NOVEL INTERMEDIATES AND PROCESS FOR THE PREPARATION OF LAPATINIB

FIELD OF INVENTION:

Present invention relates to a novel process for the preparation of lapatinib of formula-I having chemical name N-{3-Chloro-4-[(3-fluorobenzyloxy]phenyl}-6-[5-({[2-(methanesulfonyl)ethyl]-amino}methyl]-2-furyl]-4-quinazolinamine and its pharmaceutically acceptable salts. Lapatinib ditosylate of formula-II is currently marked in the United States under the trade name TYKERB by GlaxoSmithKline. It was approved by the US FDA as a drug for use in patients with advanced metastatic breast cancer.

BACKGROUND OF INVENTION:

Lapatinib of formula-I is reported for the first time by M.C. Carter et.al in PCT International Publication No. : WO 99/35146 (1999 to Glaxo). Its equivalent US Patent is US 6727256 (2004 to SmithKline Beecham). Process for the preparation of Lapatinib of formula-I, disclosed in WO 99/35146, is given in Scheme-I. Accordingly, 4-chloro-6-iodo-quinazoline of formula-Ill, is reacted with 3-chloro-4-(31-fluoro-benzyloxy)aniline to get N-[3-chloro-4-{(31-fluoro-benzyloxy)phenyl}]-6-iodo-quinazoline of formula-IV. Compound of formula-IV is reacted with (1,3-dioxolan-2-yl)-2-(tributylstannyl)furan to get the compound of formuIa-V which on reaction with HC1, gave 5-(4-{3-chloro-4-(3-fluoro-benzyloxy)anilino}-6- quinazolinyl)-furan-2-carbaldehyde of formula-VI. The compound of formula-VI is reacted with 2-methanesulfonylethylamine, followed by reduction to give the required compound Lapatinib of formula-I as an organic residue. The crude labatinib is purified by column chromatography. Scheme-I In the subsequent PCT international publication No. WO 02/02552 (Glaxo) and its equivalent US7157466; the preparation of ditosylate salt of Lapatinib of formula-II is disclosed as shown in Scheme-II.

Subsequently processes for the preparation of Lapatinib and its ditosylate are described in PCT applications WO 2002/056912, WO 2003/086467, WO 2005/046678, WO 2006/002422, WO 2006/089150, WO 2006/113649, WO 2007/121279, WO 2007/143483, WO 2008/063853, WO 2008/067144, WO 2008/154469, WO 2009/079547, WO 2009/079541, WO 2009/140144, WO 2010/017387, WO 2010/061400, WO 2010/120387, WO 2010/148163, WO 2011/035540, WO 2011/039759, WO 2011/116634, WO 2011/160594, WO 2012083440, and WO 2012/017448. Process for the preparation of lapatinib is also disclosed in EP 2468745 and EP 2489661. In these disclosed processes key reaction is based on the coupling of one arylboronic acid with one haloaryl moiety in the presence of a palladium reagent. Main drawbacks in these processes are the involvement of costly intermediates having boronic acid functionality and the palladium catalysts.

SUMMARY OF THE INVENTION:

Keeping in view of the difficulties in the above mentioned prior art processes for the preparation of Lapatinib on a commercial scale, we aimed to develop a simple, economical and commercially viable process for the preparation of Lapatinib, of formula-I. Accordingly, the main objective of the present invention is to provide an improved process for the preparation of Lapatinib of formula-I, which is simple, economical and commercially applicable. According to another objective of the present invention is to provide an improved process for the preparation of Lapatinib of formula-I, which involves readily and cheaply available raw materials. Yet another objective of the present invention is to provide an improved process for the preparation of lapatinib of formula-I which avoids the usage of costly boronic acid intermediates and palladium reagents. During our sustained research in developing a process for the preparation of Lapatinib of formula-I on a commercially viable scale, we observed that Meerwein reaction between an aryl diazonium salt and furfuraldehyde would provide the required aryl C-C coupled product. Such process would eliminate the need of aryl boronic acid and palladium catalysts. According to Meerwein reaction furfuraldehyde would react exclusively on 5-position with a diazonium salt in the presence of a metal catalyst (Scheme-Ill). Scheme-Ill Accordingly, 6-aminoquinazoline derivatives are considered as potential precursors for diazonium intermediates. Commercially and readily available 2-amino-5-nitrobenzonitrile of formula-VIII could be a suitable starting material.

DETAILED DESCRIPTION OF THE INVENTION:

Process of the present invention is given in below Scheme-IV. Commercially available 2-amino-5-nitrobenzonitrile of formula-XI is reacted with formic acid/sulfuric acid under known conditions (Bertrand Jacques Jean-Claude, et al, J. Med. Chem. 2006, 49, 3544-3552) to get 6-nitro-quinazolin-4-ol of the formula-XII. The compound of formula-XII is reduced with iron powder and catalytic quantity of ammonium chloride in the presence of aqueous isopropyl alcohol to get 6-amino-quinazolin-4-ol of formula-XIII. The amino compound of formula-XIII is diazotized with sodium nitrite in hydrochloric acid medium and coupled with 2-furfuraldehyde in the presence of cupric chloride to get the coupled aldehyde compound of formula-XIV. The key intermediate of formula-XIV was reacted with 2-methanesulfonylethylamine or its salt in the presence of triethylamine in an alcoholic solvent at reflux temperature to give the corresponding imine compound of formula-XV, which was reduced to get the amine compound of formula-XV. The amine compound of formula-XV is selectively protected on NH group with trifluoroacetic anhydride to get the corresponding trifluoroacetyl derivative of formula-XVI. Compound of formula-XVI is reacted with excess thionyl chloride or oxalyl chloride to get the chloro compound.

The chloro compound is reacted with 3-chloro-4-(3-fluorobenzyloxy)aniline at an elevated temperature to get the N-aryl derivative of formula-XVII. The N-protected group of compound of formula-XVII is removed under acidic or basic conditions to get lapatinib base of formula-I. The crude base is converted into tosylate salt by using p-toluenesulfonic acid monohydrate to get technical lapatinib ditosylate salt of formula-II. The crude salt is crystallized from aqueous isopropyl alcohol to get high purity lapatinib ditosylate monohydrate salt. Scheme-IV In one embodiment, the present invention provides an improved process for the preparation of Lapatinib of formula-I. and its pharmaceutically acceptable salts, which comprises:

(i) Reduction of 6-nitroquinazolin-4-ol of formula-XII with a metal catalyst and a catalytic quantity of ammonium chloride in the presence of aqueous alcohols at reflux temperature to get the amino compound of formula-XIII,

(ii) Diazotization of compound of formula-XIII with sodium/potassium nitrite in the presence of an acid and coupling with furfural in the presence of a copper catalyst to get the coupled product of formula-XIV,

(iii) Reaction of compound of formula-XIV with 2-methanesulfonylethylamine or its salt in a solvent medium at elevated temperature to get an imine derivative of formula-XV,

(iv) Reduction of compound of formula-XV in a solvent medium to get the amine compound of formula-XVI,

(v) Selective protection of the amino group of the compound of formula-XVI with a suitable protecting group to get the compound of formula-XVII,

Wherein R = C1-C6 alkyl, perfluoroalkyl, C1-C6 alkoxy, etc.

(vi) Conversion of hydroxyl group present in XVII into a leaving group with a suitable reagent to get the compound of formula-XVIII, Wherein X = CI, Br, I, OSO2CH3, OSO2CF3, OTs, OBs, etc., R = C1-C6 alkyl, perfluoroalkyl, C1-C6 alkoxy, etc.

(vii) Reacting the compound of the formula-XVIII with 3-chloro 4-(3- fluorobenzyloxy)aniline in a solvent medium at an elevated temperature to get the amine protected lapatinib base of formula-XIX, Wherein R = as defined above

(viii) Removal of amine protection group in compound of formula-XIX using a base or acid to get lapatinib base of formula-I,

(ix) Conversion of lapatinib base into pharmaceutically acceptable p-tolunesulfonate salt in a solvent medium to get lapatinib di-tosylate of formula-II as its monohydrate,

