Field of the Invention: The present invention provides amorphous form of 4-[(2,4-dichloro-5-methoxy phenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinoline carbonitrile represented by the following structural formula-1 and process for its preparation. Cl\ ^^ X Formula-1 It also pertains to amorphous solid dispersion of 4-[(2,4-dichloro-5-methoxy phenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinoline carbonitrile compound of formula-1 in combination with at least one excipient. Background of the Invention: 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-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 polymorphic forms of Bosutinib viz., crystalline monohydrate form-I, crystalline monohydrate form-II, IPA solvate form-Ill, crystalline hydrate form-IV, anhydrous crystalline form-V & methanol solvate form-VT. As on today, none of the literature documents has taught the existence of Bosutinib in amorphous form. The present inventors have surprisingly found the existence of Bosutinib in stable amorphous solid state form which is useful for the preparation of various pharmaceutical 5 compositions. Brief description of the invention: The first aspect of the present invention is to provide amorphous form of 4-[(2,4- dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-10 quinolinecarbonitrile compound of formula-1. The second aspect of the present invention is to provide process for the preparation of amorphous form of. 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1 -piperazinyl)propoxy]-3-quinolinecarbonitrile compound of formula-1. 15 The third aspect of the present invention is to provide amorphous solid dispersion comprising 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1 - piperazinyl)propoxy]-3-quinolinecarbonitrile and at least one excipient. 20 The fourth aspect of the present invention is to provide process for the preparation of amorphous solid dispersion comprising 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6- methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile compound of 3f formula-1 and at least one excipient. "5. E o o o 25 The fifth aspect of the present invention is to provide process for the preparation of 4- [(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]- 5 3-quinolinecarbonitrile compound of formula-1. Q is o CN ■ LU X o I CN CN CN CO CD CO CD CN CN CD O cp 11 T c 3 30 ATE NT OFFICE CBEKNAI 24/8&/2818 15=^7 CN 10 Brief Description of the Drawings: Figure-1: Illustrates the PXRD pattern of pure amorphous form of compound of formula-1. Figure-2: Illustrates the PXRD pattern of amorphous solid dispersion comprising compound of formula-1 and Povidone K-30 Figure-3: Illustrates the PXRD pattern of amorphous solid dispersion comprising compound of formula-1 and hydroxypropyl cellulose (HPC) Figure-4: Illustrates the PXRD pattern of amorphous solid dispersion comprising compound of formula-1 and hydroxypropyl methylcellulose (HPMC) Figure-5: Illustrates the PXRD pattern of amorphous solid dispersion comprising compound of formula-1 and hydroxypropyl methylcellulose acetate succinate (HPMCAS) Figure-6: Illustrates the PXRD pattern of amorphous solid dispersion comprising compound of formula-1 and Eudragit L 100-55. _0) Q. E o o, o o NH, f' ~^<^^\nj Formula-6 6a: R= CH3, Xx= CI ,R 0 Formula-4 4a: R= CH3, Xt= CI Nitration Formula-S 5a: R= CH3, X1= CI CN H.N^-'V 2-^ Cyclization 0 POC1 CI C1XX Formula-10 FormuIa-8 8a: X!= CI Formula-9 9a: Xx= CI Bosutinib Formula-1 Formula-11 lla:Xj=Cl Wherein, 'R' represents Ci-C6 straight chain or branched chain alkyl group; 'Xi' & 'X2' are same or different and represents leaving groups such as hydroxy, halogens, substituted/unsubstituted alkyl/aryl sulfonates; 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. 