-75°C and stirred for 8 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Filtered the reaction mixture and washed with acetonitrile. Distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with methanol. 400 ml of methanol was added to the obtained compound. Heated the reaction mixture to 60-65°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the compound, washed with methanol and dried the materia). Dimethylformamide (160 ml) and acetone (120 ml) were added to the obtained compound at 25-30°C and stirred for 30 min at the same temperature. A blend of hyflow (2.5 gm) and silica gel (5.0 gm) was added lo the reaction mixture at 25-30°C and stirred for 20 min at the same temperature. Charcoal (5.0 gm) was added to the reaction mixture at 25-30°C and stirred for 20 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with acetone. Methanol (800 ml) was slowly added to the filtrate at 25-30°C and stirred for 3 hrs at the same temperature. Filtered the solid, washed with methanol and suck dried the material. Dimethylformamide (120 ml) and acetone (120 ml) were added to the obtained compound at 25-30°C and stirred the reaction mixture for 15 min at the same temperature. Methanol (640 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 3 hrs at the same temperature. Filtered the solid, washed with methanol and suck dried the material. Methanol (960 ml) and water (48 ml) were added to the obtained compound at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 10 min at the same temperature. Cooled the reaction mixture to 25-30°C, water (480 ml) was added and stirred for 3 hrs at the same temperature. Filtered the solid, washed with methanol and dried to provide the title compound. The PXRD pattern of the compound is shown in figure-1. Yield: 59.18 gm; Purity by HPLC: 99.9%.
Example-7: Preparation of 4-[(2,4-dichloro-5-methoxyphenyl)amino|-6-methoxy-7-|3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile isopropyl alcohol solvate

A mixture of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l -piperazinyl)propoxy]-3-quinolinecarbonitrile (50 gm), isopropyl alcohol (400 ml) and water (200 ml) was heated to 80-85°C and stirred for 30 min at the same temperature. Filtered the reaction mixture to make it particle free and washed with mixture of isopropyl alcohol and water. Cooled the filtrate to 25-30°C and stirred for 5 hrs at the same temperature. Further cooled the reaction mixture to 0-5°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid, washed with a mixture of isopropyl alcohol and water and then dried the material to provide the title compound.
The PXRD pattern of the obtained compound is shown in figure-2. Yield: 50.0 gm.
ExampIe-8: Preparation of crystalline form-R of 4-|{2,4-dichloro-5-methoxyphenyl) amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy|-3-quinolinecarbonitrile
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl) propoxy]-3-quinolinecarbonitrile compound of formula-1 (100 gm) was added to a pre-cooled mixture of methanol (300 ml) and dichloromethane (700 ml) at 10-15°C and stirred the reaction mixture for 30 min at the same temperature. Filtered the reaction mixture to make it particle free. Methyl tert.butyl ether (2000 ml) was slowly added to the obtained solution at -15°C to -10°C and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the precipitated solid, washed with methyl tert.butyl ether and then suck dried the compound. The obtained material was added to pre-cooled methyl tert.butyl ether (1000 ml) at -15°C to -10°C and stirred the reaction mixture for I hr at the same temperature. Filtered the solid, washed with methyl tert.butyl ether and then dried the material. The obtained compound was added to pre-cooled water (1000 ml) at 0-5°C and stirred the reaction mixture for 1 hr at the same temperature. Filtered the solid, washed with water and then dried the material to provide the title compound.
The PXRD pattern of the obtained compound is shown in figure-3. Yield: 79.2 gm.
Example-9: Preparation of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-|3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile

4-[(2)4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-pipera2inyl) propoxy]-3-quinolinecarbonitrile (100 gm) was added to a pre-cooled mixture of methanol (300 ml) and dichloromethane (700 ml) at 10-15°C and stirred the reaction mixture for 30 min at the same temperature. Filtered the reaction mixture to make it particle free and washed with a mixture of methanol and dichloromethane. The obtained filtrate was slowly added to pre-cooled methyl tert.butyl ether (2000 ml) at -I5°C to -20°C and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the precipitated solid, washed with methyl tert.butyl ether and then suck dried the material. The obtained compound was added lo pre-cooled methyl tert.butyl ether (1000 ml) at -I0°C to -I5°C and stirred the reaction mixture for 1 hr at the same temperature. Filtered the compound, washed with methyl tert.butyl ether and then dried the material. The obtained compound was added to pre-cooled water (1000 ml) at 0-5°C and stirred the reaction mixture for 1 hr at the same temperature. Filtered the solid, washed with water and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown-in figure-4. Yield: 76.0 gm.
Example-10: Preparation of 4-|(2,4-dichloro-5-methoxyphenyl)amino|-6-methoxy-7-|3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl) propoxy]-3-quinolinecarbonitrile (50 gm) was added to a pre-cooled mixture of methanol (150 ml) and dichloromethane (350 ml) at 10-15°C and stiired the reaction mixture for 30 min at the same temperature. Filtered the reaction mixture to make it particle free and washed with a mixture of methanol and dichloromethane. Cooled the filtrate to -15°C to -20°C and methyl tert.butyl ether (700 ml) was slowly added to it. Methyl tert.butyl ether (300 ml) and water (150 ml) were slowly added to the reaction mixture at -15°C to -20°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 provide the title compound. The PXRD pattern of the obtained compound is shown in figure-5. Yield: 40.0 gm.

Example-11: Preparation of 4-[(2,4-diehloro-5-methoxyphenyl)amino|-6-methoxy-7-|3-(4-methy]-l-piperazinyl)propoxy]-3-quinolinecarbonitrile
A mixture of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methy!-l -piperazinyl)propoxy]-3-quinolinecarbonitrile isopropyl alcohol solvate (10 gm) and water (100 ml) was stirred for 25 hrs at 25-30°C. Filtered the solid, washed with water and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-6. Yield: 8.0 gm.
Examplc-12: Preparation of crystalline form-S of 4-|(2,4-dichloro-5-methoxyphcnyl) amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile
4-[(2,4-dichloro-5-methoxvphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl) propoxy]-3-quinolinecarbonitrile (15 gm) was added to pre-cooled dichloromethane (375 ml) at 10-15°C and stirred the reaction mixture for 30 min at the same temperature. Further cooled the reaction mixture to -25°C to -30°C, cyclohexane (750 ml) was slowly added to it and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the precipitated solid, washed with cyclohexane and then dried the material to provide the title compound. Yield: 9.0 gm.
Examplc-13: Preparation of crystalline form-S of 4-[(2,4-dichloro-5-methoxyphenyl) amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy)-3-quinolinecarbonitrile
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl) propoxy]-3-quinolinecarbonitrile (15 gm) was added to pre-cooled dichloromethane (375 ml) at 10-15°C and stirred the reaction mixture for 30 min at the same temperature. Further cooled the reaction mixture to -25°C to -30°C, methyl tert.butyl ether (750 ml) was slowly added to it and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the precipitated solid, washed with methyl tert.butyl ether and then dried the material to provide the title compound. Yield: 8.5 gm.
Example-14: Preparation of crystalline form-S of 4-[(2,4-dichloro-5-methoxyphenyl) ammo]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy|-3-quinolinecarbonitrile

4-[(2J4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl) propoxy]-3-quinolinecarbonitrile (45 gm) was added to a pre-cooled mixture of isopropyl alcohol (45 ml) and dichloromethane (450 ml) at 10-15°C and stirred the reaction mixture for 30 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with dichloromethane. Further cooled the filtrate to -25°C to -30°C. n-heptane (1035 ml) was slowly added and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the precipitated solid, washed with n-heptane and then dried the material to provide the title compound. Yield: 32.0 gm.
Example-15: Preparation of crystalline form-Rs of 4-[(2,4-dichloro-5-methoxyphenyl) amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitriIe
A mixture of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l -piperazinyl)propoxy)-3-quinolinecarbonitrile (10 gm) and acetonitrile (300 ml) was slowly heated to 60-65°C and stirred the reaction mixture for 30 min at the same temperature. Slowly cooled the obtained solution to 25-30°C and stirred for 30 min at the same temperature. Filtered the precipitated solid and dried the material to provide title compound. The PXRD pattern of the obtained compound is shown in figure-7. Yield: 7.5 gm.
Example-16: Preparation of crystalline form-R2 of 4-((2,4-dichloro-5-methoxyphenyl) amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy|-3-quinolinecarbonitrile
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl) propoxy]-3-quinolinecarbonitrile (1 gm) and a 1:1 mixture of dichloromethane (7 ml) and methanol (7 ml) were charged into a clean and dry Buchi flask at 25-30°C and stirred the reaction mixture for 15 min at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Diethyl ether (30 ml) was added to the obtained compound at 25-30°C and stirred the reaction mixture for 15 min at the same temperature. Filtered the solid and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-8. Yield: 0.7 gm.

Example-17: Preparation of crystalline form-R| of 4-[(2,4-dichloro-5-methoxyphenyl) amino]-6-mcthoxy-7-[3-(4-methyl-l-pipcrazinyl)propoxy|-3-quinolinecarbonitrile
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl) propoxy]-3-quinolinecarbonitrile (1 gm) and 70% dichloromethane in ethanol (10 ml) were charged into a clean and dry Buchi flask at 25-30°Cand stirred the reaction mixture for 5 min at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. 60% Acetone in water (50 ml) was added to the obtained compound at 25-30°C and stirred the reaction mixture for 15.mm at the same temperature. Filtered the solid and dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-9. Yield: 0.7 gm.
Examplc-18: Preparation of crystalline form-Ri of 4-[(2,4-dichJoro-5-methoxyphenyl) amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyI)propoxyj-3-quinolinecarbonitrile
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-]-piperazinyl) propoxy]-3-quinolinecarbonitrile (40 gm) was added to a pre-cooled 7:3 mixture of ethanol and dichloromethane (400 ml) at 0-5°C and stirred the reaction mixture for 15 min at the same temperature. Filtered the solution to make it particle free and kept the Filtrate aside. A 1:9 mixture of acetone and water (800 ml) was taken in another clean and dry RBF and cooled the mixture to 0-5°C. Form-Ri seed material (0.8 gm) was added to the said mixture at 0-5°C. The above obtained filtrate was slowly added to the reaction mixture at 0-5°C and stirred the reaction mixture for 30 min at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is similar to figure-9. Yield: 33.0 gm.
Example-19: Preparation of crystalline form-Ri of 4-[(2,4-dichloro-5-methoxyphenyl) amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy|-3-quinolinecarbonitrile
A 3:7 mixture of methanol and dichloromethane (200 ml) was added to 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile (20 gm) at 25-30°C and stirred for 5 min at the same temperature.

Slowly cooled the obtained solution to 0-5°C and filtered to make it particle free and kept the filtrate aside. A 1:9 mixture of acetone and water (400 ml) was taken in another clean and dry RBF and slowly cooled the mixture to 0-5°C. Form-R| seed material (0.4 gm) was added to the said mixture at 0-5°C. The above obtained filtrate was slowly added to the reaction mixture at 0-5°C and stirred the reaction mixture for 30 min at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is similar to figure-9. Yield: 17.0gm.
Example-20: Preparation of crystalline form-Ri of 4-|(2,4-dichloro-5-mcthoxypricnyl) amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy|-3-quinolinecarbonitrile
A 3:7 mixture of ethanol and dichloromethane (100 ml) was added to 4-[(2.4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile (10 gm) at 25-30°C. Slowly cooled the reaction mixture to 0-5°C and filtered the obtained solution to make it particle free. The filtrate was slowly added to pre-cooled 4:6 mixture of acetone and water (300 ml) at 0-5°C and stirred the reaction mixture for 20 min at the same temperature. Filtered the precipitated solid and dried the material to provide the title compound.
The PXRD pattern of the obtained compound is similar to figure-9. Yield: 7.8 gm.
Example-21: Preparation of crystalline form-Rj of 4-|(2,4-dichloro-5-methoxypht'nyl) amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy|-3-quinolinecarbonitrile
A mixture of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l -piperazinyl)propoxy]-3-quinolinecarbonitrile (500 mg) and cyclohexanone (5 ml) was heated to 70-75°C and stirred the reaction mixture for 15 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 5 min at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-10. Yield: 300.0 mg.

Example-22: Preparation of crystalline form-R5 of 4-[(2,4-dichloro-5-methoxyphenyl) amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyI)propoxy|-3-quinolinecarbonitrile
4-[(2,4-dichioro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl) propoxy]-3-quinolinecarbonitrile (500 mg) and a 7:3 mixture of chloroform and methanol (5 ml) were charged into a clean and dry RBF at 25-30°C. Heated the reaction mixture to 70-75°C to obtain a clear solution. Cooled the reaction mixture to 0-5°C and stirred for 5 min at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-1 I. Yield: 425.0 mg.
Example-23: Preparation of crystalline form-R^ of 4-[(2,4-dichloro-5-methoxyphenyl) amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile
A mixture of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1 -piperazinyl)propoxy]-3-quinolinecarbonitrile (500 mg) and isopropyl acetate (10 ml) was heated to 70-75°C to obtain a clear solution. Slowly cooled the reaction mixture to 0-5°C and stirred for 5 min at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound.
The PXRD pattern of the obtained compound is shown in figure-12. Yield: 340.0 mg.
Example-24: Preparation of crystalline form-R7 of 4-[(2,4-dichloro-5-methoxyphenyl) amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy|-3-quinolinecarbonitrile
A mixture of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile (500 mg) and isobutyl acetate (10 ml) was heated to 70-75°C to obtain a clear solution. Cooled the reaction mixture to 0-5°C and stirred for 10 min at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound.
The PXRD pattern of the obtained compound is shown in figure-13. Yield: 250.0 mg.
Example-25: Preparation of crystalline form-Rg of 4-|(2,4-dichloro-5-methoxyphenyl) amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyt)propoxy]-3-quinolinecarbonitrile

Amixtureof4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-|3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile (500 mg) and ethylene glycol (10 ml) was heated to 70-75°C to obtain a clear solution. Cooled the reaction mixture to 0-5°C and stirred for 10 min at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound.
The PXRD pattern of the obtained compound is shown in figure-14. Yield: 250.0 mg.
Example-26: Preparation of crystalline form-R9 of 4-[(2,4-dichloro-5-methoxyphenyl) amino]-6-mcthoxy-7-|3-(4-methyl-l-piperazinyl)propoxy|-3-quinolintcarbonitrile
A solution of 4-[(2,4-dichloro-5-methoxyphenyI)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile (500 mg) in 1:1 mixture of methanol and ethanol (10 ml) was added to water (50 ml) at 25-30X and stirred the reaction mixture for 5 min at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound.
The PXRD pattern of the obtained compound is shown in figure-15. Yield: 300.0 mg.
Example-27: Preparation of crystalline form-Rio of 4-[(2,4-diehloro-5-methoxyphenyl) amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile
A solution of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile (500 mg) in ethanol (8 ml) was added to water (50 ml) at 25-30°C and stirred the reaction mixture for 5 min at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-16. Yield: 320.0 mg.
Example-28: Preparation of crystalline form-Rn of 4-|(2,4-dichloro-5-methoxyphenyI) amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrik>
A solution of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-meihyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile (500 mg) in dichloromethane (8 ml) was

.added to water (50 ml) at 25-30°C and stirred the reaction mixture for 5 min at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-17. Yield: 290.0 mg.
Example-29: Preparation of crystalline form-R|2 of 4-[(2,4-dichloro-5-methoxyphenyl) amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile
A solution of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile (500 mg) in acetone (4 ml) was added to water (30 ml) at 25-30°C and stirred the reaction mixture for 5 min at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-18. Yield: 300.0 mg.
Example-30: Preparation of crystalline form-R13 of 4-[(2,4-dichloro-5-methoxyphenyl) amino]-6-methoxy-7-[3-(4-methyl-l-ptperazinyl)propoxy|-3-quinolinecarbonitrile
A solution of 4-[(2}4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-meihyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile (500 mg) in acetonitrile (10 ml) was added to water (10 ml) at 25-30°C and stirred the reaction mixture for 5 min at the same temperature. Filtered the precipitated solid and dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-19. Yield: 300.0 mg.
Example-31: Preparation of crystalline form-Ru of 4-[(2,4-dichloro-5-methoxyphcnyl) amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy|-3-quinolinecarbonitrile
A mixture of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-f3-(4-methyl-l -piperazinyl)propoxy]-3-quinolinecarbonitrile (3 gm) and ethanol (10 ml) was heated to 75-80°C and stirred the reaction mixture for 24 hrs at the same temperature. Filtered the solid and dried to provide the title compound. PXRD pattern of compound is shown in figure-20. Yield: 1.8'gm.

Example-32: Preparation of 4-[(2,4-dichloro-5-methoxyphenyl)amino|-6-methoxy-7-|3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile monohydrate form-I
A mixture of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile (50 gm), isopropyl alcohol (400 ml) and water (200 ml) was heated to 75-80°C and stirred the reaction mixture for 1 hr at the same temperature. Filtered the reaction mixture to make it particle free. Cooled the filtrate to 25-30°C and stirred for 45 min at the same temperature. Heated the reaction mixture to 75-80°C and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 5 his at the same temperature. Further cooled the reaction mixture to 0-5°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid, washed with aqueous isopropyl alcohol and suck dried the compound. The obtained solid was added to water (750 ml) at 25-30°C. Heated the reaction mixture to 95-100X and stirred for 7 hrs ai the same temperature. Reduced the temperature of the reaction mixture to 35-40°C and stirred for 45 min at the same temperature. Filtered the solid, washed with water and then dried the material to provide the title compound. Yield: 44.0 gm.
ExampIe-33: Preparation of methyl 4-(3-chloropropoxy)-3-methoxy benzoate
Thionyl chloride (85 Kg) was slowly added to a mixture of 4-hydroxy-3-methoxy benzoic acid (100 Kg) and methanol (500 Lt) at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 1 hr at the same temperature. Distilled off the solvent completely from the reaction mixture. Cooled the reaction mixture to 25-30°C. Dimethyl formamide (300 Lt), potassium carbonate (164 Kg) followed by l-bromo-3-chloro propane (140 Kg) were added to the obtained compound at 25-30X and stirred the reaction mixture for 6 hrs ai the same temperature. Water (900 Lt) was slowly added to the reaction mixture at 25-30°C and stirred for 3 hrs at the same temperature. Filtered the solid, washed with water and then dried the material to get the title compound. Yield: 128.0 Kg; M.R: I01.3-104.7°C. Example-34: Preparation of methyl 2-amino-4-(3-chloropropoxy)-5-methoxy benzoate
A mixture of methyl 4-(3-chloropropoxy)-3-methoxy benzoate (50 Kg) and acetic acid (75 Lt) was stirred for 10 min at 25-30°C. Heated the reaction mixture to 45-50°C. Nitric acid (50 Kg) was slowly added to the reaction mixture at 45-50°C and stirred the

reaction mixture for 5 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. water was slowly added to it and stirred the reaction mixture for 4 hrs at the same temperature. Filtered the solid, washed with water and spin dried the material. Water (150 Lt), ammonium chloride (45.8 Kg), iron powder (32.4 Kg) and methanol (375 Lt) were added to the obtained compound at 25-30°C and stirred the reaction mixture for 10 min at the same temperature. Heated the reaction mixture to 65-70°C and stirred for 4 hrs at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with methanol. Heated the filtrate to 65-70°C and stirred for 20 min at the same temperature. Filtered the reaction mixture and washed with methanol. Distilled off the solvent completely from the filtrate under reduced pressure. Water and dichloromethane were added to the obtained compound at 25-30°C and stirred for 5 min at the same temperature. Both the organic and aqueous layers were separated. Distilled off the solvent completely from the organic layer and then co-distilled with cyclohexane. Toluene (75 Lt) was added to the obtained compound and heated the reaction mixture to 55-60°C. Cyclohexane (125 Lt) was slowly added to the reaction mixture at 55-60°C and stirred the reaction mixture for 30 min 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 cyclohexane and dried the material to get the title compound. Yield: 36.2 Kg; M.R: 95.9-97.9°C.'
Example-35: Preparation of 7-(3-chloropropoxy)-6-methoxy-4-oxo-3,4-
dihydroquinotine-3-carbonitrile
A mixture of methyl 2-amino-4-(3-chloropropoxy)-5-methoxy benzoate (100 Kg) and dimethylformamide-dimethyl acetal (200 Kg) was stirred for 10 min at 25-30°C. Heated the reaction mixture to 75-80°C and stirred for 8 hrs at the same temperature. Distilled off the reaction mixture under reduced pressure and cooled the obtained compound to 25-30°C and kept aside. Acetonitrile (150 Lt) was slowly added to a pre-cooled mixture of tetrahydrofuran (600 Lt) and sodium hexamethyldisilazane (600 Lt; 40% solution in tetrahydrofuran) at -70°C to -75°C under nitrogen atmosphere and stirred the reaction mixture for 90 min at the same temperature. A solution of above obtained compound in tetrahydrofuran (200 Lt) was slowly added to the reaction mixture at -70°C to -75°C and stirred the reaction mixture for 3 hrs at the same temperature. Acetic acid (200 Lt) was slowly added to the reaction mixture ai

-70°C to -75°C. Raised the temperature of the reaction mixture to 25-30X and water was added to it. Distilled off the solvent completely from the reaction mixture under reduced pressure. Water (1000 Lt) 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 water and dried the material. Isopropyl alcohol (500 Lt) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hrs al the same temperature. Filtered the solid, washed with isopropyl alcohol and dried the material to get the title compound. Yield: 79.2 Kg; M.R: >230°C.
Example-36: Preparation of 4-chloro-7-(3-chloropropoxy)-6-methoxyquinoline-3-carbonitrile
Phosphorous oxychloride (98.31 Kg) was slowly added to a mixture of 7-(3-chloropropoxy)-6-methoxy-4-oxo-3,4-dihydroquinoline-3-carbonitrile (75 Kg) and toluene (375 Lt) at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 4 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Cooled the reaction mixture to 25-30°C, water was slowly added to it and stirred for 1 hr at the same temperature. Filtered the solid, washed with water and spin dried the material. Aqueous sodium bicarbonate solution was slowly added to the obtained compound at 25-30°C and stirred the reaction mixture for 1 hr at the same temperature. Filtered the compound, washed with water and then dried the material. Isopropyl alcohol (375 Lt) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 90 min at the same temperature. Filtered the solid, washed with isopropyl alcohol and dried the material to get the title compound. Yield: 59.0 Kg; M.R: 156-160°C.
Example-37: Preparation of 7-(3-chloropropoxy)-4-((2,4-dichloro-5-methoxyph<;nyl) amino)-6-methoxyquinoline-3-carbonitriIe hydrochloride
Isopropyl alcohol-HCl (15.2 Lt) was slowly added to a mixture of 4-chloro-7-(3-chloropropoxy)-6-methoxyquinoline-3-carbonitrile (50 Kg), 2,4-dichloro-5-methoxyaniline

(35.5 Kg) and acetonitrile (400 Lt) at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 15 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the compound, washed with acetonitrile and spin dried the material. Methanol (300 Lt) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 45 min 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 methanol and dried the material to get the title compound. Yield: 64.5 Kg.
ExampIe-38: Preparation of compound of formula-1
A mixture of 7-(3-chloropropoxy)-4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxyquinoline-3-carbonitrile hydrochloride (65 Kg), N-methyl piperazine (69.62 Kg), potassium carbonate (19.18 Kg), triethylamine (14.04 Kg), potassium iodide (2.31 Kg), tetrabutyl ammonium bromide (4.45 Kg) and acetonitrile (455 Lt) was heated to 70-75°C and stirred for 8 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Filtered the reaction mixture, distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with methanol. 260 Lt of methanol was added to the obtained compound at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the compound, washed with methanol and dried the material. Dimethylformamide (104 Lt) and acetone (78 Lt) were added to the obtained compound at 25-30°C and stirred the reaction mixture for 30 min at the same temperature. Silica gel (3.25 Kg) and hyflow (1.63 Kg) were added to the reaction mixture at 25-30°C and stirred the reaction mixture for 20 min at the same temperature. Charcoal (3.25 Kg) was added to the reaction mixture at 25-30°C and stirred for 20 min at the same temperature. Filtered the reaction mixture and methanol (520 Lt) was slowly.added to the filtrate at 25-30°C and stirred the reaction mixture for 3 hrs at the same temperature. Filtered the solid, washed with methanol and suck dried the material. Dimethylformamide (78 Lt) and acetone (78 Lt) were added to the obtained compound at 25-30°C and stirred the reaction mixture for 15 min at the same temperature. Methanol (416 Lt) was slowly added to the reaction mixture at 25-30°C and stirred for 3 hrs at the same temperature. Filtered the solid, washed with methanol and

suck dried the material. Methanol (624 Lt) followed by water (31.2 Lt) were added lo the obtained compound at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 10 min at the same temperature. Cooled the reaction mixture to 25-30°C. water (312 Lt) was slowly added to it and stirred the reaction mixture for 3 hrs at the same temperature. Filtered the solid, washed with methanol and dried the material to get the title compound. Yield: 33.5 Kg.
Example-39: Preparation of crystalline form-S of compound of formula-1
A mixture of compound of formula-1 (32 Kg), isopropyl alcohol (256 Lt) and water (128 Lt) was heated to 75-80°C and stirred for 1 hrat the same temperature. Filtered the reaction mixture and washed with a mixture of isopropyl alcohol and water. Cooled the filtrate to 25-30°C and stirred for 45 min at the same temperature. Heated the reaction mixture to 75-80°C and stirred for 1 hr at the same temperature. Cooled the reaction mixture 25-30°C and stirred for 5 hrs at the same temperature. Further cooled the reaction mixture to 0-5°C and stirred for 3 hrs at the same temperature. Filtered the solid, washed with a mixture of isopropyl alcohol and water and dried the material. The obtained compound was added to pre-cooled dichloromethane (800 Lt) at 10-15X and stirred for 20 min at the same temperature. Filtered the reaction mixture, slowly added the filtrate to a pre-cooled mixture of n-heptane (1600 Lt) and water (1.3 Lt) at -15°C to -20°C and stirred the reaction mixture for 3 hrs at the same temperature. Filtered the precipitated solid, washed with n-heptane and dried the material to get the title compound.
Yield: 24.85 Kg; Water content by KFR: 6.57% w/w; Purity by HPLC: 99.8%. Particle size distribution: D(0.1) is 2.10 urn; D(0.5) is 5.28 urn; D(0.9) is 16.04 urn; D[4:3] is 11.31 urn.
ExampIe-40: Preparation of crystalline form-I of compound of formula-1
A mixture of compound of formula-1 (4 Kg), isopropyl alcohol (32 Lt) and water (16 Lt) was heated to 75-80°C and stirred the reaction mixture for 1 hr at the same temperature. Filtered the reaction mixture and washed with a mixture of isopropyl alcohol and water. Cooled the filtrate to 25-30°C and stirred for 45 min at the same temperature. Heated the reaction mixture to 75-80°C and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 5 hrs at the same temperature. Further cooled the reaction

mixture to 0-5°C and stirred for 3 hrs at the same temperature. Filtered the solid, washed
with a mixture of isopropyl alcohol and water and suck dried the material. The obtained
compound was added to water (60 Lt) at 25-30°C. Heated the reaction mixture to 80-85°C
and stirred for 7 hrs at the same temperature. Reduced the temperature of the reaction
mixture to 35-40°C and stirred for 45 min at the same temperature. Filtered the solid, washed
with water and dried the material to get the title compound.
Yield: 3.7 Kg; Water content by KFR: 3.75% w/w; Purity by HPLC: 99.83%.
Particle size distribution:
Before micronization: D(0.1) is 4.68 urn; D(0.5) is 14.50 urn; D(0.9) is 38.0 urn; D[4,3] is
31.9 urn.
After micronization: D(0.1) is 2.81 urn; D(0.5) is 7.62 urn; D(0.9) is 20.2 urn; D[4,3] is 9.84 p.
Example-41: Preparation of crystalline form-R of compound of formula-1
A mixture of compound of formula-1 (25 Kg), dichloromethane (175 Lt) and methanol (75 Lt) was stirred for 30 min at 10-I5°C. Filtered the reaction mixture and washed with a pre-cooled mixture of dichloromethane and methanol at 10-I5°C. Cooled the filtrate to -15°C to -20°C. Methyl tert.butyl ether (500 Lt) was slowly added to the filtrate at -15°C to -20°C and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the solid. washed with pre-cooled methyl tert.butyl ether and suck dried the material. The obtained compound was added to pre-cooled methyl tert.butyl ether (250 Li) at -15°C to -20°C and stirred the reaction mixture for 1 hr at the same temperature. Filtered the compound, washed with pre-cooled methyl tert.butyl ether and dried the material. The obtained solid was added to pre-cooled water (250 Lt) at 0-5°C and stirred for 1 hr at the same temperature. Filtered the solid, washed with pre-cooled water and dried the material to get the title compound. Yield: 23.96 Kg; Purity by HPLC: 99.82%.
Particle size distribution: D(0.1) is 2.43 urn; D(0.5) is 7.43 urn; D(0.9) is 25.74 um; D[4.31 is 11.44 um.

We Claim:
1. Crystalline form-R of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile characterized by its PXRD pattern having peaks at 8.5, 18.4 and 23.0 ± 0.2° of 2-theta.
2. The crystalline form-R of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyI-l-piperazinyl)propoxy]-3-quinolinecarbonitrile according to claim I. which is further characterized by its PXRD pattern having peaks at 5.7, 8.2: 9.2; 10.1, 10.3, 12.6, 15.6, 16.1, 17.1, 21.2, 22.3, 22.6, 24.0, 25.4, 25.6, 27.3 ± 0.2° of 2-theta.
3. The crystalline form-R of 4-[(2,4-dichloro-5-methoxyphenyl)amino|-6-methoxy-7-[3-{4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile according to claims I and 2. which is further characterized by its PXRD pattern as shown in figure-3.
4. A process for the preparation of crystalline form-R of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile compound of formula-1, comprising of;

a) Dissolving the compound of formula-1 in a suitable first solvent or mixture of solvents,
b) optionally filtering the reaction mixture,
c) combining the solution with a suitable second solvent,
d) filtering the precipitated solid,
e) slurrying the obtained compound in a suitable second solvent as mentioned in step-c),
f) filtering the solid and drying,
g) slurrying the obtained compound in water,
h) filtering the solid and drying the material to provide crystalline form-R of compound of formula-1.

5. The process according to claim 4, wherein,
in step-a) the suitable first solvent is selected from chloro solvents, alcohol solvents, ketone solvents, ester solvents, nitrile solvents, polar-aprotic solvents and/or their mixtures;
in step-c) the suitable second solvent is selected from ether solvenis.
6. The process according to claims 4 and 5, wherein
in step-a) the dissolution of compound of formula-] in a suitable first solvent or mixture of solvents can be carried out at a suitable temperature ranges from 0°C to reflux temperature of the solvent used;
in step-c) combining the solution with a suitable second solvent can be carried out at a suitable temperature ranges from -40°C to reflux temperature of the solvent used:
in step-e) slurrying the compound in a suitable second solvent can be carried out at a suitable temperature ranges from -40°C to reflux temperature of the solvent used:
in step-g) slurrying the compound in water can be carried out at a suitable temperature ranges from 0°C to 60°C.
7. A process for the preparation of crystalline form-R of 4-[(2,4-dichloro-5-
methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-
quinolinecarbonitrile compound of formula-], comprising of;
a) Dissolving the compound of formula-1 ' in a mixture of methanol and dichloromethane,
b) optionally filtering the reaction mixture,
c) combining the solution with methyl tert.butyl ether,
d) filtering the precipitated solid,
e) slurrying the obtained compound in methyl tert.butyl ether,
f) filtering the solid and drying,
g) slurrying the obtained compound in water,
h) filtering the solid and drying the material to provide crystalline form-R of compound of formula-1.

8. Use of crystalline form-R of 4-[(2)4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile compound of formula-1 for the preparation of pharmaceutical formulations.
9. Pharmaceutical composition comprising crystalline form-R of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperaziny!)propoxy]-3-quinolinecarbonitrile and at least one pharmaceutically acceptable excipient.
10. Crystalline form-R of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile having particle size distribution of D90 less than 300 um.