In a preferred embodiment of the present invention metal catalyst used in step (i) is selected from iron, zinc, nickel, etc., preferably iron powder. Alcoholic solvent used in step (i) is selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, t-butanol, etc., preferably isopropanol. Acid medium used in diazotization step (ii) is selected from dilute hydrochloric acid, sulfuric acid, preferably hydrochloric acid. Copper catalyst used in step (ii) is selected from copper (II) chloride, copper (II) acetate, etc., preferably copper (II) chloride. In a preferred embodiment of the present invention solvent used in step (iii) is selected from alcoholic solvents such as methanol, ethanol, isopropanol, ethers like tetrahydrofuran, diisopropyl ether, 1,4-dioxane, nitriles like acetonitrile, amides like dimethylformamide, etc. preferably methanol or tetrahydrofuran, more preferably methanol. Salt of 2-(methylsulfonyl)ethylamine used in step (iii) is selected from hydrochloride, hydrobromide, sulphate, nitrate, phosphate, acetate, etc., preferably hydrochloride. Temperature of the reaction in step (iii) is the boiling point of the solvent or 50-70°C. When slat is used in the reaction neutralizing reagents such as triethylamine or other non-reactive bases are used to neutralize acid part.

Reducing agent used in step (iv) is selected from a borohydride reagent such lithium borohydride, sodium borohydride, sodium tri(acetoxy)borohydride, vitride, lithium aluminum hydride, catalytic reduction in the presence of metal such as Nickel, palladium, rhodium, platinum, etc., preferably 5-10% of 50% wet palladium-on-carbon. Solvent used in step (iv) is selected from methanol, isopropanol, THF, dimethylformamide or a combination thereof. Acylating agent used in step (v) is selected from C1-C6 alkanoyl/perfluoroalkanoyl halide or C1-C6 alkanoic/perfluoroalkanoic anhydride, Boc anhydride, t-butyldimethylsilyl chloride. Solvent used in step (v) is selected from tetrahydrofuran, ethyl acetate, methylene chloride, etc. Suitable reagent used in step (vi) is selected from thionyl chloride, oxalyl chloride, phosphorous trichloride, phosphorous pentachloride, thionyl bromide, phosphorous tribromide, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, p-toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, benzenesulfonyl chloride, etc., preferably oxalyl chloride or thionyl chloride.

Suitable solvent used in step (vi) is selected from tetrahydrofuran, chloroform, acetonitrile, toluene, preferably tetrahydrofuran or chloroform. Temperature of the reaction in step (vi) is ambient to reflux temperature of the solvent preferably 50-60°C. Amount of 3-chloro 4-(3-fluorobenzyloxy)aniline used in step (vii) is 1.0-2.2 molar equivalents to the compound of formula-XVII. Temperature of the reaction in step (vii) is the boiling point of the solvent employed in the reaction. Product isolated in step (vii) is a hydrochloride salt when the leaving group is a chloride. This hydrochloride salt can be neutralized with a suitable base to get N-acylated compound of formula-XIX. Acid used in step (viii) is selected from dilute hydrochloric acid, sulfuric acid, nitric acid, etc., preferably dilute sulfuric acid. Base used in step (viii) is selected from sodium/potassium hydroxide or carbonate, preferably sodium hydroxide. Solvent employed in step (viii) aqueous alcohols or ethers. Solvent used in salt formation step (ix) can be aqueous alcoholic solvent as disclosed in WO2011039759 or WO2010061400. Present process involves the usage of novel compounds of formulae-XVII, XVIII, and XIX.

EXAMPLES:

The details of the invention are given in the Examples given below which are provided to illustrate the invention only and therefore should not be construed to limit the scope of present invention.

Example 1

Preparation of 6-nitroquinazolin-4-oI (XII) Formic acid (500 ml, 85%) was charged into a 2 L, four-necked, RB flask and cooled to 15-20 °C. Cone, sulfuric acid (60 ml) was added to the mass and stirred for 15min at 15-20 °C. The reaction mass was heated to reflux temperature. Slurry of 2-amino-5-nitrobenzonitrile (200 g) in 200 ml of 85% formic acid was added to the above reaction mass over a period of 10-15 minutes at reflux temperature. The reaction mass was maintained for lhr at reflux temperature. Reaction mass was cooled to 50-60 °C and poured into ice-cold water. The reaction mass was stirred for 1 h at 25-30 °C, filtered, washed with water, and dried at 65-70 °C to get 217 g of yellow colored powder. HPLC purity is 98.9%.