14 Examples: Example-1: Preparation of methyl 4-(3-chloropropoxy)-3-methoxybenzoate (Formula-4a) Thionyl chloride (106 gm) was slowly added to a mixture of 4-hydroxy-3-methoxybenzoic acid compound of formula-2 (100 gm) and methanol (500 ml) at 25-30°C. Heated the reaction mixture to 45-50°C and stirred for 3 hrs at the same temperature. Distilled off the solvent and excess thionyl chloride completely from the reaction mixture. Cooled the reaction mixture to 25-30°C. Dimethylformamide (300 ml), potassium carbonate (164 gm) followed by l-bromo-3-chloropropane (140 gm) were slowly added to the reaction mixture at 25-30°C and stirred 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 then dried to get the title compound. Yield: 140.0 gm; M.R: 105-107°C. Example-2: Preparation of methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate (Formula-5a) A mixture of methyl 4-(3-chloropropoxy)-3-methoxybenzoate compound of formula-4a (100 gm) and acetic acid (150 ml) was heated to 45-50°C. Nitric acid (110 ml) was slowly added to the reaction mixture at 45-50°C and stirred for 2 hrs at the same temperature. Cooled the reaction mixture to 25-30°C, water was slowly added and stirred for 2 hrs at the same temperature. Filtered the solid, washed with water and then dried the material to get the title compound. Yield: 110.0 gm; M.R: 65-69°C. Example-3: Preparation of methyl 2-amino-4-(3-chloropropoxy)-5-methoxybenzoate (Formula-6a) Iron powder (60.6 gm), methanol (750 ml) and methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate compound of formula-5a (100 gm) 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 and washed with methanol. Distilled off the solvent completely 15 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 and distilled off the solvent completely from the organic layer and co-distilled with cyclohexane. Cyclohexane (500 ml) was.added to the obtained compound at 25-30°C and stirred for 2 hrs 5 at the same temperature. Filtered the solid, washed with cyclohexane and then dried to get the title compound. Yield: 80.0 gm; M.R: 95-98°C. Example-4: Preparation of 7-(3-chIoropropoxy)-6-methoxy-4-oxo-3,4-dihydroquinoline-10 3-carbonitrile (Formula-8a) Step-1: A mixture of dimethylformamide dimethyl acetal (200 gm) and methyl 2-amino-4-(3-chloropropoxy)-5-methoxybenzoate compound of formula-6a (100 gm) was heated to 75-80°C and stirred for 4 hrs at the same temperature. Distilled off the reaction mixture completely under reduced pressure and cooled to 25-30°C. Tetrahydrofuran (200 ml) was 15 added to the obtained compound and the solution was kept aside. CD _CD a E Step-2: Acetonitrile (150 ml) was slowly added to a pre-cooled mixture of sodium bis(trimethylsilyl)amide (600 ml) and tetrahydrofuran (400 ml) at -65°C to -70°C in another RBF and stirred the reaction mixture for 2 hrs at the same temperature. The solution obtained in step-1 was slowly added to the reaction mixture at -65°C to -70°C and stirred for 2 hrs at 20 the same temperature. Acetic acid (200 ml) was slowly added to the reaction mixture at - 65°C to -70°C. Raised the temperature of the reaction mixture to 25-30°C and distilled off the reaction mixture completely under reduced pressure. Water was added to the reaction mixture at 25-30°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with water and dried to get title compound. o 25 Yield: 85.0 gm; M.R: 250-260°C (decomp.). C O u ExampIe-5: Preparation of 4-chIoro-7-(3-chloropropoxy)-6-methoxyquinoIine-3- g carbonitrile (FormuIa-9a) o CM ^ Phosphorous oxychloride (162 ml) was added to a mixture of 7-(3-chloropropoxy)-6- 30 methoxy-4-oxo-3,4-dihydroquinoline-3-carbonitrile compound of formula-8a (100 gm) and toluene (300 ml) at 25-30°C. Heated the reaction mixture to 85-90°C and stirred for 7 hrs at CN CN CN 16 CO CD CO CD CN CN § PA.TFMT OFFICE CHE^SA-I 2: 4 / 8 S t 2 % I S 15- &; £ 3 CN the same temperature. Distilled off the reaction mixture completely under reduced pressure. Cooled the reaction mixture to 25-30°C and water was added. Basified the reaction mixture using aq.sodium carbonate solution at 25-30°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 85.0 gm; M.R: 144-148°C. Example-6: Preparation of 7-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxy phenylamino)-6-methoxyquinoline-3-carbonitrile(FormuIa-lla) 4-Chloro-7-(3-chloropropoxy)-6-methoxyquinoline-3-carbonitrile compound of formula-9a (100 gm) followed by 2,4-dichloro-5-methoxyaniline compound of formula-10 (62 gm) were added to a mixture of 2-ethoxyethanol (500 ml) and pyridine hydrochloride (37 gm) at 25-30°C. Heated the reaction mixture to 120-125°C and stirred for 5 hrs at the same temperature. Cooled the reaction mixture to 25-30°C, water was slowly added and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the solid, washed with water and then dried the material to get the title compound. Yield: 107.0 gm. ExampIe-7: Preparation of 7-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxyphenyl amino)-6-methoxyquinoIine-3-carbonitriIe(FormuIa-lla) 2,4-Dichloro-5-methoxyaniline compound of formula-10 (101 gm) followed by isopropyl alcohol-HCl (80 ml) were added to a mixture of 4-chloro-7-(3-chloropropoxy)-6-methoxyquinoline-3-carbonitrile compound of formula-9a (150 gm) and isopropyl alcohol (1200 ml) at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 6 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 isopropyl alcohol and then dried the material to get the title compound. Yield: 215.0 gm. 17 Example-8: Preparation of 4-[(2,4-dichIoro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyI)propoxy]-3-quinolinecarbonitriIe(FormuIa-l) Sodium iodide (16 gm) was added to a mixture of 7-(3-chloropropoxy)-4-(2,4- dichloro-5-methoxyphenylamino)-6-methoxyquinoline-3-carbonitrile compound of 5 formula-lla (50 gm) and N-methyl piperazine (600 ml) at 25-30°C. Heated the reaction mixture to 75-80°C and stirred for 8 hrs at the same temperature. Cooled the reaction mixture to 25-30°C, water was slowly added and stirred for 2 hrs at the same temperature. Filtered the solid and washed with water. Methanol (250 ml) was added to the obtained wet compound at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 30 min at the same 10 temperature. Charcoal (2.5 gm) was added to the reaction mixture and stirred for 5 min. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with methanol. Water (275 ml) was slowly added to the filtrate at 25-30°C and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the precipitated solid, washed with aqueous methanol and then dried the material to get the title compound. 15 Yield: 10.0 gm. Example-9: Preparation of compound of formula-1 a E Potassium carbonate (5.9 gm), triethylamine (4.3 gm), potassium iodide (0.7 gm) followed by tetrabutyl ammonium bromide (1.37 gm) were added to a mixture of 7-(3- 20 chloropropoxy)-4<2,4-dichloro-5-methoxyphenylamino)-6-methoxyquinoline-3-carbonitrile compound of formula-lla (20 gm), acetonitrile (140 ml) and N-methyl piperazine (21.4 ml) at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 8 hrs at the same temperature. Filtered the reaction mixture, distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with methanol. 100 ml of methanol was added £ 25 to the obtained compound at 60-65°C and stirred for 45 min at the same temperature. Cooled J the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. Filtered the ■z precipitated solid, washed with methanol and then dried to get the title compound. | Yield: 12.0 gm. o CN ■ LU 30 CN CN CN CO CD CO CD CN CN CD 18 S P ATE Ul a-FFICE C H-E N-U A-1. 2 4 r 9t £ / 7 % 1 g \ S = $ £ 3 ■ CN Example-10: Preparation of amorphous form of compound of formula-1 A mixture of compound of formula-1 (2 gm) and dichloromethane (15 ml) was stirred for 10 min at 25-30°C and the obtained solution was filtered. Charged the above clear solution to Buchi flask. Distilled off the solvent completely from the solution under reduced 5 pressure and dried the obtained solid to get the title compound. The PXRD pattern of the obtained solid is shown in figure-1. Yield: 1.4 gm. Example-11: Preparation of amorphous form of compound of formula-1 10 A mixture of compound of formula-1 (5 gm) and acetone (125 ml) was stirred for 10 min at 25-30°C and the obtained solution was filtered. The obtained clear solution was spray dried to get the title compound. The PXRD pattern of the obtained solid is similar to figure-1. Yield: 1.7 gm. 15 Example-12: Preparation of amorphous form of compound of formula-1 A mixture of compound of formula-1 (2 gm) and ethyl acetate (40 ml) was stirred for 10 min at 25-30°C and the obtained solution was filtered. Charged the above clear solution to Buchi flask. Distilled off the solvent completely from the solution under reduced pressure 20 and dried the obtained solid to get the title compound. The PXRD pattern of the obtained solid is similar to figure-1. Yield: 1.5 gm. a E o Example-13: Preparation of amorphous form of compound of formula-1 25 A mixture of compound of formula-1 (2 gm) and methanol (40 ml) was stirred for 10 £ O £ min at 25-30°C. Slowly heated the reaction mixture to 55-60°C and stirred for 5 min at the o Q Jo same temperature. Filtered the reaction mixture and the filtrate was charged in to a Buchi flask. Distilled off the solvent completely from the filtrate under reduced pressure and dried LU the obtained solid to get the title compound. S 30 The PXRD pattern of the obtained solid is similar to figure-1. Yield: 1.5 gm. CN CN CN CO CO CO CO CN CN CO 19 S p A,T EHI OFFICE CH F W H A-I 2 4 t & & / 2 81 k 1 C 3 ■ CN Example-14: Preparation of amorphous solid dispersion comprising compound of formula-l and Povidone K-30 (1:1) A mixture of compound of formula-l (0.5 gm), Povidone K-30 (0.5 gm) and methanol (30 ml) was stirred for 10 min at 25-30°C. Slowly heated the reaction mixture to 60-65°C and stirred for 1 hr at the same temperature. The obtained solution was charged in to Buchi flask. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the obtained solid to get the title compound. The PXRD pattern of the obtained compound is shown in figure-2. Yield: 740.0 mg. Example-15: Preparation of amorphous solid dispersion comprising compound of formula-l and hydroxypropyl cellulose (HPC) (1:1) A mixture of compound of formula-l (0.5 gm), hydroxypropyl cellulose (0.5 gm) and dichloromethane (30 ml) was stirred for 10 min at 25-30°C. Slowly heated the reaction mixture to 40-45°C and stirred for 30 min at the same temperature. The obtained solution was charged in to Buchi flask. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the obtained solid to get the title compound. The PXRD pattern of the obtained compound is shown in figure-3. Yield: 450.0 mg. Example-16: Preparation of amorphous solid dispersion comprising compound of formula-l and hydroxypropyl methylcellulose (HPMC) (1:1) A mixture of compound of formula-l (0.5 gm), hydroxypropyl methylcellulose (0.5 -gm) and methanol (40 ml) was stirred for 10. min at 25-30°C. Slowly heated the reaction mixture to 60-65°C and stirred for 1 hr at the same temperature. The obtained solution was charged in to Buchi flask. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the obtained solid to get the title compound. The PXRD pattern of the obtained compound is shown in figure-4. Yield: 720.0 mg. 20 Example-17: Preparation of amorphous solid dispersion comprising compound of formula-1 and hydroxypropyl methylcellulose acetate succinate (HPMCAS) (1:1) A mixture of compound of formula-1 (0.5 gm), hydroxypropyl methylcellulose acetate succinate (0.5 gm) and methanol (35 ml) was stirred for 10 min at 25-30°C. Slowly heated the reaction mixture to 60-65°C and stirred for 45 min at the same temperature. The obtained solution was charged in to Buchi flask. Distilled off the solvent completely from the reaction mixture under reduced pressure and dried the solid to get the title compound. The PXRD pattern of the obtained compound is shown in figure-5. Yield: 720.0 mg. 10 Example-18: Preparation of amorphous solid dispersion comprising compound of formula-1 and Eudragit L 100-55 (1:1) A mixture of compound of formula-1 (0.5 gm), Eudragit L 100-55 (0.5 gm) and methanol (45 ml) was stirred for 10 min at 25-30°C. Slowly heated the reaction mixture to 15 60-65°C and stirred for 45 min at the same temperature. The obtained solution was charged in to Buchi flask. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the obtained solid to get the title compound. The PXRD pattern of the obtained compound is shown in figure-6. Yield: 680.0 mg. 20 a o 25 "ST o u "^ NH2 Formula-6a with dimethylformamide dimethyl acetal followed by cyclization of the obtained compound by reacting it with acetonitrile in presence of NaHMDS in a suitable solvent to provide compound of formula-8a. Dated this day £g.M of June 2016 20 E o Jo o CN i LU X o I CN CN CN CO CO CO CO CN CN CO o CN i C 3 25 P A..TF MX 0 F F I C E CHEH & A-I A * * * it it it 26 > M /■ U\ b, Authorized Signatory (Srinivasan Thirumalai Raj an) MSN Laboratories Private Limited l 8 I■ £■ I 5 2: (? ? CN