FORM 2
THE PATENTS ACT, 1970
(Act 39 of 1970)
COMPLETE SPECIFICATION
(See Section 10; Rule 13)
Title: “An environment friendly process for the
preparation of Lapatinib Ditosylate of Formula 1(b)”.

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of Lapatinib Ditosylate of formula 1(b). More particularly, the present invention relates to environment friendly process that involves green chemistry in preparation of Lapatinib Ditosylate of formula 1(b). The said process is economically and commercially viable as initial 2 stages of processes use water as solvent avoiding hazardous reagent or solvent during the preparation of Lapatinib Ditosylate of formula 1(b).

BACKGROUND OF THE INVENTION
Lapatinib is a member of the 4-anilinoquinazoline class of kinase inhibitors. Lapatinib of formula-(1), 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, US6727256 (2004 to SmithKline Beecham). Lapatinib is present as the monohydrate of the ditosylate salt, with the chemical name N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5[[[2-(methylsulfonyl) ethyl]amino]

methyl]-2-furanyl]-4-quinazolin- aminebis - (4-methyl benzene sulfonate)monohydrate.
In vitro anti-tumor activity in combination with anti-ErbB2 antibodies is described in Oncogene, 24, 6213 (2005), biological effects on tumor growth is described in J. Clin. Oncol, 23, 2502 (2005) and pharmacokinetics and clinical activity in metastatic carcinomas is described in J. clin. oncol, 23, 5305 (2005).
It is marketed as TYKERB® (Lapatinib) and is indicated in combination with: Capecitabine for the treatment of patients with advanced or metastatic breast cancer Lapatinib inhibits ErbB-driven tumor cell growth in vitro and in various animal models.
US6713485 relates to substituted heteroaromatic compounds, methods for their preparation, pharmaceutical compositions containing them and their use in medicine. Specifically, the invention relates to quinazoline derivatives useful in treating disorders mediated by protein tyrosine kinase activity, in particular erbB-2 and/or EGFR activity.
The process for the preparation of Lapatinib of formula (1), disclosed
in WO99/35146, is given in the Scheme-A. Accordingly, 4-chloro-6-
iodo-quinazoline of formula-(2), is reacted with 3-chloro-4-(31-fluoro-
benzyloxy)-aniline yielding N-[3-chloro-4-{(31-fluoro-
benzyloxy)phenyl}]-6-iodo-quinazoline of formula-(3). The compound of
the formula-(3) reacts with (1,3-dioxolan-2-yl)-2-(tributylstannyl)furan
to get the compound of formula-(4a) which on reaction with HCl,
removes the protecting group and liberates 5-(4-{3-chloro-4-(3-fluoro-
benzyloxy)anilino}-6-quinazolinylguran-2-carbaldehyde of formula-(4).
The compound of the formula-(4) on reaction with 2-
methanesulfonylethylamine, followed by reduction using sodium
(triacetoxy)borohydride as the reducing agent gives the required
compound Lapatinib of formula (1) as an organic residue, which is

purified by column chromatography. If desired the isolated material is then converted into the hydrochloride salt of formula-1(a).
US7157466 (WO02/02552) has disclosed a process for the preparation of the preparation of ditosylate salts of Lapatinib of formula-1(b) is disclosed as shown in Scheme-(B).

In both patents i.e. WO99/35146 and US7157466 (WO02/02552), the process involves multiple steps to get the required product. The process is lengthy and cumbersome and also involves usage of corrosive chemicals like POCl3/SOCl2 etc.
WO 2010/061400 relates to an improved and novel process for the preparation of high purity crystalline base of Lapatinib and its pharmaceutically acceptable salts. The invention further relates to intermediates according to formula (8) and formula (9) used in this process. The reaction scheme of the present invention is as given the following Scheme-(C).

