反应详情

温度

85 °C

To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (prepared according to: L. B. Townsend et al., J. Med. Chem. 1990, 33 (7), 1984-92) (2.10 g, 7.51 mmol), trans-3-hydroxycyclobutanecarboxylic acid methyl ester (trans/cis=5:1) (1.11 g, 8.53 mmol), and PS-PPh3 (loading 2.21 mmol/g; 6.80 g, 15.0 mmol) in dry THF (80 mL), cooled by ice/water, was added DIAD (2.20 mL, 2.26 g, 11.2 mmol), then the cooling bath was removed, and the mixture was vortexed (150 rpm) overnight. The resin was filtered off and washed thoroughly with THF (≈400 mL), the filtrate and washings were combined, concentrated, and chromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with CH2Cl2 (1-16)→5% EtOAc in CH2Cl2 (17-40)]. Fractions 3-32 were combined, concentrated, and suspended in iPrOH (10 mL). The suspension was heated to 85° C. for 20 min and cooled to −20° C. for 2 h, the solid was filtered off, washed with cold (−20° C.) iPrOH, and dried in vacuo. One obtained the title compound as white solid. Analytically pure material with cis/trans=50:1 had a melting point of 168-169° C. 1H NMR (CDCl3, 400 MHz): δ=2.66-2.78 (m, 2H), 2.81-2.93 (m, 2H), 3.06 (quint, J=8.7 Hz, 1H), 3.76 (s, 3H), 5.32 (quint, J=8.7 Hz, 1H), 7.68 (s, 1H), 8.60 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=30.93 (+), 34.09 (2C, −), 44.65 (+), 51.58 (Cquart), 52.19 (+), 117.07 (Cquart), 131.87 (+), 150.48 (Cquart), 150.72 (+), 152.69 (Cquart), 174.31 (Cquart). MS (ES+): m/z 391.9/393.9 (100/38) [MH+]. HPLC: tR=3.5 min (OpenLynx, polar—5 min). C12H11ClIN3O2 (391.60): C: calc. 36.81. found 36.88/36.78; H: calc. 2.83. found 2.81/2.76; N: calc. 10.73. found 10.59/10.50.

1. customthe cooling bath was removed
2. custom(150 rpm) overnight
3. filtrationThe resin was filtered off
4. washwashed thoroughly with THF (≈400 mL)
5. concentrationconcentrated
6. customchromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge
7. washeluting with CH2Cl2 (1-16)→5% EtOAc in CH2Cl2 (17-40)]
8. concentrationconcentrated
9. temperaturecooled to −20° C. for 2 h
10. filtrationthe solid was filtered off
11. washwashed with cold (−20° C.) iPrOH
12. customdried in vacuo