反应详情

To a solution of (2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (250 mg, 0.93 mmol) (obtained as described in Bartroli et al J. Org. Chem, 1995, 60, 3000-3012) in NMP (5 mL) was added HOBT (132 mg, 0.98 mmol, 1.05 eq). Next, 4-chloroanthranilic acid (160 mg, 0.93 mmol, 1 eq) and DCC (202 mg, 0.98 mmol, 1.05 eq) was added and the mixture was stirred at room temperature for 18 h. Then, formamidine acetate (437 mg, 4.19 mmol, 4.5 eq) was added and the mixture was heated at 130° C. for 24 h. Water (75 mL) was added and the solid formed was collected by filtration and was then partitioned between aqueous 1N NaOH solution and EtOAc. The aqueous phase was discarded and the organic phase was washed with brine, dried over Na2SO4, filtered, concentrated and the residue purified by flash chromatography (hex: EtOAc 1:5) and recrystallized from a EtOAc: hexane: ether mixture to give the title product (268 mg, 67%) as a white solid: mp 116°-122° C.; 1H NMR (80 MHz, CDCl3) δ (TMS) 8.57 (s, 1H, N=CH--N), 8.26 (d, J=8.5Hz, 1H, arom), 7.74 (s, 2H, triazole), 7.7-7.3 (m, 3H, arom), 6.9-6.7 (m, 2H, arom), 5.91 (dq, Jd =2, Jq =7, 1H, MeCH), 5.53 (d, J=2, 1H, OH), 5.14 (d, J=14, 1H, CH(H)), 4.00 (d, J=14, 1H, CH(H)), 1.29 (d, J=7, 3H, CHMe); GC/MS 224 (Tr--CH2COHAr, C10H8F2N3O), 207 (N-ethylheterocycle, C10H9ClN2O); [a]D =-7.9° (c 1, CHCl3). Analysis calculated for C20H16ClF2N5O2 : C 55.63; H 3.73; N 16.22. Found: C 55.23; H 4.09; N 16.13.

1. temperaturethe mixture was heated at 130° C. for 24 h
2. customthe solid formed
3. filtrationwas collected by filtration
4. customwas then partitioned between aqueous 1N NaOH solution and EtOAc
5. washthe organic phase was washed with brine
6. dry with materialdried over Na2SO4
7. filtrationfiltered
8. concentrationconcentrated
9. customthe residue purified by flash chromatography (hex: EtOAc 1:5)
10. customrecrystallized from a EtOAc