WO2007129184A2 - An improved process for the preparation of phenytoin sodium - Google Patents
An improved process for the preparation of phenytoin sodium Download PDFInfo
- Publication number
- WO2007129184A2 WO2007129184A2 PCT/IB2007/001130 IB2007001130W WO2007129184A2 WO 2007129184 A2 WO2007129184 A2 WO 2007129184A2 IB 2007001130 W IB2007001130 W IB 2007001130W WO 2007129184 A2 WO2007129184 A2 WO 2007129184A2
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- WO
- WIPO (PCT)
- Prior art keywords
- phenytoin
- sodium
- water
- preparation
- dissolved
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
Definitions
- the present invention relates to an improved process for the preparation of Phenytoin Sodium, a sodium channel blocker used for the treatment of epilepsy.
- Phenytoin Sodium which is chemically known as 5,5-Diphenylhydantoin sodium salt is a sodium channel blocker, and has the following structural formula:
- Phenytoin Sodium is a well-known pharmaceutical agent having anticonvulsant and antiepileptic activity and useful in the treatment of epilepsy and it is available in the market under the various brand names such as Aleviatin ® , Persantin ® , Aurantin ® , Dilantin ® , Dintoina ® , Epanutin ® etc.
- US Pat. No. 3,646,056 describes a process for the preparation of 5,5-diarylhydantoins in one step by reacting benzoin with 1-3 equivalents of urea in an alkaline medium in the presence of 0.5-4 equivalents of elemental sulfur at a temperature between 60° C and the boiling point of the reaction mixture.
- US Pat. No. 6,245,917 teaches a process for the preparation of crystalline sodium phenytoin monohydrate by mixing sodium Phenytoin anhydrate and water in an organic solvent selected from toluene, methanol and dichloromethane, at about 30 0 C to about 40 0 C.
- the main objective of the present invention is to provide an improved process for the preparation of compound of formula (I) in high yield and high purity.
- Another objective of the present invention is to provide a process for the preparation of compound of formula (I), which uses water as a solvent and avoids organic solvents.
- Another objective of the present invention is to provide a process for the preparation of compound of formula (I), which is economical and commercially viable.
- the present invention provides a process for the preparation of Phenytoin Sodium (I), by reacting of Phenytoin of formula (II) with aqueous solution of sodium hydroxide in presence of aqueous Sodium chloride using water as a solvent at a temperature of about 25° C to 50° C to obtain Phenytoin Sodium of formula (I).
- the aqueous sodium chloride is used in different concentration with respect to Phenytoin where the concentration varies from 10 to 50% preferably 20 to 40%.
- the reaction is performed at a temperature of about 5° C to 50° C. Most preferably; the reaction step is performed at a temperature of about 5° C to 30° C.
- the starting material of this invention is prepared according to the literature available in the prior art.
- Phenytoin (2Og) was dissolved in 120 mL of DM water and Sodium hydroxide solution (3.56g dissolved in water 22.5mL) at 25-30 0 C in a 250 mL four-necked RBF. The reaction mixture was filtered and the clear filtrate was collected. The reaction mass was cooled to 5-10 0 C under nitrogen atmosphere and stirred for 60min. The solid was filtered under vacuum & nitrogen atmosphere and washed the product with 2OmL of chilled water. The solid was dried at 50-60 0 C under nitrogen atmosphere to obtain 14.4g of dry Phenytoin sodium. Yield: approx. 66.2% w.r.t. Phenytoin
- Phenytoin (2Og) was dissolved in 120 mL of DM water and Sodium hydroxide solution (3.56g dissolved in water 22.5mL) at 25-30 0 C in a 250 mL four-necked RBF. The reaction mixture was filtered and the clear filtrate was collected and Sodium chloride solution (4g Dissolved in water 1OmL) was added to it. The reaction mass was cooled to 5-10 0 C under nitrogen atmosphere and stirred for 60min. The solid was filtered under vacuum & nitrogen atmosphere and washed the product with 2OmL of chilled water. The solid was dried at 50-60 0 C under nitrogen atmosphere to obtain 18.5g of dry Phenytoin sodium. Yield : approx. 85% w.r.t. Phenytoin
- Phenytoin (25g) was dissolved in 150 mL of DM water and Sodium hydroxide solution (4.45g dissolved in water 25mL) at 25-30 0 C in a 250 mL four-necked RBF. The reaction mixture was filtered and the clear filtrate was collected and Sodium chloride solution (7.5g Dissolved in water 22mL) was added to it. The reaction mass was cooled to 5-10 0 C under nitrogen atmosphere and stirred for 60min. The solid was filtered under vacuum & nitrogen atmosphere and washed the product with 2OmL of chilled water. The solid was dried at 50-60 0 C under nitrogen atmosphere to obtain 25.3g of dry Phenytoin sodium. Yield : approx. 93% w.r.t. Phenytoin
- Phenytoin (25g) was dissolved in 150 mL of DM water and Sodium hydroxide solution (4.45g dissolved in water 25mL) at 25-30 0 C in a 250 mL four-necked RBF. The reaction mixture was filtered and the clear filtrate was collected and Sodium chloride solution (1Og Dissolved in water 28mL) was added to it. The reaction mass was cooled to 5-10 0 C under nitrogen atmosphere and stirred for 60min. The solid was filtered under vacuum & nitrogen atmosphere and washed the product with 2OmL of chilled water. The solid was dried at 50-60 0 C under nitrogen atmosphere to obtain 25.9g of dry Phenytoin sodium. Yield: approx. 95.3% w.r.t. Phenytoin
- Phenytoin (178g) was dissolved in 600 mL of DM water and Sodium hydroxide solution (16.7g dissolved in water 105mL) at 30-40 0 C in a 2 L RBF. The reaction mixture was filtered and the clear filtrate was collected and Sodium chloride solution (2 Ig dissolved in water 32mL) was added to it. The filtrate was cooled to 5-10 0 C under nitrogen atmosphere and stirred for 60min. The solid was filtered under vacuum & nitrogen atmosphere and washed with 10OmL of chilled water. The solid was dried at 50-60 0 C under nitrogen atmosphere to obtain 102.6g of dry Phenytoin sodium.
Abstract
The present invention relates to an improved process for the preparation of Phenytoin Sodium of formula (I) by reacting Phenytoin with aqueous solution of Sodium hydroxide in presence of aqueous Sodium chloride.
Description
'AN IMPROVED PROCESS FOR THE PREPARATION OF PHENYTOIN
SODIUM'
Field of the Invention
The present invention relates to an improved process for the preparation of Phenytoin Sodium, a sodium channel blocker used for the treatment of epilepsy.
Background of the Invention
Phenytoin Sodium, which is chemically known as 5,5-Diphenylhydantoin sodium salt is a sodium channel blocker, and has the following structural formula:
(I)
Phenytoin Sodium is a well-known pharmaceutical agent having anticonvulsant and antiepileptic activity and useful in the treatment of epilepsy and it is available in the market under the various brand names such as Aleviatin ®, Persantin ®, Aurantin ®, Dilantin ®, Dintoina ®, Epanutin ® etc.
US Pat. No. 2,409,754 describes a process for preparation of Phenytoin, which is generically known as 5,5-diphenyl-2,4-imidazolidinedione and also known as diphenylhydantoin. According to this patent 5,5-diarylhydantoins is prepared by reacting 1 mole of benzophenone with 1 mole of alkali-metal cyanide and 3 moles of ammonium carbonate in aqueous ethyl alcohol at about 60° C.
US Pat. No. 2,684,371 claimed a process for the preparation of highly pure diphenylhydantoin by reacting urea with benzil in an alkaline aqueous methanol reaction medium.
US Pat. No. 3,646,056 describes a process for the preparation of 5,5-diarylhydantoins in one step by reacting benzoin with 1-3 equivalents of urea in an alkaline medium in the presence of 0.5-4 equivalents of elemental sulfur at a temperature between 60° C and the boiling point of the reaction mixture.
US Pat. No. 6,245,917 teaches a process for the preparation of crystalline sodium phenytoin monohydrate by mixing sodium Phenytoin anhydrate and water in an organic solvent selected from toluene, methanol and dichloromethane, at about 300C to about 400C.
In all the above mentioned prior art the yield of Phenytoin sodium is very low. We focused our research to develop an improved and efficient process for the preparation of the compound of formula (I) which will improve the yield by 20 to 30% having high purity.
Objectives of the Invention
The main objective of the present invention is to provide an improved process for the preparation of compound of formula (I) in high yield and high purity.
Another objective of the present invention is to provide a process for the preparation of compound of formula (I), which uses water as a solvent and avoids organic solvents.
Another objective of the present invention is to provide a process for the preparation of compound of formula (I), which is economical and commercially viable.
