p-Toluenesulfonic acid → 5,6-Dichloro-2-(2-fluoro-1-methylethylamino)-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole

HRID 381646Notes

Reaction equation

HRID 381646 reaction equation
[F:1][CH2:2][C:3](=O)[CH3:4].[Cl:6][C:7]1[C:34]([Cl:35])=[CH:33][C:10]2[N:11]([C@H:15]3[O:27][C@@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:16]3[O:17][C:18](=[O:20])[CH3:19])[C:12]([NH2:14])=[N:13][C:9]=2[CH:8]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C([BH3-])#N.[Na+]>C(OCC)(=O)C>[Cl:6][C:7]1[C:34]([Cl:35])=[CH:33][C:10]2[N:11]([C@H:15]3[O:27][C@@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:16]3[O:17][C:18](=[O:20])[CH3:19])[C:12]([NH:14][CH:3]([CH3:4])[CH2:2][F:1])=[N:13][C:9]=2[CH:8]=1

Participants

6

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 9889FluoroacetoneHCID 5003444Sodium cyanoborohydrideHCID 183961315,6-dichloro-2-amino-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole

Product 1

HCID 702113445,6-Dichloro-2-(2-fluoro-1-methylethylamino)-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazoleYield 24.4%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

Fluoroacetone (5 g) and 5,6-dichloro-2-amino-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (0.38 g, 0.82 mmol) were combined with tosic acid (0.050 g, 0.26 mmol) and stirred at reflux in a flask fitted with a Dean Stark trap. After four hours sodium cyanoborohydride (0.16 g, 2.4 mmol) was added and reflux was continued for six hours. The solution was diluted with ethyl acetate (200 mL) and washed with sat'd NaCl (2×50 mL) and water (50 mL). The organics were dried (Na2SO4), decanted, and concentrated. The crude product was purified on a silica gel column (230-400 mesh, 2.5×18 cm) with 1:25 methanol:CH2Cl2 gave 0.19 g of crude product This material was further purified on a chromatotron (2 mm rotor) with 1:1 ethyl acetate hexanes to give a light yellow solid (0.10 g, 0.20 mmol, 24%); MS (API+; m/z (rel. intensity) 520 (62.63, M+); 1H NMR (DMSO-d6) d 7.66 (s, 1H, Ar—H), 7.51 (s, 1H, Ar—H), 7.30 (d, 1 H, NH, J=7.6 Hz), 6.25 (d, 1H, H-1′, J=7.5 Hz), 5.31-5.23 (m, 1H, H-2′), 5.48-5.44 (m, 1H, H-3′), 4.63-4.26 (m, 6H, 2F, CH, H-4′ and 5′), 2.21 (s, 3H, OAc), 2.19 (s, 3H, OAc), 2.02 (s,3H, OAc), 1.24 (d, 3H, CH(CH3), J=7.5 Hz).

Workup

  1. temperatureat reflux in a flask
  2. customfitted with a Dean Stark trap
  3. temperaturereflux
  4. washwashed with sat'd NaCl (2×50 mL) and water (50 mL)
  5. dry with materialThe organics were dried (Na2SO4)
  6. customdecanted
  7. concentrationconcentrated
  8. customThe crude product was purified on a silica gel column (230-400 mesh, 2.5×18 cm) with 1:25 methanol
  9. customCH2Cl2 gave 0.19 g of crude product This material
  10. customwas further purified on a chromatotron (2 mm rotor) with 1:1 ethyl acetate hexanes

Sources & evidence

ORD record
ord-4b99a53d0b1f432088c592f8445b2c22
Source dataset
uspto-grants-2001_10
Patent number
US06307043B1

Reaction notes

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