With the rapid development and complex challenges of chemical substances, new drug synthesis pathways are usually the most effective.14441-90-8,5-Phenylisoxazole-3-carboxylic acid,as a common compound, the synthetic route is as follows.
Into a 50-mL round-bottom flask, was placed a solution of l-[l-[trans-3-aminocyclobu?yl]-lH-pyrazol-4-yl]ethan-l-ol (226 mg, 1.25 mmol, 1.00 eq.) in DMF (5 mL). To the solution were added 5-phenyl-l,2-oxazole-3-carboxylic acid (282 mg, 1.49 mmol, 1.00 eq.), HATU (700 mg, 1.84 mmol, 1.50 eq.) and DIEA (560 mg, 4.33 mmol, 3.00 eq.). The resulting solution was stirred for 2 hours at 25 C. The resulting solution was diluted with 100 mL of water. The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with brine (2×100 mL), dried and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 1). The pure isomers were separated by Chiral- Prep-HPLC with the following conditions (Prep-HPLC-004): Column, Phenomenex Lux 5u Cellulose-4 AXIA Packed, 250*21.2mm,5um; mobile phase, Hex and IPA (hold 50.0% IPA in 15 min); Detector, UV 254/220nm. This resulted in 39.6 mg (9%) of 5-phenyl-N-[trans-3-[4- [(lR)-l-hydroxyethyl]-lH-pyrazol-l-yl]cyclobutyl]-l,2-oxazole-3-carboxamide as a white solid and 39.4 mg (9%) of 5-phenyl-N-[trans-3-[4-[(l S)-l-hydroxyethyl]-lH-pyrazol-l- yl]cyclobutyl]-l,2-oxazole-3-carboxamide as a white solid: [0299] Isomer 1: [0300] Analytical data: lH NMR (300 MHz, OMSO-d6): delta 9.31-9.28 (d, J= 7.2 Hz, 2H), 7.96-7.92 (m. 2H), 7.68 (s, 1H), 7.59-7.55 (m, 3H), 7.41 (s, 1H), 7.38 (s, 1H), 5.00-4.89 (m, 1H), 4.88-4.86 (d, J= 4.8Hz, 1H), 4.71-4.64 (m, 2H), 2.76-2.61 (m, 4H), 1.34-1.32 (d, J = 6.3 Hz, 3H). [0301] LC-MS: (M+H)+ = 353 [0302] HPLC purity: 99.24 at 254 nm [0303] Isomer 2: [0304] Analytical data: XH NMR (300 MHz, DMSO-c): delta 9.31-9.28 (d, J = 7.5 Hz, 2H), 7.96-7.93 (m, 2H), 7.68 (s, 1H), 7.57-7.55 (m, 3H), 7.41 (s, 1H), 7.38 (s, 1H), 4.97-4.89 (m, 1H), 4.88-4.86 (d, J= 4.8 Hz, 1H), 4.70-4.64 (m, 2H), 2.72-2.61 (m, 4H), 1.34-1.32 (d, J = 6.6 Hz, 3H). [0305] LC-MS: (M+H)+ = 353 [0306] HPLC purity: 99.74 at 254 nm.
14441-90-8, As the paragraph descriping shows that 14441-90-8 is playing an increasingly important role.
Reference£º
Patent; PROTEOSTASIS THERAPEUTICS, INC.; LEE, Po-shun; (180 pag.)WO2017/40606; (2017); A1;,
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