Summary of the Invention
Accordingly, the present invention provides a process for the preparation of Phenytoin Sodium (I), by reacting of Phenytoin of formula (II) with aqueous solution of sodium
hydroxide in presence of aqueous Sodium chloride using water as a solvent at a temperature of about 25° C to 50° C to obtain Phenytoin Sodium of formula (I).
The process is shown in the scheme given below:
(ID (D
Description of the Invention
In an embodiment of the present invention, the aqueous sodium chloride is used in different concentration with respect to Phenytoin where the concentration varies from 10 to 50% preferably 20 to 40%.
In another embodiment of the present invention, the reaction is performed at a temperature of about 5° C to 50° C. Most preferably; the reaction step is performed at a temperature of about 5° C to 30° C.
In yet another embodiment of the present invention the starting material of this invention is prepared according to the literature available in the prior art.
In the present invention none of the organic solvent is used. Moreover, the use of sodium chloride enhances the yield of the product. We carried out the same process without using sodium chloride the yield achieved was approximately 66% whereas by using sodium chloride the yield improved by 20 to 30%. This makes the invention economical and commercially viable.
The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.
Example 1
Preparation of Phenytoin Sodium in Water
Phenytoin (2Og) was dissolved in 120 mL of DM water and Sodium hydroxide solution (3.56g dissolved in water 22.5mL) at 25-300C in a 250 mL four-necked RBF. The reaction mixture was filtered and the clear filtrate was collected. The reaction mass was cooled to 5-100C under nitrogen atmosphere and stirred for 60min. The solid was filtered under vacuum & nitrogen atmosphere and washed the product with 2OmL of chilled water. The solid was dried at 50-600C under nitrogen atmosphere to obtain 14.4g of dry Phenytoin sodium. Yield: approx. 66.2% w.r.t. Phenytoin
Example 2
Preparation of Phenytoin Sodium in Water with Sodium chloride (20% w.r.t Phenvtoin)
Phenytoin (2Og) was dissolved in 120 mL of DM water and Sodium hydroxide solution (3.56g dissolved in water 22.5mL) at 25-300C in a 250 mL four-necked RBF. The reaction mixture was filtered and the clear filtrate was collected and Sodium chloride solution (4g Dissolved in water 1OmL) was added to it. The reaction mass was cooled to 5-100C under nitrogen atmosphere and stirred for 60min. The solid was filtered under vacuum & nitrogen atmosphere and washed the product with 2OmL of chilled water. The solid was dried at 50-600C under nitrogen atmosphere to obtain 18.5g of dry Phenytoin sodium. Yield : approx. 85% w.r.t. Phenytoin
Example 3
Preparation of Phenvtoin Sodium in Water with Sodium Chloride (30% w.r.t Phenvtoin)
Phenytoin (25g) was dissolved in 150 mL of DM water and Sodium hydroxide solution (4.45g dissolved in water 25mL) at 25-300C in a 250 mL four-necked RBF. The reaction mixture was filtered and the clear filtrate was collected and Sodium chloride solution (7.5g Dissolved in water 22mL) was added to it. The reaction mass was cooled to 5-100C under nitrogen atmosphere and stirred for 60min. The solid was filtered under vacuum &
nitrogen atmosphere and washed the product with 2OmL of chilled water. The solid was dried at 50-600C under nitrogen atmosphere to obtain 25.3g of dry Phenytoin sodium. Yield : approx. 93% w.r.t. Phenytoin
Example 4
Preparation of Phenytoin Sodium in Water with Sodium Chloride (40% w.r.t Phenvtoin)
Phenytoin (25g) was dissolved in 150 mL of DM water and Sodium hydroxide solution (4.45g dissolved in water 25mL) at 25-300C in a 250 mL four-necked RBF. The reaction mixture was filtered and the clear filtrate was collected and Sodium chloride solution (1Og Dissolved in water 28mL) was added to it. The reaction mass was cooled to 5-100C under nitrogen atmosphere and stirred for 60min. The solid was filtered under vacuum & nitrogen atmosphere and washed the product with 2OmL of chilled water. The solid was dried at 50-600C under nitrogen atmosphere to obtain 25.9g of dry Phenytoin sodium. Yield: approx. 95.3% w.r.t. Phenytoin
Example 5
In-situ preparation of Phenytoin Sodium in Water with Sodium chloride (20% w.r.t phenvtoin)
Potassium hydroxide (152g) was dissolved in 96mL of DM water in a 3 L RBF. Methanol (48OmL) was charged at 25-300C and cooled to 0-50C. Urea (49.5g) and lOOg of Benzil was charged at 0-50C. The reaction mixture was refluxed for 60min and 144OmL of water was added to it and was cooled to 00C. 1Og of hyflo & 1Og of activated carbon was added and stirred for 30-60min at 0-5° C. The reaction mixture was filtered through hyflo bed and washed with chilled 10OmL of water and collected into a 3 L RBF. The pH was adjusted to 6.0 - 7.0 with cone, hydrochloric acid at 30-45° C. The slurry was stirred for 30min, filtered and washed with 100OmL hot water to obtain 178. Ig wet Phenytoin having moisture contents 38.7%w/w. The anhydrous weight was found to be 109.2g.
