DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Lapatinib compound of Formula (I) and its salts such as Lapatinib Ditosylate Monohydrate compound of Formula (II), which is substantially free from impurities.

Lapatinib
(I)

Lapatinib Ditosylate Monohydrate
(II)

More specifically it relates to the purification of an intermediate of Lapatinib of N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-iodoquinazolin-4-amine (Formula III).

(III)
BACKGROUND OF THE INVENTION
Lapatinib (I) is chemically known as N- (3-chloro-4- {[(3-fluorophenyl) methyl] oxy} phenyl) -6- [5-({[2- (methylsulfonyl) ethyl] amino} methyl)-2-furanyl] -4- quinazolinamine and is marketed as a Ditosylate monohydrate salt (II), chemically represented as N-(3-chloro-4-{[ (3-fluorophenyl) methyl] oxy} phenyl) -6- [5-({[2- (methylsulfonyl) ethyl] amino} methyl) -2-furanyl]-4-quinazolinamine-bis(4-methylbenzenesulfonate)monohydrate, under the trade name TYKERB® by GlaxoSmithKline (GSK) and is used for the treatment of advanced metastatic Breast cancer.
Lapatinib (I) inhibits the activity of both Erb B1 and Erb B2; this reversible and dual-acting inhibitory nature allows for the drug is able to overcome problems of resistance encountered with single inhibitors.
PCT International Publication No. WO 1999035146 and its US equivalent Patent No. 6,727,256 assigned to SmithKline Beecham Corporation discloses Lapatinib (I) and the process for its preparation.
US Patent No. 7,157,466 assigned to SmithKline Beecham Limited discloses Ditosylate salt of Lapatinib (II) and its process for preparation and during the synthesis, various impurities are formed and need to be eliminated to yield the final product with high purity that conform to the ICH guidelines.
US Patent No. 8,927,558 assigned to Fabbrica Italiana Sintetici SpA discloses the ortho impurities associated with Lapatinib (I) and its salts.
Impurities are the raw materials used, residue of synthetic intermediates, regioisomers, by-products of the reaction, product degradation etc. are formed or carried forward during synthesis. These pharmaceutical impurities may affect both efficiency and safety of the drug, and in extreme cases can also harm the patient on administration. Hence, yielding a highly purified active pharmaceutical ingredient (API) devoid of such impurities is essential and a critical step during commercialization.
In the view of the above problem, our inventors of the present invention have made various attempts by adopting the techniques to develop a process for the synthesis of Lapatinib (I) and its ditosylate monohydrate salt (II), and surprisingly resulted into the final compounds of Lapatinib with substantially free or lower levels of impurities.
The present invention provides for a method of synthesis of Lapatinib (I) and its ditosylate monohydrate salt (II), wherein the final products have shown to have substantially free or lower levels of impurities, wherein the process is commercially scalable with consistent levels of purity.
SUMMARY OF INVENTION
The present invention provides a method of synthesis of Lapatinib (I) and its salts, wherein the final product is substantially free or has very low levels of impurities.
In an embodiment of the present invention, the impurities of Lapatinib (I) and its salts, are below the level of detection or =0.02%, but not >0.03% AUC; as detected by HPLC.
An added embodiment of the present invention, provides a process wherein the impurities present in the final product of Lapatinib Ditosylate Monohydrate (II) are below the level of detection or =0.02%, but not >0.03% AUC; as detected by HPLC when compared with Lapatinib Ditosylate Monohydrate compound of Formula (II).
In an embodiment of the present invention the regioisomeric impurities (Ia, IIa, IIIa, Ib, IIb, and IIIb) of Lapatinib (I), its salts and intermediates are structurally represented by the following formulas:

Ortho Impurities

(Ia)

(IIa)

(IIIa)

Para Impurities

(Ib)

(IIb)

(IIIb)

