反应详情

Ethyl trans-4-(7-{[2-({4-[(diethoxyphosphoryl)methyl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylate (Example 88, 40.0 mg, 0.055 mmol) was taken up in THF (0.073 mL, 0.90 mmol) and MeOH (0.073 mL, 1.8 mmol). This was treated with a solution of Lithium hydroxide, monohydrate (11.4 mg, 0.27 mmol) in H2O (0.073 mL, 4.1 mmol) and allowed to stir at rt for 30 hrs during which, the reaction mixture transformed from a thick slurry to a homogenous solution. The reaction was concentrated in vacuo to a solid. The product was purified by CombiFlash®Rf 4X Organic Purification System [24 g RediSep® Normal-phase GOLD Silica Flash Column, dried loaded, elution gradient: 0→5% MeOH in DCM] to afford 38.7 mg (100% yield) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.95 (s, 1H), 8.38 (s, 1 H), 7.52 (br. s., 1 H), 7.19 (br. s., 1 H), 7.05 (s, 1 H), 6.90 (d, J=8.59 Hz, 1 H), 4.50 (s, 2 H), 3.95-4.06 (m, 4 H), 3.77 (s, 3 H), 3.21-3.29 (m, 2 H), 3.08 (s, 3 H), 2.67 (br. s., 1 H), 2.60 (br. s., 1 H), 2.15 (d, J=7.83 Hz, 2 H), 1.55-1.69 (m, 6 H), 1.21 (t, 6 H). MS (ES+): m/z 706.22 [MH+]. HPLC: tR=1.55 min (UPLC TOF, polar—3 min). Example 90 may be further prepared as a salt. Non-limiting examples include the sodium, potassium, ammonium, and 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium salts. This can be achieved by dissolving the compound in methanol or ethanol with a suitable co-solvent such as DCM or THF and treating the resulting solution with the necessary amount of an aqueous stock solution of known concentration of sodium hydroxide, potassium hydroxide, or 2-amino-2-(hydroxymethyl)propane-1,3-diol. The resulting mixture can be thoroughly stirred or sonicated to ensure dissolution and mixing. The solvents can then be removed under reduced pressure to afford the appropriate salt.

1. concentrationThe reaction was concentrated in vacuo to a solid
2. customThe product was purified by CombiFlash®Rf 4X Organic Purification System [24 g RediSep® Normal-phase GOLD Silica Flash Column, dried loaded, elution gradient: 0→5% MeOH in DCM]