With the rapid development and complex challenges of chemical substances, new drug synthesis pathways are usually the most effective.110256-15-0,5-Cyclopropylisoxazole-3-carboxylic acid,as a common compound, the synthetic route is as follows.
Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed tert-butyl 4-amino-2-benzylpiperidine-1-carboxylate (5 g, 17.22 mmol, 1.00 equiv), dichloromethane (100 mL), TEA (8.707 g, 86.05 mmol, 5.00 equiv), 5-cyclopropyl-1,2-oxazole-3-carboxylic acid (3.957 g, 25.84 mmol, 1.50 equiv), HATU (19.655 g, 51.69 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 200 mL of EA. The resulting mixture was washed with 3×200 mL of brine (sat.). The organic phase was collected and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). The collected fractions were combined and concentrated under vacuum. The crude product 2.9 g was purified by Prep-SFC with the following conditions (prep SFC 350-2): Column, Chiralpak AD-H, 5x25cm, 5um; mobile phase, CO2(70%), IPA(30%) and DCM/MeOH=1/3:100 ; Detector, uv 210nm yielding two fractions: first peak – cis enantiomers 1.7 g, second peak trans enantiomers 0.6 g. [0279] These products were further purified by SFC. The cis mixtures were purified by Prep-SFC with the following conditions (prep SFC 350-2): Column, Chiralpak AS-H, 5*25cm, 5um; mobile phase, CO2 (70%), IPA (30%) and MeOH (50%); Detector, uv 210nm. This resulted in 820 mg of (2R,4R)-tert-butyl 2-benzyl-4-(5- cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylate as yellow oil and 870 mg of(2S,4S)-tert-butyl 2-benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1- carboxylate as yellow oil. (2R,4R)-tert-butyl 2-benzyl-4-(5-cyclopropylisoxazole-3- carboxamido)piperidine-1-carboxylate: 1H-NMR (300 MHz, CD3Cl) : 7.26-7.17(m, 5H), 6.88 (d, J = 6.9 Hz, 1H), 6.32(d, J = 0.6 Hz, 1H), 4.38-4.28 (m, 1H), 4.27-4.16 (m, 1H), 4.09-3.98(m, 1H), 3.18-2.99 (m, 2H), 2.82-2.75 (m,1H), 2.12-1.98(m, 2H), 1.91- 1.66 (m, 3H), 1.37(d, J = 2.7 Hz, 9H), 1.18-1.09 (m, 2H), 1.02-0.92 (m, 2H) ppm. LCMS (method A, ESI): RT =1.59 min, m/z =326.0 [M-Boc+H]+. (2S,4S)-tert-butyl 2-benzyl-4- (5-cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylate: 1H-NMR (300 MHz, CD3Cl) : 7.26-7.17(m, 5H), 6.88(d, J = 6.9 Hz, 1H), 6.32(d, J = 0.6Hz, 1H), 4.38-4.28 (m, 1H), 4.27-4.16 (m, 1H), 4.09-3.98(m, 1H), 3.18-2.99 (m, 2H), 2.82-2.75 (m, 1H), 2.12-1.98(m, 2H), 1.91-1.66 (m, 3H), 1.37(d, J = 2.7 Hz, 9H), 1.18-1.09(m, 2H), 1.02- 0.92(m, 2H) ppm. LCMS (method A, ESI): RT =1.59 min, m/z = 326.0 [M-Boc+H]+. [0280] The trans mixture was purified by Prep-SFC with the following conditions (prep SFC 350): Column, Phenomenex Lux 5u Cellulose-4250*50mm00G-4491-V0- AX664184-1; mobile phase, CO2(50%) and MeOH(50%) ,Detector, uv 220 nm. This resulted in 250 mg of (2S,4R)-tert-butyl 2-benzyl-4-(5-cyclopropylisoxazole-3- carboxamido)piperidine-1-carboxylate as yellow oil and 260 mg of (2R,4S)-tert-butyl 2- benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylate as yellow oil. (2S,4R)-tert-butyl 2-benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1- carboxylate: 1H-NMR (300 MHz, CD3Cl) : 7.26-7.17(m, 5H), 6.88(d, J = 6.9 Hz, 1H), 6.32(s, 1H), 4.81-3.91 (m, 3H), 3.08(t, J = 13.5 Hz, 1H), 2.96-2.81(m, 2H), 2.11-2.02(m, 2H), 1.95(d, J = 10.5 Hz, 1H), 1.52-1.22(m, 11H), 1.15-1.05(m, 2H), 1.02-0.92(m, 2H) ppm. LCMS (method A, ESI): RT = 1.58 min, m/z = 448.0 [M+Na]+. (2R,4S)-tert-butyl 2-benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylate: 1H-NMR (300 MHz, CD3Cl) : 7.26-7.17(m, 5H), 6.88(d, J = 6.9 Hz, 1H), 6.32(s, 1H), 4.81-3.91 (m, 3H), 3.08(t, J = 13.5 Hz, 1H), 2.96-2.81(m, 2H), 2.11-2.02(m, 2H), 1.95(d, J = 10.5 Hz, 1H), 1.52-1.22(m, 11H), 1.15-1.05(m, 2H), 1.02-0.92(m, 2H) ppm. LCMS (method A, ESI): RT = 1.58 min, m/z = 448.0 [M+Na]+.
110256-15-0, 110256-15-0 5-Cyclopropylisoxazole-3-carboxylic acid 1092113, aIsoxazoles compound, is more and more widely used in various fields.
Reference£º
Patent; EPIZYME, INC.; MITCHELL, Lorna Helen; BELL, Andrew Simon; CHESWORTH, Richard; FOLEY, Megan Alene Cloonan; KUNTZ, Kevin Wayne; MILLS, James Edward John; MUNCHHOF, Michael John; (375 pag.)WO2016/40515; (2016); A1;,
Isoxazole – Wikipedia
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