5-Chloro-2-benzofurancarboxylic acid

Light red powder

Preparation 5 Preparation 5 5-Chlorobenzofuran-2-carboxylic acid. A suspension of 5-chlorosalicyl aldehyde (10.62 g, 67.8 mmol), ethyl bromomalonate (25.3 g, 105.8 mmol) and anhydrous potassium carbonate (9.37 g, 67.8 mmol) in ethylmethylketone (50 ml) was refluxed for 5 hours, then kept under stirring at RT overnight. The solvent was evaporated and the residue was diluted with water (500 ml), then the pH was neutralized with 1N HCl. The suspension was extracted with Et2 O, then the organic phase was dried (MgSO4) and concentrated. The oily residue was dissolved in absolute EtOH (50 ml) and added to a 10% ethanolic solution of KOH. The thick suspension was refluxed under vigorous stirring overnight then after cooling to RT the solvent was taken off and water was added. The aqueous phase was washed with Et2 O, then the pH adjusted to 2 with 1N HCl. The aqueous suspension was extracted with EtOAc and the organic phase after drying (MgSO4) and concentration produced pure title compound (7.4 g, 37.6 mmol, yield 55.5%) as a yellow oil.PREPARATION 27 PREPARATION 18 To a stirred solution of tert-butyi (l-aminopiperidin-4-yl)carbaniate (0.100 g, 0.46 mmol, 1.0 equiv) in DMF (05 mL) was added HATU (0.265 g, 0.69 mmol, 1.5 equiv) at RT and stirred for 10 minutes. Then 5 -chlorobenzofuran-2 -carboxylic acid (0.137 g, 0.69 mmol, 1.5 equiv) was added followed by the addition of DIPEA (0.35 mL, 1.86 mmol, 4.0 equiv). The resulting reaction mixture was allowed to stir at RT for overnight. Product formation was confirmed by LCMS. The reaction mixture was diluted with water (50 mL). The resulting solid was filtered off, washed with water (20 mL c 4) and dried under vacuum to obtain tert-butyl (1- (5-chlorobenzofuran-2-carboxamido)piperidin-4-yl)carbamate (0.150 g, 82 % Yield) as an yellow solid LCMS 394.2 ] H | : Ti NMR (400MHz, DMSO-de) 6 9.75 (s, 1 H), 7.86 (s, 1 H), 7.69 (d, J = 8.8 Hz, 1 H), 7.58 - 7.33 (m, 2 H), 6.85 (d , J= 7.5 Hz, 1 H), 3.25 (br. s., 1 H), 2.96 (d, J = 11.0 Hz, 2 H), 2.82 - 2.63 (m, 2 H), 1.74 (d, J = 11.8 Hz, 2 H), 1.66 - 1.45 (m, 2 H), 1.45 - 1 28 (m, 9 H).To a stirred solution of tert-butyl 4-aminopiperidine-l-carboxylate (1.02 g, 5.10 mmol, 1.0 equiv) in DMF (10 mL) was added 5-chlorobenzofuran-2 -carboxylic acid (1 .0 g, 5.1 mmol, 1.0 equiv) and HATU (3.800 g, 10.02 mmol, 2.0 equiv) at RT. The resulting reaction mixture was stirred for 10 minutes and DIPEA (2.5 mL, 15.00 mmol, 3.00 equiv) was added. The reaction mixture was allowed to stir at RT for overnight. Product formation was confirmed by LCMS. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL c 2). Combined organic extracts were washed with water (20 mL *4), dried over anhydrous NaaSOr and concentrated. The crude product obtained was treated w ith ether- hexane (50:50) to obtain tert-butyl 4-(5-chlorobenzofuran-2-carboxaniido)piperidine-1 - carboxylate (0.800 g, 43% yield) as an off-white solid. LCMS: 379.2 [M+H] 2To a stirred solution of 5-chlorobenzofuran-2 -carboxylic acid (0.100 g, 0.50 mmol, 1.0 equiv) in DMF (05 mL) was added HATH (0.380 g, 1.01 mmol, 2.0 equiv) at RT and stirred for 10 minutes. Then tert-butyi 4-aminopiperazine-l -carboxylate (0.112 g, 0.55 mmol, 1.1 equiv) was added followed by the addition of DIPEA (0 2 mL, 1.52 mmol, 3 0 equiv). The resulting reaction mixture was allowed to stir at RT for overnight. Product formation was confirmed by LCMS The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL c 2). Tire combined organic layer was washed with water (30mL), brine solution (30 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure, to obtain tert-butyl 4-(5-chlorobenzofuran-2-carboxamido)piperazine-l-carboxylate (0.140 g, 66 % Yield) as an off-white solid. LCMS 380.3 [M+H]+; NMR (400MHz, DMSO-de) d 9.90 (s, 1 H), 7.87 (s, 1 H), 7.70 (d, J= 8 8 Hz, 1 H), 7.57 - 7.44 (m, 2 H), 3 42 (br. s, 4 H), 2.83 (br. s , 4 H), 1.50 - 1.29 (m, 9 H).

Molecular Weight:196.58
XLogP3:3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:195.9927217
Monoisotopic Mass:195.9927217
Topological Polar Surface Area:50.4
Heavy Atom Count:13
Complexity:219
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes