反应详情
EQUATION
反应方程式
REACTANTS
反应物
PRODUCTS
生成物
AUXILIARIES
试剂、催化剂与溶剂
PROCEDURE
实验过程
To a slurry of 2,4-dichloropyrimidine (2.05 g, 13.7 mmol) and N,N-diisopropylethylamine (3.60 mL, 20.6 mmol) in i-PrOH (12 mL) was added (R)-3-N-Boc-amino pyrrolidine (2.69 g. 14.4 mmol). The mixture was heated at 160° C. in a microwave for 2 h. The reaction was cooled to rt and concentrated, and the crude residue was purified by FCC (0 to 50% EtOAc/hexanes) to yield a white solid (2.10 g, 51%). MS (ESI): mass calcd. for C13H19ClN4O2, 298.1; m/z found, 299.1 [M+H]+. 1H NMR (CDCl3): 8.02 (d, J=6.0, 1H), 6.19 (d, J=6.0, 1H), 4.85-4.47 (m, 1H), 4.40-4.16 (m, 1H), 3.94-3.08 (m, 4H), 2.46-2.17 (m, 1H), 2.12-1.78 (m, 1H), 1.45 (s, 9H). [(3R)-1-(2-Isobutylamino-pyrimidin-4-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester. To a slurry of [(3R)-1-(2-chloro-pyrimidin-4-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (103 mg, 0.35 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.52 mmol) in i-PrOH (1.5 mL) was added isobutylamine (30 mg. 0.41 mmol). The mixture was heated to 140° C. in a microwave for 6 h. The reaction was cooled to room temperature and concentrated. The crude residue was purified by FCC (0 to 10% MeOH/CH2Cl2) to yield the desired product (93 mg, 80%). MS (ESI): mass calcd. for C17H29N5O2, 335.2; m/z found, 336.3 [M+H]+. 1H NMR (CDCl3): 7.83 (d, J=5.9, 1H), 5.64 (d, J=5.9, 1H), 4.98-4.80 (m, 1H), 4.78-4.61 (m, 1H), 4.38-4.20 (m, 1H), 3.79-3.26 (m, 4H), 3.23-3.11 (m, 2H), 2.32-2.09 (m, 1H), 1.99-1.77 (m, 2H), 1.45 (s, 9H), 0.95 (d, J=6.7, 6H). 4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(2-methylpropyl)pyrimidin-2-amine. To a solution of [(3R)-1-(2-isobutylamino-pyrimidin-4-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (93 mg, 0.28 mmol) in MeOH (0.5 mL) was added HCl (4.0 M in 1,4-dioxane; 1.0 mL). The reaction was stirred at rt for 2 h, concentrated, and the crude residue was purified by FCC (0 to 20% 2 M NH3 in MeOH/CH2Cl2) to yield the desired product (65 mg, 100%). MS (ESI): mass calcd. for C12H21N5, 235.2; m/z found, 236.2 [M+H]+. 1H NMR (CDCl3): 7.82 (d, J=5.9, 1H), 5.65 (d, J=5.9, 1H), 4.87 (s, 1H), 3.75-3.51 (m, 3H), 3.48-3.38 (m, 1H), 3.20 (dd, J=6.7, 6.1, 3H), 2.16 (d, J=6.3, 1H), 1.87 (dt, J=13.4, 6.7, 1H), 1.81-1.71 (m, 1H), 1.47 (s, 2H), 0.95 (d, J=6.7, 6H). The compounds in Example 24 through Example 30 were prepared using methods analogous to those described for Example 23.
WORKUP
后处理
- concentrationconcentrated
- customthe crude residue was purified by FCC (0 to 20% 2 M NH3 in MeOH/CH2Cl2)