WO2011145007A1 - A process for the preparation of amorphous warfarin sodium - Google Patents
A process for the preparation of amorphous warfarin sodium Download PDFInfo
- Publication number
- WO2011145007A1 WO2011145007A1 PCT/IB2011/051657 IB2011051657W WO2011145007A1 WO 2011145007 A1 WO2011145007 A1 WO 2011145007A1 IB 2011051657 W IB2011051657 W IB 2011051657W WO 2011145007 A1 WO2011145007 A1 WO 2011145007A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- warfarin sodium
- amorphous
- methanol
- warfarin
- preparation
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
- C07D311/44—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3
- C07D311/46—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3 unsubstituted in the carbocyclic ring
Definitions
- the present invention relates to process for the preparation of Amorphous Warfarin sodium.
- Warfarin sodium is chemically known as 3-( ⁇ -acetonylbenzyl)-4-hydroxycoumarin sodium salt , having molecular formula C 19 H 15 O 3 Na and molecular weight 330.32.
- Warfarin sodium is a racemic mixture known chemically by the chemical name 4- hydroxy-3-(3-oxo-l-phenylbutyl)-2H-l-benzopyran-2-one sodium salt, is a well established, widely used oral anticoagulant and rodenticide.
- Warfarin was firstly disclosed in US 2,427,578. This patent also discloses process for the prepration of Warfarin.
- WO 02/070503 disclosed a process for the pure Warfarin and Warfarin sodium from non-aqueous media. This process is silent about the purity of final product.
- an object of the present invention is to provide a process for the preparation of amorphous Warfarin sodium.
- Another object of the present invention is to provide a process for the preparation of amorphous Warfarin sodium which is operationally simple, easy to handle and applicable at an industrial scale.
- Further object of the present invention is to provide a process for the preparation of amorphous Warfarin sodium comprising steps of:
- amorphous Warfarin sodium comprising steps of:
- Warfarin sodium clathrate' used as starting material hereinabove that includes but not limited to Warfarin sodium clathrate is any state of purity.
- step (i) Warfarin sodium clathrate is treated with methanol at about temperature of 20-75 0 C.
- step (ii) methanol is evaporated under atmospheric pressure optionally under high vacuum at about temperature of 60-75 0 C.
- the residue as mentioned in step (ii) may be mass, oily mass, semisolid, optionally solid.
- step (iii) cyclohexane is added to residue at about temperature of 20-30 0 C.
- step (iv) filtering and washing takes place at about temperature of 20-30 0 C and drying takes place under vacuum optionally at atmospheric pressure.
- Warfarin sodium clathrate was treated with Methanol and the mixture was heated to obtain solution. The solution was evaporated till large amount of Methanol was recovered. Again Methanol was added and the solution was evaporated till large amount of Methanol was recovered. High Vacuum was applied. Again Methanol was added and the mixture was filtered through hyflo and washed with Methanol. The filtrate was evaporated till large amount of. High Vacuum was applied to obtained mass. Cyclohexane was added to obtain amorphous Warfarin sodium.
- Warfarin sodium clathrate used as starting material in the examples is prepared according to methods reported in the literature and prior art.
- Warfarin sodium clathrate 100 g was treated with Methanol (400 ml) at 20-25°C. The mixture was heated to 65-70°C. The solution was evaporated under atmospheric pressure at 65-70°C till 375-385 ml of Methanol was recovered. Again Methanol (400 ml) was added at 50-60°C and the solution was evaporated under atmospheric pressure at 65-70°C till 375-385 ml of Methanol was recovered. High Vacuum was applied for 15-20 min to remove traces of solvent at 65-70°C. Again Methanol (300 ml) was charged at 50-60°C. The mixture was filtered through hyflo and washed with Methanol (100 ml) at 20-25°C.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to process for the preparation of Amorphous Warfarin sodium.
Description
The present invention relates to process for
the preparation of Amorphous Warfarin sodium.
Warfarin sodium is chemically known as
3-(α-acetonylbenzyl)-4-hydroxycoumarin sodium salt , having
molecular formula
C19H15O3Na and molecular
weight 330.32.
Warfarin sodium is a racemic mixture known
chemically by the chemical name 4-
hydroxy-3-(3-oxo-l-phenylbutyl)-2H-l-benzopyran-2-one
sodium salt, is a well established, widely used oral
anticoagulant and rodenticide.
Warfarin was firstly disclosed in US
2,427,578. This patent also discloses process for the
prepration of Warfarin.
US 2,765,321 disclose crystalline Warfarin
sodium prepared by utilizing ethanol and lithium salts.
US 3,077,481 disclose preparation of
Warfarin sodium IPA clathrate. This patent is silent about
the yield and purity of final product. It also discloses
amorphous Warfarin sodium was obtained by evaporating
organic solvent from solution of Warfarin sodium in organic solvent.
US 3,192,232 disclose Amorphous Warfarin
sodium prepared by evaporation to dryness, spray drying or
drum drying. These processes are disadvantages as they are
less efficient for isolation of product as well as due to
time consumption.
US 3,246,013 describe a process for
preparing crystalline Warfarin sodium IPA clathrate
through neutralization of Warfarin acid 2-propanol slurry.
Indian J. Chem., VoI 10 (1972) p 461
reported Freeze-drying of Warfarin sodium aq solution.
Biosci. Biotech. Biochem. 59(6) (1995) p 995 (CA123.
105246) reported the isolation of Warfarin sodium salts by lyophilization.
WO 02/070503 disclosed a process for the
pure Warfarin and Warfarin sodium from non-aqueous media.
This process is silent about the purity of final product.
US 6,512,005 reported an improved method
for the preparation of Warfarin and its salts to meet the
pharmacopeial grade.
US 6,673,944 disclose a method for the
direct preparation of pure Warfarin sodium from Warfarin
using a volatile base.
US 6,610,862 disclose a method for drying
of Warfarin sodium IPA clathrate.
Accordingly, there is a need to prepare
amorphous Warfarin sodium by a process which not only
overcomes disadvantages associated with prior art but also
gives high yield and purity of final product.
It is therefore an object of the present
invention is to provide a process for the preparation of
amorphous Warfarin sodium.
Another object of the present invention is
to provide a process for the preparation of amorphous
Warfarin sodium which is operationally simple, easy to
handle and applicable at an industrial scale.
Further object of the present invention is
to provide a process for the preparation of amorphous
Warfarin sodium comprising steps of:
i) treating Warfarin sodium clathrate with
methanol to obtain a solution;
ii) evaporating methanol from solution
obtained in step (i) to obtain residue;
iii) adding cyclohexane to the residue
obtained in step (ii);
iv) isolating amorphous Warfarin sodium.
According to one aspect of the present
invention, it provides a process for the preparation of
amorphous Warfarin sodium comprising steps of:
i) treating Warfarin sodium clathrate with
methanol to obtain a solution;
ii) evaporating methanol from solution
obtained in step (i) to obtain residue;
iii) adding cyclohexane to the residue
obtained in step (ii);
iv) isolating amorphous Warfarin sodium.
The meaning of the term 'Warfarin
sodium clathrate' used as starting material
hereinabove that includes but not limited to Warfarin
sodium clathrate is any state of purity.
The meaning of the term
'treating' as used hereinabove that includes but
not limited to dissolving, suspending and mixing. In step
(i), Warfarin sodium clathrate is treated with methanol at
about temperature of 20-75 0 C.
The meaning of the term
'evaporating' as used hereinabove that includes
but not limited to evaporating organic solvent totally or
in large extent. In step (ii), methanol is evaporated under
atmospheric pressure optionally under high vacuum at about
temperature of 60-75 0 C. The residue as
mentioned in step (ii) may be mass, oily mass, semisolid,
optionally solid.
In step (iii), cyclohexane is added to
residue at about temperature of 20-30 0 C.
The meaning of the term
'isolating' as used hereinabove that includes
but not limited to filtering, centrifuging, washing and
drying. In step (iv), filtering and washing takes place at
about temperature of 20-30 0 C and drying takes
place under vacuum optionally at atmospheric pressure.
In embodiment, Warfarin sodium clathrate
was treated with Methanol and the mixture was heated to
obtain solution. The solution was evaporated till large
amount of Methanol was recovered. Again Methanol was added
and the solution was evaporated till large amount of
Methanol was recovered. High Vacuum was applied. Again
Methanol was added and the mixture was filtered through
hyflo and washed with Methanol. The filtrate was
evaporated till large amount of. High Vacuum was applied to
obtained mass. Cyclohexane was added to obtain amorphous
Warfarin sodium.
Warfarin sodium clathrate used as starting
material in the examples is prepared according to methods
reported in the literature and prior art.
The process of the present invention is
described by the following example, which is illustrative
only and should not be construed so as to limit the scope
of the invention in any manner.
Example 1
Warfarin sodium clathrate (100 g) was
treated with Methanol (400 ml) at 20-25°C. The mixture was
heated to 65-70°C. The solution was evaporated under
atmospheric pressure at 65-70°C till 375-385 ml of
Methanol was recovered. Again Methanol (400 ml) was added at
50-60°C and the solution was evaporated under atmospheric
pressure at 65-70°C till 375-385 ml of Methanol was
recovered. High Vacuum was applied for 15-20 min to remove
traces of solvent at 65-70°C. Again Methanol (300 ml) was
charged at 50-60°C. The mixture was filtered through hyflo
and washed with Methanol (100 ml) at 20-25°C. The filtrate
was evaporated under atmospheric pressure at 65-70°C to
recover 375-385 ml Methanol. High Vacuum was applied for
25-30 min to remove traces of solvent at 65-70°C to
obtained mass. The mass was cooled to 20-25°C. Cyclohexane
(500 ml) was added to mass at 20-25°C. The mixture was
stirred, filtered, washed and dried to obtain amorphous
Warfarin sodium.
Purity ~ 99.5 % (by HPLC)
Yield (w/w) ~ 0.80-0.90
Claims (4)
1. A process for the preparation of amorphous
Warfarin sodium comprising steps of:
i) treating Warfarin sodium clathrate with
methanol to obtain a solution;
ii) evaporating methanol from solution
obtained in step (i) to obtain residue;
iii) adding cyclohexane to the residue
obtained in step (ii);
iv) isolating amorphous Warfarin sodium.
2. The process according to claim 1, wherein
treating is done at about temperature of 20-75
0 C.
3. The process according to claim 1, wherein
evaporating is done at about temperature of 60-75
0 C.
4. The process according to claim 1, wherein
adding is done at about temperature of 20-30
0 C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1578MU2010 | 2010-05-20 | ||
| IN1578/MUM/2010 | 2010-05-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2011145007A1 true WO2011145007A1 (en) | 2011-11-24 |
Family
ID=44242551
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2011/051657 WO2011145007A1 (en) | 2010-05-20 | 2011-04-18 | A process for the preparation of amorphous warfarin sodium |
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Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2427578A (en) | 1945-04-02 | 1947-09-16 | Wisconsin Alumni Res Found | 3-substituted 4-hydroxycoumarin and process of making it |
| US2765321A (en) | 1955-05-27 | 1956-10-02 | Wisconsin Alumni Res Found | Process of making crystalline warfarin sodium |
| US3077481A (en) | 1961-02-21 | 1963-02-12 | Wisconsin Alumni Res Found | Warfarin sodium |
| US3192232A (en) | 1961-02-21 | 1965-06-29 | Wisconsin Alumni Res Found | Warfarin alkali metal derivative process |
| US3246013A (en) | 1963-02-15 | 1966-04-12 | Wisconsin Alumni Res Found | Preparation of crystalline warfarin sodium-isopropyl alcohol complex |
| GB1056291A (en) * | 1963-05-14 | 1967-01-25 | Frosst & Co Charles E | Improved process for preparing sodium warfarin |
| WO2002070503A1 (en) | 2001-02-28 | 2002-09-12 | Taro Pharmaceuticals U.S.A., Inc. | Process for purification of warfarin acid, warfarin alkali metal salts and corresponding clathrates |
| US6512005B2 (en) | 2001-02-28 | 2003-01-28 | Taro Pharmaceutical Industries, Ltd. | Process for synthesis of pure warfarin acid, warfarin alkali metal salts and corresponding clathrates |
| US6610862B2 (en) | 2001-02-28 | 2003-08-26 | Taro Pharmaceutical Industries Ltd. | Preparation of warfarin sodium from warfarin sodium-2-propanol clathrate by solvent expulsion |
| US6673944B2 (en) | 2001-02-28 | 2004-01-06 | Taro Pharmaceutical Industries, Ltd. | Preparation of warfarin sodium from warfarin acid |
-
2011
- 2011-04-18 WO PCT/IB2011/051657 patent/WO2011145007A1/en active Application Filing
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2427578A (en) | 1945-04-02 | 1947-09-16 | Wisconsin Alumni Res Found | 3-substituted 4-hydroxycoumarin and process of making it |
| US2765321A (en) | 1955-05-27 | 1956-10-02 | Wisconsin Alumni Res Found | Process of making crystalline warfarin sodium |
| US3077481A (en) | 1961-02-21 | 1963-02-12 | Wisconsin Alumni Res Found | Warfarin sodium |
| US3192232A (en) | 1961-02-21 | 1965-06-29 | Wisconsin Alumni Res Found | Warfarin alkali metal derivative process |
| US3246013A (en) | 1963-02-15 | 1966-04-12 | Wisconsin Alumni Res Found | Preparation of crystalline warfarin sodium-isopropyl alcohol complex |
| GB1056291A (en) * | 1963-05-14 | 1967-01-25 | Frosst & Co Charles E | Improved process for preparing sodium warfarin |
| WO2002070503A1 (en) | 2001-02-28 | 2002-09-12 | Taro Pharmaceuticals U.S.A., Inc. | Process for purification of warfarin acid, warfarin alkali metal salts and corresponding clathrates |
| US6512005B2 (en) | 2001-02-28 | 2003-01-28 | Taro Pharmaceutical Industries, Ltd. | Process for synthesis of pure warfarin acid, warfarin alkali metal salts and corresponding clathrates |
| US6610862B2 (en) | 2001-02-28 | 2003-08-26 | Taro Pharmaceutical Industries Ltd. | Preparation of warfarin sodium from warfarin sodium-2-propanol clathrate by solvent expulsion |
| US6673944B2 (en) | 2001-02-28 | 2004-01-06 | Taro Pharmaceutical Industries, Ltd. | Preparation of warfarin sodium from warfarin acid |
Non-Patent Citations (2)
| Title |
|---|
| BIOSCI. BIOTECH. BIOCHEM., vol. 59, no. 6, 1995, pages 995 |
| INDIAN J. CHEM., vol. 10, 1972, pages 461 |
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