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Structure of 73101-64-1

Chemical Structure| 73101-64-1

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Product Details of [ 73101-64-1 ]

CAS No. :73101-64-1
Formula : C8H6NNaO4S
M.W : 235.19
SMILES Code : O=S(CC1=NOC2=CC=CC=C12)([O-])=O.[Na+]
MDL No. :MFCD07782146
InChI Key :QILCHBOPDIODSB-UHFFFAOYSA-M
Pubchem ID :23674934

Safety of [ 73101-64-1 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P280-P305+P351+P338

Computational Chemistry of [ 73101-64-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 15
Num. arom. heavy atoms 9
Fraction Csp3 0.12
Num. rotatable bonds 2
Num. H-bond acceptors 5.0
Num. H-bond donors 0.0
Molar Refractivity 47.66
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

91.61 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

-11.38
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

0.43
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

1.8
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

0.36
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

0.52
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

-1.65

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-1.88
Solubility 3.09 mg/ml ; 0.0131 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-1.92
Solubility 2.82 mg/ml ; 0.012 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-2.68
Solubility 0.496 mg/ml ; 0.00211 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

No
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

Yes
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-7.43 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

1.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

2.85

Application In Synthesis of [ 73101-64-1 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 73101-64-1 ]

[ 73101-64-1 ] Synthesis Path-Downstream   1~1

  • 1
  • [ 4865-84-3 ]
  • [ 73101-64-1 ]
YieldReaction ConditionsOperation in experiment
1) A mixture of hydroxylamine sulfate (43 g), water (113 ml) and a 25% aqueous sodium hydroxide solution (57 ml) is stirred, and thereto are added 4-hydroxycoumarin (21 g) and ethylenediamine-tetraacetic acid disodium salt dihydrate (0.4 g), and the mixture is stirred with heating at 84 C. to 86 C. for 4 hours. The reaction mixture is cooled, and thereto are added 1,2-dichloroethane (30 ml) and water (43 ml), and the mixture is stirred. The 1,2-dichloroethane layer is removed, and the pH value thereof is adjusted to pH 1-2 with 62.5% sulfuric acid. The mixture is extracted twice with 1,2-dichloroethane (120 ml and 10 ml) to give a mixture of <strong>[4865-84-3]1,2-benzisoxazole-3-acetic acid</strong> and 1,2-dichloroethane. The purity of <strong>[4865-84-3]1,2-benzisoxazole-3-acetic acid</strong> in this mixture is 98%. 2) Water is removed by distillation from the above mixture of <strong>[4865-84-3]1,2-benzisoxazole-3-acetic acid</strong> and 1,2-dichloroethane, and thereto is added dropwise chlorosulfonic acid (15.5 g) while the internal temperature is kept at 63 C.-79 C. After the addition, the mixture is stirred for 90 minutes while the reaction temperature is kept at 63 C.-79 C. After cooling, a 25% aqueous sodium hydroxide solution is added to the reaction mixture so as to adjust the pH value thereof to pH 11 or above. Water is removed by distillation from the reaction mixture to give a mixture of sodium 1,2-benzisoxazole-3-methanesulfonate and 1,2-dichloroethane. Triethylamine (2.4 g) and phosphoryl chloride (17.5 g) are added to this mixture, and the mixture is stirred at a temperature of 77 C.-83 C. for 6 hours. After cooling, to the reaction mixture is added 1,2-dichloroethane (80 ml), and ammonia gas is blown into the mixture until saturated while the reaction temperature is kept at 30 C.-60 C. The reaction mixture is concentrated, and water is added thereto. The mixture is stirred, and the precipitated crystals are collected by filtration, and washed with water to give crude crystals of 1,2-benzisoxazole-3-methanesulfonamide. The purity of the crude crystals is 96%. 3) The above crude crystals are recrystallized from a 50% aqueous isopropanol, and dried at 80 C. for 16 hours to give crystals of 1,2-benzisoxazole-3-methanesulfonamide having a purity of 99%.