Phenytoin (178g) was dissolved in 600 mL of DM water and Sodium hydroxide solution (16.7g dissolved in water 105mL) at 30-400C in a 2 L RBF. The reaction mixture was filtered and the clear filtrate was collected and Sodium chloride solution (2 Ig dissolved in
water 32mL) was added to it. The filtrate was cooled to 5-100C under nitrogen atmosphere and stirred for 60min. The solid was filtered under vacuum & nitrogen atmosphere and washed with 10OmL of chilled water. The solid was dried at 50-600C under nitrogen atmosphere to obtain 102.6g of dry Phenytoin sodium.
Claims
WE CLAIM:
l A process for the preparation of Phenytoin Sodium (I), by reacting Phenytoin of formula (II) with aqueous solution of sodium hydroxide in presence of aqueous Sodium chloride using water as a solvent.
(H)
(D
2. A process according to claim 1, where the sodium chloride is used in the range of 20-40% (w/w) w.r.t. Phenytoin.
3. A process according to claim 1, where the reaction is carried out at a temperature in the range of 25° C to 50° C.
4. A process according to claim 1, where the reaction is carried out at a temperature in the range of 25° C to 30° C.
5. A process according to claim 1, where the obtained Phenytoin sodium is isolated at a temperature in the range of 5-100C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN806CH2006 | 2006-05-04 | ||
| IN806/CHE/2006 | 2006-05-04 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2007129184A2 true WO2007129184A2 (en) | 2007-11-15 |
| WO2007129184A3 WO2007129184A3 (en) | 2009-06-04 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2007/001130 WO2007129184A2 (en) | 2006-05-04 | 2007-05-02 | An improved process for the preparation of phenytoin sodium |
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| Country | Link |
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| WO (1) | WO2007129184A2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109456271A (en) * | 2018-11-20 | 2019-03-12 | 宁波职业技术学院 | A kind of synthetic method of dilantin sodium |
| CN111978258A (en) * | 2020-08-13 | 2020-11-24 | 山西新宝源制药有限公司 | Method for preparing phenytoin sodium |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6245917B1 (en) * | 1998-03-20 | 2001-06-12 | Warner-Lambert Company | Crystalline sodium phenytoin monohydrate |
-
2007
- 2007-05-02 WO PCT/IB2007/001130 patent/WO2007129184A2/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6245917B1 (en) * | 1998-03-20 | 2001-06-12 | Warner-Lambert Company | Crystalline sodium phenytoin monohydrate |
Non-Patent Citations (2)
| Title |
|---|
| NI, N. ET AL.: 'Estimation of the effect of NaCl on the solubility of organic compounds in aqueous solutions' JOURNAL OF PHARMACEUTICAL SCIENCES vol. 89, no. ISS.12, 17 October 2000, ISSN 0022-3549 pages 1620 - 1625 * |
| SWABRICK, J ET AL. ENCYCLOPEDIA OF PHARMACEUTICAL TECHNOLOGY, [Online] vol. 20, no. SUPPLE, 2001, page 500 ISBN: 082472819X Retrieved from the Internet: <URL:http://books.***.com/books?id=gJYv8 mdG0iEC8&pg=PP1&dq= Encyclopedia+of+Pharmaceutical+Technology:+ Volume+20+- +Supplement+3&client=firefox-a> * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109456271A (en) * | 2018-11-20 | 2019-03-12 | 宁波职业技术学院 | A kind of synthetic method of dilantin sodium |
| CN109456271B (en) * | 2018-11-20 | 2022-06-21 | 宁波职业技术学院 | Synthesis method of phenytoin sodium |
| CN111978258A (en) * | 2020-08-13 | 2020-11-24 | 山西新宝源制药有限公司 | Method for preparing phenytoin sodium |
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| Publication number | Publication date |
|---|---|
| WO2007129184A3 (en) | 2009-06-04 |
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