WO2012069946A1 - Process for the preparation of deferasirox - Google Patents
Process for the preparation of deferasirox Download PDFInfo
- Publication number
- WO2012069946A1 WO2012069946A1 PCT/IB2011/054916 IB2011054916W WO2012069946A1 WO 2012069946 A1 WO2012069946 A1 WO 2012069946A1 IB 2011054916 W IB2011054916 W IB 2011054916W WO 2012069946 A1 WO2012069946 A1 WO 2012069946A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- deferasirox
- water
- solution
- reaction mass
- preparation
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
Definitions
- the present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of Deferasirox of formula (I) in high yield and purity.
- Deferasirox is chemically known as 4-[3, 5-bis (2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid. It is a rationally-designed oral ironchelator. Its main use is to reduce chronic iron overload in patients who are receiving long-term blood transfusions for conditions such as beta-thalassemia and other chronic anemias.
- the current pharmaceutical product containing this drug is being sold by Novartis using the tradename Exjade ® in the form of tablets.
- US 6,465,504 discloses a process for preparing Deferasirox wherein the process includes reacting salicyloyl chloride with salicylamide at 170 0 C to obtain 2-(2- hydroxyphenyl) benz [e] [1, 3] oxazin-4-one, and further crystallization in ethanol to obtain slight yellow color crystals of 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one.
- 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one which is further reacted with 4-hydrazinebenzoic acid in presence of ethanol to give Deferasirox.
- Major drawback of this process is preparation of 2-(2- hydroxyphenyl) benz [e] [1, 3] oxazin-4-one at high temperature and in the absence of solvent which causes formation of several impurities which is difficult to avoid.
- WO2009/094956 disclose the process for preparing Deferasirox where in the process includes the reaction of 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one with 4-hydrazinebenzoic acid is carried out in the presence of organic acid such as C1 to C4 carboxylic acid.
- the object of the present invention is to provide improved process for the preparation of Deferasirox which gives Deferasirox with greater yield and purity and also process for the preparation of Deferasirox form I.
- the object of the present invention is to provide improved process for the preparation of Deferasirox comprising step of treating 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one with 4-hydrazinebenzoic acid in the presence of dehydrating agent, suitable solvent and optionally in the presence of water.
- Further object of present invention is to provide a process for preparation of Deferasirox Form I
- the present invention provides a process for preparation of Deferasirox which comprises: reacting 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one with 4-hydrazinebenzoic acid in the presence of dehydrating agent such as potassium hydrogen sulphate, sodium hydrogen sulphate and the like or mixture thereof in suitable solvent and optionally in the presence of water.
- dehydrating agent such as potassium hydrogen sulphate, sodium hydrogen sulphate and the like or mixture thereof in suitable solvent and optionally in the presence of water.
Abstract
The present invention provides improved process for the preparation of Deferasirox of formula (I).
Description
The present invention relates to an
improved, commercially viable and industrially
advantageous process for the preparation of Deferasirox of
formula (I) in high yield and purity.
Deferasirox is chemically known as 4-[3,
5-bis (2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.
It is a rationally-designed oral ironchelator. Its main
use is to reduce chronic iron overload in patients who are
receiving long-term blood transfusions for conditions such
as beta-thalassemia and other chronic anemias. The current
pharmaceutical product containing this drug is being sold
by Novartis using the tradename Exjade® in the
form of tablets.
US 6,465,504 discloses a process for
preparing Deferasirox wherein the process includes
reacting salicyloyl chloride with salicylamide at 170
0C to obtain 2-(2- hydroxyphenyl) benz [e] [1,
3] oxazin-4-one, and further crystallization in ethanol to
obtain slight yellow color crystals of 2-(2-hydroxyphenyl)
benz [e] [1, 3] oxazin-4-one. 2-(2-hydroxyphenyl) benz [e]
[1, 3] oxazin-4-one which is further reacted with
4-hydrazinebenzoic acid in presence of ethanol to give
Deferasirox. Major drawback of this process is preparation
of 2-(2- hydroxyphenyl) benz [e] [1, 3] oxazin-4-one at
high temperature and in the absence of solvent which causes
formation of several impurities which is difficult to avoid.
US 6,465,504 disclose process for the
preparation of Deferasirox which require unwieldy steps
for the preparation and purification of Deferasirox. The
reaction conditions employed for the production of
Deferasirox results in formation of large amount of impurities.
WO2009/094956 disclose the process for
preparing Deferasirox where in the process includes the
reaction of 2-(2-hydroxyphenyl) benz [e] [1, 3]
oxazin-4-one with 4-hydrazinebenzoic acid is carried out in
the presence of organic acid such as C1 to C4 carboxylic acid.
Therefore, there is a need of process for
the preparation of Deferasirox which not only devoid
disadvantages of prior process as mentioned hereinabove
but also gives high yield and purity of Deferasirox. The
process of present invention overcomes disadvantages of
prior process and gives high yield and purity of Deferasirox.
The object of the present invention is to
provide improved process for the preparation of
Deferasirox which gives Deferasirox with greater yield and
purity and also process for the preparation of Deferasirox
form I.
The object of the present invention is to
provide improved process for the preparation of
Deferasirox comprising step of treating
2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one with
4-hydrazinebenzoic acid in the presence of dehydrating
agent, suitable solvent and optionally in the presence of water.
Further object of the present invention is
to provide a purification process for preparation of
highly pure Deferasirox comprising
a) Suspending Deferasirox in a solvent
selected from the group consisting of polar organic solvent.
b) Adding 30% H2O2
and water.
c) Heat the said reaction mass at 25-35
0C optionally.
d) Filter the reaction mass and wash it
with water.
e) Charge the wet cake in water and stirred
at 55-85 0C.
f) Filter the solid product and wash it by
water to get pure Deferasirox substantially free of
hydrazine impurity.
Further object of present invention is to
provide a process for preparation of Deferasirox Form I
a) Suspending Deferasirox in a Methanol:
Ethyl acetate mixture.
b) Heat the said solution.
c) Optionally, subjecting the said solution
to carbon treatment or silica gel treatment.
d) Add water and heat the said solution.
e) Partially removing the solvent from the solution
f) Precipitating pure Deferasirox form I.
The present invention provides a process
for preparation of Deferasirox which comprises: reacting
2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one with
4-hydrazinebenzoic acid in the presence of dehydrating
agent such as potassium hydrogen sulphate, sodium hydrogen
sulphate and the like or mixture thereof in suitable
solvent and optionally in the presence of water.
In another embodiment of the present
invention provides a purification process for preparation
of highly pure Deferasirox comprising
a) Suspending Deferasirox in a solvent
selected from the group consisting of polar organic
solvent preferably from Dimethyl sulfoxide, Dimethyl
formamide, Hexamethyl phosphorotriamide, Tetrahydrofuran
b) Adding 30% H2O2
and water.
c) Heat the said reaction mass at 25-35
0C optionally.
d) Filter the reaction mass and wash it
with water.
e) Charge the wet cake in water and
stirred at 55-85 0C.
f) Filter the solid product and wash it by
water to get pure Deferasirox substantially free of
hydrazine impurity.
Further embodiment of present invention is
to provide a process for preparation of Form I of Deferasirox
a) Suspending Deferasirox in a Methanol:
Ethyl acetate mixture.
b) Heat the said solution.
c) Optionally, subjecting the said
solution to carbon treatment or silica gel treatment.
a) Add water and heat the said solution.
b) Partially removing the solvent from the solution.
c) Precipitating pure Deferasirox form I.
The term 'dehydrating agent' as
used hereinabove includes but not limited to a reagent
which absorbs water formed during reaction and avoids
contamination of water which causes further progress of
reaction. These includes but not limited to potassium
hydrogen sulphate, sodium hydrogen sulphate and the like
or mixture thereof.
The term suitable solvent as used here in
above includes any alcoholic solvent containing
C1-C8 carbon atom.
The embodiments of present invention are
shown in below given scheme.
The process for preparation of Deferasirox
is shown in the scheme I.
The present invention further illustrated
in detail by the below examples which are however not
limit to the scope of the invention.
Example-I
Preparation of 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one
Xylene (1.5 L) and salicylic acid (1 Kg.)
was added to a 5 L 4-neck round bottom flask equipped with
a mechanical stirrer and thermocouple. Thionyl chloride
(1.29 kg) was added at 10 oC to
15oC. After addition of thionyl chloride reaction
mass is stirred at 10 0C to 15oC for
30 minutes. Reaction mass is heated at 35-40 0C
for 1 hr. Salicylamide solution (0.891 kg in 2.0 lit of
Xylene) was added in reaction mass at 25 0 C -30
0 C. After addition reaction mass was
gradually heated at 80 0C - 126 0C
and stirred for 2 hrs. After the completion of reaction
excess of Xylene was distilled out. Methanol was added in
the reaction mass at 70 0C -80 0C
and stirred for 1 hr. gradually cooled the reaction mass
at 25-30 0C. Filtered the solid and washed with
Methanol and sucked it dry. Dry the obtained solid at 55-60
0C under vacuum tray drier.