Example 1 To a mixture of <strong>[4865-84-3]1,2-benzisoxazole-3-acetic acid</strong> (1.77 g), ethyl isobutyrate (3.48 g) and toluene (15 ml) was added dropwise chlorosulfonic acid (1.40 g) with stirring at room temperature and the resulting mixture was heated with stirring at 80 C. for 2 hours. It was confirmed that there were 70%, 21% and 8% of 1,2-benzisoxazole-3-methane sulfonic acid, starting material and a by-product, respectively, in the reaction solution. Water was added to the reaction mixture and the mixture was extracted with aqueous layer. The aqueous layer was adjusted with 25% aqueous sodium hydroxide to pH 10 and concentrated under reduced pressure. To the residue was added water until total weight became approximately 7 g and the mixture was cooled in an ice water bath. The precipitated crystals were collected by filtration and dried at room temperature to give 1.23 g of sodium 1,2-benzisoxazole-3-methanesulfonate (purity of 99%).
Example 10 To a mixture of <strong>[4865-84-3]1,2-benzisoxazole-3-acetic acid</strong> (1.77 g), ethyl acetate (2.64 g) and toluene (15 ml) was added dropwise a solution of chlorosulfonic acid (1.75 g) in dichloromethane (5 ml) with stirring at room temperature and the resulting mixture was heated with stirring at 70 C. for 2 hours. It was confirmed that 84%, 5% and 7% of 1,2-benzisoxazole-3-methane sulfonic acid, starting material and a by-product respectively, were present in the reaction solution. Water was added to the reaction mixture and the mixture was extracted with aqueous layer. The aqueous layer was adjusted with 25% aqueous sodium hydroxide to pH. 10 and concentrated under reduced pressure. To the residue was added water until the total weight became approximately 7 g and the mixture was cooled in an ice water bath. The precipitated crystals were collected by filtration and dried at room temperature to give 2.38 9 of sodium 1,2-benzisoxazole-3-methane sulfonate (purity of 96%).
Example 10 To a mixture of <strong>[4865-84-3]1,2-benzisoxazole-3-acetic acid</strong> (1.77 g), ethyl acetate (2.64 g) and toluene (15 ml) was added dropwise a solution of chlorosulfonic acid (1.75 g) in dichloromethane (5 ml) with stirring at room temperature and the resulting mixture was heated with stirring at 70 C. for 2 hours. It was confirmed that 84%, 5% and 7% of 1,2-benzisoxazole-3-methane sulfonic acid, starting material and a by-product respectively, were present in the reaction solution. Water was added to the reaction mixture and the mixture was extracted with aqueous layer. The aqueous layer was adjusted with 25% aqueous sodium hydroxide to pH. 10 and concentrated under reduced pressure. To the residue was added water until the total weight became approximately 7 g and the mixture was cooled in an ice water bath. The precipitated crystals were collected by filtration and dried at room temperature to give 2.38 9 of sodium 1,2-benzisoxazole-3-methane sulfonate (purity of 96%). Examples 11-13; 1,2-Benzisoxazole-3-acetic acid (1.77 grams) was treated in a similar manner in Example 10 to give the following results in Table 3. TABLE 3 Contents in a reaction mixture Chlorosulfonic Desired Starting By- Yield Example Toluene acid Solvent Lewis base compound materialproduct1) (Purity) 10 15 ml 1.75 g Dichloroethane Ethyl 84% 5% 7% 2.38 g 5 ml acetate (96%) 2.64 g 11 15 ml 1.75 g Chloroform Ethyl 86% 4% 6% 2.41 g 5 ml acetate (96%) 2.64 g 12 15 ml 1.75 g 1,2-Dichloroethane Acetonitrile 78% 5% 9% - 5 ml 1.23 g 13 15 ml 2.10 g 1,2-Dichloroethane tert-Butyl 74% 11% 12% - 5 ml cyanide 2.49 g 1)A reaction product of toluene with chlorosulfonic acid.