In another embodiment, the present invention provides a process for purification of intermediate N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-iodoquinazolin-4-amine (Formula III).
(III)
Further in an added embodiment, the present invention provides a process for purification of intermediate N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-iodoquinazolin-4-amine (Formula III) wherein the ortho-isomer (o-isomer) Formula IIIa and para-isomer (p-isomer) Formula IIIb impurities in purified product are below the level of detection or =0.02%, but not >0.03% AUC; as detected by HPLC.
Another embodiment of the present invention, wherein the impurities ortho-isomer (o-isomer) Formula IIIa and para-isomer (p-isomer) Formula IIIb of Lapatinib (I) and its salts, are below the level of detection or =0.02%, but not >0.03% AUC; as detected by HPLC.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1: HPLC chromatogram of Lapatinib monohydrate Ditosylate of formula (II), wherein the impurity, compound of Formula IIIa is absence or below level detection.
Fig. 2: HPLC chromatogram of Lapatinib monohydrate Ditosylate of formula (II), wherein the impurity, compound of Formula IIIb is =0.02%, but not >0.03% AUC.

DETAILED DESCRIPTION
The present invention provides for an improved and commercially viable process for the preparation of Lapatinib (I) and its salts, wherein the impurities, in particular the isomeric impurities of compound of Formulas Ia, Ib, IIa, IIb, IIIa and IIIb are controlled and found to be absent, or below the level of detection.
The present invention is mainly related to an improved process for the preparation of Lapatinib (I) and its Ditosylate Monohydrate salt (II), wherein the process involves the use of intermediate compound of Formula III during synthesis. Here, the compound of Formula III is a known impurity and in addition its regioisomeric impurities, compound of Formula IIIa and IIIb also need to be controlled, such that they are absent or at a level below detection in the final product.
((III)

The present invention relates to a process used to control the isomeric impurities N-(3-Chloro-4-((2-fluorobenzyl)oxy)phenyl)-6-iodoquinazolin-4-amine compound of Formula IIIa, N-(3-Chloro-4-((4-fluorobenzyl)oxy)phenyl)-6-iodoquinazolin-4-amine compound of Formula IIIb, N-(3-chloro-4-((2-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(methylsulfonyl)ethyl) amino)methyl)furan-2-yl)quinazolin-4-amine compound of Formula Ia, N-(3-chloro-4-((4-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(methylsulfonyl)ethyl)amino)methyl)furan-2-yl)quinazolin -4-amine compound of Formula Ib, and their respective Ditosylate monohydrate salts compound of Formulas IIa and IIb.

Ortho Impurities

(Ia)

(IIa)

(IIIa)

Para Impurities

(Ib)

(IIb)

(IIIb)