Example 2

Preparation of 6-aminoquinazoIin-4-ol (XIII) Method 1: Into a 5 L, four-necked, RB flask was charged isopropyl alcohol (2 L), water (1 L), iron powder (248 g), and ammonium chloride (13 g). The reaction mass was heated to 70-75 °C and added 6-nitroquinazolin-4-ol (100 g) in 3-4 lots keeping the mass under reflux temperature. After the addition of final lot reaction mass was maintained at reflux for 1.5 h and monitored the progress of reaction by TLC. Reaction mass was cooled to 50-60 °C, and filtered through Buchner funnel and flask. The filtrate was transferred into a single-necked RB flask and distilled off solvent partially under reduced pressure keeping the temperature below 60 °C. The product was filtered and dried in the oven at 60-65 °C to get 70 g of 6-aminoquinazolin-4-ol as a brown colored powder. HPLC purity is 99.25%. 'H-NMR (400 MHz, DMSO-De): 5 5.61 (s, 2H), 7.05-7.07 (m, 1H), 7.17-7.18 (d, 1H), 7.36-7.38 (d, 1H), 7.75 (s, 1H), and 11.80 (s, 1H).

Method-2: Into a 250 ml, four-necked, RB flask was charged 5.0 g of 6-nitroquinazolin-4-ol and 100 ml of N,N-dimethylformamide. The reaction mass was heated to 50-60 °C and maintained for 30 minutes to dissolve the solid. The solution was transferred into a 1 L stainless steel hydrogenation kettle. Raney nickel (5.0 g, wet) was charged into the reaction mass. The kettle was connected to hydrogenation set up and shaken at 50-60 psi hydrogen pressure. After completion of hydrogen consumption the kettle was removed from the hydrogenation set up and filtered. DMF was distilled of from the filtrate under reduced pressure. Ethyl acetate (20 ml) was added to the residue, filtered the solid and dried in a oven at 60-65 °C to get 4.0 g of 6-aminoquinazolin-4-ol as a yellow colored powder. HPLC purity is 93.0%.

Example 3

Preparation of 5-(4-hydroxyquinazolin-6-yl)furan-2-carbaxaldehyde (XIV) Method 1: Into a 250 ml, four-necked, RB flask was charged cone, hydrochloric acid (32.7 ml), water (20 ml), and 6-aminoquinazolin-4-ol (10 g). The reaction mass was cooled to 0-5 °C and added a solution of sodium nitrite (4.2 g) in water (24 ml) at below 5 °C. After maintaining for 30 minutes at 0-5 °C, a solution of furfural (6.6 g) in acetone (15 ml) was added to the reaction mass over a period of 30 minutes at 0-5 °C followed by a solution of cupric chloride (1.06 g) in water (30 ml). The reaction mass was maintained for 1.5 h at 0-5 °C and allowed to reach 10-15 °C and maintained for 4.0 h at that temperature. The reaction mass was filtered, washed the wet cake with water. The wet solid was taken into a flask and purified through its bisulphite adduct to get 6.5g of 5-(4-hydroxyquinazolin-6-yl)furan-2-carbaxaldehyde. Purity by HPLC is 96.55%. 'H-NMR (400 MHz, DMSO-D6): 8 7.45-7.46 (d, 1H), 7.68-7.75 (dd, 2 H), 8.16 (s, 1H), 8.24-8.26 (d, 1H), 8.53 (s, 1H), 9.64 (s, 1H), and 12.77 (s, 1H).

Example 4

Preparation of 6-(5-((2-(methylsuIfonyl)ethylamino)methyI)furan-2- yI)quinazolin-4-ol (XVI) Step-I: Preparation of (E/Z)-6-(5-((2-(methyIsulfonyI)ethylimino)methyI)furan- 2-yl)quinazolin-4-ol (XV) Into a 1 L, four-necked, RB flask was charged 500 ml of methanol and 50.0 g of 5-(4- hydroxyquinazolin-6-yl)furan-2-carbaxaldehyde. 2-(Methylsulfonyl)ethylamine hydrochloride (50.0 g) was added to the reaction mass under stirring. Triethylamine (51.0 g) was added to the reaction at 25-30 °C, heated to reflux temperature, and maintained for 7.0 h. The reaction mass was cooled to 25-35 °C and filtered under suction to get 67g of the title compound as wet solid. The wet solid was directly used in the next step. Step-II: Preparation of 6-(5-((2-(methyIsuIfonyl)ethylamino)methyl)furan-2-yl)quinazo!in-4-ol (XVI) Method 1: Into a 2 L, four-necked, RB flask was charged 875 ml of N,N-dimethylformamide and the above wet solid compound.