Example 1; To a mixture of <strong>[4865-84-3]1,2-benzisoxazole-3-acetic acid</strong> (1.77 g), ethyl isobutyrate (3.48 g) and toluene (15 ml) was added dropwise chlorosulfonic acid (1.40 g) with stirring at room temperature and the resulting mixture was heated with stirring at 80 C. for 2 hours. It was confirmed that there were 70%, 21% and 8% of 1,2-benzisoxazole-3-methane sulfonic acid, starting material and a by-product, respectively, in the reaction solution. Water was added to the reaction mixture and the mixture was extracted with aqueous layer. The aqueous layer was adjusted with 25% aqueous sodium hydroxide to pH 10 and concentrated under reduced pressure. To the residue was added water until total weight became approximately 7 g and the mixture was cooled in an ice water bath. The precipitated crystals were collected by filtration and dried at room temperature to give 1.23 g of sodium 1,2-benzisoxazole-3-methanesulfonate (purity of 99%). ; Examples 2-9; 1,2-Benzisoxazole-3-acetic acid (1.77 g) was treated in a similar manner in Example 1 to give the following results in Table 1. TABLE 1 Contents in a reaction mixture Chlorosulfonic Desired Starting By- Yield Example Toluene acid Lewis base compound materialproduct1) (Purity) 1 15 ml 1.40 g Ethyl isobutyrate 70% 21% 8% 1.23 g 3.48 g (99%) 2 15 ml 1.40 g Ethyl acetate 67% 26% 6% 1.48 g 2.64 g (90%) 3 15 ml 1.75 g Ethyl acetate 64% 23% 12% 1.75 g 2.64 g (94%) 4 15 ml 1.40 g Ethyl propionate 63% 28% 7% 1.29 g 3.06 g (93%) 5 15 ml 1.40 g Methyl pivalate 60% 25% 8% 1.21 g 3.48 g (93%) 6 15 ml 1.40 g Ethyl pivalate 62% 29% 9% - 3.91 g 7 15 ml 1.40 g Ethyl benzoate 63% 28% 9% 1.29 g 4.51 g (91%) 8 18 ml 1.40 g Benzonitrile 53% 23% 8% 1.25 g 1.55 g (91%) 9 18 ml 1.40 g tert-Butyl cyanide 66% 23% 8% 1.12 g 1.25 g (92%) 1)A reaction product with toluene and chlorosulfonic acid.
Example 1; To a mixture of <strong>[4865-84-3]1,2-benzisoxazole-3-acetic acid</strong> (1.77 g), ethyl isobutyrate (3.48 g) and toluene (15 ml) was added dropwise chlorosulfonic acid (1.40 g) with stirring at room temperature and the resulting mixture was heated with stirring at 80 C. for 2 hours. It was confirmed that there were 70%, 21% and 8% of 1,2-benzisoxazole-3-methane sulfonic acid, starting material and a by-product, respectively, in the reaction solution. Water was added to the reaction mixture and the mixture was extracted with aqueous layer. The aqueous layer was adjusted with 25% aqueous sodium hydroxide to pH 10 and concentrated under reduced pressure. To the residue was added water until total weight became approximately 7 g and the mixture was cooled in an ice water bath. The precipitated crystals were collected by filtration and dried at room temperature to give 1.23 g of sodium 1,2-benzisoxazole-3-methanesulfonate (purity of 99%). ; Reference Examples 1-5; 1,2-Benzisoxazole-3-acetic acid (1.77 grams) was treated in a similar manner in Example 1 to give the following results in Table 2. TABLE 2 Contents in a reaction mixture Reference Chlorosulfonic Desired Starting By- Yield Example Toluene acid Lewis base compound materialproduct1) (Purity) 1 18 ml 1.40 g 1,4-Dioxane 81% 12% 5% 1.59 g 1.32 g (92%) 2 15 ml 1.40 g 1,2-Diethoxyethane 51% 24%5%, 18%2) - 3.54 g 3 18 ml 1.40 g DMF 3% 88% 9% - 1.10 g 4 36 ml 2.10 g 1-methyl-2-pyrrolidone 4% 80% 13% - 2.23 g 5 18 ml 2.33 g none 25% 29% 44% - 1)A reaction product of toluene with chlorosulfonic acid. 2)By-products other than a reaction product of toluene with chlorosulfonic acid.
Example 1; To a mixture of <strong>[4865-84-3]1,2-benzisoxazole-3-acetic acid</strong> (1.77 g), ethyl isobutyrate (3.48 g) and toluene (15 ml) was added dropwise chlorosulfonic acid (1.40 g) with stirring at room temperature and the resulting mixture was heated with stirring at 80 C. for 2 hours. It was confirmed that there were 70%, 21% and 8% of 1,2-benzisoxazole-3-methane sulfonic acid, starting material and a by-product, respectively, in the reaction solution. Water was added to the reaction mixture and the mixture was extracted with aqueous layer. The aqueous layer was adjusted with 25% aqueous sodium hydroxide to pH 10 and concentrated under reduced pressure. To the residue was added water until total weight became approximately 7 g and the mixture was cooled in an ice water bath. The precipitated