Thymidine → 9-(2,3-dideoxy-3-fluoro-beta-D-erythro-pentofuranosyl)-6-(methylamino)-9H-purine

HRID 1376462Notes

Reaction equation

HRID 1376462 reaction equation
[CH3:1][NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][NH:7]2.[F:12][C@@H:13]1[C@@H:17]([CH2:18][OH:19])[O:16][C@@H:15](N2C=CC(=O)NC2=O)[CH2:14]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[F:12][C@@H:13]1[C@@H:17]([CH2:18][OH:19])[O:16][C@@H:15]([N:7]2[CH:6]=[N:5][C:4]3[C:8]2=[N:9][CH:10]=[N:11][C:3]=3[NH:2][CH3:1])[CH2:14]1

Participants

7

Reactant 4

HCID 5789ThymidineHCID 1624502',3'-Dideoxy-3'-fluorouridineHCID 10290740Potassium azideHCID 178482413HCID 178482413, compound

Product 1

HCID 121159519-(2,3-dideoxy-3-fluoro-beta-D-erythro-pentofuranosyl)-6-(methylamino)-9H-purineYield 73%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 62657Potassium Phosphate, TribasicSolvent

Conditions

Temperature
45 °C

Procedure

6-Methylamino-9H-purine (0.41 g, 2.7 moles) (Sigma Chemical Company) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 moles) were suspended in 50 ml 10 mM potassium phosphate buffer, pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky, et al., Biochemistry, 20, 3615, 1981 and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 2 days, 150 ml MeOH was added to the reaction. The reaction was applied to a column containing AG1-X2 (OH-- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone (6:4). Solvent was removed and lyophilization yielded 0.45 g of 9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-6-(methylamino)-9H-purine (73%): mp 100°-103° C.; TLC Rf 0.69 (Silica gel, MeCN:15N NH4OH:H2O/85:5:10); [α]D20 -23.8° C. (c=0.5, DMF); UV λmax (ε×10-3) at pH 7, 265 (15.6); at pH 13, 265 (16.0); 1H NMR (300 MHz, DMSO-d6) δ8.34 and 8.24 (2s, 2H, H2 and H8), 7.86 (b, 1H, NH), 6.41 (dd, 1H, H1', J=9.3 Hz, J=5.6 Hz), 5.37-5.37 and 5.52-5.56 (2m, 2H, OH5' and H3'), 4.25 (dt, 1H, H4', J=27.0 Hz, J=4.2 Hz), 3.60-3.64 (m, 2H, H5' and H5"), 3.03-3.16 (m, 1H, H2'), 2.92-2.99 (b, 3H, CH3), and 2.57-2.74 (m, 1H, H2"); MS (ci) 268 (M+1), 248 (M-F), 150 (MH2C5H8FO2).

Workup

  1. additionwas added to the reaction
  2. additioncontaining AG1-X2 (OH-- form, 2.5×10 cm)
  3. washeluted with MeOH
  4. additionFractions containing product
  5. concentrationconcentrated
  6. customflash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone (6:4)
  7. customSolvent was removed

Sources & evidence

ORD record
ord-8ba707a5a9504589a6640faf175088ae
Source dataset
uspto-grants-1997_09
Patent number
US05663154

Reaction notes

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