Each compound has different characteristics, and only by selecting the characteristics of the compound suitable for a specific situation can the compound be applied on a large scale. 17366-48-2, name is exo-8-Azabicyclo[3.2.1]octan-3-ol hydrochloride. This compound has unique chemical properties. The synthetic route is as follows. Product Details of 17366-48-2
To a stirred solution of exo-8-azabicyclo[3.2.1]octan-3-ol hydrochloride (2.049 g, 12.52 mmol) and DIPEA (5.96 ml, 34.1 mmol) in DMF (15 ml) was added 5-bromo-2-chlorobenzenesulfonyl chloride (3.30 g, 11.38 mmol) at 0 C., the mixture was slowly rose to rt in 2 h and stirred at rt for 1 h. The solution was partitioned (EtOAc-brine). The organic layer was dried (Na2SO4), filtered and concentrated. The residue was used directly for next step. ESI-MS (M+H): 380.0, 382.0. To a mixture of the compound from Step 23a (4.3 g, 11.30 mmol) and imidazole (1.922 g, 28.2 mmol) in DMF (15 ml) was added TBSCl (2.043 g, 13.55 mmol) at 0 C. The resulting mixture was stirred overnight at rt. The solution was partitioned (EtOAc-brine). The organic layer was dried (Na2SO4), filtered and concentrated. The crude residue was chromatographed (silica, ethyl acetate/petroleum ether) to give the desired compound as a white solid (3.92 g, 70% over 2 steps). ESI-MS (M+H): 494.1, 496.1.H NMR (400 MHz, CDCl3) delta 8.21 (d, J=2.4 Hz, 1H), 7.55 (dd, J=8.4, 2.4 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 4.27 (dd, J=4.7, 2.8 Hz, 2H), 3.95 (td, J=10.6, 5.4 Hz, 1H), 1.97 (dd, J=8.3, 4.3 Hz, 2H), 1.83 (ddd, J=13.2, 5.9, 3.1 Hz, 2H), 1.77-1.60 (m, 4H), 0.83 (s, 9H), 0.00 (s, 6H). To a stirred solution of the compound from Step 23b (1.00 g, 2.02 mmol) in THF (30.0 ml) was added a solution of 2.5 M n-BuLi (0.889 ml, 2.22 mmol) in hexanes at -78 C. and DMF (0.469 ml, 6.06 mmol). The resulting mixture was stirred at -78 C. for 30 minutes. The solution was partitioned (EtOAc-brine). The organic layer was dried (Na2SO4), filtered and concentrated. The crude residue was chromatographed (silica, ethyl acetate/petroleum ether) to give the desired compound as a white solid (250 mg, 28%). ESI-MS (M+H): 444.2, 446.2. To a stirred solution of the compound from Step 23c (340 mg, 0.766 mmol) in DMF (8.0 ml) was added trimethyl(trifluoromethyl)silane (654 mg, 4.60 mmol) at 0 C. The resulting mixture was warmed up slowly to rt and kept for 30 minutes. The solution was partitioned (EtOAc-brine). The organic layer was dried (Na2SO4), filtered and concentrated. The crude residue was taken into next step without further purification. ESI-MS (M+H): 586.1, 588.1.To a stirred solution of the compound from Step 23d (90 mg, 0.154 mmol) in MeOH (4.0 ml) was added K2CO3 (212 mg, 1.535 mmol) at 0 C. The resulting mixture was stirred at 0 C. for 1 h. The solution was partitioned (EtOAc-brine). The organic layer was dried (Na2SO4), filtered and concentrated. The crude residue was chromatographed (silica, ethyl acetate/petroleum ether) to give the desired compound as a white solid (62 mg, 79%). ESI-MS (M+H): 514.2, 516.2.To a stirred solution of the compound from Step 23e (50 mg, 0.097 mmol) in DCM (2 ml) was added Dess-Martin periodinane (61.9 mg, 0.146 mmol) at 0 C. . The resulting mixture was stirred at 0 C. for 1 h. The solution was partitioned between EtOAc and Na2S2O3 aqueous solution. The organic layer was dried (Na2SO4), filtered and concentrated. The crude residue was chromatographed (silica, ethyl acetate/petroleum ether) to give the desired compound as a white solid (40 mg, 80%). ESI-MS (M+H): 512.2, 514.2.To a stirred solution of the compound from Step 23f (15 mg, 0.029 mmol) and 3,4,5-trifluoroaniline (10.77 mg, 0.073 mmol) in toluene (1 mL) was added titanium(IV) isopropoxide (0.051 ml, 0.176 mmol). The resulting mixture was stirred at reflux (120 C.) for 15 h. The mixture was cooled to rt. Then sodium triacetoxyborohydride (18.63 mg, 0.088 mmol) was added. The mixture was stirred at rt for 1 h. The solution was partitioned (EtOAc-brine). The organic layer was dried (Na2SO4), filtered and concentrated. The crude residue was chromatographed (silica, ethyl acetate/petroleum ether) to give the desired compound as a white solid (5 mg, 27%). ESI-MS (M+H): 643.2, 645.2.To a stirred solution of the compound from Step 23g (6 mg, 9.3 mumol) in MeOH (1.0 ml) was added a solution of 4N HCl (0.12 ml, 0.47 mmol) at 0 C. The resulting mixture was stirred at 0 C. for 45 minutes. The solution was partitioned (EtOAc-brine). The organic layer was dried (Na2SO4), filtered and concentrated. The crude residue was chromatographed (silica, MeOH/DCM) to give the title compound as a white solid (4 mg, 81%). ESI-MS (M+H): =529.1, 531.1.1H NMR (400 MHz, MeOH-d4) delta 8.30 (d, J=2.2 Hz, 1H), 7.78 (dd, J=8.3, 2.2 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 6.62-6.39 (m, 2H), 5.50 (q, J=7.5 Hz, 1H), 4.33-4.16 (m, 2H), 3.98 (dt, J=10.8, 5.1 Hz, 1H), 2.02-1.86 (m, 2H), 1.84-1.55 (m, 6H).
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Reference:
Patent; Enanta Pharmaceuticals, Inc.; Or, Yat Sun; Jin, Meizhong; Kass, Jorden; Cao, Hui; Gao, Xuri; Li, Wei; Peng, Xiaowen; Qiu, Yao-Ling; (43 pag.)US2017/217974; (2017); A1;,
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