crystals were collected by filtration and dried at room temperature to give 1.23 g of sodium 1,2-benzisoxazole-3-methanesulfonate (purity of 99%). ; Reference Examples 1-5; 1,2-Benzisoxazole-3-acetic acid (1.77 grams) was treated in a similar manner in Example 1 to give the following results in Table 2. TABLE 2 Contents in a reaction mixture Reference Chlorosulfonic Desired Starting By- Yield Example Toluene acid Lewis base compound materialproduct1) (Purity) 1 18 ml 1.40 g 1,4-Dioxane 81% 12% 5% 1.59 g 1.32 g (92%) 2 15 ml 1.40 g 1,2-Diethoxyethane 51% 24%5%, 18%2) - 3.54 g 3 18 ml 1.40 g DMF 3% 88% 9% - 1.10 g 4 36 ml 2.10 g 1-methyl-2-pyrrolidone 4% 80% 13% - 2.23 g 5 18 ml 2.33 g none 25% 29% 44% - 1)A reaction product of toluene with chlorosulfonic acid. 2)By-products other than a reaction product of toluene with chlorosulfonic acid.
Example 1; To a mixture of <strong>[4865-84-3]1,2-benzisoxazole-3-acetic acid</strong> (1.77 g), ethyl isobutyrate (3.48 g) and toluene (15 ml) was added dropwise chlorosulfonic acid (1.40 g) with stirring at room temperature and the resulting mixture was heated with stirring at 80 C. for 2 hours. It was confirmed that there were 70%, 21% and 8% of 1,2-benzisoxazole-3-methane sulfonic acid, starting material and a by-product, respectively, in the reaction solution. Water was added to the reaction mixture and the mixture was extracted with aqueous layer. The aqueous layer was adjusted with 25% aqueous sodium hydroxide to pH 10 and concentrated under reduced pressure. To the residue was added water until total weight became approximately 7 g and the mixture was cooled in an ice water bath. The precipitated crystals were collected by filtration and dried at room temperature to give 1.23 g of sodium 1,2-benzisoxazole-3-methanesulfonate (purity of 99%). ; Reference Examples 1-5; 1,2-Benzisoxazole-3-acetic acid (1.77 grams) was treated in a similar manner in Example 1 to give the following results in Table 2. TABLE 2 Contents in a reaction mixture Reference Chlorosulfonic Desired Starting By- Yield Example Toluene acid Lewis base compound materialproduct1) (Purity) 1 18 ml 1.40 g 1,4-Dioxane 81% 12% 5% 1.59 g 1.32 g (92%) 2 15 ml 1.40 g 1,2-Diethoxyethane 51% 24%5%, 18%2) - 3.54 g 3 18 ml 1.40 g DMF 3% 88% 9% - 1.10 g 4 36 ml 2.10 g 1-methyl-2-pyrrolidone 4% 80% 13% - 2.23 g 5 18 ml 2.33 g none 25% 29% 44% - 1)A reaction product of toluene with chlorosulfonic acid. 2)By-products other than a reaction product of toluene with chlorosulfonic acid.
Example 10 To a mixture of <strong>[4865-84-3]1,2-benzisoxazole-3-acetic acid</strong> (1.77 g), ethyl acetate (2.64 g) and toluene (15 ml) was added dropwise a solution of chlorosulfonic acid (1.75 g) in dichloromethane (5 ml) with stirring at room temperature and the resulting mixture was heated with stirring at 70 C. for 2 hours. It was confirmed that 84%, 5% and 7% of 1,2-benzisoxazole-3-methane sulfonic acid, starting material and a by-product respectively, were present in the reaction solution. Water was added to the reaction mixture and the mixture was extracted with aqueous layer. The aqueous layer was adjusted with 25% aqueous sodium hydroxide to pH. 10 and concentrated under reduced pressure. To the residue was added water until the total weight became approximately 7 g and the mixture was cooled in an ice water bath. The precipitated crystals were collected by filtration and dried at room temperature to give 2.38 9 of sodium 1,2-benzisoxazole-3-methane sulfonate (purity of 96%). Examples 11-13; 1,2-Benzisoxazole-3-acetic acid (1.77 grams) was treated in a similar manner in Example 10 to give the following results in Table 3. TABLE 3 Contents in a reaction mixture Chlorosulfonic Desired Starting By- Yield Example Toluene acid Solvent Lewis base compound materialproduct1) (Purity) 10 15 ml 1.75 g Dichloroethane Ethyl 84% 5% 7% 2.38 g 5 ml acetate (96%) 2.64 g 11 15 ml 1.75 g Chloroform Ethyl 86% 4% 6% 2.41 g 5 ml acetate (96%) 2.64 g 12 15 ml 1.75 g 1,2-Dichloroethane Acetonitrile 78% 5% 9% - 5 ml 1.23 g 13 15 ml 2.10 g 1,2-Dichloroethane tert-Butyl 74% 11% 12% - 5 ml cyanide 2.49 g 1)A reaction product of toluene with chlorosulfonic acid.