In an embodiment of the present invention the identified impurities of compound of Formula IIIa or IIIb has been formed from the starting material of compound of Formula IV i.e. 3-chloro-4-(3-fluorobenzyloxy) aniline.
((IV)
In particular, during the process for the preparation of Lapatinib (I) the intermediate compound of Formula III is prepared from the starting material compound of Formula IV. The product (Formula III) of the process is purified by removing the impurities of Formula IIIa and/or IIIb, thus avoiding the carrying forward of impurities, that may result in additional impurities.
An embodiment of the present invention for the synthesis of Lapatinib (I) and its salts, purification is carried out using an acid or solvent to wash out the isomeric impurities such as compound of Formula IIIa (o-isomer) and Formula IIIb (p-isomer) impurities in intermediate N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-iodoquinazolin-4-amine of Compound of Formula III, prior to development of the product Lapatinib.
In particular, during the process for the preparation of Lapatinib (I), the intermediate compound of Formula III is prepared from the starting material compound of Formula IV, which is purified to remove the impurities of Formula IIIa and/or IIIb. Hence there is no impurities that are carried further during the preparation of Lapatinib (I), resulting in a final product with either no impurities or below the level of detection.
As the result of the initial purification of Formula III, the impurities Ia, Ib, IIa and IIb are either absent or below the level of detection in the final product of Lapatinib (I) and/or its ditosylate monohydrate salt (II).
One of the embodiments of the present invention, the purification process of N-(3-Chloro-4-((3-fluorobenzyl) oxy) phenyl)-6-iodoquinazolin-4-amine of Compound of Formula III involves the use of acid at reflux temperature.
In second embodiment of the present invention, the acid used for washing out the isomeric impurities is selected from acetic acid, aqueous acetic acid, aqueous hydrochloric acid and aqueous citric acid.
In another embodiment, the acid used for washing out the isomeric impurities is selected from acetic acid and aqueous hydrochloric acid.
In a further embodiment, the acid used for washing out the isomeric impurities is preferably acetic acid.
In another embodiment of the present invention, the purification process of N-(3-Chloro-4-((3-fluorobenzyl) oxy) phenyl)-6-iodoquinazolin-4-amine of Compound of Formula III involves the use of a solvent selected from Methanol (MeOH), Tetrahydrofuran (THF), Dichloromethane (MDC), 1,4-Dioxane, Isopropyl alcohol (IPA), Dimethylformamide (DMF), N-Methyl-2-pyrrolidone (NMP), Acetone, Ethyl acetate (EtOAc), Water and a combination thereof.
In another embodiment, the solvent used for washing out the isomeric impurities is selected from Acetic acid, Tetrahydrofuran (THF), Dichloromethane (MDC), Acetic acid and Isopropyl alcohol (IPA), Methanol (MeOH) and Dichloromethane (MDC), Dimethylformamide (DMF) and Water.
In a further embodiment of the present invention, the temperature maintained between 60-80°C.
In another embodiment, the temperature maintained is particularly between 70 -75°C.
In another embodiment of the present invention, the acid washing procedure is repeated until the desired content of isomeric impurity is achieved.
An embodiment of the present invention, the desired content of isomeric impurity i.e. o-isomer impurity N-(3-Chloro-4-((2-fluorobenzyl)oxy)phenyl)-6-iodoquinazolin-4-amine of Formula IIIa is below level of detection (not detected) by HPLC as compared with the final compound Lapatinib (I).
In another embodiment of the present invention, the desired content of another isomeric impurity i.e. p-isomer impurity N-(3-Chloro-4-((4-fluorobenzyl) oxy) phenyl)-6-iodoquinazolin-4-amine of Formula IIIb is ‘substantially free means’ is below the level of detection or =0.02%, but not >0.03% AUC; as detected by HPLC as compared with the final compound Lapatinib Ditosylate Monohydrate (II).
The impurities compounds of Formulas Ia and Ib of Lapatinib (I) and its salts, are important to reduce to gain a highly purified product. For this instance, the impurities Formula Ia and Ib need to be below the level of detection or =0.02% AUC of HPLC to ensure the quality of the final compound.
During the development of process of synthesis of Lapatinib Ditosylate monohydrate compound of Formula II, it was surprisingly discovered that these impurities of compound of Formula Ia and Ib of Lapatinib are being reduced significantly when acid is used repeatedly for washing.
In yet another embodiment, the main advantage of the process is that isolated API is substantially free from isomeric impurities and degradants.
Lapatinib Ditosylate Monohydrate (II) obtained according to the process of the present invention results in the final API purity by HPLC of more than 99.9 % w/w.
The purity of the samples of compounds is measured using HPLC Chromatography. Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner. Experimental methods are without specific conditions in the examples below and may be altered in accordance with conventional methods and conditions, according to the product specification or selection.

