73101-64-1

Basic information

• Product Name: 1,2-Benzisoxazole-3-methanesulfonic acid sodium salt
• Synonyms: 1,2-benzisoxazole-3-methanesulfonic acid sodium salt;1.2-Benzisoxazole-3-methanesulfonic acid sodium;1,2-Benzisoxazole-3-MethanesulfonicAcidSodiumSalt(ForZonisamide);ZonisanideIntermediate,1,2-Benzisoxazole-3-MethanesulfonicAcidSodiumSalt;forZonisamide;1,2-Benzisoxazole-3-methane sodium sulphonate;Sodium 2-(1,2-benzisoxazol-3-yl)methanesulfonate;(1,2-Benzisoxazol-3-yl)methanesulfonic acid sodium salt
• CAS NO: 73101-64-1
• Molecular Formula: C₈H₆NO₄S*Na
• Molecular Weight: 235.19
• Product Categories: Zonisamide;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Neurochemicals;Pharmaceuticals
• Mol File: 73101-64-1.mol
• Article Data: 8

Chemical Properties

• Melting Point: 275°C dec.
• Appearance: /
• Storage Temp.: -20?C Freezer
• CAS DataBase Reference: 1,2-Benzisoxazole-3-methanesulfonic acid sodium salt(CAS DataBase Reference)
• NIST Chemistry Reference: 1,2-Benzisoxazole-3-methanesulfonic acid sodium salt(73101-64-1)
• EPA Substance Registry System: 1,2-Benzisoxazole-3-methanesulfonic acid sodium salt(73101-64-1)

Safety Data

• Hazardous Substances Data: 73101-64-1(Hazardous Substances Data)

Usage

Chemical Properties

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Uses

Zonisamide intermediate

InChI:InChI=1/C8H7NO4S.Na/c10-14(11,12)5-7-6-3-1-2-4-8(6)13-9-7;/h1-4H,5H2,(H,10,11,12);/q;+1/p-1

Synthetic route

4-oximino-3,4-dihydro-1,2-benzoxathiin-4-one-2,2-dioxide (597563-86-5) → 1,2-benzisoxazole-3-methanesulfonic acid sodium salt (73101-64-1)

Conditions	Yield
With sodium hydroxide In monoethyleneglycol at 25 - 90℃; for 3h; Product distribution / selectivity; Heating;	93.26%
With sodium hydroxide In water at 20℃; for 3h;	70%
With sodium methylate In methanol at 25 - 30℃; for 9 - 10h; Product distribution / selectivity;

2-[(E)-Hydroxyimino]-2-(2-hydroxy-phenyl)-ethanesulfonic acid amide (74538-98-0) → 1,2-benzisoxazole-3-methanesulfonic acid sodium salt (73101-64-1) + 2-(o-hydroxyphenyl)-2-hydroxyiminoethanesulfonic acid ammonium salt (81516-48-5)

Conditions	Yield
With sodium carbonate at 95℃; for 3h;	A n/a B 10%

1,2-benzisoxazole-3-methanesulfonamide (68291-97-4) → 1,2-benzisoxazole-3-methanesulfonic acid sodium salt (73101-64-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 30 percent / H2 / 5percent Pd-C / ethanol 2: 89 percent / hydroxylamine / ethanol / 3 h / Heating 3: 5percent Na2CO3 / 3 h / 95 °C View Scheme

2-Sulfamoylacetylphenol (74538-97-9) → 1,2-benzisoxazole-3-methanesulfonic acid sodium salt (73101-64-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 89 percent / hydroxylamine / ethanol / 3 h / Heating 2: 5percent Na2CO3 / 3 h / 95 °C View Scheme

2-(benzo[d]isoxazol-3-yl)acetic acid (4865-84-3) → 1,2-benzisoxazole-3-methanesulfonic acid sodium salt (73101-64-1)

Conditions	Yield
Stage #1: 2-(benzo[d]isoxazol-3-yl)acetic acid With chlorosulfonic acid In 1,2-dichloro-ethane at 63 - 79℃; for 1.5h; Stage #2: With sodium hydroxide In water; 1,2-dichloro-ethane pH=>= 11;
Stage #1: 2-(benzo[d]isoxazol-3-yl)acetic acid With chlorosulfonic acid; Ethyl isobutyrate In toluene at 80℃; for 2h; Stage #2: With sodium hydroxide In water pH=10; Product distribution / selectivity;
Stage #1: 2-(benzo[d]isoxazol-3-yl)acetic acid With chlorosulfonic acid; ethyl acetate In dichloromethane; toluene at 70℃; for 2h; Stage #2: With sodium hydroxide In water pH=10; Product distribution / selectivity;

3-bromomethyl-1,2-benzisoxazole (37924-85-9) → 1,2-benzisoxazole-3-methanesulfonic acid sodium salt (73101-64-1)

Conditions	Yield
With sodium sulfite In methanol; water at 50℃; for 4h;

1,2-benzisoxazole-3-methanesulfonic acid sodium salt (73101-64-1) → 1,2-benzoxazol-3-ylmethanesulfonyl chloride (73101-65-2)

Conditions	Yield
With thionyl chloride; N,N-dimethyl-formamide In toluene at 25 - 50℃; for 6h;	80.9%
With thionyl chloride; N,N-dimethyl-formamide In toluene at 20 - 60℃; for 5 - 8h;
With thionyl chloride; N,N-dimethyl-formamide at 5 - 10℃;
With phosgene; N,N-dimethyl-formamide In toluene at 25 - 35℃; for 4h; Reagent/catalyst; Green chemistry;

1,2-benzisoxazole-3-methanesulfonic acid sodium salt (73101-64-1) → 1,2-benzisoxazole-3-methanesulfonamide (68291-97-4)

