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-piperazinyl)propoxy]-3-quinoline carbonitrile represented by the following structural formula-1 and process for their preparation.
Formula-1

Background of the invention:

4-[(2,4-dichloro-5-methox>'phenyl)amino]-6-methoxy-7-[3-(4-methyl-1 -piperazinyl) propoxy]-3-quinolinecarbonitrile, commonly known as Bosutinib, 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!, monohydrate form-I, monohydrate form-II, IPA solvate form-Ill, hydrate form-IV, anhydrous form-V and methanol solvate form-VI.

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-M) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7- [3 -(4-methyl-1 -piperazinyl)propoxy] -3 -quinolinecarbonitrile compound of formula-1.

The second aspect of the present invention is to provide novel crystalline polymorph
(herein designated as crystalline form-S) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-
methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile compound of
fbrmula-1.

The third aspect of the present invention is to provide process for the preparation of crystalline form-M of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1 -piperazinyl)propoxy]-3-quinolinecarbonitrile compound of formula-1.
' " ■ i ■•-...... P . ' T t

The fourth aspect of the present invention is to provide process for the preparation of crystallineform-Sof4-[(2,4-dichloro-5-meth6xyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile compound of formula-1.

Brief description of the drawings:

Figure-1: Illustrates the PXRD pattern of crystalline form-M of 4-[(2,4-dichloro-5-
methoxyphenyl)amino]-6-methoxy-7- [3 -(4-methyl-1-piperazinyl)propoxy] -3 -quinoline
carbonitrile compound of formula-1 obtained according to example-1.

Figure-2: Illustrates the PXRD pattern of crystalline form-S of 4-[(2,4-dichloro-5-
methoxypheny l)amino]-6-methoxy-7- [3 -(4-methyl- l-piperazinyl)propoxy]- 3 -quinoline
carbonitrile compound of formula-1 obtained according to example-2.

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-butyl 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 the like; "riitrile- solvents" refers to acetonitrile, propionitrile/isobutyronitrile and the like; "alcohol solvents" refers to methanol, ethanbl, n-propahol, iso-propanol, n-butanol, iso-butanol, t-butanol, ethane-1,2-dioI, 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-[(2,4-dichioro-5-methoxyphehyl)aminb]-6-methoxy-7-[3-(4-methyl-l-
propoxy]-3-quinolirieearbonitrile compound of formula-1. The said novel crystalline fonn is designated herein as crystalline form-M and it is characterized by its PXRD diffractogram as illustrated in figure-1.

The second aspect of the present invention provides novel crystalline polymorph of 4- [(2,4-dichloro-5 -methoxypheny l)amino] -6-methoxy-7 - [3 -(4-methy 1-1 -piperaziny 1) propoxy]-3-quinolinecarbonitrile compound of formula-1. The said novel crystalline form is designated herein as crystalline form-S and it is characterized by its PXRD pattern having peaks at 5.8, 15.2 and 26.9 ± 0.2° of 2-theta. The crystalline form-S of compound of formula-1 is further characterized by its PXRD pattern, having peaks at 9.4, 12.4, 18.8, 19.7 and 24.8 ± 0.2° of 2-theta and its PXRD diffractogram as illustrated in figure-2.

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, solubi.lizing agents^ pH buffering agents, perfuming
agents,' surface stabilizing agents, suspending agents and' 'other conventional
pharmaceutically inactive agents.

The third aspect of the present invention provides process'for the preparation of crystalline form-M of 4-[(2,4-dichl6ro-5-meth6xyphenyl)amino]-6-me'thoxy-7-[3-(4-methyl-l-piperazinyOpropoxyJ-S-quinoliriecarbonitrile compound of formula-1. The said process comprising of;
a) Dissolving the compound of formula-1 in asuitable solvent,
b) optionally filtering the solution,
c) combining the solution obtained in step-a) or step-b) with a suitable anti -solvent,
d) filtering the precipitated solid and suck dry the material under vacuum to provide crystalline form-M of compound of formula-1.

Wherein, in step-a) the suitable solvent is selected from chloro solvents, alcohol solvents, ketone solvents, ester solvents, nitrile solvents, polar-aprotic solvents or their mixtures; the dissolution of compound of formula-1 in the said solvent/solvent mixture can be carried out at a suitable temperature generally ranges between 10°C to reflux temperature of the solvent used;

In step-c) the suitable anti-solvent is selected from hydrocarbon, solvents,. ether solvents, water or their mixtures; combining the solution of step-a) or step-b) with suitable anti-solvent can be carried out at a temperature ranging from -60°C to 35°C.

A preferred embodiment of the present invention provides process for preparation of crystalline form-M of compound of formula-1, comprising of;
a) Dissolving the compound of formula-1 in dichloromethane,
b) combining the solution obtained in step-a) with pre-cooled n-heptane,
c) filtering the precipitated solid and suck dry the material under vacuum to provide crystalline form-M of compound of formula-1.

The fourth aspect of the present invention provides process for the preparation of crystalline form-S of 4-[(2,4-dichioro-5-me l-piperazinyl)propoxy]-3-quinolinecarbohitrile compound of formula-1, comprising of;
a) Dissolving the compound of formula-1 in a suitable solvent,
b) optionally filtering the solution.
c) combining the solution obtained in step-a) or step-b) with a suitable anti-solvent, ■
d) filtering the precipitated solid and suck dry the material under vacuum,
e) further drying the solid obtained in step-d) under vacuum to provide crystalline form-S of compound of formula-1.

Wherein, in step-a) the suitable'solvent and the suitable temperature are same as defined in step-a) of the third aspect of the present invention;
In step-c) the suitable anti-solvent and the suitable temperature are same as defined in step-c) of the third aspect'of the present invention;
In step-e) the said drying process is carried out at a temperature ranging from 35°C to 70°C and the drying is carried out for 2-6 hrs.

A preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of compound of formula-1, comprising of;
a) Dissolving the compound of formula-1 in dichloromethane,
b) combining the solution obtained in step-a) with pre-cooled n-heptane,
c) filtering the precipitated solid and suck dry the material under vacuum,
d) further drying the solid obtained in step-c) under vacuum to provide crystalline form-S of compound of formula-1.

A more preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of compound of formula-1, comprising of;
a) Dissolving the compound of formula-1 in dichloromethane,
b) combining the solution obtained in step-a) with a pre-cooled mixture of n-heptane and water,
c) filtering the precipitated solid and suck dry the material under vacuum,
d) further drying the solid obtained in step-c) under vacuum to provide crystalline form-S of compound of formula-1.

The compound of formula-! which is used as'input-for the preparation of novel crystalline polymorphs of the present invention can be prepared by any of the processes known in the art or it can be'prepared by1 the process described in' our co-pending Indian patent applications.
In the above described processes, any'physical form of compound of formula-1 including solvates and hydrates known in the art can be utilized as input for the preparation of novel crystalline polymorphs of the present invention.
In one embodiment, methanol solvate form or isopropyl alcohol solvate form of compound of formula-1 which are described in US7767678B2 can be used as input for the preparation of novel crystalline forms of the present invention.
• . * * *: * ■
In a preferred embodiment, isopropyl alcohol solvate form of compound of formula-1 which is described in US77676V8B2 is used as input for the preparation of novel crystalline forms of. the present invention. The said isopropyl alcohol solvate form can be prepared as per the process, described in US7767678B2. or according.to the process described in the present application or according to the process described in.our co-pending Indian patent applications.

The novel crystalline forms of the present invention can be utilized as input for the preparation of amoiphous form or other crystalline polymorphs of compound of formula-1.

The novel crystalline forms of the present invention are useful for the preparation of various pharmaceutical compositions.

The PXRD analysis of crystalline polymorphs of compound of formula-1 of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using CuKa radiation of wavelength 1.5406 A° arid at a continuous scan speed of 0.037min.

The novel crystalline polymorphs of compound of formula-1 of the present invention can be further microriized or milled to get desired particle size to achieve desired solubility profile based oh 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 examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.

Examples:

Example-1: Preparation of crystalline form-M of 4-[(2,4-dichloro-5-methoxyphenyl)
amino]-6-methoxy-7-[3-(4-methyI-l-piperazinyl)propoxy]-3-quinolinecarbonitrile

Dichloromethane (200 ml) was added to 4-[(2,4-dichloro-5-methoxyphenyl)amino]-
6-methoxy-7- [3 -(4-methyl-1 -piperaziriyl)pr6poxy] -3 :quinolinecarbonitrile ' compound of
formula-1 (10 gm) at 25-30°C and stirred the reaction mixture for 10'rhih at' the same
temperature. The obtained solution was slowly added to pre-cooled n-heptane (500 ml) at
-45°C to -50°C and stirred for 5 min at the same temperature. Filtered the precipitated solid
and suck dried the material for 1 hi' under vacuum to get the title compound.
The PXRD pattern of the obtained compound is shbwn in figure-1.
Yield: 8.0 gm.

Exaniple-2: Preparation of crystalline form-S of 4-[(2,4-dichloro-5-meth6xyphenyl) amino]-6-rnethoxy-7-[3-(4-methyl-l-piperazinyl)propoxyJ-3-quinolinecarbonitrile
,
The crystalline solid form of compound of formula-1 obtained in above example-1
was further dried at 65-70°C for 5 hrs under vacuum to get the title compound.
The PXRD pattern of the obtained1 compound is shown in figure-2.
Yield: 7.0 gm;

Example-3: 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 compound of formula-1 (33 Kg) was added to dichloromethane (800 Lt) at 15-20°C and stirred the reaction mixture for 20 min at the same temperature. Filtered the solution, 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 suck dried the material. Further dried the material at 40-45°C for 3 hrs to get the title compound. The PXRD pattern of the obtained compound is similar to figure-2. Yield: 2.4.95 Kg.

Example-4: Preparation of 7-(3-chloropropoxy)-4-((2,4-dichloro-5-methoxyphenyl) amino)-6-methoxyquinoIine-3-carbonitrile hydrochloride

Isopropyl alcohol-HCl (25 Lt) was slowly added to a mixture of 4-chloro-7-(3-
chloropropoxy)-6-methoxyquinoline-3-carbonitrile t (50 Kg),;x2,4-dichloro-5-methpxyaniline
(35.5 Kg).and acetonitrile (400 Lt) at 25-3p°C. Heated the reaction; mixture/to 75-80°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 precipitated solid, washed with acetonitrile and
spin dried the material. The obtained solid was added to methanol (300 Lt) 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 2 hrs at the same temperature. Filtered
the solid, washed with methanol and dried the material to provide the title compound;
Yield:66.0Kg
ExahipIe-5: Preparation of 4-[(24-dichi6r65meth6xyphehyl)amind]6-niethoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-qiiinolinecarbonitrile methanol solvate

N-methyl piperazine: (69.62 Kg)' was added to a mixture of 7-(3-chloro propoxy)-4-((2,4-dichloro-5-methoxyphenyl)amino)-6-meth6xyquiholine-3-carbonitrile: hydrochloride (65 Kg) and acetonitrile (455 Lt) at 25-30°C. Potassium carbonate (19.18 Kg), triethylamine (14.04 Kg),-potassium iodide (2.3 Kg) and tetrabutyl ammonium bromide (4.45 Kg) were added to the reaction mixture 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 distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with methanol. Methanol (260 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 25-306C and stirred for 2 hrs at the same temperature. Filtered the compound, washed with methanol and dried the material. The

obtained compound was added to dimethylformamide (100 Lt) at 25-30°C. Acetone (78 Lt) were added to the reaction mixture at 25-30°C and stirred 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 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 for 3 hrs at the same temperature. Filtered the solid, washed with methanol and suck dried the material. The obtained solid was added to dimethylformamide (73 Lt) at 25-30°C. Acetone (78 Lt) was added to the reaction mixture at 25-30°C and stirred the reactiori 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! The obtained compound was added to methanol (620 Lt) at 25-30°C. Water (31.2 Lt) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 10 min at the same temperature. Cooled the reactiori mixture to 25-30°C, water (312 Lt) was added ana! stirred the reaction mixture for 3 hrs at the same temperature. Filtered the solid, washed with methanol and dried the material to provide the title compound. Yield: 39.0 Kg.

Example-6: Preparation of crystalline form-S of 4-[(2,4-dichlor6-5-methoxyphenyl) amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinoline carbonitrile

4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl) propoxy]-3-quinolinecarbonitrile methanol solvate (32 Kg) was added to a mixture of isopropyl alcohol (256 Lt) and water (128 Lt) at 25-30°C. Heated the reaction mixture to 75-80°C and stirred for 1 hr at the same temperature. Filtered the reaction mixture and 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 precipitated solid, washed with aqueous isopropyl alcohol and dried the material. The obtained solid was added to dichloromethane (800 Lt) at 15-20°C and stirred the reaction mixture for 20 min at the same

temperature. Filtered the solution, 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 suck
dried the material. Further dried the material at 40-45°C for 3 hrs to get the title compound.
The PXRD pattern of the obtained compound is similar to figure-2.
Yield: 24.95 Kg.

Particle size distribution: D(0.1) is 1.98 urn; D(0.5) is 5.46 urn; D(0.9) is 18.24 urn

We Claim:
1. Crystallineform-Mof4-[(2;4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile compound of formula-1 characterized by its PXRD diffractogram as shown in figure-1.
2. Crystallineform-Sof4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile compound of formula-1 characterized by its PXRD pattern having peaks at 5.8, 15.2 and 26.9 ± 0.2° of 2-theta.
3.Thecrystallineform-Sof4-[(2i4-dichlor6-5-methoxyphenyl)amind]-6^methoxy-7-[3-(4-methyl-l-piperaziriyl)propoxy]-3-quinoliriecarbonitrile compound of formula-1 according to claim 2, which is further characterized by its PXRD pattern having peaks at 9.4, 12.4, 18.8, 19.7 and 24.8 ± 0.2° of 2-theta.
4. The crystalline form-S of 4-'[(2,4-clichlbro-5-methoxyphenyi)amino]-6-methoxy-7-ti3-(4-. methyl-l-piperazinyl)prdpoxy]-3-quinolinecarbonitriie compound of formula-1 according ■ to claims 2 & 3, which is further characterized by its PXRD pattern as shown in figure-2.
5'. A process for the preparation of crystalline form-M ' of 4-[(2,4-dichlor6-5-methoxyphenyl)amino]-6-meth6xy-7-[3-(4-methyl-1 -piperazinyl)propoxy]-3-quinoline carbonitrile compound of formula-1, comprising of;
a) Dissolving the compound of formula-1 in a suitable solvent,
b) optionally filtering the solution,
c) combining the solution obtained in step-a) or step-b) with a suitable anti-solvent,
d) filtering the precipitated solid and suck dry the material under vacuum to provide crystalline form-M of compound of formula-1.

6. A process according to claim 5, wherein,
in step-a) the suitable solvent is selected from chloro solvents, alcohol solvents, ketone solvents, ester solvents, nitrile solvents, polar-aprotic solvents or their mixtures;
in step-c) the suitable anti-solvent is selected from hydrocarbon solvents, ether solvents, water or their mixtures.
7. A process for the preparation of crystalline form-M of 4-[(2,4-dichloro-5-
methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinoline cafbdnitrile compound of formula-1, comprising of;
a) Dissolving the compound of formula-1 in dichloromethane,
b) combining the solution bbtainediri step-a) with pre-cooled n-heptane,
c) filtering the precipitated solid and suck dry the material under vacuum to provide crystalline form-M of compound of formula-1.
8. A process for the preparation of crystalline fbrm-S of 4-[(2,4-dichloro-5-
methbxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinoline carbonitrile compound of formula-1, comprising of;
a) Dissolving the compound of formula-1 in a suitable solvent,
b) optionally filtering the solution, '
c) combining the' solution obtained in step-a) or step-b) with' a suitable anti-solvent, !
d) filtering the precipitated solid and suck dry the material under vacuum,
e) further drying the solid obtained in step-d) under vacuum to provide crystalline form-S of compound of formula-1.
9. A process according to claim 8, wherein,
in step-a) the suitable solvent is selected from chloro solvents, alcohol solvents, ketone solvents, ester solvents,1 nitrile solvents, polar-aprotic solvents or their mixtures;
i r
in step-c) the suitable anti-solvent is selected from hydrocarbon solvents, ether solvents, water or their mixtures. '

10. A process for the preparation of crystalline form-S of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinoline carbonitrile compound of formula-1, comprising of;
a) Dissolving the compound of formula-1 in dichloromethane,
b) combining the solution obtained in step-a) with a pre-cooled mixture of n-heptane and water,
c) filtering the precipitated solid and suck dry the material under vacuum,
d) further drying the solid under vacuum to provide crystalline form-S of compound of formula-1.