ORIGINAL

FORMl
THE PATENTS ACT, 1970
(39 of 1970)
and
The Patents Rules, 2003
APPLICATION FOR GRANT OF PATENT
[See sections 7, 54, 135 and rule 20(1)]

(FOR OFFICE USE ONLY)

Apphcation No. :
Filing Date:
Amount of Fee Paid:
CBR No.:
Signature:.

I. APPLICANT(S)
Name

Nationality

CADILA HEALTHCARE
LIMITED

Address

Indian

Zydus Tower, Satelhte Cross Roads,

Ahmedabad 380 015, Gujarat, India,

2. INVENTOR(S)
Name

Nationality

Address

[i] SINGH, Kumar Kamlesh

Indian

CadiIa Healthcare Limited, Zydus Tower,

Satelhte Cross Roads, Ahmedabad - 380
015, Gujarat, India

[ii] SINGH, NikhilAmar

Indian

Cadila Healthcare Limited, Zydus Tower,

Satelhte Cross Roads, Ahmedabad 380
015, Gujarat, India

[iii] NARODE, Sunil Dnyaneshwar

Indian

Cadila Healthcare Limited, Zydus Tower,

Satelhte Cross Roads, Ahmedabad - 380
015, Gujarat, India

3. TITLE OF THE INVENTION

"AN IMPROVED PROCESS FOR THE PREPARATION OF AXITINIB"

4. ADDRESS FOR CORRESPONDENCE OF
APPLICANT/ AUTHORISED PATENT AGENT
IN INDIA

Telephone Nos.:
+91-11-30165700
Fax Nos.:
+91-11 30165798 / 30165799
E-mail: sna@sna-ip.com

SUBRAMANIAM &c ASSOCIATES

Attorneys - at - law
Central Square, Suite-328, Plaza III,
20 Manoharlal Khurana Marg, Bara Hindu Rao .
(off Rani Jhansi Road), Delhi-110006

5. PRIORITY PARTICULARS OF THE APPLICATION(S) FILED IN CONVENTION

COUNTRY
Country

Application No.

Filing Date

N/A

N/A

N/A

'

Name of the
Applicants

Title of the Invention

N/A

N/A

rc 4 SEP ZflH

ORIGINAL
6. PARTICULARS FOR FILING PATENT COOPERATION TREATY (PCT) NATIONAL
PHASE APPLICATION
International filing date as allotted by the Receiving
Office

International application Number

Not Applicable

Not Applicable

7. PARTICULARS FOR FILING DIVISIONAL APPLICATION

Date of filing of original (first) application

Original (first) application number

Not Applicable

Not Applicable
8. PARTICULARS FOR FILING PATENT OF ADDITION
Main application /Patent Number

Date of filing of main application

Not Applicable

Not Applicable

9. DECLARATIONS
(i) Declaration by the inventors:
Wej the above-named inventors are the true and first inventors for this invention and declare that the
applicants herein are our assignees
(a) Date: 24th July 2014

(b) Signature of the inventor............................. (b) Signature of the inventor .

(c) Name: SINGHj Kumar Kamlesh
(c) Name: SINGH, NikhiJ Amar

(b) Signature of the inventor

(c) Name: NARODE, Sunil

yaneshwar

(ii) Declaration by the applicant(s) in the convention country:

Wej the applicant(s) in the convention country declare that the applicant(s) herein are our assignees
- NOT APPLICABLE (iii) Declaration by the applicant(s):
We, the applicants hereby declare that:0 We are in possession of the above-mentioned invention,
0 The provisional/complete specification relating to the invention is filed with this application
0 The invention as disclosed in die specification uses the biological material from India and the
necessary' permission from the competent authority' shall be submitted by us before the grant of
patent to us.
0 There is no lawful ground of objection to the grant of the patent to us.
0 We are the assignees of true and fust inventors.
0 The application, particulars of which are given in Para. 5 was the first application in convention
country in respect of our invention.
0 We claim the priority' from the above-mentioned application filed in convention country and state
that no application for protection in respect of the invention had been made in a convention country
before that date by us or by any person from which we derive the title.__________________________

F 4 SEP 2014

0 Our application in India is based on International application under Patent Cooperation Treaty
(PCT) as mentioned in Para. 6.
0 The application is divided out of our application particulars of which are given in Para. 7 and pray
that this application may be treated as deemed to have been filed on......................................under
Section 16 of the Act.
0 The said invention is an improvement in or modification of the invention particulars of which are
given in Para. 8._______________________________________________________________________
10. Following are the attachments with the application:
[a] Provisional specification, as applicable [No. of pages 16 (electronically filed)]
[b] Statement and undertaking on Form-3 [electronically filed]
[d] Copy of General Power of Authority
Fee Rs. 8000.00 in cash/ Cheque/Bank Draft bearing No..................................... dated.......................
on......................................Bank.
We hereby declare that to the best of our knowledge, information and belief the facts and matters stated
herein are correct and we request that a patent may be granted to us for the said invention.
Dated this 24'1' day of Julv 2014.

To,
The ControOer of Patents
The Patent Office
At Mumbai

o/SUBRAMANIAM & ASSOCIATES

Attorneys for the applicants

4 SEP ZOH

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)

&
The Patent Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

TITLE OF THE INVENTION

"AN IMPROVED PROCESS FOR THE PREPARATION OF

AXITINIB AND INTERMEDIATE THEREOF"

We, CADILA HEALTHCARE LIMITED, an Indian company incorporated under the

Companies Act, 1956, of Zydus Tower, Satellite Cross Roads, Ahmedabad - 380 015, Gujarat,
India,

The following specification particularly describes the invention and the manner in which it is to be
performed:

ABSTRACT

AN IMPROVED PROCESS FOR THE PREPARATION OF AXITINIB AND

INTERMEDIATE THEREOF
5

The present invention provides an improved process for the preparation of

axitinib. The process comprises reacting 2-mercapto-N-methylbenzamide of
Formula (IV) with 6-halo-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyroan-2-yl)1H-indazole of Formula (III) to obtain protected axitinib of Formula (II);
10

deprotecting the protected axitinib of Formula (II) with an acid in one or more of
organic solvents to obtain axitinib of Formula (I); and purifying the axitinib of
Formula (I) to obtain pure axitinib. The invention also provides a process for the
preparation of 2-mercapto-N-methylbenzamide of Formula (IV).

15

(I)

22

FIELD OF THE INVENTION

The field of invention relates to an improved process for the preparation of axitinib
and intermediates thereof.
5

BACKGROUND OF THE INVENTION

The following discussion of the prior art is intended to present the invention in an
appropriate technical context and allow its significance to be properly appreciated.
10

Unless clearly indicated to the contrary, however, reference to any prior art in this
specification should be construed as an admission that such art is widely known or
forms part of common general knowledge in the field.
Axitinib (previously identified as AG013736, CAS No. [319460-85-0]) is a tyrosine

15

kinase inhibitor. It inhibit multiple targets including Vascular Endothelial Growth

Factor (VEGFR-1), VEGFR-2, VEGFR-3, platelet derived growth factor and cKIT. It
has been shown to significantly inhibit growth of breast cancer in xenograft models
and has been successful in trials with renal cell carcinoma (RCC) and several other
tumor types.

20

Axitinib is chemically describe as N-Methyl-2-[[3-[(.,)-2-pyridin-2-ylethenyl]-1#indazol-6-yl]sulfanyl]benzamide, having molecular weight 386.469 g/mol and
empirical formula is C22H18N4OS. Axitinib can be structurally represented as Formula
(I).

25

U.S. Patent No. 6,534,524 B1 (the US 524 Patent) discloses indazole compounds
including Axitinib and process for preparation thereof.

U.S. Patent No. 6,531,491 B1 (the US 491 Patent) discloses several protein kinases
5

including indazole class of compounds and process for preparation thereof.

U.S. Patent No. 7,232,910 B2 (the US 910 Patent) discloses methods for preparing
indazole compounds which includes Axitinib, and an intermediate for the preparation
thereof.
10
International (PCT) publication WO 2006/048744 A1 discloses a process for
preparation of Axitinib and intermediates thereof.

International (PCT) publication WO 2006/048745 A1 discloses a process for

15

preparation of Axitinib and intermediates thereof.

Org. Process Res. Dev., Vol.12, No.4, pp. 637-645 (2008) also discloses the similar
process for preparation of Axitinib.

20

Recently published article in Org. Process Res. Dev. published online on 24th May,
2013 entitled Development of an efficient Pd-Catalyzed coupling process for

Axitinib also discloses the process for preparation of Axitinib and intermediates
thereof.

25

In view of the above, it is therefore, desirable to provide an efficient process for the
preparation of Axitinib. Synthetic process as available in the existing art is suffering
from the one or more disadvantage like long steps synthesis and tedious process and
problem related to palladium removal. A process of present invention is efficient to
provide high yield which makes this process suitable for large scale production

having economic significance. The present invention thereby provides useful

alternative for the preparation of Axitinib with substantial purity.

SUMMARY OF THE INVENTION

5

In one general aspect, there is provided a process for the preparation of 2-mercaptoN-methylbenzamide of Formula (IV),

N
H

(IV)
10

the process comprising:

(a) reacting a dithiosalicylic acid of Formula (VII) with a chlorinating agent in one or
more solvents to obtain a 2,2-dithiosalicylic acid dichloride compound of
Formula (VI),

s
HO'

15

NT

"

cr "

(VII)

(VI)

(b) reacting the 2,2-dithiosalicylic acid dichloride of Formula (VI) with

methylamine to obtain a 2,2-dithio-N-methylbenzamide of Formula (V), and

(V)

(c) reducing the 2, 2-dithio-N-methylbenzamide of Formula (V) with a reducing

agent comprising of zinc-acetic acid or zinc-HCl to obtain the 2-mercapto-Nmethylbenzamide of Formula (IV).

In another general aspect, there is provided a process for the preparation of pure
axitinib of Formula (I),

the process comprising:

10

(a) reacting 2-mercapto-N-methylbenzamide of Formula (IV) prepared by the above

process with 6-halo-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyroan-2-yl)-1Hindazole of Formula (III) to obtain protected axitinib of Formula (II),

(IV)
15

wherein, X represents any halogen selected from I, Br, Cl or F;

(II)
(b) deprotecting the protected axitinib of Formula (II) with an acid in one or more of
solvents to obtain axitinib of Formula (I); and
5

(c) purifying the axitinib of Formula (I) to obtain pure axitinib.

In another general aspect, there is provided pure axitinib having a purity of at least
about 99% or more, particularly of at least about 99.5% or more, more particularly at
least about 99.8% or more and most particularly at least about 99.9% or more, when
10

measured by area percentage of HPLC.

In another general aspect, there is provided a pharmaceutical composition comprising

pure axitinib together with one or more pharmaceutically acceptable carrier, diluents
and excipients.
15

DETAILED DESCRIPTION OF THE INVENTION

The above and other objects of the present invention are achieved by the process of
the present invention, which leads to an improved process for the preparation of
20

axitinib.

Optionally, the solution, prior to any solids formation, can be filtered to remove any
un-dissolved solids, solid impurities and the like prior to removal of the solvent. Any
filtration system and filtration techniques known in the art can be used.

All ranges recited herein include the endpoints, including those that recite a range
between two values. Terms such as about, generally, substantially, and the
like are to be construed as modifying a term or value such that it is not an absolute.
This includes, at very least, the degree of expected experimental error, technique error
5

and instrument error for a given technique used to measure a value.

As used herein, the terms pure axitinib refers to axitinib which has a purity of at
least about 99%, particularly of at least about 99.5%, more particularly of at least
about 99.8% and most particularly of at least about 99.9%, by area percentage of
10

HPLC.

As used herein, the term purifying refers to a process comprises heating a mixture
of axitinib and a solvent to a temperature of between about 10C below and above the
reflux temperature of the solvent to obtain a solution, and cooling the solution to a
15

temperature of about 0C to about 30C.

In one general aspect, there is provided a process for the preparation of 2-mercaptoN-methylbenzamide of Formula (IV),

20

the process comprising:

(a) reacting a dithiosalicylic acid of Formula (VII) with a chlorinating agent in one or
more solvents to obtain a 2,2-dithiosalicylic acid dichloride compound of
Formula (VI),

XH

HO' "'O

Xl

sXj

Cl

X s

(VII)

(VI)

(b) reacting the 2,2-dithiosalicylic acid dichloride of Formula (VI) with methylamine
to obtain a 2,2-dithio-N-methylbenzamide of Formula (V), and

(c) reducing the 2,2-dithio-N-methylbenzamide of Formula (V) with a reducing

agent comprising of zinc-acetic acid or zinc-HCl to obtain the 2-mercapto-Nmethylbenzamide of Formula (IV).
10

In general, the chlorinating agent comprises one or more of thionyl chloride,

phosgene,

phosphorus

oxychloride,

phosphorus

trichloride,

and phosphorus

pentachloride. In particular, thionyl chloride may be used.

15

In general aspect, the solvent comprises one or more of alcohols selected from
methanol, ethanol, n-propanol, isopropanol and n-butanol; nitriles selected from
acetonitrile, propionitrile, butyronitrile and valeronitrile; ketones selected from
acetone, methyl ethyl ketone and methyl isobutyl ketone; esters selected from ethyl
acetate, propyl acetate, isopropyl acetate and butyl acetate; chlorinated solvents

20

selected

from

methylene

dichloride,

chloroform,

ethylene

dichloride

and

chlorobenzene; ethers selected from diethyl ether, diisopropyl ether, methyl tert-butyl
ether, tetrahydrofuran and dioxane; amides selected from dimethylformamide,
dimethylacetamide

and

N-methylformamide;

dimethylsulfoxide;

hydrocarbons

selected from toluene, xylene, and ethyl benzene. In particular, toluene may be used
in presence of dimethylformamide catalytic amount.

In general, the compound 2, 2-dithiosalicylic acid dichloride of Formula (VI) may be

5

treated with methylamine in presence of one or more solvents. The solvent comprises
one or more of alcohols selected from methanol, ethanol, n-propanol, isopropanol and
n-butanol; nitriles selected from acetonitrile, propionitrile, butyronitrile and
valeronitrile; ketones selected from acetone, methyl ethyl ketone and methyl isobutyl
ketone; esters selected from ethyl acetate, propyl acetate, isopropyl acetate and butyl

10

acetate; chlorinated solvents selected from methylene dichloride, chloroform,

ethylene dichloride and chlorobenzene; ethers selected from diethyl ether, diisopropyl
ether, methyl tert-butyl ether, tetrahydrofuran and dioxane; amides selected from
dimethylformamide,

dimethylacetamide

and

N-methylformamide;

and

dimethylsulfoxide; hydrocarbons selected from toluene, xylene, and ethyl benzene. In

15

particular, tetrahydrofuran may be used.

In general, 2 to 6 mol equivalent of methylamine 2M solution in THF may be used. In

particular, 4 mol equivalent of methylamine 2M solution in THF may be used. The
process of the present invention provides 85% yield in comparison to 57% as per
20

prior art.

In general, the reducing agent comprises of NaBH4, Fe/HCl, Sn/HCl, Na2Sx, Pd/C,
Pt/C, Raney Nickel, ammonium chloride-Iron powder or zinc powder to obtain 2mercapto-N-methylbenzamide of Formula (IV). In particular, the reducing agent
25

comprising of zinc-acetic acid or zinc-HCl.

In general, the reduction of 2,2-dithio-N-methylbenzamide of Formula (V) with

NaBH4 as reported in prior art is a reversible reaction on holding. The use of zincacetic acid or zinc-HCl is an irreversible reaction upon holding.

In another general aspect, there is provided a process for the preparation of pure
axitinib of Formula (I),

(I)
the process comprising:
(a) reacting 2-mercapto-N-methylbenzamide of Formula (IV) prepared by the above
process with 6-halo-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyroan-2-yl)-1Hindazole of Formula (III) to obtain protected axitinib of Formula (II),

10

N
H

(IV)
wherein, X represents any halogen selected from I, Br, Cl or F;

(II)

10

(b) deprotecting the protected axitinib of Formula (II) with an acid in one or more of
organic solvents to obtain axitinib of Formula (I); and
(c) purifying the axitinib of Formula (I) to obtain pure axitinib.

In general, the compound 6-halo-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydro- pyroan2-yl)-1H-indazole of Formula (III) may be selected from
(a) 6-iodo-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyroan-2-yl)-1H-indazole

of

Formula (IIIa),
(b) 6-bromo-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyroan-2-yl)-1H-indazole
10

of

Formula (IIIb),
(c) 6-chloro-3 -((E)-2-pyridin-2-yl-vinyl)-1 -(tetrahydropyroan-2-yl)-1H-indazole

of

Formula (IIIc); or
(d) 6-flouro-3-((E)-2-pyridin-2-yl-vinyl)-1 -(tetrahydropyroan-2-yl)-1 H-indazole

of

Formula (IIId).
15

In general, the reaction of 2-mercapto-N-methylbenzamide of Formula (IV) prepared

by the above process with 6-iodo-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyroan-2yl)-1H-indazole of Formula (IIIa) is carried out in the presence of a catalyst. The
catalyst may be selected from Pd2(dba)3, Xanthfos, Palladium diacetate, Pd(O-tol)3
and Pd(dppf) Cl2.DCM. In particular Pd(dppf)Cl2.DCM catalyst may be used from

20

about 0.02% to about 0.05%. More particularly, the catalyst may be 0.03%.

The coupling reaction may be from 4 hours to about 16 hours. The protected axitinib
of Formula (II) may be obtained by removal of the solvent after completion of the
reaction in 90% yield having a purity of about 99% or more.
25

In general, the acid for deprotection of protected axitinib comprises p-toluene

sulphonic acid monohydrate, aqueous phosphoric acid, aqueous hydrochloric acid and
sulfuric acid.

11

In general, the organic solvent for deprotection of protected axitinib comprises one or
more of alcohols selected from methanol, ethanol, n-propanol, isopropanol and nbutanol;

nitriles

selected

from

acetonitrile,

propionitrile,

butyronitrile

and

valeronitrile; ketones selected from acetone, methyl ethyl ketone and methyl isobutyl
5

ketone; esters selected from ethyl acetate, propyl acetate, isopropyl acetate and butyl
acetate; chlorinated solvents selected from methylene dichloride, chloroform,
ethylene dichloride and chlorobenzene; ethers selected from diethyl ether, diisopropyl
ether, methyl tert-butyl ether, tetrahydrofuran and dioxane; amides selected from
dimethylformamide,

10

dimethylacetamide

and

N-methylformamide;

and

dimethylsulfoxide; hydrocarbons selected from toluene, xylene, and ethyl benzene. In

particular, methanol may be used.

The embodiments of the process further include purifying axitinib obtained after
deprotection of protected axitinib. The purification comprises heating a mixture of
15

axitinib and one or more solvents at a temperature of between about 10C below and
above the reflux temperature of the solvent to obtain a solution, and cooling the
solution to a temperature of about 0C to about 30C.

In another general aspect, there is provided axitinib of having particle size

20

distributions wherein the (D10) is of about 50 m or less, (D50) is of about 200 m or

less, or the (D90) is of about 400 m or less, or any combination thereof.

In further aspect, the axitinib may be micronized to achieve the better particle size
distribution in order to make a suitable Formulation. Such micronized active
25

ingredient may be produced by using a high energy media mill or an agitator bead
mill, for example, the Netzsch high energy media mill, or the DYNO-mill (Willy A.
Bachofen AG, Switzerland).

12

In another general aspect, there is provided pure axitinib which is substantially free
from one or more of impurities.

In another general aspect, there is provided a pharmaceutical composition comprising

5

pure axitinib together with one or more pharmaceutically acceptable carrier, diluents
and excipients.

In another general aspect, there is provided an improved process for the preparation
of axitinib of Formula (I) as shown in reaction scheme-I.

10

Scheme-1
A = Chlorinating agent, Toluene
B = Methylamine 2M in THF
C = Zn-Acetic acid or Zn-HCl
15

D = Pd(dppf)Cl2-DCM, DMF
E = PTSA, Methanol

13

F = Purification

In another general aspect, there is provided pure axitinib having a purity of at least
about 99% or more, particularly of at least about 99.5% or more, more particularly at
5

least about 99.8% or more and most particularly at least about 99.9% or more, when
measured by area percentage of HPLC.

The invention also encompasses pharmaceutical compositions comprising Axitinib of

10

the invention. As used herein, the term "pharmaceutical compositions" includes

pharmaceutical formulations like tablets, pills, powders, liquids, suspensions,
emulsions, granules, capsules, suppositories, or injection preparations.

In another general aspect, there is provided a pharmaceutical composition comprising

15

pure axitinib together with one or more pharmaceutically acceptable carrier, diluents
and excipients.

Having described the invention with reference to certain preferred embodiments,

other embodiments, reaction conditions, temperature control and solvent system may
20

become apparent to one skilled in the art from consideration of the examples provided
herein after.

Example
Example-1: Preparation of 2,2-dithiosalicylic acid dichloride
25

In a 100 mL three necked round bottom flask equipped with nitrogen atmosphere
facility, mechanical stirrer, thermometer and an addition funnel, toluene (8 mL),
dimethylformamide (0.05 mL) and dithiosalicylic acid (2 g) were stirred at 25C35C. Thionyl chloride (1.12 mL) was added to the reaction mixture and heated at 80
to 90C. The reaction was monitored by TLC. Hexane (10 mL) was added and cooled

14

to 0 to 5C. The reaction mixture was stirred for 1 hour. The product was filtered and
washed with hexane. The product was dried under vacuum at 60C for 4 hours to
obtain 1.88 g (84%) of 2,2-dithiosalicylic acid dichloride having purity of 93.8% by
HPLC.
5

Example-2: Preparation of 2,2-dithio-N-methylbenzamide

In a 100 mL three necked round bottom flask equipped with nitrogen atmosphere
facility, mechanical stirrer, thermometer and an addition funnel, tetrahydrofuran (12
mL), 2,2-dithiosalicylic acid dichloride (3 g) were added and cooled to 0 to -5C.
10

Methyl amine 2M solution in tetrahydroufran (18 mL) was added to the reaction
mixture and stirred till completion of reaction as monitored by TLC. The reaction
mixture was distilled completely under vacuum to remove tetrahydrofuran. Water (20
mL) was added to the concentrated mass and stirred for 1 hour. The reaction mixture
was filtered, washed with water and dried under vacuum at 50C for 4 hours to obtain

15

2.5 g (85.4%) of 2, 2-dithio-N-methyl- benzamide.

Example-3: Preparation of 2-mercapto-N-methylbenzamide

In a 100 mL three necked round bottom flask equipped with nitrogen atmosphere
facility, mechanical stirrer, thermometer and an addition funnel, methanol (4 mL), 2,
20

2-dithio-N-methylbenzamide (0.2 g), Zinc powder (0.162 g) and acetic acid (1 mL)
were added. The reaction mixture was stirred at 60 to 65C till completion of reaction
as monitored by TLC. Ethyl acetate (5 mL) and water (5 mL) was added and pH
below 1 was adjusted by aq. HCl. The reaction mixture was concentrated completely.
Ethyl acetate (5 mL) and water (5 mL) were added to the residue and layers were

25

separated. The aq. layer was extracted with ethyl acetate (3 mL) and the organic layer
was washed with brine solution (5 mL). The organic layer was distilled completely
under vacuum. Heptane (5 mL) was added to the residue and stirred for 1 hour. The
precipitated solid for 1 hour at 25 to 35C, filtered and washed with heptane. The

15

wet-cake was dried under vacuum at 40C for 4 hours to obtain 0.131 g (65.5%) of 2mercapto-N-methylbenzamide having purity of 98.41% by HPLC.

Example-4: Preparation of 2-mercapto-N-methylbenzamide

5

In a 100 mL three necked round bottom flask equipped with nitrogen atmosphere
facility, mechanical stirrer, thermometer and an addition funnel, methanol (12 mL), 2,
2-dithio-N-methylbenzamide (0.6 g), Zinc powder (0.264 g) and Conc. HCl (0.35
mL) were added. The reaction mixture was heated at 60 to 65C till the completion of
reaction as monitored by TLC. The reaction mixture was distilled to remove methanol

10

completely. Ethyl acetate (12 mL) and water (12 mL) were added and pH below 1
was adjusted by HCl. The reaction mixture was stirred and layers were separated. The
organic layer was washed with brine solution. The organic layer was concentrated
completely under vacuum till semisolid mass. Heptane (6 mL) was added and stirred
for 1 hour. The precipitated solid was filtered, washed with heptane and dried under

15

vacuum at 40C for 4 hours to obtain 0.435 g (70.8%) of 2-mercapto-Nmethylbenzamide having purity of 91.3% by HPLC.

Example-5: Preparation of protected axitinib

In a 100 mL three necked round bottom flask equipped with nitrogen atmosphere
20

facility, mechanical stirrer, thermometer and an addition funnel, dimethylformamide

(5 mL), 6-iodo-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydro- pyroan-2-yl)-1H-indazole
(1 g) were added. Pd(dppf)2Cl2.CH2Cl2 (57 mg), cesium carbonate (1.13 g) and 2mercapto-N-methylbenzamide (0.5 g) were added to the reaction mixture and heated
to 80 to 90C. The progress of the reaction was monitored by TLC. The reaction

25

mixture was cooled to 25 to 35C. Ethyl acetate (5 mL) and water (5 mL) were added
and stirred for 1 hour. The solid was filtered, washed with ethyl acetate and dried
under vacuum at 60C for 6 hours to obtain protected Axitinib 0.97 g (88.9%) having
purity of 99.5% by HPLC.

16

Example-6: Preparation of axitinib

In a 100 mL three necked round bottom flask equipped with nitrogen atmosphere
facility, mechanical stirrer, thermometer and an addition funnel, methanol (12.6 mL),
water (1.8 mL) and protected axitinib (1.8 g) were added. PTSA.H2O (3.64 g) was
5

added to the reaction mixture and heated to reflux for 3 hours. The reaction mixture
was distilled out to remove methanol under vacuum. Methanol (12.6 mL) and water
(1.8 mL) were added to the residue and heated to reflux for 1 hour. After completion
of reaction, methanol was distilled completely under vacuum and water (9 mL),
methanol (1.8 mL) was added. The reaction mixture was cooled to 25 to 35C and the

10

pH of reaction mixture was adjusted to 9.5 to 10.5 using aq. sodium carbonate
solution. The reaction mixture was further stirred for 2 hours and filtered. The solid
was washed with water and the wet-solid was dried under vacuum for 4 hours at 50C
to obtain 1.33 g (89.97%) axitinib.

15

Example-7: Purification of axitinib

In a 100 mL three necked round bottom flask equipped with nitrogen atmosphere
facility, mechanical stirrer, thermometer and an addition funnel, methanol (24 mL),
acetic acid (12 mL) and axitinib (1.2 g) were heated to reflux to get clear solution.
The clear solution was cooled 0 to 5C and stirred for 1 hour. The solid was filtered

20

and washed with methanol followed by hexane. The product was dried under vacuum
at 50C for 6 hours to obtain 0.93 g (77.5%) axitinib having purity of 99.88% by
HPLC.