Accordingly, the basic raw material selected for the synthesis of
Lapatinib of formula (1) is commercially available 2-amino benzonitrile
of formula-(6), which reacts with iodine or iodinemonochloride to get
2-amino-5-iodobenzonitrile of the formula-(7). The compound of the
formula-(7) on reaction with a novel compound N1-(3-chloro-4-(3-
fluorobenzyloxy)phenyl)-N,N-dimethylformamidine (8) at elevated
temperature gives the compound N-[3-chloro-4-[(3-
fluorobenzyloxy)phenyl]-6-iodo-quinazolinamine of formula-(3), The compound of the formula-(3) on reaction with 5-formyl-2-furyl boronic acid, in presence of triethylamine and Pd/C gives the compound 5-[4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6-quinazolinyl)-furan-2-carbaldehyde of the formula-(4). The compound of the formula-(4), on reaction with 2-methanesulfonylethylamine hydrochloride gives the novel compound N[3-chloro-4[(3-fluorobenzyloxy]phenyl[-6-[5-({[2-methanesulphonyl)-ethyl]imino}-2-furyl]-4-quinazolinamine of the formula-(9). The novel imine compound of formula-(9) on reduction, using sodium borohydride gives the compound of the formula-(1), which is Lapatinib base.
Novelty of the process disclosed in present invention resides in stage-01 and stage-3 of the process for the preparation of Lapatinib Ditosylate as both stage-01 & 03 involve water as a solvent. The said 2 stages have avoided the use of any organic solvents during the reaction. Further, water used in the stage-01 is recyclable and reusable that shows that the process is environment friendly and commercially viable.
None of the prior art reference has disclosed use of water in any steps of the process for preparing Lapatinib Ditosylate of formula 1(b).
There is a demand of providing environment friendly process which is of having no or minimal use of solvents or chemicals, a simple, easy to operate, economically viable process for the preparation of Lapatinib Ditosylate of formula 1(b).

OBJECTS OF THE INVENTION
Accordingly, the main object of the present invention is to overcome the problems faced by the prior art processes in the preparation of Lapatinib ditosylate of formula 1(b).
There is an object of the present invention is to provide a simple, environment friendly, robust, easy to operate, economically viable process for the preparation of compound of formula (P) of stage-01.
There is an object of the present invention is to provide a simple, environment friendly, robust, easy to operate, economically viable process for the preparation of compound of formula (R) of stage-03.
Yet there is an object to provide a simple, environment friendly, robust, easy to operate, economically viable process for the preparation of Lapatinib ditosylate of formula 1(b).
BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of Lapatinib Ditosylate of formula 1(b).

More particularly, the present invention relates to environment friendly process that involves green chemistry in preparation of Lapatinib Ditosylate of formula 1(b). The said process is economically and commercially viable in which 2 stages do not require hazardous

chemicals to be used during the preparation of Lapatinib Ditosylate of formula 1(b).
The present innovators have comprehensively and successfully investigated the possibility of developing a new process for the preparation of Lapatinib Ditosylate of formula 1(b).
Proposed Route of synthesis for the preparation of Lapatinib Ditosylate is shown as follows:
Scheme-1: Route of Synthesis for Preparation of Lapatinib Ditosylate of formula 1(b):

According to the embodiment (Scheme-D) of the present invention, there is provided a process for the preparation of Lapatinib Ditosylate of formula 1(b), the process for the preparation of Lapatinib Ditosylate of formula 1(b) comprises, the stages of:
(01) Reacting 4-chloro-6-iodo-quinazoline of formula (KSM-01) and 3-
chloro-4-(3'-fluoro-benzyloxy)-aniline of formula (KSM-02) in water as solvent at 50-700C for 2-4 hrs to give N-[3-chloro-4-{(3'-fiuoro-benzyloxy) phenyl}]-6-iodo-quinazoline of formula (P) of stage-01;
(02) Reacting N-[3-chloro-4-{(3'-fiuoro-benzyloxy) phenyl}]-6-iodo-
quinazoline of formula (P) of stage-01 with 2-Formylfuran-5-boronic acid of formula (KSM-03) in presence of Pd/C and base in a mixture of 1:4dioxane:methanol solvents at a temperature 30-600C for 2-4 hrs to give 5-[4-[3-chloro-4-(3- fluorobenzyloxy) anilino]-6-quinazolinyl)-furan-2-carbaldehyde of formula (Q) of stage-02;
(03) Reacting 5-[4-[3-chloro-4-(3- fluorobenzyloxy)anilino]-6-
quinazolinyl)-furan-2-carbaldehyde of formula(Q) of stage-02 with 2-methanesulfonylethylamine hydrochloride of formula (KSM-04) at a pH between 6.5 to 7.5 in water as solvent at a temperature 50-700C for 5-10 hrs to give N[3-chloro-4[(3-fluorobenzyloxy]phenyl[-6-[5-({[2- methane sulphonyl)-ethyl] imino}-2-furyl]-4-quinazolin amine of formula (R) of stage-03;
(04) reacting N[3-chloro-4[(3-fluorobenzyloxy]phenyl[-6-[5-({[2-
methane sulphonyl)-ethyl] imino}-2-furyl]-4-quinazolinamine of formula (R) of stage-03 with sodium borohydride (NaBH4) in methanol as solvent at a temperature between 0-100C and extracting it with dichloromethane and collecting dichloro methane extraction;
(05) taking dichloro methane extraction for insitu reaction with p-
toluene sulphonic acid (PTSA) in methanol at a temperature between 20-300C to give Lapatinib Ditosylate of formula 1(b).

In stage-01, IPA is used in the prior art processes. Inventors have replaced IPA with water and they have found surprising results. Inventors have obtained yield and purity of compound of stage-01 of formula (P) reasonably and comparatively good then prior art processes. Further, water is used in 15-20 volumes in the said reaction. In case if less water is used as solvent or if used it with mixing with IPA as solvent, the yield is lesser than if water is used. Inventors have also found that if water is used in an amount of less than 15V then the reaction mass becomes thick that makes reaction commercially not viable due to presence of unreacted KSM-01 and reaction handling problems. It is also observed by the inventors that if KSM-01 in 1.1 molar ratio provides good results with comparison to 1 molar ratio of KSM-01. It is also observed that the temperature should be maintained between 55-600C during the reaction as low temperature will make the conversion into stage-01 slow while higher temperature will create unwanted degradation in the reaction. Inventors have also tried to conduct experiments with recycled water and re-recycled water, the results obtained with recycled water and re-recycled water is at par and complies the requirement to obtain stage-01 of formula (P). The details about the solvent change and yield of stage-01 of formula (P) are provided in table-1 with examples 1 to 8.
Stage-01 may be used directly as a wet cake in the next stage or it can be dried in oven as if required. In stage-02, water may be added as an additional solvent and may be mixed with methanol and dioxane, addition of water as an additional solvent reduces the use of organic solvents without affecting the yield and purity of stage-02 thus use of water as solvent contributes towards the greener chemistry and process. Base is selected from triethylamine (TEA), diisopropylethylamine (DIPEA), ammonia, sodium carbonate (Na2CO3) and sodium bicarobonate (NaHCO3).
As shown in Table-2, Stage-02 is carried out using desired mole ratio of Stage-01 & KSM-03 and addition of water in the reaction. Table-2

also provides comparative study of process with prior art processes and the change of base and selection of water as solvent in the reaction according to the present invention.
In stage-03, prior art processes have used organic bases such as Triethyl amine (TEA), diisoproplylethyl amine (DIPEA) in organic solvent such as methanol (MeOH), tetrahydrofuran (THF) or methylene dichloride (MDC).
Inventors have surprisingly found that usage of water as solvent along with inorganic bases gives similar or better yield and purity compared to the prior art processes. Further use of water as solvent avoids the use of organic solvents like methanol, THF or MDC and thus contributes towards greener chemistry and process for the preparation of stage-03. It is to be noted that less quantity of KSM-04 may not react with compound of stage-02 of formula (Q) completely so unreacted compound of formula (Q) will remain present after completion of the reaction. In case if KSM-04 is used more in quantities against the required quantity then purification may be required to remove excess of KSM-04 from stage-03 product. So the ratio of stage-02 and KSM-04 should be kept at 1:1.1 to get expected yield and purity of stage-03 of formula (R). pH between 6.5 to 7.5 is maintained using inorganic base selected from sodium carbonate (Na2CO3), Ammonia and sodium bicarbonate (NaHCO3). As shown in Table-3, Stage-03 is carried out using desired mole ratio of Stage-02 & KSM-04 and addition of water in the reaction. Table-3 also provides comparative study of process known in the prior art references and the change of base, solvent and selection of water as solvent in the reaction according to the present invention.
Stage-04 & 05, a process for the preparation of Lapatinib ditosylate is known in the prior art references. It can be prepared from any process known in the art. As shown in Table-4, Stage-04 is carried out using desired mole ratio of Stage-03. Table-4 provides details on selection of solvent(s) for carrying out reaction and comparative yield of stage-04.

Novelty of the process disclosed in present invention resides in stage-01 and stage-03 of the process for the preparation of Lapatinib Ditosylate as both stage-01 & 03 involve water as a solvent. The said 2 stages have avoided the use of any organic solvents during the reaction. Further, the water used in the stage-1 is recyclable and reusable that shows that the process is environment friendly and commercially viable.
After completion of the reaction, Lapatinib Ditosylate of formula 1(b) may be isolated in pure form using prior art technologies. Lapatinib Ditosylate of formula 1(b) may be isolated as anhydrous form or may be in hydrated form or may be in the forms known in the prior art technologies.
For Example: Lapatinib ditosylate with higher purity is obtained by suspending or dissolving Lapatinib ditosylate of formula 1(b) in a mixture of water and organic solvents like ethanol, methanol, isopropanol, N,N-dimethylformamide (DMF), tetrahydrofuran (THF), 2-methyltetrahydrofiιran, acetonitrile, acetone, methylethylketone, methylenechloride (MDC) and isolating it in pure form with a crystalline structure or form known in the prior art technologies,
The reaction of all stages was monitored by HPLC. The present invention demonstrated examples cited below, which are provided as illustration only and therefore should not be construed as limitation of the possible and future invention.
EXAMPLES: Preparation of Lapatinib Ditosylate of formula 1(b): Stage-01: Preparation of N-[3-chloro-4-{(3'-fiuoro-benzyloxy) phenyl}]-6-iodo-quinazoline of formula (P):
KSM-01 1.1mol and KSM-02 1mole charge to the reactor followed by 15Vol water and allow to stir for 30min at 25-300C. Allow to heat for 5.5hrs at 55-600C and cool the reaction mass at 25-300C. Filter the reaction mass and suck dry well to get stage-01 of formula (P) as wet cake 2.5times (w/w).

Yield: 2.15 (on dry basis w/w)
HPLC purity: 99.187%.
Example 1 to 8 of stage-01 of formula (P):
In a similar manner, as shown in Table-1, Stage-01 is carried out using different mole ratio of KSM-01 and KSM-02. Table-1 also provides comparative study of process with prior art processes and the change of solvent from IPA to water. Table-1 also provides the process carried out with recycled water and re-recycled water.
Table-1

Ex. No. KSM-01
(in moles) KSM-02
(in moles) Solvent(s) (in volume) Remarks Yield (w/w)
1 1 1 IPA (15V) As per prior art process 2
2 1 1 IPA:Water (10:5 V) As per prior art process 1.8
3 1 1 Water (5V) Thick mass,
unreacted
KSM-01 Failed
4 1 1 Water (10V) unreacted KSM-01 2.1
5 1.1 1 Water (10V) Reaction completed 2.1
6 1.1 1 Water (15V) Reaction completed 2.2
7. 1.1 1 Recycled Water (15V) Reaction completed 2.2
8. 1.1 1 Re-recycled Water (15V) Reaction completed 2.2
Wet cake directly used in next stage & filter ml also directly use for next batch.
Stage-02: 5-[4-[3-chloro-4-(3- fluorobenzyloxy)anilino]-6-
quinazolinyl)-furan-2-carbaldehyde of formula(Q):
Stage-01 wet cake 1mole charge in the reactor followed by methanol: dioxane (1:3) 10vol at 25-300C. Add TEA 0.28mole to the reaction and add 10% palladium on charcoal 5% slurry in dioxane 0.5Vol at 25-300C. Allow to heat at 45-500C for 4.0hrs. Filter the catalyst to use in next batch and clear reaction mass transfer to the clean reactor and

cool the reaction mass at 25-300C. add water 10Vol to the reaction
mass to get yellowish material and filter to get the material and suck
dry well to get wet cake of stage-02 of formula (Q).
Yield: 95%
HPLC Purity: 99.24%
Example 1 to 7 of stage-02 of formula (Q):
In a similar manner, as shown in Table-2, Stage-02 is carried out using desired mole ratio of Stage-01 & KSM-03 and addition of water in the reaction. Table-2 also provides comparative study of process with prior art processes and the change of base and selection of water as solvent in the reaction according to the present invention.
Table-2

