反应详情

温度

0 °C

Dissolve 2-chloro-4-fluoro-N-((2S,4S)-3-(2-methyl-piperidin-4-ylamino)-phenyl)-benzamide hydrochloride (Example 39, 50 mg, 0.125 mmol) in methanol (5 mL). Add acetic acid (22 μL, 0.375 mmol) followed by sodium cyanoborohydride (11.8 mg, 0.188 mmol). Cool to 0° C. and add 37% formaldehyde (11.2 μL, 0.138 mmol). Warm to room temperature and stir for 18 hr. Add aqueous saturated sodium bicarbonate and dichloromethane. Separate organic layer and extract aqueous with dichloromethane (2×25 mL). Combine organic extracts, dry (MgSO4), filter, and concentrate in vacuo. Purify by column chromatography (0%–10% 2M NH3 in methanol/CH2Cl2) to yield an oil. Make the hydrochloride salt by sonication with one equivalent of ammonium chloride dissolved in methanol to yield 28 mg (54%) of the title compound: mass spectrum (ion spray): m/z 376.2 (M+1); 1H NMR δ (D2O/DCl, ppm) 7.71 (s, 1H), 7.90 (m, 3H), 7.16 (m, 2H), 7.02 (m, 1H), 3.82 (m, 1H), 3.48 (m, 1H), 3.12 (m, 1H), 2.98 (m, 1H), 2.68 (s, 3H), 2.15 (m, 2H), 1.83 (s, 1H), 1.72 (m, 1H), 1.20 (d, J=6.3 Hz, 3H); mp 91–4° C.

1. temperatureWarm to room temperature
2. extractionSeparate organic layer and extract aqueous with dichloromethane (2×25 mL)
3. dry with materialCombine organic extracts, dry (MgSO4)
4. filtrationfilter
5. concentrationconcentrate in vacuo
6. customPurify by column chromatography (0%–10% 2M NH3 in methanol/CH2Cl2)
7. customto yield an oil