反应详情

温度

77 °C

A suspension of (3R)-3-cyclopropyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile ((R)-30, 60.0 g, 0.2158 mol, 1.0 equiv) in isopropanol (IPA, 900 mL) was heated to 77° C. to give a clear pale yellow solution. A solution of crystalline H3PO4 (23.3 g, 0.2374 mol, 1.1 equiv) in IPA (200 mL) was added in a steady stream from an addition funnel at 77-79° C., rinsing the addition funnel with IPA (25 mL). An immediate turbidity was developed followed by formation of a white suspension. After about half amount of the H3PO4 solution had been added the suspension became extremely thick. An additional amount of IPA (100 mL) was added to facilitate stirring. When addition was complete the suspension was heated at 75° C. for 1 h with the suspension becoming more mobile but remaining very thick. The suspension was cooled to room temperature over 1 h and the solids were collected by filtration and washed with 50% IPA/heptane (750 mL) and dried. The solids were triturated with heptane (1.2 L) with stirring for overnight before being collected by filtration and washed with heptane (300 mL) and dried in vacuum oven at 40-50° C. to constant weight to afford (3R)-3-cyclopropyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate salt ((R)-31, Phosphate, 76.7 g, 81.2 g theoretical, 94.5% yield) as a fine white crystalline solid. For (R)-31: 1H NMR (DMSO-d6, 400 MHz) δ ppm 12.2 (bs, 1H), 9.62 (bs, 3H, H3PO4), 8.77 (s, 1H), 8.69 (s, 1H), 8.39 (s, 1H), 7.59 (q, 1H, J=2.0 Hz), 6.98 (d, 1H, J=2.7 Hz), 4.04 (m, 1H), 3.37 (dd, 1H, J=16.8, 8.0 Hz), 3.28 (dd, 1H, J=16.8, 5.1 Hz), 1.43 (m, 1H), 0.68 (m, 1H), 0.49 (m, 3H); 13C NMR (DMSO-d6, 100 MHz) δ ppm 152.2, 150.9, 149.9, 139.3, 130.4, 127.0, 120.8, 118.1, 112.9, 100.0, 62.6, 23.3, 15.7, 4.3, 3.8; C15H14N6 (MW, 278.31), LCMS (EI) m/e 279.1 (M++H).

1. customto give a clear pale yellow solution
2. washrinsing the addition funnel with IPA (25 mL)
3. additionAfter about half amount of the H3PO4 solution had been added the suspension
4. additionAn additional amount of IPA (100 mL) was added
5. additionWhen addition
6. temperaturewas heated at 75° C. for 1 h with the suspension
7. temperatureThe suspension was cooled to room temperature over 1 h
8. filtrationthe solids were collected by filtration
9. washwashed with 50% IPA/heptane (750 mL)
10. customdried
11. customThe solids were triturated with heptane (1.2 L)
12. stirringwith stirring for overnight
13. filtrationbefore being collected by filtration
14. washwashed with heptane (300 mL)
15. customdried in vacuum oven at 40-50° C. to constant weight