Ex. No.
1
2
3
4 5
6
7. Stage-01 (in moles) KSM-03 ( in moles) Base Solvent(s) (in volume) Yield (w/w)

1 1 TEA MeOH;Dioxane (1:3) (Prior art process) 0.9

1 1 DIPEA MeOH;Dioxane (1:3) (Prior art process) 0.8

1 1 Ammonia MeOH;Dioxane (1:3) (Prior art process) 0.8

1 1 Na2CO3 MeOH;Dioxane (1:3) Failed

1 1 TEA MeOH;Dioxane:water (1:3:1) 0.94

1 1 TEA MeOH;Dioxane:water (1:3:1) 0.94

1 1 TEA MeOH;Dioxane:water (1:3:1) 0.94
Stage-02 of formula (Q) is used directly in next stage synthesis.
Stage-03: N[3-chloro-4[(3-fluorobenzyloxy]phenyl[-6-[5-({[2-
methane sulphonyl)-ethyl] imino}-2-furyl]-4-quinazolinamine of formula (R):
KSM-04 charge in the reactor followed by water 10vol and add Sodium carbonate solution 10% to the reaction mass at 25-300C, allow to stir for 30 to 40min at 25-300C. Charge stage-02 wet cake 1mole to the reaction mass at 25-300C and allow to stir for 30min. heat the reaction mass at 60-650C for 8hrs. cool the reaction mass at 25-300C

and filter the reaction mass to get wet cake 2times and dry at 500C to
get Stage-03 of formula (R).
Yield: 96%
HPLC purity: 98.58%.
Example 1 to 9 of stage-03 of formula (R):
In a similar manner, as shown in Table-3, Stage-03 is carried out using desired mole ratio of Stage-02 & KSM-04 and addition of water in the reaction. Table-3 also provides comparative study of process known in the prior art references and the change of base, solvent and selection of water as solvent in the reaction according to the present invention.
Table-3

Ex. No. Stage-02 (in moles) KSM-04 ( i n moles) Base Solvent(s) (in volume) Our Remarks Yield (%)
1 1 1 TEA MeOH Reaction complies 95
2 1 1 DIPEA THF:Water Reaction complies Not isolated
3 1 1 TEA MDC Reaction complies Not isolated
4 1 1 TEA MeOH:Water Reaction complies Not isolated
5 1 1 NaHCO3 water Unreacted
Stage-02
observed Not isolated
6 1 1.1 NaHCO3 water Unreacted Stage-02 observed 94
7. 1 1.1 Na2CO3 water Reaction complies 96
8 1 1.1 NaOH water Reaction complies 85
9 1 1.1 Na2CO3 water Reaction complies 96
Stage-04 & 05: Lapatinib Ditosylate of formula 1(b):
Stage-03 1mole charge to the reactor followed by methanol 8Vol and cool the reaction mass at 10-150C. add portion wise sodium borohydride to the reaction mass with carefully and allow to stir for

4hrs. Add water 3vol to the reaction mass and allow to stir for 1hr.
add DCM 5vol to the reaction mass and exctrat the material in organic
layer. Collect organic layer in clean reactor followed by 2micron
filtration. Add PTSA 1.1mole (solution in methanol 1vol) to the
reaction mass to get yellowish material. filter the reaction mass and
dry the wet cake at 55-600C for 8hrs to get pure lapatinib ditosyalte
monohydrate.
Yield: 97%
HPLC purity: 99.79%.
Example 1 to 5 for preparation of Lapatinib ditosylate (1b):
In a similar manner, as shown in Table-4, Stage-04 is carried out using desired mole ratio of Stage-03. Table-4 provides details on selection of solvent(s) for carrying out reaction and comparative yield of stage-04.
Table-4

Ex. No.
1
2 3 4 5 Stage-03 (in moles) Solvent 1 Solvent 2 Catalyst Our Remarks Yield (%)

