Реакция #1708636

Уравнение реакции

water

6-(5-(1,3-Dioxolan-2-yl)-2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine

5-amino-2-methoxypyridine

LiHMDS

→

5-(1,3-dioxolan-2-yl)-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine

Выход 77.8%

Растворители

tetrahydrofuran

Условия реакции

Обработка

1. 1
   Температураcooled in an ice water bath
2. 2
   Температураwarmed to room temperature
3. 3
   ДругоеThe layers were separated
4. 4
   Экстракцияthe aqueous phase was extracted with DCM
5. 5
   workup.ADDITIONThe aqueous phase was diluted with brine and extraction with DCM
6. 6
   Сушкаdried over sodium sulfate
7. 7
   Фильтрацияfiltered
8. 8
   Концентрированиеconcentrated
9. 9
   Другоеpurified on a silica gel
10. 10
    Фильтрацияfilter (600 mL fritted filter, about 3 inches of silica gel, 80:1 DCM/2N ammonia in MeOH to 50:1 DCM/2N ammonia in MeOH)

Методика

6-(5-(1,3-Dioxolan-2-yl)-2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (4.557 g, 11.82 mmol) and 5-amino-2-methoxypyridine (1.507 g, 12.14 mmol) were dissolved in tetrahydrofuran (80 mL) and cooled in an ice water bath. Then, LiHMDS (Aldrich 1.0 M in THF, 36.0 mL, 36.0 mmol) was added via syringe over about 10 minutes. The reaction was stirred under nitrogen at 0° C. for 40 minutes, and then the reaction was treated with water (100 mL) and warmed to room temperature. The layers were separated, and the aqueous phase was extracted with DCM. The aqueous phase was diluted with brine and extraction with DCM was continued. The combined organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (600 mL fritted filter, about 3 inches of silica gel, 80:1 DCM/2N ammonia in MeOH to 50:1 DCM/2N ammonia in MeOH) to give 5-(1,3-dioxolan-2-yl)-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine (4.500 grams, 71% purity, 52% yield over two steps). MS MS (ESI pos. ion) m/z 446. Calculated exact mass for C23H23N7O3: 445 (M+—C2H4O). 1H NMR (CDCl3, 400 MHz) δ 12.69 (s, 1H), 9.91 (s, 1H), 8.44 (d, J=2.74 Hz, 1H), 8.41 (d, J=2.15 Hz, 1H), 8.29 (s, 1H), 8.23 (dd, J=8.80 Hz, 2.74 Hz, 1H), 6.79 (d, J=8.80 Hz, 1H), 5.94 (s, 1H), 5.87 (dd, J=10.56 Hz, 2.15 Hz, 1H), 4.24-4.17 (m, 3H), 4.12-4.05 (m, 2H), 3.96 (s, 3H), 3.88-3.79 (m, 1H), 2.91 (s, 3H), 2.19-2.00 (m, 3H), 1.93-1.77 (m, 3H).

Источник