Palladium-on-carbon (10%, 10.0 g, 50% wet) was added to the reaction mass under nitrogen atmosphere. Hydrogen gas was bubbled into the reaction mass at 25-30 °C under stirring. After completion of the reaction, mass was filtered and concentrated under reduced pressure to get crude compound. Methanol (400 ml) was added to the residual mass and stirred for 30 min. The solid thus formed was filtered and dried at 60-65 °C to get 49.0 g of title compound as a greenish yellow powder. HPLC purity is 95.1%>. 'H-NMR (400 MHz, DMSO-D6): 5 2.96 (broad s, 2H), 3.02 (s, 3H), 3.24-3.27 (t, 2H), 3.80 (broad s, 2H), 6.43-6.44 (d, 1H), 7.05-7.06 (d, 1H), 7.68-7.70 (d, 1H), 8.08-8.13 (t, 2H), 8.33 (s, 1H), and 12.29 (s, 1H).

Method 2: Reduction with sodium borohydride Into 3 L, 4-necked RB flask was charged 55 g of (E/Z)-6-(5-((2-(methylsulfonyl)ethylimino)-methyl)furan-2-yl)quinazolin-4-ol, 1 L THF, and 250 ml of methanol. The reaction mass was cooled to 0-5 °C and added solid sodium borohydride (17 g) in lots. Reaction mass was maintained at RT for overnight. Solvent was distilled of from the reaction mass under reduced pressure at 45-50 °C. To the residue water (250 ml) was added, extracted the product into ethyl acetate, dried and distilled of solvent under reduced pressure to get 48 g of title compound as beige color solid. 'H NMR supported the structure of compound.

Example 5

Preparation of 2,2,2-trifluoro-N-((5-(4-hydroxyquinazolin-6-yl)furan-2- yI)methyl)-N-(2-(methylsulfonyl)ethyl)acetamide (XVII, R=CF3) Into a 250 ml, four-necked, RB flask was charged 120 ml of tetrahydrofuran and 24.0 g of 6-(5-((2-(methylsulfonyl)ethylamino)methyl)furan-2-yl)quinazolin-4-ol under nitrogen atmosphere. 4-Dimethylaminopyridine (0.85 g) was added to the reaction mass. Trifluoroacetic anhydride (29.0 g diluted with 20.0 ml of tetrahydrofuran) was added to the reaction mass over a period of 1 h at 25-30 °C. After the addition, reaction mass was maintained for 1.5 h at 25-30 °C. The reaction mass was filtered and the wet solid dried at 60-65 °C to get 23.0 g of title compound as brown colored solid. HPLC purity is 99.0%. 'H-NMR spectrum showed a mixture two tautomers at 7:3 ratio in DMSO-d6 solvent. IR (KBr, cm"1): 3339.7, 2928.0, 2362.4, 1637.3, 1608.6, 1593.4, 1572.1, 1539.1, 1497.9, 1445.9, 1425.6, 1394.3, 1371.0, 1330.5, 1294.8, 1216.9, 1198.2, 1171.6, 1123.8, 1061.4, 1026.5, 956.6, 927.8, 888.3, 868.1, 839.9, 789.7, 748.5, 679.9, 643.2, 628.7, 544.4, 517.6, and 501.5. 'H-NMR (400 MHz, DMSO-De): 3.05 (s, 3H), 3.44 (t, 2H), 3.81 (t, 2H), 4.84 (s, 2H), 6.71 (d, 1H) 7.17 (d, 1H), 7.72 (d, 1H), 8.12 (dd, 1H), 8.19 (br. s, 1H), 8.35 (triplet, 1H), 12.3 (br. s, 1H).

Example 6

Preparation of N-((5-(4-chIoroquinazolin-6-yI)furan-2-yl)methyl)-2,2,2-trifluoro- N-(2-(methylsuIfonyl)ethyl)acetamide (XVIII, R=CF3) Into a 250 ml, four-necked, RB flask was charged 125 ml of chloroform and 5.0 g of 2,2,2-trifluoro-N-((5-(4-hydroxyquinazolin-6-yl)furan-2-yl)methyl)-N-(2-(methylsulfonyl)ethyl)aceta-mide under N2 atmosphere. N,N-dimethylformamide (0.5 ml) was added to the reaction mass and heated to reflex temperature. Thionyl chloride (16.0 ml) was added to the reaction mass over a period of 30-45 minutes. After the addition, the reaction mass was maintained at reflux for 5 h. The reaction mass was cooled to 50° C and distilled of solvent under reduced pressure. Finally, 2 x 50 ml of toluene was added and distilled under reduced pressure to remove traces of thionyl chloride to get the crude title compound. It was directly used in next step.

Example 7

Preparation of N-((5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin- 6-yI)furan-2-yl)methyl)-2,2,2-trifluoro-N-(2-(methylsulfonyl)ethyI)acetamide (XIX, R=CF3) Into a 250 ml, four-necked, RB flask was charged the above crude and 100 ml of tetrahydrofuran under nitrogen atmosphere. 3-Chloro-4-(3-fluorobenzyloxy)aniline (4.22 g) was added to the reaction mass. The reaction mass was heated to 60-65 °C, and maintained for 4 h at 60-65 °C. Reaction mass was cooled to 25-30 °C and maintained for 2-3 h at 25-30 °C. The reaction mass was filtered and dried the wet material in oven at 60-65 °C to get 10.1 g of title compound as yellow solid. HPLC purity is 87.36% containing 3-chloro-4-(3-fluorobenzyloxy)aniline 4.39%. 'H-NMR (400 MHz,CDCi3): 5 2.99 (s, 3H), 3.38-3.42 (m, 2H), 4.22-4.26 (t, 2H), 4.77 (s, 2H), 5.17 (s, 2H), 6.51-6.52 (d,lH), 6.75-6.78 (m, 2H), 6.99-7.02 (m, 3H), 7.19-7.24 (t, 2H), 7.34-7.39 (m, 2H), 7.72-775 (dd, 1H), 7.89-7.90 (m,2H), 7.94-7.97(dd, 1H), 8.41-8.44 (d, 2H), and 8.71 (s, 1H).

Example 8

Preparation of N-(3-chIoro-4-(3-fluorobenzyloxy)phenyl)-6-(5-((2- (methylsulfonyl)ethyI-amino)methyl)furan-2-yI)quinazolin-4-amine Into a 500 ml, four-necked, RB flask was charged 180 ml of methanol and 9.0 g of N-((5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-yl)methyl)-2,2,2-trifluoro-N-(2-(methylsulfonyl)ethyl)acetamide under stirring. Aqueous sodium hydroxide (2.52 g of sodium hydroxide dissolved in 22.5 ml of water) was added to the reaction mass at 25-30 °C. The reaction mass was stirred for 2 h at 25-30 °C. Solvent was evaporated under reduced pressure. Water (75 ml) was added to the residue and the product extracted into ethyl acetate. The organic layer was treated with carbon and distilled of solvent partially under reduced pressure. Residual mass was cooled to 25-30 °C, stirred for 30 minutes, and filtered. The wet solid was dried in oven at 60 °C to get 4.2 g of title compound. HPLC purity is 98.85%.

Example 9

Preparation of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(5-((2- (methyIsulfonyl)ethyl-amino)methyl)furan-2-yI)quinazolin-4-amine ditosylate salt Into a 100 ml, four-necked, RB flask was charged methanol (60 ml) and 2.0 g of lapatinib base. The reaction mass was heated to reflex temperature and maintained for 30 minutes. The reaction mass was cooled to 45-50 °C and added a solution of p-toluenesulfonic acid monohydrate (1.4 g dissolved in 10 ml of methanol). Reaction crystalline solid. HPLC purity is 93.7%. IR (KBr, cm"1): 3445.1, 3024.1, 2828.7, 2344.6, 1681.2, 1645.6, 1610.7, 1545.2, 1473.2, 1420.4, 1365.2, 1342.2, 1328.2, 1285.2, 1246.1, 1214.2, 1132.0, 1027.2, 971.8, 919.0, 835.5, 795.2, 663.5, 624.1. 'H NMR (400MHz, CDC13): 5 2.35 (s, 3H), 2.99 (s, 3H) 3.32-3.35 (t, 2H), 3.86-3.90 (t, 2H), 4.66 (s, 2H), 6.44-6.45 (d, 1H), 6.80-6.8l(d, 1H), 7.78-7.81 (d, 1H); 8.03-8.06 (m, 2H), 8.51 (s, 1H), 9.22 (broad s, 1H). El-Mass: 389.2.