Example- II
Preparation of Deferasirox
2-(2-hydroxyphenyl) benz [e] [1, 3]
oxazin-4-one (1.0 kg) and 4-Hydrazino benzoic acid (0.699
kg), Ethanol (9.0 lit), Water (1.0 lit) was stirred at
25-350C in round bottom flask. Followed by
addition of Potassium hydrogen sulphate (0.15 kg) into the
reaction mass and heated the reaction mass at 70-75
0 C for two hrs. Cooled the reaction mass at 25-30
0C and stirred for 45 minutes. Filtered off the
solid and washed with ethanol. Obtained solid and water
(1.0 lit) stirred at 25-30 C for 15 minutes and then
heated at 50- 55 0C. for 1 hr. The solid was
filtered at 50-55 0C and washed with water.
Charge this wet cake in DMF (5.0 lit) and stirred at 25-30
0C. In this solution 30%
H2O2 was added at 25-30 0C
within 1 hr. Followed by addition of water at 25-30
0C and stirred for 30 minutes. Filtered off the
solid and washed it with water. The obtained solid was
added in pre heated water and stirred at 45-50
0C. Gradually increased the temperature up to
65-75 0C & stir it for 60 min. cooled the
reaction mass at 45-50 0C and stirred it for 40
minutes. The precipitated Deferasirox filtered off and
washed with water. Dry the solid at 65-75 0C in
vacuum tray drier.
Example III
Preparation of form I of Deferasirox
Crude Deferasirox was suspended in
Methanol: Ethyl acetate (1:1) (2.2 L) mixture. Followed by
heating at 65-75 0C until obtaining a clear
solution. Activated carbon was added to the reaction mass
and heated for 20 minutes at 65-70 0C. Cooled
the reaction mass at 45-50 0C and filtered off
through hyflow. Again reaction mass is heated at 65-70
0C followed by addition of process water at 65-70
0C and stirred for 15 minutes. The solvent was
distilled out at 65-80 0C. Cooled the reaction
mass at 25-30 0C and stirred for 45 minutes.
The precipitated Deferasirox filtered off and washed with
water. Dry the form I of Deferasirox at 65-70 0C
in vacuum tray drier.
Claims (7)
1) Process for the preparation of Deferasirox
comprising step of treating 2-(2-hydroxyphenyl) benz [e]
[1, 3] oxazin-4-one with 4-hydrazinebenzoic acid in
the presence of dehydrating agent, suitable solvent
and optionally in the presence of water.
2) A process according to claim 1 where in
dehydrating reagent is Potassium hydrogen sulphate,
sodium hydrogen sulphate and mixture thereof.
3) A process according to claim 1 where in
suitable solvent is any alcoholic solvent selected
from the group consisting of
C1-C8 carbon atom.
4) A purification process for preparation of
highly pure Deferasirox comprising
a) Suspending Deferasirox in a solvent
selected from the group consisting of polar
organic solvent.
b) Adding 30% H2O2 and
water in said reaction mass.
c) Heat the said reaction mass at 25-35
0C optionally.
d) Filter the reaction mass and wash it with water.
e) Charge the wet cake in water and stirred
at 55-85 0C.
f) Filter the solid product and wash it by
water to get pure Deferasirox substantially free
of hydrazine impurity.
5) A Process according to claim 4 where in polar
organic solvent preferably from Dimethyl sulfoxide,
Dimethyl formamide, Hexamethyl phosphorotriamide,
Tetrahydrofuran
6) A Process according to claim 5 where in polar
organic solvent is Dimethyl formamide.
7) A process of preparing Deferasirox form I comprising
a) Suspending Deferasirox in a Methanol:
Ethyl acetate mixture.
b) Heat the said solution.
c) Optionally, subjecting the said solution
to carbon treatment or silica gel treatment.
d) Add water and again heat the said solution.
