反应详情

To a 25-mL round-bottom flask containing a solution of 23.1 (195 mg, 0.35 mmol, 1.00 equiv) in dichloromethane (15 mL) was added hydrochloric acid (12 M, 2 mL) at 0° C. under nitrogen. The resulting solution was stirred for 2 h at room temperature and concentrated under vacuum. The resulting N-(5-fluoropyridin-2-yl)-2-[(3S)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetamide hydrochloride (130 mg, crude) was used in the next step directly without further purification. A solution of this material (130 mg, crude) and HCHO (37%, 1 mL) in methanol (10 mL) was stirred at room temperature for 30 min, whereupon NaBH3CN (55 mg, 0.78 mmol, 3.06 equiv) was added and the mixture stirred for an additional 2 h at room temperature. The reaction was then quenched by the addition of 20 mL of water and extracted with 3×30 mL of ethyl acetate. The combined organic layers were concentrated under vacuum. The crude product (70 mg) was purified by preparative HPLC(SHIMADZU) under the following conditions: column: Xbridge Prep C18 5 um, 19*150 mm; mobile phase: water (0.05% NH4HCO3) and CH3CN (6.0% CH3CN up to 50.0% in 25 min); UV detection at 254 and 220 nm. The fractions were collected and evaporated under reduced pressure to give the 2-[(3S)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]-N-(5-fluoropyridin-2-yl)acetamide (I-38, 21.4 mg) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 8.20 (m, 2H), 7.63 (m, 1H), 5.28 (m, 1H), 3.93 (t, 1H), 3.33 (m, 2H), 3.03 (m, 1H), 2.82 (m, 1H), 2.77 (m, 1H), 2.55 (m, 10H), 2.03 (m, 2H), 1.55 (m, 4H). MS: m/z 470 (M+H)+.

1. concentrationconcentrated under vacuum
2. customThe resulting N-(5-fluoropyridin-2-yl)-2-[(3S)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetamide hydrochloride (130 mg, crude) was used in the next step directly without further purification
3. additionwas added
4. stirringthe mixture stirred for an additional 2 h at room temperature
5. customThe reaction was then quenched by the addition of 20 mL of water
6. extractionextracted with 3×30 mL of ethyl acetate
7. concentrationThe combined organic layers were concentrated under vacuum
8. customThe crude product (70 mg) was purified by preparative HPLC(SHIMADZU) under the following conditions
9. waitmobile phase: water (0.05% NH4HCO3) and CH3CN (6.0% CH3CN up to 50.0% in 25 min)
10. customThe fractions were collected
11. customevaporated under reduced pressure