Example 12

Preparation of N-((5-(4-(3-chloro-4-(3-fluorobenzyIoxy)phenyIamino)quinazoIin- 6-yl)furan-2-yl)methyl)-N-(2-(methylsulfonyl)ethyl)acetamide(XIX, R=CH3) Into a 1 L, four-necked, RB flask was charged 300 ml of chloroform, 1.0 g of N-((5-(4-hydroxyquinazolin-6-yl)furan-2-yl)methyl)-N-(2-(methylsulfonyl)-ethyl)acetamide (XVII, R = CH3), 200ml of acetonitrile and 0.1 ml of DMF under N2 atmosphere. Reaction mass was heated to reflex temperature. Thionyl chloride (1.6 ml) was added to the reaction mass over a period of 30-45 minutes. Reaction mass was maintained at reflux for 5 h, cooled to 50 °C and distilled of solvent under reduced pressure. To the residue charged 2 x 40 ml of chloroform and distilled under vacuum. Finally, 40 ml of acetonitrile is charged and distilled under vacuum. To the residual solid acetonitrile (120ml) and 3-chloro-4-(3-fluorobenzyloxy)aniline (1.7g) were added and heated to reflux temperature. Reaction was maintained at reflux for 6h, cooled to RT and filtered the solids. The wet cake was washed with acetonitrile and dried to get 1.1 g of title compound as solid. *H NMR (400MHz, CDCI3): 6 2.25 (s, 3H), 2.94 (s, 3H), 3.45 (t, 2H), 4.08 (t, 2H), 4.60 (s, 2H), 5.16 (s, 2H), 6.43 (d, 1H), 6.74 (d, 1H), 7.00 (t, 2H), 7.23 (t, 2H), 7.35 (t, 1H), 7.69 (dd, 1H), 7.90 (dt, 3H), 8.40 (s, 1H), 1.00 (s, 1H), and 8.69 (s, 1H).

Example 13

Preparation of tert-butyl (5-(4-hydroxyquinazoIin-6-yl)furan-2-yI)methyl(2- (methylsulfo-nyI)ethyl)carbamate (XVII, R=t-BuO) Into a 50ml, three-necked RB flask was charged 0.5 g of 6-(5-((2-(methylsulfonyl)ethylamino)-methyl)furan-2-yl)quinazolin-4-ol, 10 ml of THF, 0.82g of Boc anhydride, 0.32g of TEA and 0.04g of DMAP. Reaction was stirred at RT for 3h, distilled of solvent under vacuum. To the residue 5ml of ethyl acetate and 5ml of IPE were added and filtered to get 0.5 g of title compound as a brown colored solid. 'H-NMR (400 MHz, CDC13): 5 1.53 (s, 9H), 2.95 (s, 3H), 3.34 (broad s, 2H), 3.78-3.81 (t, 2H), 4.54 (s, 2H), 6.37(broad s, 1H), 6.76-6.77(d, 1H), 7.76-7.78 (d, 1H), 8.03-8.06 (m, 1H), 8.1 l(s, 1H), 8.50 (s, 1H), and 11.45 (broad s, 1H exchangeable withD20).

ADVANTAGES OF PRESENT PROCESS:

1. Purity of lapatinib and its pharmaceutically acceptable ditosylate salt obtained by this process is high (>99.6%).

2. Present process does not require any chromatographic purification.

3. All the raw materials used in the present process are commercially readily available and cheap.

4. Present process does not require costly reagents like 5-formyl-furanboronic acid or (5-(l,3-dioxolan-2-yl)furan-2-yl)tributylstannane, or any other boronic acid derivative.

CLAIMS

We claim

1. An improved process for the preparation of Lapatinib of formula-l, and its pharmaceutically acceptable salts, which comprises:

(i) Reduction of 6-nitroquinazolin-4-ol of formula-XII with a metal catalyst in the presence of a solvent medium at elevated temperature to get the amino compound of formula-XIII,

(ii) Diazotization of compound of formula-XIII with sodium/potassium nitrite in the presence of an acid and coupling with furfural in the presence of a copper catalyst to get the coupled product of formula-XIV,

(iii) Reaction of compound of formula-XIV with 2-methanesulfonylethylamine or its salt in a solvent medium at elevated temperature to get an imine derivative of formula-XV,

(iv) Reduction of compound of formula-XV in a solvent medium to get the amine compound of formula-XVI,

(v) Selective protection of the amino group of the compound of formula-XVI with a suitable protecting group to get the compound of formula-XVII, Wherein R = C1-C6 alkyl, perfluoroalkyl, C1-C6 alkoxy, etc.

(vi) Conversion of hydroxyl group present in XVII into a leaving group with a suitable reagent to get the compound of formula-XVIII, Wherein X - CI, Br, I, OSO2CH3, OSO2CF3, OTs, OBs, etc., R = C1-C6 alkyl, perfluoroalkyl, C1-C6 alkoxy, etc (

vii) Reacting the compound of the formula-XVIII with 3-chloro 4-(3- fluorobenzyloxy)aniline in a solvent medium at an elevated temperature to get the amine protected lapatinib base of formula-XIX, Wherein R = as defined above

(viii) Removal of amine protection group in compound of formula-XIX using a base or acid to get lapatinib base of formula-I,

(ix) Conversion of lapatinib base into pharmaceutically acceptable p-tolunesulfonate salt in a solvent medium to get lapatinib di-tosylate of formula-II as its dihydrate, N,N-dimethylformamide, etc. preferably methanol or tetrahydrofuran, more preferably methanol.

7. An improved process as claimed in claims 1-6 wherein the salt of 2- methanesulfonylethylamine used in step (iii) is selected from hydrochloride, hydrobromide, sulphate, nitrate, phosphate, acetate, etc., preferably hydrochloride.

8. An improved process as claimed in claims 1-7 wherein the temperature of the reaction in step (iii) is the boiling point of the solvent or 50-70°C.

9. An improved process as claimed in claims 1-8 wherein the neutralizing reagent used in step (iii) is selected from trialkylamine such as triethylamine.

10. An improved process as claimed in claims 1-9 wherein the reducing agent used in step (iv) is selected from a borohydride reagent such as lithium borohydride, sodium borohydride, sodium tri(acetoxy)borohydride, vitride, lithium aluminum hydride, a metal catalyst such as such as Raney nickel, palladium, rhodium, platinum, etc., in the presence of hydrogen gas, preferably sodium borohydride or 5-10% of 50% wet palladium-on-carbon.

11. An improved process as claimed in claims 1-10 wherein the solvent used in step (iv) is selected from methanol, isopropanol, THF, N,N-dimethylformamide or a combination thereof.

12. An improved process as claimed in claims 1-11 wherein the acylating agent used in step (v) is selected from C1-C6 alkanoyl/perfluoroalkanoyl halide or C1-C6 alkanoic/perfluoroalkanoic anhydride, Boc anhydride, t-butyldimethylsilyl chloride, preferably acetic anhydride or trifluoroacetic anhydride.

13. An improved process as claimed in claims 1-12 wherein the solvent used in step (v) is selected from tetrahydrofuran, ethyl acetate, methylene chloride, etc.

14. An improved process as claimed in claims 1-13 wherein the suitable reagent used in step (vi) is selected from thionyl chloride, oxalyl chloride, phosphorous trichloride, phosphorous pentachloride, thionyl bromide, phosphorous tribromide, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, p-toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, benzenesulfonyl chloride, etc., preferably oxalyl chloride or thionyl chloride. Suitable solvent used in step (vi) is selected from tetrahydrofuran, chloroform, acetonitrile, toluene, preferably tetrahydrofuran or chloroform.

15. An improved process as claimed in claims 1-14 wherein the temperature of the reaction in step (vi) is ambient to reflux temperature of the solvent, preferably 50-60°C.

16. An improved process as claimed in claims 1-15 wherein the temperature of the reaction in step (vii) is the boiling point of the solvent employed in the reaction.

17. An improved process as claimed in claims 1-16 wherein the acid used in step (viii) is selected from dilute hydrochloric acid, sulfuric acid, nitric acid, etc., preferably dilute sulfuric acid.

18. An improved process as claimed in claims 1-17 wherein the base used in step (viii) is selected from sodium/potassium hydroxide or carbonate, preferably sodium hydroxide.

19. An improved process as claimed in claims 1-18 wherein the solvent employed in step (viii) is aqueous alcohols or ethers, preferably aqueous IPA.