Conditions	Yield
Stage #1: 1,2-benzisoxazole-3-methanesulfonic acid sodium salt In DMF (N,N-dimethyl-formamide); toluene at 10 - 40℃; for 2h; Stage #2: With oxalyl dichloride In DMF (N,N-dimethyl-formamide); toluene at 10 - 18℃; for 2h; Stage #3: With ammonia In DMF (N,N-dimethyl-formamide); toluene at 10 - 18℃; for 2h; Product distribution / selectivity;	75%
Stage #1: 1,2-benzisoxazole-3-methanesulfonic acid sodium salt In DMF (N,N-dimethyl-formamide); toluene at 10 - 40℃; for 1.5h; Stage #2: With oxalyl dichloride In DMF (N,N-dimethyl-formamide); toluene at 10 - 18℃; for 2h; Stage #3: With ammonia In DMF (N,N-dimethyl-formamide); toluene at 10 - 18℃; for 2h; Product distribution / selectivity;	74.5%
Stage #1: 1,2-benzisoxazole-3-methanesulfonic acid sodium salt With triethylamine; trichlorophosphate In 1,2-dichloro-ethane at 77 - 83℃; for 6h; Stage #2: With ammonia In 1,2-dichloro-ethane at 30 - 60℃;
Multi-step reaction with 2 steps 1: phosgene; N,N-dimethyl-formamide / toluene / 4 h / 25 - 35 °C / Green chemistry 2: ammonia / 1 h / 10 - 15 °C / pH 9-10 / Green chemistry View Scheme

Upstream product

• 37924-85-9 3-bromomethyl-1,2-benzisoxazole 
• 4865-84-3 2-(benzo[d]isoxazol-3-yl)acetic acid 
• 74538-97-9 2-Sulfamoylacetylphenol 
• 68291-97-4 1,2-benzisoxazole-3-methanesulfonamide 
• 74538-98-0 2-[(E)-Hydroxyimino]-2-(2-hydroxy-phenyl)-ethanesulfonic acid amide 
• 597563-86-5 4-oximino-3,4-dihydro-1,2-benzoxathiin-4-one-2,2-dioxide 

Downstream Products

• 73101-65-2 1,2-benzoxazol-3-ylmethanesulfonyl chloride 
• 68291-97-4 1,2-benzisoxazole-3-methanesulfonamide 

Relevant articles and documents

PURE 1,2-BENZISOXAZOLE-3-METHANE-SULFONIC ACID SODIUM SALT AND PURIFICATION PROCESS

The present invention provides chemically pure sodium salt of 1,2-benzisoxazofe-3-methane-sulfonic acid, the sodium salt of 1,2-benzisoxazole-3-methane-sulfonic acid of high assay, or chemically pure sodium salt of 1,2-benzisoxazole-3-methane-sulfonic acid of high assay, and processes for preparing the same via purification. The present invention also provides monohydrate form of the chemically pure sodium salt of 1,2-benzisoxazole-3-methane-sulfonic acid, the sodium salt of 1,2-benzisoxazole-3-methane-sulfonic acid of high assay, or chemically pure sodium salt of 1,2-benzisoxazole-3-methane-sulfonic acid of high assay. Furthermore, the present invention provides anhydrous form of the chemically pure sodium salt of 1,2-benzisoxazole-3-methane-sulfonic acid, the sodium salt of 1,2-benzisoxazole-3-methane-sulfonic acid of high assay, or chemically pure sodium salt of 1,2-benzisoxazole-3-methane-sulfonic acid of high assay. One of the embodiments of the present invention is directed to a process for preparing zonisamide using the chemically pure sodium salt of 1,2-benzisoxazole-3-methane-sulfonic acid, the sodium salt of 1,2-benzisoxazole-3- methane-sulfonic acid of high assay, or chemically pure sodium salt of 1,2-benzisoxazole-3-methane-sulfonic acid of high assay.

Novel crystalline forms of sodium 1,2-benzisoxazole-3-methanesulfonate, processes of preparing same and use thereof in the synthesis of zonisamide

Disclosed is a process of preparing 1,2-benzisoxazole-3-methanesulfonamide (zonisamide). Also disclosed is a method of dehydrating sodium 1,2-benzisoxazole-3-methanesulfonate, a compound useful in the preparation of 1,2-bisoxazole-3-methanesulfonamide (zonisamide) as well as new crystalline forms of sodium 1,2-benzisoxazole-3-methanesulfonate.

IMPROVED PROCESS FOR THE PREPARATION OF INTERMEDIATES USEFUL FOR THE PREPARATION OF ZONISAMIDE

The invention relates to an improved process for the preparation of 1,2-benzisoxazole-3--methane sulfonates and a novel compound 4-oximino-2,3-dihydrobenzoxathiin-2, 2--dioxides. The 1,2-benzisoxazole-2-methane sulfonates and 4-oximino-2, 3--dihydrobenzoxathiin-2, 2-dioxides prepared by the processes of the present invention have the general formula (2) and (3) respectively . The compounds of the formulae (2) and (3) are important intermediates for the preparation of Zonisamide of the formula (1) (an anticonvulsant drug). The compounds of the formula (2) is prepared from hitherto unknown compound 4-oximino-2,3-dihydrobenzoxathiin-2, 2-dioxides of the formula (3) using strong bases with suitable solvents. The novel compounds of the formula (3) is prepared by the intramolecular Cyclocondensation of the compound of the formula (4) to get the compound of the formula (5) and subsequent reaction with hydroxylamine hydrochloride to get the novel intermediates of the formula (3). In the above mentioned formulae R1 to R4 - may be the same or different and represents hydrogen, alkyl, (with carbons, 2-5), chloro, bromo, S- alkyl, o- alkyl, NO2, N- Me2, CF3. and where X represents Na or K.