FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
& THE PATENTS RULES, 2003 Complete Specification [See Sections 10 and rule 13]
Title: "Process For Preparation Of Lapatinib And Novel Intermediates Thereof
Applicant: (a) INTAS Pharmaceuticals Limited
(b) Company Registered under Indian Company ACT
(c) 2nd Floor; Chinubhai Centre, Ashram Road, Ahmedabad 380009 Gujarat, India
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to novel process for preparation of lapatinib (I) and its pharmaceutically acceptable salt. The invention also relates to novel intermediates used in the synthesis of lapatinib and process for their preparation.
BACKGROUND OF THE INVENTION
Lapatinib, chemically known as N-{3-chloro-4-[3-fluorobenzyloxy] phenyl}-6-[5-9-{[2-(methanesulfonylethyl]amino}methyl]-2-furyl-4-quinazoIinamine is represented by following structural formula

Lapatinib was first disclosed in US 6,727,256, the process disclosed therein can be depicted as below:


US 7,157,466 relates to lapatinib ditsoylate anhydrate and hydrate. The process for preparation of lapatinib is also reported in WO 2011/039759 and WO 2010/017387.


The process of WO 2010/017387 includes preparation of lapatinib comprising reduction of compound of following formula:
in presence of iron/ammonium chloride system, to this 4-chloro-6-iodoquinazoline and 5-formyl-2-furanboronic acid are added; lapatinib aldehyde base thus prepared is reacted with methylsulfonylethylarnine and a reducing agent to obtain lapatinib which is further converted to its pharmaceutically acceptable salts.
The present application provides a new and commercially viable process for preparation of lapatinib; the process also avoids some of the isolation steps thus making the overall process more effective.
OBJECTS OF THE INVENTION
The main objective of the! present invention is to provide more efficient and industrially feasible process for preparation of Lapatinib.
Another object of the invention is to provide novel intermediates of Lapatinib and their preparation.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for preparation of lapatinib or its pharmaceutically acceptable salts which comprises converting compound of formula (IX) to a compound of formula (XII);


Wherein R1 is selected from -OR2; R2 is selected from hydrogen, aryloyl such as benzoyl; alkyloyl such as acetyl


Wherein R is selected from S-CH3 or S02CH3 and R1 is as defined above; and further converting compound of formula (XII) to lapatinib or its salt.

Wherein R and R1 are as defined above.
In another aspect the present application provides novel intermediates (VIII), (IX), (X), (XI), (XII) and (XIII) of following structural formulae

BRIEF DESCRIPTION OF DRAWINGS
1. Figure 1 'H NMR of compound of formula VIII
2. Figure 2 Mass Spectra of compound of formula (IX)
3. Figure 3 'H NMR of Compound of formula (IX)
4. Figure 4 Mass spectra of compound of formula (X)
5. Figure 5 'H NMR of compound of formula (X)
6. Figure 6 Mass spectra of compound of formula (XI)
7. Figure 7 'H NMR of compound of formula (XI)
8. Figure 8 Mass spectra of compound of formula (XII)
9. Figure 9 'H NMR of compound of formula (XII)
10. Figure 10 Mass spectra of compound of formula (XIII)
11. Figure 11 'H NMR of compound of formula (XIII)
DETAILED DESCRIPTION
Accordingly, the present invention provides an improved process for preparation of lapatinib of formula (I) and its pharmaceutically acceptable salts, which comprises:
(i) Reduction of compound of formula (VIII) wherein R1 is as defined above.

Reduction can be carried out in presence of any suitable catalyst preferably Pt/C is used as reducing agent. The compound of formula (VIII) (wherein R1 is as defined above) can be obtained by reacting 2-chloro-4-nitrophenol with benzoyl chloride or acetyl chloride

This reaction is carried out in presence of any suitable organic solvent such as methylene dichloride, tetrahydrofuran and a base which can be selected from organic or inorganic class of base. The reaction can be carried out under heating, cooling or at ambient temperature preferably the reaction is carried out at ambient temperature.
(ii) In the next step compound of formula (IX) is reacted with 4-chloro-6-iodo quinazoline to obtain protected 2-chloro-4-[(6-iodoquinazolin-4-yl) amino] phenyl
(X)

(iii) In next step compound of formula (X) is reacted with 2-formyl-furan-5-boronic acid.

to obtain compound of formula (XI)


(iv) The intermediate of formula (XI) is reacted with 2-methanesulfonyl-ethylamine or 2-(methylthio) ethylamine in presence of sodium borohydride or sodium cyanoborohydride, solvent and base to obtain compound of formula (XII).

Wherein R is as defined above
(v) In the next step the compound of formula (XII) is reacted with di-tertiary butyl dicarbonate (Boc) to obtain Boc protected intermediate of formula (XIII).

The reaction can be carried out in presence of solvent and base, preferably the reaction is carried out at around ambient temperature. After completion of reaction the product can be separated by layer separation followed by distillation of solvent from organic layer.
The compound of formula (XIII) wherein R is S-CH3 is subjected to oxidation to obtain compound of formula (XIV); wherein R1 is as defined earlier. The oxidation can be carried out in presence of any suitable oxidising agent such as oxone or sodium metaperiodate (NaOL4).

The compound of formula (XIII) wherein R=SPO2CH3; R1 is as defined above or compound of formula (XIV) is subjected to deprotection to obtain compound of formula (XV).

(vi) The intermediate of formula (XV) is reacted with 3-fluoro benzyl bromide to obtain compound of formula (XVI)

Boc protected intermediate (XVI) is subjected to deprotection to obtain lapatinib base of formula (I)
(vii) Lapatinib free base can be converted to its pharmaceutically acceptable salts by reacting with suitable acid. Preferably lapatinib ditosylate is prepared and for this Lapatinib base is reacted with toluene sulphonic acid monohydrate


The lapatinib ditosylate thus obtained can be converted to its monohydrate by treating with organic solvent and water. The solvent can be selected from isopropanol, methanol and acetone.
Alternatively the intermediate of formula (XIV) is converted to lapatinib ditosylate or ditosylate monohydrate without isolation of any intermediate.
The following examples are illustrative of the invention but not limitative of the scope thereof:
Examples:
Example:-!: Preparation of 2-chloro-4-nitrophenyl benzoate (VIII)
2-chloro-4-nitrophenol (100 g) was dissolved in methylene dichloride (1000 ml). Triethyl amine (241 ml) was added to reaction mass and resultant reaction mass stirred at 8-10 °C for 15 min. To this benzoyl chloride (80.3 ml) was added drop wise within 60 min. at 8-10 °C. The temperature is increased to 25-30 °C and stirred at the same for two hours. After completion of reaction (monitored by TLC), water (500 ml) was added to reaction mass. Organic layer was separated and solvent was evaporated to get crude product which was stirred in Cyclohexane (1000 ml) for 12 hrs. Filtered and dried to get 150 g of title compound. 1H-NMR(d6-DMSO)

7.64-7.68 (t, 2H), 7.79-7.82 (m, 1H), 7.84-7.86 (d, 1H), 8.17-8.18 (m, 1H), 8.19 8.20 (m, 1H), 8.33-8.36 (dd, 1H), 8.54 (d, 1H)
Example II: Preparation of 4-amino-2-chlorophenyI benzoate (IX)
5 % Pt/C (0.5 gm) was charged in autoclave vessel which contains solution of 2-chloro-4-nitrophenyl benzoate (10 g) in methanol (150 ml) and THF (150 ml). Reaction mass in vessel stirred at room temperature under 3 kg H2 (g) for 2hrs. After completion of reaction (monitored by TLC), catalyst was then removed by filtration through celite and filtrate was concentrated to afford 8.5 g of light yellow solid. Mass (M+l): 248.1 1H-NMR (d6-DMSO)
7.37-7.43 (m, 1H), 7.47-7.63 (m, 4H), 7.72-7.78 (m, 1H), 8.13-8.14 (d, 1H), 8.83 (bs, 2H)
Example-Ill: Preparation of 2-chloro-4-((6-iodoquinazoIin-4-vl)amino)phenvl benzoate (X)

4-amino-2-chlorophenyl benzoate (87 g) and 4-chloro-6-iodoquinazoline (102 g) was suspended in isopropyl alcohol (1740 ml). Reaction mass was stirred for 3 hrs. at 80 °C. After completion of reaction (monitored by TLC) reaction mass was cooled to room temperature and solid was filtered, dried. Dry solid (147 g) was dissolved in dimethylformamide (441 ml), heated to 60 °C. After addition of triethyl amine (62 ml), stirred reaction mass for 30 min. at 60 °C. Reaction mass was cooled to 25-30 °C and poured into distilled water (4000 ml). Solid formed was filtered, dried under reduced pressure to get 136 g of title compound. Mass (M+l): 502.1 1H-NMR (d6DMSO)

7.49-7.51 (d, 1H), 7.57-7.60 (d, 1H), 7.62-7.66 (t, 2H), 7.77-7.81 (d, 1H), 7.93-7.95 (dd, 1H), 8.12 (d, 1H), 8.14 (d, 2H), 8.17-8.18 (d,lH), 8.69 (s.lH), 8.99 (s.lH), 10.02 (d,lH)
Example:-IV: Preparation of 2-chloro-4-((6-(5-formylfuran-2-yl)quinazolin-4-yl)amino)phenyl benzoate (XI)
2-chloro-4-((6-iodoquinazolin-4-yl) amino)phenylbenzoate (20 g), 2-formyl-furan-5-
boronic acid (10 g), triethyl amine (16.6 ml) was dissolved in DMF (200 ml), bis
(triphenylphosphine) palladium (II) dichloride (2.8g) was added to reaction mass.
Resulting reaction mass was heated for 80°C for 3 hrs. After completion of reaction
(monitored by TLC), reaction mass was poured into cold water. Solid was filtered
and dried to get 16 g of title compound.
Mass (M+l): 470.14
1H-NMR(d6-DMSO)
7.42-7.43 (m, 2H), 7.51-7.53 (d, 1H), 7.62-7.66 (t, 2H), 7.74-7.75 (d, 1H), 7.78-7.81
(t, 1H), 7.87-7.95 (m, 1H), 8.17-8.19 (m, 2H), 8.22 (s, 1H), 8.30-8.32 (d, 1H), 8.67
(s, 1H), 8.98 (s, 1H), 9.67 (s, 1H), 1017 (s, 1H),
Example V: Preparation of 2-chloro-4-((6-(5-(((2-(methylsulfonvl)ethyl)amino) methyl)furan-2-yl)quinazolin-4-yl)amino)phenyl benzoate (XII)
2-chloro-4-((6-(5-formylfuran-2-yl)quinazolin-4-yl)amino)phenylbenzoate (11 g) was added to solution of 2-methanesulfonyI-ethylamine hydrochloride (6.15 g) and triethyl amine (5.44 ml) in tetrahydrofuran (110 ml) and methanol (110 ml). After stirring 3 hrs at 65-70 °C, reaction mass cooled to 0-5 °C. Sodium borohydrate (1.77 g) was added lot wise in 30 min. After completion of reaction (monitored by TLC), reaction was quenched with water (220 ml). Organic solvents were evaporated under reduced pressure and resulted solution was extracted with Ethyl acetate. Organic

layer was washed with brine and water then dried with Na2S04. The solution was concentrated under reduced pressure and diluted with 140 ml methanol. After heating at 55-60 °C, clear solution was concentrated to get 10 g titled compound. Mass (M+l): 577.22 lH-NMR(d6-DMSO)
2.98-3.01 (t, 2H), 3.03 (s, 3H), 3.27-3.31 (t, 3H), 3.85 (s, 2H), 6.50-6.51 (d, 1H), 7.10-7.11 (d, 1H), 7.51-7.54 (d, 1H), 7.63-7.67 (t, 2H), 7.78-7.85 (m, 2H), 7.95-7.97 (dd, 1H), 8.18-8.8.21 (m, 3H), 8.27-8.28 (d, 1H), 8.64 (s, 1H), 8.81 (s, 1H), 10.154 (s, 1H).
Example VI: Preparation of 4-((6-(5-(((tert-butoxycarbonyl)(2-(methylsulfonyl) ethy1)amino)methyl)furan-2-yl)quinazoIin-4-yl)amino)-2-ch]orophenyl benzoate
(XIII)
2-chloro-4-((6-(5-(((2-(methylsulfonyl) ethyl) amino) methyl) furan-2-yl) quinazolin-4-yl) amino) phenyl benzoate (7.4 g) was dissolved in methylene dichloride (185 ml) followed by addition of triethylamine (2.96 ml). After stirring at 25-30 °C for 15 min., di tertiary butyl carbonate (3.7 ml) was added. Resultant reaction mass was stirred for 4 hrs. After completion of reaction (monitored by TLC), reaction was quenched by water (100 ml). Organic layer was distilled off and the residue was stirred in diisopropyl ether (50 ml) to get 8 g of title compound. Mass (M+l): 677.30. lH-NMR(d6-DMSO)
1.44 (s, 9H), 3.03 (s, 3H), 3.39-3.40 (t, 2H), 3.70 (bs, 2H),4.56 (s, 2H), 6.54-6.54 (d, 1H), 7.10-7.11 (d, 1H), 7.51-7.54 (d, 1H), 7.63-7.67 (t, 2H), 7.78-7.87 (m, 2H), 7.94-7.96 (dd, 1H), 8.16-8.8.20 (m, 3H), 8.65 (s, 1H), 8.77-8.78 (d, 1H), 10.07 (bs, 1H).

Example VII; Preparation of tert-butyl ((5-(4-((3-chloro-4-hydroxyphenyI) amino)quinazolin-6-yl)furan-2-yl)methyl)(2-(methylsuIfonyl)ethyl)carbamate
(XIV)
4-((6-(5-(((tert-butoxycarbonyl) (2-(methylsulfonyl) ethyl) amino) methyl) furan-2-yl) quinazolin-4-yl) amino)-2-chlorophenyl benzoate (8 g) was dissolved in methanol (150 ml). After stirring at 25-30 °C for 15 min, potassium carbonate (4.0 g) was added to reaction mass. Stir reaction mass for additional 2 hrs. After completion of reaction (monitored by TLC), evaporated solvent under reduced pressure and resultant mass was diluted with water (100 ml). Adjust pH to 6.5-7.0 by acetic acid (3.3 ml). Solid formed was filtered to get 6.8 g title compound. Mass (M+l): 573.23 lH-NMR(d6-DMSO)
1.43 (s, 9H), 3.02 (s, 3H), 3.38 (bs, 2H), 3.68 (bs, 2H), 4.53 (s, 2H), 6.51 (d, 1H), 7.02 (d, 1H), 7.06 (d, 1H), 7.46-7.50 (dd, 2H), 7.76-7.80 (m, 2H), 7.94-7.96 (dd, 1H), 8.50 (s, 1H), 8.76 (d, 1H), 9.84 (s, 1H)
Example VIII: Preparation of tert-butvl ((5-(4-((3-ch]oro-4-((3-fluorobenzyl) oxy)pheny])amino)quinazoIin-6-yl)furan-2-yl)methyl)(2-(methylsulfonyl) ethyl) Carbamate (XV)
Potassium hydroxide (0.25 g) was dissolved in methanol (50 ml). Tert-butyl ((5-(4-((3-chloro-4-hydroxyphenyl) amino) quinazolin-6-yl) furan-2-yl) methyl) (2-(methylsulfonyl) ethyl) carbamate (2.5 g) was added to reaction mass and stirred for 2hrs at 25-30°C. Methanol was evaporated and resultanant mass was diluted with Dimethylformamide (25 ml). 3-fluorobenzyl bromide (0.86 g) was added slowly to reaction mass. Reaction was stirred at 75-80 °C for 3 hrs. After completion of reaction (monitored by TLC), cooled to 25-30 °C and quenched by water (250 ml).

Reaction mass was extracted by ethyl acetate (2 X 150 ml). Organic layer was distilled off to get 2.7g of title compound. Mass (M+l): 681.32 1H-NMR (d6-DMSO)
1.43 (s, 9 H), 3.02 (s, 3H), 3.4 (bs, 2H), 3.69 (bs, 2H), 4.54 (s, 2H), 5.26 (s, 2H), 6.52-6.53 (d, 1H), 7.08 (d, 1H), 7.16-7.21 (m, 1H), 7.28-7.7.34 (m, 3H), 7.44-7.50 (m, 1H), 7.73-7.76 (dd, 1H), 7.80-7.82 (d, 1H), 8.02 (d, 1H), 8.12-8.15 (dd, 1H), 8.56 (s, 1H), 8.74 (d, 1H), 9.88 (s, 1H)
Example IX Preparation of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenylV6-(5-(((2- (methylsulfonyI)ethyl)amino)methyl)furan-2-yI)quinazolin-4-amine ditosylate (I)
Tert-butyl ((5-(4-((3-chloro-4-((3-fluorobenzyl) oxy) phenyl) amino) quinazolin-6-yl) furan-2-yl) methtyl) (2-(methylsulfonyl) ethyl) carbamate was (3 g) dissolved in methanol (80 ml). Reaction mass was heated up to 50-55 °C. The solution of para toluene sulfonic acid (4.18 g) in methanol (10 ml) was added to reaction mass and stirred resultant reaction mass for 4 hrs at 50-55 °C. Reaction mass was cooled to 25-30 °C and stirred for 30 min. Solid formed was filtered, washed with methanol (10 ml) and dried to get title compound. Yield (w/w): 2.3g Mass (M+l): 581.31 lH-NMR(d6-DMSO)
2.27 (s, 6H), 3.12 (s, 3H), 3.47-3.51 (t, 2H), 3.58-3.3.62 (t, 2H), 4.50 (s, 2H), 5.31 (s, 2H), 6.88-6.89 (d, 1H), 7.09-7.11 (d, 4H), 7.18-7.23 (m, 1H), 7.28-7.7.35 (m, 4H), 7.47-7.52 (m, 5H), 7.59-7.62 (dd, 1H), 7.84-7.825 (d, 1H), 7.91-7.93 (d, 1H), 8.43-8.46 (dd, 1H), 8.96 (s, 1H), 9.07 (s, 1H), 9.39 (bs, 1H)

Claims:
1. A process to prepare lapatinib or its pharmaceutically acceptable salts, comprising converting compound of formula (VIII)

to lapatinib; wherein R1 is -OR2; R2 is selected from hydrogen, aryloyl, alkyloyl.
2. The process as claimed in claim 1, wherein aryloyl is benzoyl and alkyloyl is
acetyl
3. The process as claimed in claim 1, comprising
a. reducing compound of formula (VIII) to give amine of formula (IX)

b. reacting amine of formula (IX) with 4-chloro-6-iodoquinazoline to
give compound of formula (X);

c. reacting compound of formula (X) with 2-formyl-furan-5-boronic
acid to give compound of formula (XI);

d. reacting compound of formula (XI) with 2-methanesulfonylethyl
amine or 2-(mehylthio)ethylamine to give compound of formula (XII);

R= S-CH3 or SO2CH3
e. protecting compound of formula (XII) to get compound of formula
(XIII);

f. oxidising compound of formula (XIII) wherein R=S-CH3 to obtain
compound of formula (XIV)

g. converting the compound of formula ((XIV) to lapatinib.
4. The process as claimed in claim 3, wherein converting involves deprotection of compound of formula (XIV)



to obtain compound of formula (XV),
reacting compound of formula (XV) with 3-fluorobenzyl bromide to obtain compound of formula (XVI),

deprotecting compound of formula (XVI) to obtain lapatinib (I), optionally converting lapatinib to its pharmaceutically acceptable salt.
5. The compounds of formulae (VIII), (IX), (X), (XI), (XII) and (XIII)



Wherein R is S-CH3 or S02CH3 and Rl is -OR2; R2 is selected from hydrogen, aryloyl, alkyloyl.
6. The compounds as claimed in claim 5, wherein aryloyl is benzoyl and alkyloyl
is acetyl
7. Use of compounds of formulae (VIII), (IX), (X), (XI), (XII) or (XIII) in the
preparation of lapatinib.