85% |
With lithium hydroxide; water; In tetrahydrofuran; methanol; at 0℃; for 0.5h; |
To a solution of 4-bromophthalic acid (3.0 g, 12.24 [MMOL)] in 30 mL of THF was added a solution of borane-THF complex (1. OM) dropwise at 0 [C.] The solution was warmed to rt and stirred for 3 h. The reaction mixture was quenched by addition of HCI (2N) at 0 [C.] The product was extracted with ethyl acetate and washed with sat. [NACI,] dried over [NA2SC4,] and concentrated under reduced pressure to afford 2.8 g (100%) of 4-bromo-2- hydroxymethylbenzyl alcohol as a [COLORLESS OIL.'H] NMR [(CDCK)] 7.28 (m, 2 H), 7.26 (m, 1 H), 4.69 (s, 4 H), 2.80 (bs, [2 H).] To a solution of oxalyl chloride (2.37 mL, 4.607 mmol) in DCM (20 mL) was added dropwise DMSO (1.95 mL) [AT-78 C.] The mixture was stirred at-78 C for 30 min and a solution of the diol (1.00 g, 4.607 [MMOL)] was added dropwise. The reaction mixture was stirred for 2 hr and TEA (11.5 mL) was added. The reaction mixture was warmed to rt and water was added. The organic layer was separated and washed with sat. NaCl, dried over Na2SO4, and concentrated under reduced pressure to give [4-BROMO-BENZENE-1,] 2- dicarbaldehyde as a yellow oil (0.450 g, 46%). A mixture of [4-BROMO-BENZENE-1,] [2-DICARBALDEHYDE] (0.450 g, 2.137 mmol), diethylamino malonate (0.452 g, 2.137 mmol), and sodium ethoxide (0.218 g, 3.20 [MMOL)] in anhydrous ethanol (15 mL) was refluxed for 4 hr. The solution was cooled to rt and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica gel, 0. 5% MeOH in [CHCI3)] to obtain 0.460 g (78%) of the [7-BROMO-] isoquinoline-3-carboxylic acid ethyl ester which was [HYDROLYZED] according to general procedure C yielding the 0.350 g (85%) of 7-bromo-isoquinoline-3-carboxylic acid as a white solid. LC/MS [(M/Z)] : 253 (M+1) [+.] [(2S)-AMINO-3-BIPHENYL-4YL-PROPIONIC] acid methyl ester (340 mg, 13.9 [MMOL)] was reacted with 7-bromo-isoquinoline-3-carboxylic acid (350 mg, 13.9 [MMOL)] as described in general procedure A. The resulting compound was hydrolyzed by following general procedure C yielding the title compound (132 mg, 81 %) as a white solid |
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With lithium hydroxide monohydrate; In tetrahydrofuran; methanol; water; at 0 - 20℃; for 0.5h; |
To a stirred solution of <strong>[660830-62-6]ethyl 7-bromoisoquinoline-3-carboxylate</strong> (1 .2 g, 4.28 mmol, 1 .0 equiv) in MeOH: THF: H20 (2:2:1 ) (35 mL) was added LiOH monohydrate (0.9 g, 21 .42 mmol, 5 equiv) at 0C and stirring was continued at room temperature for 0.5 h. The reaction mixture was evaporated and quenched with 1 N HCI. The reaction mixture was extracted with 5% MeOH in DCM (3 x 50 mL), and the combined organics was dried over sodium sulphate, filtered and concentrated to give 7-bromoisoquinoline-3-carboxylic acid (1 .0 g, crude) as an off-white solid. LCMS (ES) m/z = 252.0, 254.0 [M+H]+. 1H NMR (400 MHz, DMSO-de) delta ppm 8.01 (dd, J=2.0, 8.8 Hz, 1 H), 8.16 ((d, J=8.8 Hz, 1 H), 8.54 (s, 1 H), 8.64 (s, 1 H), 9.37 (s, 1 H), 13.16 (br. s., 1 H). |