While the present invention has been described in terms of its specific embodiments,
25

certain modifications and equivalents will be apparent to those skilled in the art and
are intended to be included within the scope of the present invention.

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We Claim:
1. A process for the preparation of 2-mercapto-N-methylbenzamide of Formula (IV),

(IV)
5

the process comprising:

(a) reacting a dithiosalicylic acid of Formula (VII) with a chlorinating agent in one or
more solvents to obtain a 2,2-dithiosalicylic acid dichloride compound of
Formula (VI),

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(VI)

(VII)

(b) reacting the 2,2-dithiosalicylic acid dichloride of Formula (VI) with methylamine
to obtain a 2,2-dithio-N-methylbenzamide of Formula (V), and

(V)
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(c) reducing the 2,2-dithio-N-methylbenzamide of Formula (V) with a reducing

agent comprising of zinc-acetic acid or zinc-HCl to obtain the 2-mercapto-Nmethylbenzamide of Formula (IV).

2. The process according to claim 1, wherein the chlorinating agent comprises one
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or more of thionyl chloride, phosgene, phosphorus oxychloride, phosphorus

trichloride, and phosphorus pentachloride.

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3. The process according to claim 1, wherein 2 to 6 mol equivalent of methylamine

2M solution in THF is used.

4. A process for the preparation of pure axitinib of Formula (I),

the process comprising:

(a) reacting 2-mercapto-N-methylbenzamide of Formula (IV) according to claim 1
with 6-halo-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyroan-2-yl)-1H-indazole of
10

Formula (III) to obtain protected axitinib of Formula (II),

(IV)
wherein, X represents any halogen selected from I, Br, Cl or F;

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(II)

19

(b) deprotecting the protected axitinib of Formula (II) with an acid in one or more of
organic solvents to obtain axitinib of Formula (I); and
(c) purifying the axitinib of Formula (I) to obtain pure axitinib.

5. The process according to claim 4, wherein the compound 6-halo-3-((E)-2-pyridin2-yl-vinyl)-1-(tetrahydropyroan-2-yl)-1H-indazole of Formula (III) is be selected
from
(i)

6-iodo-3 -((E)-2-pyridin-2-yl-vinyl)-1 -(tetrahydropyroan-2-yl)-1H-indazole

of

Formula (IIIa),
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(ii) 6-bromo-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyroan-2-yl)-1H-indazole of
Formula (IIIb),
(iii) 6-chloro-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyroan-2-yl)-1H-indazole of
Formula (IIIc); or
(iv) 6-flouro-3 -((E)-2-pyridin-2-yl-vinyl)-1 -(tetrahydropyroan-2-yl)-1H-indazole

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of

Formula (IIId).

6. The process according to claim 4, wherein the reaction of 2-mercapto-Nmethylbenzamide of Formula (IV) with 6-halo-3-((E)-2-pyridin-2-yl-vinyl)-1(tetrahydropyroan-2-yl)-1H-indazole of Formula (IIIa) is carried out in the
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presence of a catalyst selected from Pd2(dba)3, Xanthfos, Palladium diacetate,

Pd(O-tol)3 and Pd(dppf)Cl2.DCM.

7. The process according to claim 4, wherein the protected axitinib of Formula (II) is
obtained in 90% yield and having a purity of about 99% or more.
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8. The process according to claim 4, wherein the acid in step (b) comprises ptoluene sulphonic acid monohydrate, aqueous phosphoric acid, aqueous
hydrochloric acid and sulfuric acid.

20

9. The process according to claim 4, wherein the pure axitinib in step (c) is obtained
by heating a mixture of axitinib and one or more solvents at a temperature of
between about 10C below and above the reflux temperature of the solvent to
obtain a solution, and cooling the solution to a temperature of about 0C to about
5

30C.

10. The process according to claim 9, wherein the pure axitinib is having a purity of
at least about 99% or more, when measured by area percentage of HPLC.

10

Dated this 20th day of July 2015.

(RITU GANDHI)
of SUBRAMANIAM & ASSOCIATES
Attorneys for the applicants

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