EXPERIMENTAL PROCEDURES:
Example 1: Purification of Formula III
90g (0.177mol) of N-(3-chloro-4-((3-fluorobenzyl) oxy) phenyl)-6-iodoquinazolin-4-amine (Formula III) is charged into a mixture of 270 ml of acetic acid at 25-35°C. Reaction mixture is heated to 70-75°C (reflux) and maintained for 30-60 min, gradually cooled the reaction mass to 25-35°C (4-5 h), stirred at room temperature for 1-2 h. The product was isolated by filtration and repeated the same purification until the o-Isomer and p-Isomer content is below quantitative level, yielded 45.0g (50.0%) of the product as off white to light brown color powder. HPLC purity: 99.91%.
Specification of Input material Before purification Input Material HPLC without purification After purification
Formula III
(Purified) Formula III
(Purified)
o-Isomer content NMT 0.07 0.03 Not Detected Not Detected
p-Isomer content NMT 0.75 0.61 0.06 0.06

Experiment on cooling pattern - Fast cooling:
100g (0.177mol) of N-(3-chloro-4-((3-fluorobenzyl) oxy) phenyl)-6-iodoquinazolin-4-amine (Formula III) is charged into a mixture of 300 ml of acetic acid at 25-35°C. Reaction mixture is heated to 70-75°C (reflux) and maintained for 30-45 min, the reaction mass is cooled to 25-35°C within 60 min, stirred at room temperature for 1-2 h. The product was isolated by filtration and repeated the same purification until the o-Isomer and p-Isomer content is below the below quantitative level, yielded 61.3 g (61.3%) of the product as off white to light brown color powder. HPLC purity: 97.86%.
S# Batch Input Output
(g) Yield
% RS by HPLC
Purity Ortho-isomer Para- isomer Specification limit
1 KSM:
Formula III
(Crude) Input Material NA 97.82 0.02 0.38 Ortho-isomer: NMT:0.07
2 Formula III
(Purified) 100 61.3 63.3 97.86 Not Detected 0.34 Para-isomer: NMT:0.08

Example 1a (Formula III):
90g (0.177mol) of N-(3-chloro-4-((3-fluorobenzyl) oxy) phenyl)-6-iodoquinazolin-4-amine (Formula III) is charged into a mixture of 270 ml of aqueous HCl at 25-35°C. Reaction mixture is heated to 70-75°C (reflux) and maintained for 30-45 min, gradually cooled the reaction mass to 25-35°C (4-5 h), stirred at room temperature for 1-2 h. The product was isolated by filtration and repeated the same purification until the o-Isomer and p-Isomer content is below quantitative level, yielded 45.0g (50.0%) of the product as off white to light brown color powder. HPLC purity: 99.91%.

Example 1b (Formula III):
90g (0.177mol) of N-(3-chloro-4-((3-fluorobenzyl) oxy) phenyl)-6-iodoquinazolin-4-amine (Formula III) is charged into a mixture of 270 ml of acetic acid (in water) at 25-35°C. Reaction mixture is heated to 70-75°C (reflux) and maintained for 30-45 min, gradually cooled the reaction mass to 25-35°C (4-5 h), stirred at room temperature for 1-2 h. The product was isolated by filtration and repeated the same purification until the o-Isomer and p-Isomer content is below quantitative level, yielded 54.0g (60.0%) of the product as off white to light brown color powder. HPLC purity: 99.91%.

Example 1c (Formula III):
90g (0.177mol) of N-(3-chloro-4-((3-fluorobenzyl) oxy) phenyl)-6-iodoquinazolin-4-amine (Formula III) is charged into a mixture of 270 ml of aqueous citric acid (in water) at 25-35°C. Reaction mixture is heated to 70-75°C (reflux) and maintained for 30-45 min, gradually cooled the reaction mass to 25-35°C (4-5 h), stirred at room temperature for 1-2 h. The product was isolated by filtration and repeated the same purification until the o-Isomer and p-Isomer content is below quantitative level, yielded 45.0g (50.0%) of the product as off white to light brown color powder. HPLC purity: 99.91%.