Example 10 To a mixture of <strong>[4865-84-3]1,2-benzisoxazole-3-acetic acid</strong> (1.77 g), ethyl acetate (2.64 g) and toluene (15 ml) was added dropwise a solution of chlorosulfonic acid (1.75 g) in dichloromethane (5 ml) with stirring at room temperature and the resulting mixture was heated with stirring at 70 C. for 2 hours. It was confirmed that 84%, 5% and 7% of 1,2-benzisoxazole-3-methane sulfonic acid, starting material and a by-product respectively, were present in the reaction solution. Water was added to the reaction mixture and the mixture was extracted with aqueous layer. The aqueous layer was adjusted with 25% aqueous sodium hydroxide to pH. 10 and concentrated under reduced pressure. To the residue was added water until the total weight became approximately 7 g and the mixture was cooled in an ice water bath. The precipitated crystals were collected by filtration and dried at room temperature to give 2.38 9 of sodium 1,2-benzisoxazole-3-methane sulfonate (purity of 96%). Examples 11-13; 1,2-Benzisoxazole-3-acetic acid (1.77 grams) was treated in a similar manner in Example 10 to give the following results in Table 3. TABLE 3 Contents in a reaction mixture Chlorosulfonic Desired Starting By- Yield Example Toluene acid Solvent Lewis base compound materialproduct1) (Purity) 10 15 ml 1.75 g Dichloroethane Ethyl 84% 5% 7% 2.38 g 5 ml acetate (96%) 2.64 g 11 15 ml 1.75 g Chloroform Ethyl 86% 4% 6% 2.41 g 5 ml acetate (96%) 2.64 g 12 15 ml 1.75 g 1,2-Dichloroethane Acetonitrile 78% 5% 9% - 5 ml 1.23 g 13 15 ml 2.10 g 1,2-Dichloroethane tert-Butyl 74% 11% 12% - 5 ml cyanide 2.49 g 1)A reaction product of toluene with chlorosulfonic acid.
Example 1; To a mixture of <strong>[4865-84-3]1,2-benzisoxazole-3-acetic acid</strong> (1.77 g), ethyl isobutyrate (3.48 g) and toluene (15 ml) was added dropwise chlorosulfonic acid (1.40 g) with stirring at room temperature and the resulting mixture was heated with stirring at 80 C. for 2 hours. It was confirmed that there were 70%, 21% and 8% of 1,2-benzisoxazole-3-methane sulfonic acid, starting material and a by-product, respectively, in the reaction solution. Water was added to the reaction mixture and the mixture was extracted with aqueous layer. The aqueous layer was adjusted with 25% aqueous sodium hydroxide to pH 10 and concentrated under reduced pressure. To the residue was added water until total weight became approximately 7 g and the mixture was cooled in an ice water bath. The precipitated crystals were collected by filtration and dried at room temperature to give 1.23 g of sodium 1,2-benzisoxazole-3-methanesulfonate (purity of 99%). ; Examples 2-9; 1,2-Benzisoxazole-3-acetic acid (1.77 g) was treated in a similar manner in Example 1 to give the following results in Table 1. TABLE 1 Contents in a reaction mixture Chlorosulfonic Desired Starting By- Yield Example Toluene acid Lewis base compound materialproduct1) (Purity) 1 15 ml 1.40 g Ethyl isobutyrate 70% 21% 8% 1.23 g 3.48 g (99%) 2 15 ml 1.40 g Ethyl acetate 67% 26% 6% 1.48 g 2.64 g (90%) 3 15 ml 1.75 g Ethyl acetate 64% 23% 12% 1.75 g 2.64 g (94%) 4 15 ml 1.40 g Ethyl propionate 63% 28% 7% 1.29 g 3.06 g (93%) 5 15 ml 1.40 g Methyl pivalate 60% 25% 8% 1.21 g 3.48 g (93%) 6 15 ml 1.40 g Ethyl pivalate 62% 29% 9% - 3.91 g 7 15 ml 1.40 g Ethyl benzoate 63% 28% 9% 1.29 g 4.51 g (91%) 8 18 ml 1.40 g Benzonitrile 53% 23% 8% 1.25 g 1.55 g (91%) 9 18 ml 1.40 g tert-Butyl cyanide 66% 23% 8% 1.12 g 1.25 g (92%) 1)A reaction product with toluene and chlorosulfonic acid.
