反应详情

To a solution of 55A (5.03 g, 13.3 mmol) in DCM (250 mL) was added (4-methylpiperidin-4-yl)methanol hydrochloride (2.4 g, 14.6 mmol) followed by DIPEA (2.5 mL, 14.6 mmol). The mixture was stirred at RT for 20 min before the addition of sodium triacetoxyborohydride (5.6 g, 26.5 mmol) and MeOH (5 mL). The reaction mixture was stirred at RT overnight. Further (4-methylpiperidin-4-yl)methanol (360 mg, 2.7 mmol), DIPEA (0.5 ml) and sodium triacetoxyborohydride (1.1 g, 5.2 mmol) were added and the mixture was stirred at RT for 3 days. Even more sodium triacetoxyborohydride (2 g, 9.5 mmol) was added and the mixture was stirred for another 2 h. Yet another portion of sodium triacetoxyborohydride (4 g, 19 mmol) was added and the mixture was left at RT overnight. The mixture was then washed with a saturated aqueous solution of Na2CO3. The organic layer was filtered through a phase separator and the solvent was removed by evaporation. The crude product was purified by flash chromatography starting with EtOAc and then eluting the product with 5% methanol in DCM where the methanol contained ammonia (2 M). The pure fractions were combined and evaporated. The residue was triturated with diethyl ether and there was obtained 3.55 g (54%) of the product as a crystalline solid, m. p. 102° C. and 146° C. 1H NMR (500 MHz, CDCl3): δ 0.94 (s, 3H), 1.33 (m, 2H), 1.55 (m, 2H), 2.28 (m, 2H), 2.53 (m, 2H), 3.37 (m, 2H), 3.47 (s, 2H), 3.88 (s, 3H), 4.33 (m, 1H), 4.62 (m, 1H), 4.72 (m, 1H), 5.06 (m, 1H), 5.11 (m, 1H), 6.71 (d, 2H), 7.00 (d, 2H), 7.26 (m, 2H), 8.08 (d, 2H), MS (APCI+) m/z 493 [M+H]+, LC purity: 97%.

1. stirringthe mixture was stirred at RT for 3 days
2. stirringthe mixture was stirred for another 2 h
3. waitthe mixture was left at RT overnight
4. washThe mixture was then washed with a saturated aqueous solution of Na2CO3
5. filtrationThe organic layer was filtered through a phase separator
6. customthe solvent was removed by evaporation
7. customThe crude product was purified by flash chromatography
8. washeluting the product with 5% methanol in DCM where the methanol
9. customevaporated
10. customThe residue was triturated with diethyl ether