Example 1d (Formula III):
90g (0.177mol) of N-(3-chloro-4-((3-fluorobenzyl) oxy) phenyl)-6-iodoquinazolin-4-amine (Formula III) is charged into a mixture of 270 ml of acetic acid at 25-35°C. Reaction mixture is heated to 70-75°C (reflux) and maintained for 30-45 min, gradually cooled the reaction mass to 25-35°C (4-5 h), stirred at room temperature for 1-2 h. The product was isolated by filtration and repeated the purification using citric acid until the o-Isomer and p-Isomer content is below quantitative level, yielded 45.0g (50.0%) of the product as off white to light brown color powder. HPLC purity: 99.91%.

Example 1e (Formula III):
90g (0.177mol) of N-(3-chloro-4-((3-fluorobenzyl) oxy) phenyl)-6-iodoquinazolin-4-amine (Formula III) is charged into a mixture of 270 ml of acetic acid at 25-35°C. Reaction mixture is heated to 70-75°C (reflux) and maintained for 30-45 min, gradually cooled the reaction mass to 25-35°C (4-5 h), stirred at room temperature for 1-2 h. The product was isolated by filtration and repeated the same purification using an aqueous hydrochloric acid until the o-Isomer and p-Isomer content is below quantitative level, yielded 40.0g (44.0%) of the product as off white to light brown color powder. HPLC purity: 99.91%.

Example 1f (Formula III):
100g (0.2mol) of N-(3-chloro-4-((3-fluorobenzyl) oxy) phenyl)-6-iodoquinazolin-4-amine (Formula III) as formed in the examples 1a to 1e is dissolved in a solvent at 25-35°C. Reaction mixture is heated to reflux and maintained for 30-60 min, gradually cooled the reaction mass to 25-35°C (4-5 h), stirred at room temperature for 1-2 h. The product was isolated by filtration to yield 36.9g (36.9%) of the product as off white to light brown color powder. HPLC purity: 99.81%.
The solvent use in the above experiment are is selected from Acetic acid, Tetrahydrofuran (THF), Dichloromethane (MDC), Acetic acid and Isopropyl alcohol (IPA), Methanol (MeOH) and Dichloromethane (MDC), Dimethylformamide (DMF) and Water.

Further various purification experiments have attempted and tried using combinations of acids selected from citric acid, acetic acid, hydrochloric acid and solvents selected from Methanol (MeOH), Tetrahydrofuran (THF), Dichloromethane (MDC), 1,4-Dioxane, Isopropyl alcohol (IPA), Dimethylformamide (DMF), N-Methyl-2-pyrrolidone (NMP), Acetone, Ethyl acetate (EtOAc), Water and a combination thereof, wherein the target is to reduce the o-Isomer and p-Isomer content to below quantitative level, yielded product that is off-white to light brown color powder, with highest possible purity.

Example 2: Synthesis of 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl) furan-2-carbaldehyde
4.0 Kg (0.0988 mol) of N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-iodoquinazolin-4-amine (III) is charged into a mixture of 750 L of Tetrahydrofuran at 25-35°C. 1.8 Kg (0.128) of 5-Formyl-2-furanboronic acid is charged at 25-35°C, Triethylamine 1.0 volume is added, 5% Pd Carbon and methanol is charged, further the reaction mixture is heated to 50-60°C and maintained for 4-5 h, the reaction mass is slowly cooled down to 25-35°C, filtered on Hyflo bed and washed with Tetrahydrofuran. The product is isolated from the clear filtrate by adding water into it; stirred for 2 h at 25-35°C, material is isolated by filtration followed by washing with water methanol mixture, yielded 3.6 Kg (96.05%) of the title product as Yellow to light brown color powder. HPLC purity: 99.70%.