e) Partially removing the solvent from the solution
f) Filtering the said crystals
g) Vacuum drying the said crystals.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP11807989.6A EP2643306B1 (en) | 2010-11-24 | 2011-11-04 | Process for the preparation of deferasirox |
| US13/988,361 US9018389B2 (en) | 2010-11-24 | 2011-11-04 | Process for the preparation of Deferasirox |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN3214/MUM/2010 | 2010-11-24 | ||
| IN3214MU2010 | 2010-11-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2012069946A1 true WO2012069946A1 (en) | 2012-05-31 |
Family
ID=45476544
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2011/054916 WO2012069946A1 (en) | 2010-11-24 | 2011-11-04 | Process for the preparation of deferasirox |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US9018389B2 (en) |
| EP (1) | EP2643306B1 (en) |
| WO (1) | WO2012069946A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103554040A (en) * | 2013-11-08 | 2014-02-05 | 南京靖龙药物研发有限公司 | Preparation method of deferasirox derivative |
| CN104098519A (en) * | 2013-04-08 | 2014-10-15 | 江苏豪森药业股份有限公司 | Refining method for deferasirox |
| WO2015028536A1 (en) | 2013-09-02 | 2015-03-05 | Henkel Ag & Co. Kgaa | Cleaning and detergent agent with improved performance |
| KR20150123934A (en) * | 2013-03-06 | 2015-11-04 | 바이오콘 리미티드 | Process for the preparation of deferasirox |
| DE102020214069A1 (en) | 2020-11-10 | 2022-05-12 | Henkel Ag & Co. Kgaa | Metal complexes and dishwashing detergents containing them |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997049395A1 (en) * | 1996-06-25 | 1997-12-31 | Novartis-Erfindungen Verwaltungsgesellschaft M.B.H. | Substituted 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators |
| EP1927591A1 (en) * | 2006-11-29 | 2008-06-04 | Novartis AG | Polymorphic Forms of Deferasirox (ICL670) |
| WO2008065123A2 (en) * | 2006-11-29 | 2008-06-05 | Novartis Ag | Polymorphic forms of deferasirox ( icl670a) |
| WO2009094956A1 (en) | 2008-01-30 | 2009-08-06 | Farmak, A.S. | A method for preparing 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-benzoic acid |
| WO2009130604A2 (en) * | 2008-04-21 | 2009-10-29 | Actavis Group Ptc Ehf | Solid state forms of deferasirox salts and process for the preparation thereof |
-
2011
- 2011-11-04 US US13/988,361 patent/US9018389B2/en not_active Expired - Fee Related
- 2011-11-04 WO PCT/IB2011/054916 patent/WO2012069946A1/en active Application Filing
- 2011-11-04 EP EP11807989.6A patent/EP2643306B1/en not_active Not-in-force
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997049395A1 (en) * | 1996-06-25 | 1997-12-31 | Novartis-Erfindungen Verwaltungsgesellschaft M.B.H. | Substituted 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators |
| US6465504B1 (en) | 1996-06-25 | 2002-10-15 | Novartis Ag | Substituted 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators |
| EP1927591A1 (en) * | 2006-11-29 | 2008-06-04 | Novartis AG | Polymorphic Forms of Deferasirox (ICL670) |
| WO2008065123A2 (en) * | 2006-11-29 | 2008-06-05 | Novartis Ag | Polymorphic forms of deferasirox ( icl670a) |
| WO2009094956A1 (en) | 2008-01-30 | 2009-08-06 | Farmak, A.S. | A method for preparing 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-benzoic acid |
| WO2009130604A2 (en) * | 2008-04-21 | 2009-10-29 | Actavis Group Ptc Ehf | Solid state forms of deferasirox salts and process for the preparation thereof |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20150123934A (en) * | 2013-03-06 | 2015-11-04 | 바이오콘 리미티드 | Process for the preparation of deferasirox |
| JP2016515103A (en) * | 2013-03-06 | 2016-05-26 | バイオコン・リミテッドＢｉｏｃｏｎ Ｌｉｍｉｔｅｄ | Method for preparing deferasirox |
| EP2964659A4 (en) * | 2013-03-06 | 2016-11-02 | Biocon Ltd | Process for the preparation of deferasirox |
| KR102282372B1 (en) | 2013-03-06 | 2021-07-27 | 바이오콘 리미티드 | Process for the preparation of deferasirox |
| CN104098519A (en) * | 2013-04-08 | 2014-10-15 | 江苏豪森药业股份有限公司 | Refining method for deferasirox |
| CN104098519B (en) * | 2013-04-08 | 2018-08-21 | 江苏豪森药业集团有限公司 | The process for purification of Deferasirox |
| WO2015028536A1 (en) | 2013-09-02 | 2015-03-05 | Henkel Ag & Co. Kgaa | Cleaning and detergent agent with improved performance |
| DE102013217390A1 (en) | 2013-09-02 | 2015-03-05 | Henkel Ag & Co. Kgaa | Detergents and cleaning agents with improved performance |
| CN103554040A (en) * | 2013-11-08 | 2014-02-05 | 南京靖龙药物研发有限公司 | Preparation method of deferasirox derivative |
| CN103554040B (en) * | 2013-11-08 | 2015-12-02 | 南京靖龙药物研发有限公司 | A kind of preparation method of deferasirox derivative |
| DE102020214069A1 (en) | 2020-11-10 | 2022-05-12 | Henkel Ag & Co. Kgaa | Metal complexes and dishwashing detergents containing them |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2643306B1 (en) | 2015-09-23 |
| US20140039199A1 (en) | 2014-02-06 |
| EP2643306A1 (en) | 2013-10-02 |
| US9018389B2 (en) | 2015-04-28 |
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