1 Methanol MDC NaBH4 As per prior art process 90

1 Methanol Ethyl acetate NaBH4 Reaction complies 85

1 Methanol MDC NaBH4 Reaction complies 95

1 Methanol MDC NaBH4 Reaction complies 97

1 Methanol MDC NaBH4 Reaction complies 89
ADVANTAGES OF THE PRESENT INVENTION
1) Lapatinib Ditosylate of formula 1(b) obtained by this process is of high purity.
2) In the present process the number of discrete synthetic steps is reduced.
3) The process for the preparation of Lapatinib Ditosylate of formula 1(b) is cost-effective, environment friendly and commercially viable as

it avoids the use of hazardous chemicals and reactants, especially in stage-01 and stage-03 of the process.
4) Stage-01 and stage-03 of the process is carried out in water as solvent by avoiding the use of organic or hazardous solvents and chemicals.
5) In stage-01 of the present invention, water used in the reaction is recyclable and reusable thus it ensures minimum use of water in the reaction.
6) The present process does not require any chromatographic
purification.

We claim:
1. A process for the preparation of Lapatinib Ditosylate of formula
1(b) comprises, the stages of:
(01) Reacting 4-chloro-6-iodo-quinazoline of formula (KSM-01) and 3-chloro-4-(3'-fluoro-benzyloxy)-aniline of formula (KSM-02) in water as solvent at 50-700C for 2-4 hrs to give N-[3-chloro-4-{(3'-fiuoro-benzyloxy) phenyl}]-6-iodo-quinazoline of formula (P) of stage-01;
(2) Reacting N-[3-chloro-4-{(3'-fiuoro-benzyloxy) phenyl}]-6-iodo-quinazoline of formula (P) of stage-01 with 2-Formylfuran-5-boronic acid of formula (KSM-03) in presence of Pd/C and base in a mixture of 1:4dioxane:methanol solvents at a temperature 30-600C for 2-4 hrs to give 5-[4-[3-chloro-4-(3- fluorobenzyloxy) anilino]-6-quinazolinyl)-furan-2-carbaldehyde of formula (Q) of stage-02;
(3) Reacting 5-[4-[3-chloro-4-(3- fluorobenzyloxy)anilino]-6-quinazolinyl)-furan-2-carbaldehyde of formula(Q) of stage-02 with 2-methanesulfonylethylamine hydrochloride of formula (KSM-04) at a pH between 6.5 to 7.5 in water as solvent at a temperature 50-700C for 5-10 hrs to give N[3-chloro-4[(3-fluorobenzyloxy]phenyl[-6-[5-({[2- methane sulphonyl)-ethyl] imino}-2-furyl]-4-quinazolin amine of formula (R) of stage-03;
(4) reacting N[3-chloro-4[(3-fluorobenzyloxy]phenyl[-6-[5-({[2-methane sulphonyl)-ethyl] imino}-2-furyl]-4-quinazolinamine of formula (R) of stage-03 with sodium borohydride (NaBH4) in methanol as solvent at a temperature between 0-100C and extracting it with dichloro methane and collecting dichloro methane extraction;
(5) taking dichloro methane extraction for in-situ reaction with p-toluene sulphonic acid (PTSA) in methanol at a

temperature between 20-300C to give Lapatinib Ditosylate of formula 1(b).
2. The process for the preparation of Lapatinib Ditosylate of formula 1(b) wherein in stage-01, water is added as solvent in a volume between 10v to 15v.
3. The process for the preparation of Lapatinib Ditosylate of formula 1(b) wherein in stage-01, KSM-01 is added in a molar ratio 1.1 and KSM-02 is added in a molar ratio 1.0.
4. The process for the preparation of Lapatinib Ditosylate of formula 1(b) wherein in stage-02, base is selected from triethylamine (TEA), diisopropylethylamine (DIPEA), ammonia, sodium carbonate (Na2CO3) and sodium bicarobonate (NaHCO3).
5. The process for the preparation of Lapatinib Ditosylate of formula 1(b) as claimed in claim 1 wherein in stage-03, pH 6.5 to 7.5 is maintained by addition of inorganic base.
6. The process for the preparation of Lapatinib Ditosylate of formula 1(b) as claimed in claim 5 wherein inorganic base is selected from sodium carbonate (Na2CO3), Ammonia and sodium bicarbonate (NaHCO3).