Example 3: Synthesis of Lapatinib (I)
3.2 Kg (0.0067 mol) of 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl) furan-2-carbaldehyde is charged into 32 L of Dichloromethane at 25-35°C. 1.50 Kg (0.0093) of 2-aminoethylmethylsulfone hydrochloride is charged at 25-35°C, N,N-Diisopropylethylamine and Acetic acid are added then at 30-35°C the reaction mass is stirred for 1 h at 20-25°C, the reaction mass is cooled down to 20-25°C, Sodium triacetoxyborohydride is added lot wise into the reaction mass at 20-25°C, maintained for 2-3h, cooled to 20-25°C, 25% Sodium hydroxide solution is slowly added and maintained the reaction mass for 2-3 h then filtered and washed with Dichloromethane, followed by water slurry, finally product is isolated from Isopropyl alcohol at 25-35°C, yielded 2.9 Kg (90.6%) of the title product as light brown to brownish color powder. HPLC purity NLT 95.0%.

Example 4: Synthesis of Lapatinib Ditosylate Monohydrate (II)
2.8 Kg (0.0048mol) N-(3-chloro-4-(3-fluorobenzyloxy) phenyl)-6-(5-((2-(methyl sulfonyl) ethyl amino) methyl) furan-2-yl) quinazolin-4-amine was charged into 16.8 ml of Dimethylformamide at 25-35°C. Para toluene sulphonic acid 1.92 Kg (0.0111 moles) is charged at 25-35°C, temperature is raised to 80-90°C, Acetonitrile 16.8 ml is added at 80-90°C, the reaction mass is stirred at 80-90°C and cooled to 25-35°C, stirred for 1 h, filtered and washed with acetonitrile, the wet crude is taken into Dimethylformamide 16.8 ml, temperature is raised to 80-90°C, Acetonitrile 16.8 ml is added at 80-90°C, stir the reaction mass at 80-90°C for 1 h, cool the reaction mass to 25-35°C, stir for 1 h filter and wash with acetonitrile, finally title product is isolated from Acetone and water mixture at reflux, filtered at 25-35°C after 18 h stirring at 25-35°C yielded 3.2 Kg (77.0%) of the title product as light yellow to yellow color powder. HPLC purity 99.9 % (area by HPLC).
o-Isomer content: Not Detected;
p-Isomer content: equal to or less than 0.02% but not more than 0.03%.

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein may be interpreted as mere illustrative of the invention and not in a limiting sense.
,CLAIMS:We Claim:
1. A process for the purification of compound of Formula III, comprising of treating the compound of Formula III with an acid.

Formula III
2. The process as claimed in claim 1 for the purification of compound of Formula III, wherein the acid used is selected from acetic acid, hydrochloric acid, citric acid, or its aqueous solutions.
3. The process as claimed in claim 1 for the purification of compound of Formula III, wherein the acid used is acetic acid.
4. A process for the purification of compound of Formula III, comprising of treating the compound of Formula III with a solvent.

Formula III
5. The process as claimed in claim 4 for the purification of compound of Formula III, wherein the solvent used is selected from Acetic acid, Methanol (MeOH), Tetrahydrofuran (THF), Dichloromethane (MDC), 1,4-Dioxane, Isopropyl alcohol (IPA), Dimethylformamide (DMF), N-Methyl-2-pyrrolidone (NMP), Acetone, Ethyl acetate (EtOAc), Water or a combination thereof.
6. A process for the synthesis of Lapatinib or pharmaceutically acceptable salts thereof comprising of treating the compound of Formula III with an acid

Formula III
and further converting compound of formula III to Lapatinib or pharmaceutically acceptable salts thereof.
7. The process as claimed in claims 1, 4 and 6 wherein the impurities in the final compound is =0.02%, but not >0.03% AUC.
8. The process as claimed in the above claims wherein the impurities are regioisomers ortho-isomer (o-isomer) and para-isomer (p-isomer) of the compound of Formula III, Lapatinib (I) and its salts.
9. The process as claimed in claims 1, 4 and 6 for the purification of compound of Formula III, wherein the desired content of o-isomer is not detected less than 0.02% by the HPLC method.
10. The process as claimed in claims 1, 4 and 6 for the purification of compound of Formula III, wherein the desired content of o-isomer is equal to or less than 0.02% by the HPLC method.