6-Bromo-1,2-benzisothiazole-3-carboxylic acid

Step 2: 1 ON NaOH solution (10 mL, 100 mmol) was added to a solution of 6- bromobenzo[b]thiophene-3-carboxamide (1.20 g, 4.67 mmol) in MeOH (80 mL). The mixture was heated at reflux overnight. After cooling, the mixture was acidified with 2N HCl. The resulting precipitate was filtered and dried to give 6-bromobenzo[d]isothiazole-3- carboxylic acid (1.10 g, 91percent) as a solid. Step 5; Sulfuryl dichloride (86.7 mg, 728 mumol) is added to a solution of6-bromobenzo[d]-isothiazole-3-carboxylic acid (188 mg, 728 mumol). The reaction mixture is stirred for 30 min before removing the volatiles by rotovap. The residue is taken up in CH2Cl2 (0.587 ml) and a solution of 2-prorhoylamine (62.5 muL, 728 mumol) and triethylamine (101 mul, 728 mumol) in CHjCl2 (1.2 ml) is added. The reaction mixture is stirred at room temperature until LC/MS analysis indicates complete conversion to the desired product. The reaction mixture is diluted with distilled water and ethyl acetate. The layers are separated and the aqueous is extracted with ethyl acetate. The combined organics are washed with brine and dried over Na2SO4, filtered and concentrated to give 6-bromo-N-isopropylbenzo[d]isothiazole- 3-carboxamide.Intermediate Preparation 40A- 1; Methyl 6-bromobenzord isothiazole-3-carboxylate; To a solution of 6-bromobenzo[Step 3: DIEA (11.7 mL, 67.4 mmol) and HBTU (7.03 g, 18.5 mmol) were added to a solution of Step 5[00200] Sulfuryl dichloride (86.7 mg, 728 mumol) was added to a solution of 6- bromobenzo[d]-isothiazole-3-carboxylic acid (188 mg, 728 mumol). The reaction mixture was stirred for 30 min before removing the volatiles by rotovap. The residue was taken up in Step 2: 1 ON NaOH solution (10 mL, 100 mmol) was added to a solution of 6- bromobenzo[b]thiophene-3-carboxamide (1.20 g, 4.67 mmol) in MeOH (80 mL). The mixture was heated at reflux overnight. After cooling, the mixture was acidified with 2N HCl. The resulting precipitate was filtered and dried to give 6-bromobenzo[d]isothiazole-3- carboxylic acid (1.10 g, 91%) as a solid. 1H NMR (DMSO-d6, 400 MHz) delta 8.65 (s, IH), 8.55 (d, J = 8.8 Hz, IH), 7.77 (d, J = 8.8 Hz, IH).Step 4[00199] A suspension of 6-bromobenzo[d]isothiazole-3-carboxamide (274 mg, 1066 mumol) in EtOH (5.9 mL) and 6N sodium hydroxide (356 muL, 2135 mumol) was heated to reflux for 2 hrs. LCMS analysis indicated complete conversion to the acid. The reaction mixture was cooled to room temperature, acidified with IN HCl, and extracted with ethyl acetate.The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give Step 4; A suspension of 6-bromobenzo[d]isothiazole-3-carboxamide (274 mg, 1066 mumol) in EtOH (5.9 mL) and 6N sodium hydroxide (356 muL, 2135 mumol) is heated to reflux for 2 hrs. LC/MS analysis can be used to confirm complete conversion to the acid. The reaction mixture is cooled to room temperature, acidified with IN HCl, and extracted with ethyl acetate. The combined organics are washed with brine, dried over MgSO4, filtered and concentrated to give Preparation 39 e-Bromo-benzord'lisothiazole-S-carobxyllic acidThe title compound is prepared essentially as described in Procedure 3 of WO2005/092890 A2 using 3-brotauno-be'zenetrrioi. ES/MS m/e 255.0 (M-1 ).The following procedure was used to prepare benzisothiazole fer/-butyl esters:Di-ferz'-butyldicarbonate (128 mmol) was added to a suspension of 6-bromo-l, 2- benzisothiazole-3-carboxyIic acid (46.5 mmol) and 4-dimethylaminopyridine (4.26 mmol) in tert-buty alcohol (40.0 mL) and tetrahydrofuran (40.0 mL) and the reaction mixture was heated at 65 0C for 16 hours. There was vigorous carbon dioxide evolution which gradually subsided as the mixture become homogeneous. The reaction mixture was concentrated and the residue was dissolved in dichloromethane. The dichloromethane solution was filtered through silica gel (ca. 5Og) and the eluent was The following procedure was used to prepare benzisothiazole tert-butyl esters: Di-tert-butyldicarbonate (128 mmol) was added to a suspension of 6-bromo-1, 2-benzisothiazole-3-carboxylic acid (46.5 mmol) and 4-dimethylaminopyridine (4.26 mmol) in tert-butyl alcohol (40.0 mL) and tetrahydrofuran (40.0 mL) and the reaction mixture was heated at 65 C. for 16 hours. There was vigorous carbon dioxide evolution which gradually subsided as the mixture become homogeneous. The reaction mixture was concentrated and the residue was dissolved in dichloromethane. The dichloromethane solution was filtered through silica gel (ca. 50 g) and the eluent was concentrated to provide the ester product in 99% yield.The following esters were prepared from the acid using ethanol and sulfuric acid: Ethyl 6-bromobenzisothiazole-3-carboxylate. Ethyl 6-methoxybenzisothiazole-3-carboxylate. tert-Butyl 5-bromo-1, 2-benzisothiazole-3-carboxylate.The following acids were prepared using this method: -Bromobenzisothiazole-S-carboxylic acid. 5-Bromobenzisothiazole-3-carboxy lie acid. 6-Methoxybenzisothiazole-3-carboxylic acid.The following esters were prepared from the acid using ethanol and sulfuric acid:Ethyl 6-bromobenzisothiazole-3-carboxylate. Ethyl 5-bromobenzisothiazole-3-carboxylate. Ethyl 6-methoxybenzisothiazole-3-carboxylate.

Molecular Weight:258.09
XLogP3:2.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:256.91461
Monoisotopic Mass:256.91461
Topological Polar Surface Area:78.4
Heavy Atom Count:13
Complexity:226
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes