5-CHLORO-1-METHYL-1H-INDOLE-2-CARBOXYLIC ACID

77 mg (0.34 mmol) of the compound prepared in the above step 1 was dissolved in ethanol, 2M sodium hydroxide was added, and the mixture was stirred at 50 ° C for 30 minutes. After completion of the reaction, the reaction mixture was extracted with 50 ml of ethyl acetate, washed with 4N hydrochloric acid and water, and dried over anhydrous sodium sulfate.And concentrated under reduced pressure to obtain 67 mg (0.32 mmol) of the title compound as white solid in 94percent yield.Step 2: Synthesis of 5-chloro-l-methyl-lH-indole-2-carboxylic acid 43.2 [00509] To a solution of methyl 5 -chloro-1 -methyl- lH-indole-2-carboxylate (43.1, 224 mg, 1.0 mmol) in THF (10ml) was added LiOH (36 mg, 1.5 mmol) in water (2ml) and the resulting mixture was stirred under air at rt. After 2h the solvent was removed under reduced pressure and the residue was taken up in IN aqueous hydrochloric acid (10ml). The resulting suspension was allowed to stand for ten minutes, then was filtered through filter paper and the solid was collected and dried under vacuum to afford 163 mg (77.6percent) of 43.2 5 -chloro-1 -methyl- 1H- indole-2-carboxylic acid as a beige powder.General procedure: To a solution of 1a (100 mg, 510 μmol) in DMF (1.89 mL) were added K): To a stirred solution of ethyl 18 (1 g, 4.48 mmol) in DMF (10 ml) was added NaH (0.215 g, 5.4 mmol, 60percent dispersion in mineral oil) at 0 °C, and stirred for 30 min followed by the addition of MeI (0.764 g, 5.4 mmol). After stirred at room temperature for about 20 min, the reaction mixture was quenched with 4 N HCl at 0 °C and extracted with EtGeneral procedure: To lnt-029 (12.0 g, 47.7 mmol) in THF (70 ml_)/water (25 mL) lithium hydroxide monohydrate (8.01 g, 191 mmol) is added at 0 C and stirred at ambient temperature for 2 h. 4 N HCI (10 mL) is added, and the mixture is extracted exhaustively with EtOAc. The combined organic layer is washed with water and brine, dried (MgS04), filtered and concentrated in vacuo. The residue is triturated with ether and pentane.General procedure: To a solution of 1a (196 mg, 1.00 mmol) in DMF (3.30 mL) were added HOBt·H2O (149 mg, 1.10 mmol), EDCI·HCl (211 mg, 1.10 mmol), 2, 2, 6, 6-tetramethylpiperidin-4-amine (156 muL, 900 mumol) and Et3N (152 muL, 1.10 mmol) at 0 C. The reaction mixture was heated to room temperature and stirred for 20 h. The reaction was quenched with saturated aqueous NaHCO3 solution and extracted with CHCl3. The extract was washed with brine and dried over MgSO4. Concentration under reduced pressure provided the title compound 9a (210 mg, 74% yield) as a white powder.): To a stirred solution of ethyl 18 (1 g, 4.48 mmol) in DMF (10 ml) was added NaH (0.215 g, 5.4 mmol, 60% dispersion in mineral oil) at 0 C, and stirred for 30 min followed by the addition of MeI (0.764 g, 5.4 mmol). After stirred at room temperature for about 20 min, the reaction mixture was quenched with 4 N HCl at 0 C and extracted with Et2O for four times. The organic layers were combined, washed with brine, and dried over Na2SO4. The solvent were evaporated under reduced pressure and the crude was purified using silica gel chromatography (10% EtOAc / hexane) to afford ethyl 5-chloro-1H-indole-2-carboxylate (1 g, 94%). HRMS (ESI) m/z calcd for [C12H13ClNO2]+: 238.0629 found 238.0678. 1H NMR (400 MHz, CDCl3): delta 7.64 (s, 1H), 7.30 (d, J = 1.9 Hz, 2H), 7.22 (s, 1H), 4.38 (q, J = 7.1 Hz, 2H), 4.06 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz): delta 161.95, 137.92, 129.20, 126.66, 126.19, 125.35, 121.62, 111.39, 109.30, 60.75, 31.84, 14.35General procedure: Version B: 780 mg of 1 d and 1747 mg of HATU were first dissolved in 10 ml DMSO. Next, 314 mg of 2-methoxyethylamine and 1080 mg of N, N-diisopropylethylamine were added. The mixture was stirred for 1 hr at RT. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue was purified chromatographically on the Biotage SP4. Gradient: ethyl acetate/methanol 0-10%. Yield: 740 mg of the title compound. Analogously to Example 1b, Version B, 43 mg of the title compound was obtained from 100 mg of 71a and 89 mg of Step 3: Synthesis of 5-chloro-l-methyl-N-{4-[(pyrimidin-2-yl)({[2- (trimethylsilyl)ethoxy] methyl})sulfamoyl]phenyl}-lH-indole-2-carboxamide 43.3 [00511] To a solution of 5-chloro-l-methyl-lH-indole-2-carboxylic acid (43.2, 81 mg, 0.39 mmol) in MeCN (dry, 5ml) was added 4-amino-N-phenyl-N-{[2- (trimethylsilyl)ethoxy]methyl}benzene-l-sulfonamide (150 mg, 0.4 mmol) and 3-picoline (57 mu, 0.58 mmol). To this solution was added methanesulfonyl chloride (36 mu, 0.46 mmol) and the mixture was stirred under nitrogen at rt. After 60h the solvent was removed in vacuo and the crude material purified by flash column chromatography (heptane/EtOAc 80/20 to 60/40) to obtain 97 mg (43%) of 5-chloro-l-methyl-N-{4-[(pyrimidin-2-yl)({[2- (trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}-lH-indole-2-carboxamide 43.3 as a white powder.

Molecular Weight:209.63
XLogP3:2.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:209.0243562
Monoisotopic Mass:209.0243562
Topological Polar Surface Area:42.2
Heavy Atom Count:14
Complexity:246
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes