HRID77304

反应详情

EQUATION

反应方程式

HRID 77304 的结构方程式

AUXILIARIES

试剂、催化剂与溶剂

1

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

  1. concentrationconcentrated
  2. customthe crude residue was purified by FCC (0 to 20% 2 M NH3 in MeOH/CH2Cl2)