WO2008026217A1 - Improved and simplified process for the preparation of 1,2-benzisoxazole-3-acetic acid - Google Patents
Improved and simplified process for the preparation of 1,2-benzisoxazole-3-acetic acid Download PDFInfo
- Publication number
- WO2008026217A1 WO2008026217A1 PCT/IN2006/000313 IN2006000313W WO2008026217A1 WO 2008026217 A1 WO2008026217 A1 WO 2008026217A1 IN 2006000313 W IN2006000313 W IN 2006000313W WO 2008026217 A1 WO2008026217 A1 WO 2008026217A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- process according
- benzisoxazole
- acid
- acetic acid
- reaction
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
Definitions
- the present invention relates to a process for preparation of l,2-benzisoxazole-3-acetic acid.
- l,2-benzisoxazole-3-acetic acid is a key material for the preparation of l,2-benzisoxazole-3-methane sulfonamide ( Zonisamide) anti-epileptic agent which possesses anti-convulant and anti neurotoxic effects.
- Zonisamide l,2-benzisoxazole-3-acetic acid
- the l,2-benzisoxazole-3-acetic acid (BOA) preparation was reported in literature using 4- hydroxyl coumarin and hydroxylamine acid salt using different bases Scheme -1
- the present invention relates to a process for the preparation of 1,2-benzisoxazole- 3-acetic acid .by reacting 4-hydroxy coumarin with hydroxylamine in water as solvent.
- l,2-benzisoxazole-3 -acetic acid is obtained in quantitative yield by reacting 4-hydroxy coumarin with hydroxylamine in water as solvent.
- decomposition of hydroxylamine which will occur during the reaction. It is reported that such decomposition is controlled by addition of chelating agents by which the reaction temperatures can be controlled.
- the present invented process does not involve neither high temperature nor chelating agent.
- Hydroxylamine decomposition is avoided by maintained the reaction at temperature below 50 C and a pH of between 4.5 to 5.5. It is found by the applicant that use of temperatures above 50 C ( 55 to 95C) and pH above 6.0 ( 6.0 to basic) may lead to formation of the oxime impurity to the extent of about 25 % in some cases. Also at pH below 4.5 the reaction incomplete ( formation of product is not observed) even after maintaining more than 50 hours.
- Example 1 100 gms 4-hydroxy coumarin is added to hydroxy 1 amine solution in water (from 200 gms Hydroxylamine Hydrochloride and 1200 ml 10% sodium carbonate solution ) at room temperature. pH of the reaction mass maintained in the range of 4.5 to 5.5. Reaction mass is warmed to 40 0 C and maintained at 40-45 0 C for 12 hours till the reaction completes . Reaction mass is cooled to 10 0 C and pH of the mass is adjusted to 1 to 1.5 with dilute hydrochloric acid. Precipitated l,2-Benzisoxazole-3-acetic acid is cooled to 0-5 °Cand maintained at 0-5° C for lhour and isolated and dried at 60-70 0 C.
- Dry weight 105 gms ( 96% by theory on 4-Hydroxy coumarin, 1.05 wt/wt)
- Precipitated l,2-benzisoxazole-3 ⁇ acetic acid is further cooled to 0-5° C, maintained for one hour at 0-5 C, isolated by centrifuging and dried at 60-70 0 C.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
A process for preparation of 1,2-benzisoxazole-3-acetic acid reacting 4-hydroxy coumarin and hydroxylamine in water according to the following scheme of reaction. Formula (I).
Description
IMPROVED AND SIMPLIFIED PROCESS FOR THE PREPARATION OF 1.2-BENZISOXAZOLE-S-ACETIC ACID
FIELD OF INVENTION
The present invention relates to a process for preparation of l,2-benzisoxazole-3-acetic acid.
BACKGROUND OF INVENTION l,2-benzisoxazole-3-acetic acid (BOA) is a key material for the preparation of l,2-benzisoxazole-3-methane sulfonamide ( Zonisamide) anti-epileptic agent which possesses anti-convulant and anti neurotoxic effects.The l,2-benzisoxazole-3-acetic acid (BOA) preparation was reported in literature using 4- hydroxyl coumarin and hydroxylamine acid salt using different bases Scheme -1
4-hydroxy-coumarin Hydroxylamine l,2-benzisoxazole-3acetic acid hydrochloride (BOA)
Scheme -1
Different bases were reported in literature
Chem.Pharma., Bull., (Tokyo), 24, 632, 1976 and
T. Posner and R.Hess, Ber., 46, 3816 ( 1913 ) reported sodium as base in solvent ethanol. G. Casini, F. Gualtieri, M.L, Stern, J. Heterocyclic Chem., 2, 385, 1965 claims with base sodium acetate and mixture of water and ethanol as solvent.