Example 1; To a mixture of <strong>[4865-84-3]1,2-benzisoxazole-3-acetic acid</strong> (1.77 g), ethyl isobutyrate (3.48 g) and toluene (15 ml) was added dropwise chlorosulfonic acid (1.40 g) with stirring at room temperature and the resulting mixture was heated with stirring at 80 C. for 2 hours. It was confirmed that there were 70%, 21% and 8% of 1,2-benzisoxazole-3-methane sulfonic acid, starting material and a by-product, respectively, in the reaction solution. Water was added to the reaction mixture and the mixture was extracted with aqueous layer. The aqueous layer was adjusted with 25% aqueous sodium hydroxide to pH 10 and concentrated under reduced pressure. To the residue was added water until total weight became approximately 7 g and the mixture was cooled in an ice water bath. The precipitated crystals were collected by filtration and dried at room temperature to give 1.23 g of sodium 1,2-benzisoxazole-3-methanesulfonate (purity of 99%). ; Examples 2-9; 1,2-Benzisoxazole-3-acetic acid (1.77 g) was treated in a similar manner in Example 1 to give the following results in Table 1. TABLE 1 Contents in a reaction mixture Chlorosulfonic Desired Starting By- Yield Example Toluene acid Lewis base compound materialproduct1) (Purity) 1 15 ml 1.40 g Ethyl isobutyrate 70% 21% 8% 1.23 g 3.48 g (99%) 2 15 ml 1.40 g Ethyl acetate 67% 26% 6% 1.48 g 2.64 g (90%) 3 15 ml 1.75 g Ethyl acetate 64% 23% 12% 1.75 g 2.64 g (94%) 4 15 ml 1.40 g Ethyl propionate 63% 28% 7% 1.29 g 3.06 g (93%) 5 15 ml 1.40 g Methyl pivalate 60% 25% 8% 1.21 g 3.48 g (93%) 6 15 ml 1.40 g Ethyl pivalate 62% 29% 9% - 3.91 g 7 15 ml 1.40 g Ethyl benzoate 63% 28% 9% 1.29 g 4.51 g (91%) 8 18 ml 1.40 g Benzonitrile 53% 23% 8% 1.25 g 1.55 g (91%) 9 18 ml 1.40 g tert-Butyl cyanide 66% 23% 8% 1.12 g 1.25 g (92%) 1)A reaction product with toluene and chlorosulfonic acid.
Example 1; To a mixture of <strong>[4865-84-3]1,2-benzisoxazole-3-acetic acid</strong> (1.77 g), ethyl isobutyrate (3.48 g) and toluene (15 ml) was added dropwise chlorosulfonic acid (1.40 g) with stirring at room temperature and the resulting mixture was heated with stirring at 80 C. for 2 hours. It was confirmed that there were 70%, 21% and 8% of 1,2-benzisoxazole-3-methane sulfonic acid, starting material and a by-product, respectively, in the reaction solution. Water was added to the reaction mixture and the mixture was extracted with aqueous layer. The aqueous layer was adjusted with 25% aqueous sodium hydroxide to pH 10 and concentrated under reduced pressure. To the residue was added water until total weight became approximately 7 g and the mixture was cooled in an ice water bath. The precipitated crystals were collected by filtration and dried at room temperature to give 1.23 g of sodium 1,2-benzisoxazole-3-methanesulfonate (purity of 99%). ; Examples 2-9; 1,2-Benzisoxazole-3-acetic acid (1.77 g) was treated in a similar manner in Example 1 to give the following results in Table 1. TABLE 1 Contents in a reaction mixture Chlorosulfonic Desired Starting By- Yield Example Toluene acid Lewis base compound materialproduct1) (Purity) 1 15 ml 1.40 g Ethyl isobutyrate 70% 21% 8% 1.23 g 3.48 g (99%) 2 15 ml 1.40 g Ethyl acetate 67% 26% 6% 1.48 g 2.64 g (90%) 3 15 ml 1.75 g Ethyl acetate 64% 23% 12% 1.75 g 2.64 g (94%) 4 15 ml 1.40 g Ethyl propionate 63% 28% 7% 1.29 g 3.06 g (93%) 5 15 ml 1.40 g Methyl pivalate 60% 25% 8% 1.21 g 3.48 g (93%) 6 15 ml 1.40 g Ethyl pivalate 62% 29% 9% - 3.91 g 7 15 ml 1.40 g Ethyl benzoate 63% 28% 9% 1.29 g 4.51 g (91%) 8 18 ml 1.40 g Benzonitrile 53% 23% 8% 1.25 g 1.55 g (91%) 9 18 ml 1.40 g tert-Butyl cyanide 66% 23% 8% 1.12 g 1.25 g (92%) 1)A reaction product with toluene and chlorosulfonic acid.
Example 1; To a mixture of <strong>[4865-84-3]1,2-benzisoxazole-3-acetic acid</strong> (1.77 g), ethyl isobutyrate (3.48 g) and toluene (15 ml) was added dropwise chlorosulfonic acid (1.40 g) with stirring at room temperature and the resulting mixture was heated with stirring at 80 C. for 2 hours. It was confirmed that there were 70%, 21% and 8% of 1,2-benzisoxazole-3-methane sulfonic acid, starting material and a by-product, respectively, in the reaction solution. Water was added to the reaction mixture and the mixture was extracted with aqueous layer. The aqueous layer was adjusted with 25% aqueous sodium hydroxide to pH 10 and concentrated under reduced pressure. To the residue was added water until total weight became approximately 7 g and the mixture was cooled in an ice water bath. The precipitated crystals were collected by filtration and dried at room temperature to give 1.23 g of sodium 1,2-benzisoxazole-3-methanesulfonate (purity of 99%). ; Examples 2-9; 1,2-Benzisoxazole-3-acetic acid (1.77 g) was treated in a similar manner in Example 1 to give the following results in Table 1. TABLE 1 Contents in a reaction mixture Chlorosulfonic Desired Starting By- Yield Example Toluene acid Lewis base compound materialproduct1) (Purity) 1 15 ml 1.40 g Ethyl isobutyrate 70% 21% 8% 1.23 g 3.48 g (99%) 2 15 ml 1.40 g Ethyl acetate 67% 26% 6% 1.48 g 2.64 g (90%) 3 15 ml 1.75 g Ethyl acetate 64% 23% 12% 1.75 g 2.64 g (94%) 4 15 ml 1.40 g Ethyl propionate 63% 28% 7% 1.29 g 3.06 g (93%) 5 15 ml 1.40 g Methyl pivalate 60% 25% 8% 1.21 g 3.48 g (93%) 6 15 ml 1.40 g Ethyl pivalate 62% 29% 9% - 3.91 g 7 15 ml 1.40 g Ethyl benzoate 63% 28% 9% 1.29 g 4.51 g (91%) 8 18 ml 1.40 g Benzonitrile 53% 23% 8% 1.25 g 1.55 g (91%) 9 18 ml 1.40 g tert-Butyl cyanide 66% 23% 8% 1.12 g 1.25 g (92%) 1)A reaction product with toluene and chlorosulfonic acid.
Example 1; To a mixture of <strong>[4865-84-3]1,2-benzisoxazole-3-acetic acid</strong> (1.77 g), ethyl isobutyrate (3.48 g) and toluene (15 ml) was added dropwise chlorosulfonic acid (1.40 g) with stirring at room temperature and the resulting mixture was heated with stirring at 80 C. for 2 hours. It was confirmed that there were 70%, 21% and 8% of 1,2-benzisoxazole-3-methane sulfonic acid, starting material and a by-product, respectively, in the reaction solution. Water was added to the reaction mixture and the mixture was extracted with aqueous layer. The aqueous layer was adjusted with 25% aqueous sodium hydroxide to pH 10 and concentrated under reduced pressure. To the residue was added water until total weight became approximately 7 g and the mixture was cooled in an ice water bath. The precipitated crystals were collected by filtration and dried at room temperature to give 1.23 g of sodium 1,2-benzisoxazole-3-methanesulfonate (purity of 99%). ; Examples 2-9; 1,2-Benzisoxazole-3-acetic acid (1.77 g) was treated in a similar manner in Example 1 to give the following results in Table 1. TABLE 1 Contents in a reaction mixture Chlorosulfonic Desired Starting By- Yield Example Toluene acid Lewis base compound materialproduct1) (Purity) 1 15 ml 1.40 g Ethyl isobutyrate 70% 21% 8% 1.23 g 3.48 g (99%) 2 15 ml 1.40 g Ethyl acetate 67% 26% 6% 1.48 g 2.64 g (90%) 3 15 ml 1.75 g Ethyl acetate 64% 23% 12% 1.75 g 2.64 g (94%) 4 15 ml 1.40 g Ethyl propionate 63% 28% 7% 1.29 g 3.06 g (93%) 5 15 ml 1.40 g Methyl pivalate 60% 25% 8% 1.21 g 3.48 g (93%) 6 15 ml 1.40 g Ethyl pivalate 62% 29% 9% - 3.91 g 7 15 ml 1.40 g Ethyl benzoate 63% 28% 9% 1.29 g 4.51 g (91%) 8 18 ml 1.40 g Benzonitrile 53% 23% 8% 1.25 g 1.55 g (91%) 9 18 ml 1.40 g tert-Butyl cyanide 66% 23% 8% 1.12 g 1.25 g (92%) 1)A reaction product with toluene and chlorosulfonic acid.
Example 1; To a mixture of <strong>[4865-84-3]1,2-benzisoxazole-3-acetic acid</strong> (1.77 g), ethyl isobutyrate (3.48 g) and toluene (15 ml) was added dropwise chlorosulfonic acid (1.40 g) with stirring at room temperature and the resulting mixture was heated with stirring at 80 C. for 2 hours. It was confirmed that there were 70%, 21% and 8% of 1,2-benzisoxazole-3-methane sulfonic acid, starting material and a by-product, respectively, in the reaction solution. Water was added to the reaction mixture and the mixture was extracted with aqueous layer. The aqueous layer was adjusted with 25% aqueous sodium hydroxide to pH 10 and concentrated under reduced pressure. To the residue was added water until total weight became approximately 7 g and the mixture was cooled in an ice water bath. The precipitated crystals were collected by filtration and dried at room temperature to give 1.23 g of sodium 1,2-benzisoxazole-3-methanesulfonate (purity of 99%). ; Reference Examples 1-5; 1,2-Benzisoxazole-3-acetic acid (1.77 grams) was treated in a similar manner in Example 1 to give the following results in Table 2. TABLE 2 Contents in a reaction mixture Reference Chlorosulfonic Desired Starting By- Yield Example Toluene acid Lewis base compound materialproduct1) (Purity) 1 18 ml 1.40 g 1,4-Dioxane 81% 12% 5% 1.59 g 1.32 g (92%) 2 15 ml 1.40 g 1,2-Diethoxyethane 51% 24%5%, 18%2) - 3.54 g 3 18 ml 1.40 g DMF 3% 88% 9% - 1.10 g 4 36 ml 2.10 g 1-methyl-2-pyrrolidone 4% 80% 13% - 2.23 g 5 18 ml 2.33 g none 25% 29% 44% - 1)A reaction product of toluene with chlorosulfonic acid. 2)By-products other than a reaction product of toluene with chlorosulfonic acid.
Example 1; To a mixture of <strong>[4865-84-3]1,2-benzisoxazole-3-acetic acid</strong> (1.77 g), ethyl isobutyrate (3.48 g) and toluene (15 ml) was added dropwise chlorosulfonic acid (1.40 g) with stirring at room temperature and the resulting mixture was heated with stirring at 80 C. for 2 hours. It was confirmed that there were 70%, 21% and 8% of 1,2-benzisoxazole-3-methane sulfonic acid, starting material and a by-product, respectively, in the reaction solution. Water was added to the reaction mixture and the mixture was extracted with aqueous layer. The aqueous layer was adjusted with 25% aqueous sodium hydroxide to pH 10 and concentrated under reduced pressure. To the residue was added water until total weight became approximately 7 g and the mixture was cooled in an ice water bath. The precipitated crystals were collected by filtration and dried at room temperature to give 1.23 g of sodium 1,2-benzisoxazole-3-methanesulfonate (purity of 99%). ; Examples 2-9; 1,2-Benzisoxazole-3-acetic acid (1.77 g) was treated in a similar manner in Example 1 to give the following results in Table 1. TABLE 1 Contents in a reaction mixture Chlorosulfonic Desired Starting By- Yield Example Toluene acid Lewis base compound materialproduct1) (Purity) 1 15 ml 1.40 g Ethyl isobutyrate 70% 21% 8% 1.23 g 3.48 g (99%) 2 15 ml 1.40 g Ethyl acetate 67% 26% 6% 1.48 g 2.64 g (90%) 3 15 ml 1.75 g Ethyl acetate 64% 23% 12% 1.75 g 2.64 g (94%) 4 15 ml 1.40 g Ethyl propionate 63% 28% 7% 1.29 g 3.06 g (93%) 5 15 ml 1.40 g Methyl pivalate 60% 25% 8% 1.21 g 3.48 g (93%) 6 15 ml 1.40 g Ethyl pivalate 62% 29% 9% - 3.91 g 7 15 ml 1.40 g Ethyl benzoate 63% 28% 9% 1.29 g 4.51 g (91%) 8 18 ml 1.40 g Benzonitrile 53% 23% 8% 1.25 g 1.55 g (91%) 9 18 ml 1.40 g tert-Butyl cyanide 66% 23% 8% 1.12 g 1.25 g (92%) 1)A reaction product with toluene and chlorosulfonic acid.
Example 1; To a mixture of <strong>[4865-84-3]1,2-benzisoxazole-3-acetic acid</strong> (1.77 g), ethyl isobutyrate (3.48 g) and toluene (15 ml) was added dropwise chlorosulfonic acid (1.40 g) with stirring at room temperature and the resulting mixture was heated with stirring at 80 C. for 2 hours. It was confirmed that there were 70%, 21% and 8% of 1,2-benzisoxazole-3-methane sulfonic acid, starting material and a by-product, respectively, in the reaction solution. Water was added to the reaction mixture and the mixture was extracted with aqueous layer. The aqueous layer was adjusted with 25% aqueous sodium hydroxide to pH 10 and concentrated under reduced pressure. To the residue was added water until total weight became approximately 7 g and the mixture was cooled in an ice water bath. The precipitated crystals were collected by filtration and dried at room temperature to give 1.23 g of sodium 1,2-benzisoxazole-3-methanesulfonate (purity of 99%). ; Reference Examples 1-5; 1,2-Benzisoxazole-3-acetic acid (1.77 grams) was treated in a similar manner in Example 1 to give the following results in Table 2. TABLE 2 Contents in a reaction mixture Reference Chlorosulfonic Desired Starting By- Yield Example Toluene acid Lewis base compound materialproduct1) (Purity) 1 18 ml 1.40 g 1,4-Dioxane 81% 12% 5% 1.59 g 1.32 g (92%) 2 15 ml 1.40 g 1,2-Diethoxyethane 51% 24%5%, 18%2) - 3.54 g 3 18 ml 1.40 g DMF 3% 88% 9% - 1.10 g 4 36 ml 2.10 g 1-methyl-2-pyrrolidone 4% 80% 13% - 2.23 g 5 18 ml 2.33 g none 25% 29% 44% - 1)A reaction product of toluene with chlorosulfonic acid. 2)By-products other than a reaction product of toluene with chlorosulfonic acid.

 

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