反应详情

温度

25 °C

To a solution of 4-{[(2,4-dichloro-thiazol-5-yl)methyl]-amino}-piperidine-1-carboxylic acid t-butyl ester (330 g, 0.9 mol, 1 equiv. mol) in 3.5 L MTBE is added acetic acid (57.2 g, 0.95 mol, 1.06 equiv. mol), isobutyraldehyde (97.3 g, 1.35 mol, 1.5 equiv. mol) and sodium triacetoxy borohydride (305 g, 1.44 mol, 1.6 equiv. mol) suspension in 0.5 L of MTBE. A slight exotherm takes place temperature increases from 24 to 26° C. After 5 h at room temperature the reaction mixture is quenched with 1.3 L water and 30% sodium hydroxide (500 ml). The yellow organic upper phase is washed with 2 L water, then with 2 L of brine. The organic layer is then concentrated under vacuum. The crude product is isolated as yellow powder, 395 g (HPLC 92% area), contaminated by ˜7% of (2,4-dichloro-thiazol-5-yl)-methanol. Purification is done by dissolution of the crude in 900 ml isopropanol/water 8/2 v/v, stirring at 80° C. until complete dissolution, then cool down to room temperature. Filtered at 0° C., the solid is washed with 150 ml of cold isopropanol. The cake is then dried under vacuum at 50° C., to afford 4-{[(2,4-dichloro-thiazol-5-yl)methyl]-isobutyl-amino}-piperidine-1-carboxylic acid t-butyl ester as a white crystalline powder, 293 g (78% yield for the two first steps). Mass spectrum (ion spray): m/z=422 (M+1); 1H NMR (250 MHz, CDCl3): δ=4.35 (2H, brd), 3.87 (2H, s), 2.80 (3H, m), 2.42 (2H,d), 1.86 (3H, m), 1.61 (11H, m), 1.06 (6H, d); 13C NMR (62 MHz, CDCl3): δ=155.02, 150.71, 137.29, 132.52, 79.95, 58.81, 58.44, 47.64, 43.93, 28.82, 28.03, 27.48, 21.03.

1. customAfter 5 h at room temperature the reaction mixture is quenched with 1.3 L water and 30% sodium hydroxide (500 ml)
2. washThe yellow organic upper phase is washed with 2 L water
3. concentrationThe organic layer is then concentrated under vacuum
4. customThe crude product is isolated as yellow powder, 395 g (HPLC 92% area)
5. customPurification
6. dissolutionis done by dissolution of the crude in 900 ml isopropanol/water 8/2 v/v
7. temperaturecool down to room temperature
8. filtrationFiltered at 0° C.
9. washthe solid is washed with 150 ml of cold isopropanol
10. customThe cake is then dried under vacuum at 50° C.