Tetarhydron (1963) 1831 and J.Heterocyclic Chem., 6, 279, 1969 reported aqueous pyridine as base.US2002/0183525Al and US2003/0144527A1 discloses a process for
the preparation of l,2-benzisoxazole-3 -acetic acid or its derivatives from 4- hydroxycoumarin or its derivatives in presence of a base and alcohol as solvent
Teva patent WO 02/070495 Al ( US 02/06419) reported bases such as carbonate salts aqueous ammonia and organic bases like Triethylamine, tributyl amine and diethylamine in presence of alcohol( methanol, ethanol and n-butanol) . None of these references used water only as a solvent for the condensation of 4-hydroxy coumarin with Hydroxylamine. For all the above references various bases like sodium, sodium acetate, sodium carbonate, potassium carbonate organic bases like Triethyl amine, Diethyl amine , either in aqueous pyridine or in solvent medium are involved resulting formation of major impurity hydroxyl acetophenone Oxime , in some cases to the extent of 15% wt/wt and above also observed. Additional purification is involved to remove this impurity resulting very low yields.
US 2005 0215796 claimed the preparation of BOA (l,2-benzisoxazole-3-acetic acid) by the reaction of 4-Hydroxy coumarin with Hydroxylamine sulfate in presence of base sodium hydroxide in aqueous media at elevated temperatures involving a chelating agent and solvent 1,2-dichloroethane for isolation.
The disadvantages of reported processes include
• use of solvents,
• use of hazardous bases like pyridine, sodium and sodium methoxide,
• carrying out reaction at high temperatures leading to the possibility of decomposition of hydroxylamine, • avoiding the chelating agents, contamination of product with impurities like hydroxyl acetophenone oxime,
It is an object of the invention to provide l,2-benzisoxazole-3-acetic acid by a process that is simple and economical and that uses only water as solvent and does not use any chelating agent or any other catalyst/chemical.
It is an object of the invention to provide l,2-benzisoxazole-3-acetic acid by a novel process whereby the presence of the impurity oxime does not exceed 0.50% and preferably 0.20% and provides a quantitative yield of 95% to 97%.
SUMMARY OF THE INVENTION
Thus the present invention relates to a process for the preparation of 1,2-benzisoxazole- 3-acetic acid .by reacting 4-hydroxy coumarin with hydroxylamine in water as solvent.
DETAILED DESCRIPTION l,2-benzisoxazole-3-acetic acid .by reacting 4-hydroxy coumarin with hydroxylamine in water as solvent according to Scheme 2 shown below
4-hydroxy-coumarin Hydroxylamine l,2-benzisoxazole-3acetic acid (BOA)
Scheme-2.
l,2-benzisoxazole-3 -acetic acid is obtained in quantitative yield by reacting 4-hydroxy coumarin with hydroxylamine in water as solvent. There is a possibility of decomposition of hydroxylamine which will occur during the reaction. It is reported that such decomposition is controlled by addition of chelating agents by which the reaction temperatures can be controlled. The present invented process does not involve neither high temperature nor chelating agent. In this present invention Hydroxylamine decomposition is avoided by maintained the reaction at temperature below 50 C and a pH of between 4.5 to 5.5.
It is found by the applicant that use of temperatures above 50 C ( 55 to 95C) and pH above 6.0 ( 6.0 to basic) may lead to formation of the oxime impurity to the extent of about 25 % in some cases. Also at pH below 4.5 the reaction incomplete ( formation of product is not observed) even after maintaining more than 50 hours.
The invention will now be demonstrated with reference to non limiting examples as under:
Example 1: 100 gms 4-hydroxy coumarin is added to hydroxy 1 amine solution in water (from 200 gms Hydroxylamine Hydrochloride and 1200 ml 10% sodium carbonate solution ) at room temperature. pH of the reaction mass maintained in the range of 4.5 to 5.5. Reaction mass is warmed to 40 0C and maintained at 40-45 0C for 12 hours till the reaction completes . Reaction mass is cooled to 10 0C and pH of the mass is adjusted to 1 to 1.5 with dilute hydrochloric acid. Precipitated l,2-Benzisoxazole-3-acetic acid is cooled to 0-5 °Cand maintained at 0-5° C for lhour and isolated and dried at 60-700C.
Dry weight : 105 gms ( 96% by theory on 4-Hydroxy coumarin, 1.05 wt/wt)
HPLC purity : 99.68%, Oxime impurity :0.16%. Melting point: 125-126 0C.
Example 2: ■*•
10% sodium hydroxide solution ( 450 ml) is added to the aqueous Hydroxylamine hydrochloride solution ( 200 gms in 500 ml water) till the pH of the mass is around 5.0. At room temperature. 100 gms 4-hydroxy coumarin is added to above solution at room temperature. Reaction mass is warmed to 40° C and maintained at 40-45 0C for 12 hours till the reaction completes. Reaction mass is colled to 10 0C and pH of the mass is adjusted to 1 to 1.5 with dilute hydrochloric acid. Precipitated l,-benzisoxazole-3acetic acid is cooled further to 0-5 0C and maintained at 0-5 0C for 1 hour, isolated by filtration and dried at 60-70 0C.
Dry weight : 102 gms ( 93.3 % on theory on 4-Hydroxy coumarin, 1.04 Wt/Wt)
HPLC purity : 99.86% Oxime impurity: 0.06%
Example 3:
Mixture of 4-hydroxy coumarin (100 Kg), 10% aqueous sodium carbonate solution (1200 Lts) and hydroxylamine hydrochloride ( 200 Kgs) stirred for 0.5 hour at 20-25 0C and pH around 4.5 to 5.5 for uniform solution. Reaction mass was warmed to 40 0C and maintained at 40-45 0C and pH 4.5 to 5.5 for 20-24 hours till the reaction completes.
Reaction mass pH adjusted to 1.0 to 1.5 with dilute hydrochloric acid below 10 0C. Precipitated l,2-benzisoxazole-3τacetic acid is further cooled to 0-5° C, maintained for one hour at 0-5 C, isolated by centrifuging and dried at 60-700C.
Dry weight: 105 Kgs . LOD ( at 105C for 4 hours ) : 0.35%. Oxime impurity: 0.27%. Melting point : 124-1260C.
Percentage of formation of product and impurity at various pH ranges and temperatures recorded in the table below ( process same as example 1)
Claims
1. Process for the preparation of l,2-benzisoxazole-3-acetic acid comprising reacting 4- hydroxy coumarin and hydroxylamine in water.
2. The process according to claim 1 where in hydroxylamine is liberated from Hydroxyl amine acid salts with base.
3. The process according to claim 2, where in the base is selected from sodium hydroxide, carbonate salts, aqueous ammonia and organic bases.
4. The process according to claim 3, where in the -carbonate salt is selected from sodioum carbonate, potassium carbonate and sodium bicarbonate.
5. The process according to claim 1, where in the process is performed at pH 3.5 to 6.5 , prepferably at pH 4.5 to 5.5.
6. The process according to claiml,where in the reaction is performed at 30-700C preferably 40-45° C.
7. The process according to claim 1 where in the reaction is performed for 16 -24 hours.
8. The process according to claim 7 where in the reaction is performed for 20-22 hours
9. The process according to claim 1 where in pH is adjusted to 0.5 to2.0 preferably 1.0 to 1.5. with acid.
10. The process according to claim 8 where in acid is selected from Hydrochloric acid or sulfuric acid.
11. The process according to claim 10 where in the acid is Hydrochloric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2006/000313 WO2008026217A1 (en) | 2006-08-28 | 2006-08-28 | Improved and simplified process for the preparation of 1,2-benzisoxazole-3-acetic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2006/000313 WO2008026217A1 (en) | 2006-08-28 | 2006-08-28 | Improved and simplified process for the preparation of 1,2-benzisoxazole-3-acetic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2008026217A1 true WO2008026217A1 (en) | 2008-03-06 |
Family
ID=37963708
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2006/000313 WO2008026217A1 (en) | 2006-08-28 | 2006-08-28 | Improved and simplified process for the preparation of 1,2-benzisoxazole-3-acetic acid |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2008026217A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018229197A1 (en) | 2017-06-14 | 2018-12-20 | European Molecular Biology Laboratory | Bicyclic heteroaromatic urea or carbamate compounds for use in therapy |
| WO2018229195A1 (en) | 2017-06-14 | 2018-12-20 | European Molecular Biology Laboratory | Bicyclic heteroaromatic amide compounds for use in therapy |
| CN113651767A (en) * | 2021-09-18 | 2021-11-16 | 江西中医药大学 | Benzisoxazole heterocyclic compound and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002070495A1 (en) * | 2001-03-02 | 2002-09-12 | Teva Pharmaceutical Industries Ltd. | Process for the preparation of 1,2-benzisoxazole-3-acetic acid |
| US20050215796A1 (en) * | 2004-03-25 | 2005-09-29 | Yoshikazu Ueno | One-pot process for the preparation of 1,2-benzisoxazole-3-methanesulfonamide |
| US20060084814A1 (en) * | 2004-05-20 | 2006-04-20 | Siva Kumar Bobba V | Process for the preparation of zonisamide |
-
2006
- 2006-08-28 WO PCT/IN2006/000313 patent/WO2008026217A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002070495A1 (en) * | 2001-03-02 | 2002-09-12 | Teva Pharmaceutical Industries Ltd. | Process for the preparation of 1,2-benzisoxazole-3-acetic acid |
| US20050215796A1 (en) * | 2004-03-25 | 2005-09-29 | Yoshikazu Ueno | One-pot process for the preparation of 1,2-benzisoxazole-3-methanesulfonamide |
| US20060084814A1 (en) * | 2004-05-20 | 2006-04-20 | Siva Kumar Bobba V | Process for the preparation of zonisamide |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018229197A1 (en) | 2017-06-14 | 2018-12-20 | European Molecular Biology Laboratory | Bicyclic heteroaromatic urea or carbamate compounds for use in therapy |
| WO2018229195A1 (en) | 2017-06-14 | 2018-12-20 | European Molecular Biology Laboratory | Bicyclic heteroaromatic amide compounds for use in therapy |
| CN113651767A (en) * | 2021-09-18 | 2021-11-16 | 江西中医药大学 | Benzisoxazole heterocyclic compound and preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6514398B2 (en) | Process for the preparation and medicinal use of methyl {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} methyl carbamate Process for its purification for use as active compound | |
| US7081539B2 (en) | One-pot process for the preparation of 1,2-benzisoxazole-3-methanesulfonamide | |
| KR20120098815A (en) | Method for producing methyl- {4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo [3,4-b]pyridino-3-yl] pyrimidino-5-yl} carbamate and its purification for use thereof as pharmaceutical substance | |
| US20240317773A1 (en) | High-purity thienopyrimidine compound and preparation method therefor | |
| WO2005105755A1 (en) | Process for the production of 5-difluoromethoxy -4-thiomethylpyrazoles | |
| WO2008026217A1 (en) | Improved and simplified process for the preparation of 1,2-benzisoxazole-3-acetic acid | |
| WO2011021218A2 (en) | Process for the preparation of 4-[3,5-bis(2-hydroxyphenyl)-1h-1,2,4-triazol-1-yl]-benzoic acid and its amine salts | |
| US6936720B2 (en) | Method for preparing benzisoxazole methane sulfonyl chloride and its amidation to form zonisamide | |
| WO2002070495A1 (en) | Process for the preparation of 1,2-benzisoxazole-3-acetic acid | |
| TW202102477A (en) | Production method of quinolinecarboxamide derivative or production intermediate thereof | |
| CN110878101A (en) | Novel method for preparing cefixime mother nucleus 7-AMOCA | |
| EP4232442A1 (en) | A process for the preparation of chlorantraniliprole | |
| US20080058550A1 (en) | Chemical process | |
| EP1728786B1 (en) | One-pot process for producing 1,2-benzisoxazole-3-methanesulfonamide | |
| CN101180289B (en) | Method for the production of substituted 2-alkoxycarbonyl-3-aminothiophenes | |
| US10259770B2 (en) | Process for the preparation of ethacrynic acid | |
| US20050014739A1 (en) | Aztreonam beta polymorph with very low residual solvent content | |
| WO2008092410A1 (en) | Preparation method of thioureas or salts thereof | |
| JP5414163B2 (en) | Process for producing 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} thiazolidine-2,4-dione hydrochloride | |
| SE124934C1 (en) | ||
| JPS6117591A (en) | Manufacture of cephalosporin compound | |
| CN109912673A (en) | Cangrelor intermediate and preparation method thereof | |
| JP2005139098A (en) | Method for producing 1-thio-2-propanone derivative and 5-methyl-5-thiomethylhydantoin derivative | |
| JP2006056832A (en) | Method for producing and purifying 4-hydroxyquinolines | |
| JPH0211580B2 (en) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 06796192 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 1316/CHENP/2009 Country of ref document: IN |
|
| NENP | Non-entry into the national phase |
Ref country code: RU |
|
| 32PN | Ep: public notification in the ep bulletin as address of the adressee cannot be established |
Free format text: "NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC, FORM 1205A DATED 11.08.09 |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 06796192 Country of ref document: EP Kind code of ref document: A1 |