Deamination of organophosphorus-nucleosides
A technology of nucleoside deaminase and cytidine deaminase, which is applied to the deamination of intermediates or prodrugs, cytidine organophosphate NA and its pharmaceutical fields, and can solve the problems of inability to obtain deamination products and the like
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Embodiment 9
[0198] Embodiment 9: ((((2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) Preparation of (phenoxy)phosphoryl)-L-leucine methyl ester hydrochloride (compound 10):
[0199] - Step 1: Protection of cytidine (compound 1) to provide 2',3'-protected cytidine (compound 8):
[0200]
[0201] To a 100 mL round bottom flask equipped with a reflux condenser was added cytidine (4.41 g, 18.1 mmol) suspended in anhydrous acetone (44 mL). To the stirred suspension, add activated Molecular sieves and H 2 SO 4 98% (0.145 mL, 2.7 mmol, 0.15 equiv). The suspension was stirred at 50°C. After 16 h at room temperature, NaHCO was added 3 (2 g), and the mixture was stirred for 0.5 hours. Then, the crude mixture was vacuum filtered. The resulting solid was washed with MeOH / EtOH 1 / 1 (2 x 20 mL). The organic phases were combined and evaporated to dryness to obtain 2',3'-protected cytidine (Compound 8, 1.33 g, 25.8%) as a white solid.
[0202] 1...
Embodiment 10
[0216] Example 10: ((((2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) Preparation of (phenoxy)phosphoryl)-L-valine methyl ester hydrochloride (compound 12):
[0217] - Step 1: Preparation of ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-valine methyl ester (compound 5):
[0218]
[0219] Following the procedure described for compound 4, using 4-phosphoryl 4-nitrophenyl dichloride (0.5 g, 1.95 mmol) and L-valine methyl ester hydrochloride (0.327 g, 1.95 mmol), to give ((4-Nitrophenoxy)(phenoxy)phosphoryl)-L-valine methyl ester (654 mg, yield 81.9%) as a colorless oil.
[0220] 1 H-NMR (δ, ppm): 8.28 (d, J=8.8Hz, 2H), 7.46 (dd, J=8.9, 3.4, 2H), 7.38 (t, J=7.6Hz, 2H), 7.26 (m, 3H), 3.75 (dt, J = 10.4, 6.3, 1H), 3.60 (s, 3H), 2.02 (m, 1H), 0.87 (t, J = 7.8Hz, 6H).
[0221] - Step 2: Coupling compound (8) with compound (5) to provide ((((3aR,4R,6R,6aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl )-2,2-Dimethyltetrahydrofuro[3,4-d][1,3]dioxola...
Embodiment 11
[0229] Example 11: ((((2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) Preparation of (phenoxy)phosphoryl)-L-alanine isopropyl hydrochloride (compound 14):
[0230] - Step 1: Preparation of ((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester (compound 6):
[0231]
[0232] Following the procedure for compound 4 using 4-phosphoryl 4-nitrophenyl dichloride (1.0 g, 3.90 mmol) and L-alanine isopropyl ester hydrochloride (0.655 g, 3.90 mmol) gave ( (4-Nitrophenoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester (1.11 g, 70% yield) as a colorless oil.
[0233] 1 H-NMR (δ, ppm): 8.28 (d, J=8.8Hz, 2H), 7.46 (dd, J=15.8, 8.4, 2H), 7.39 (m, 2H), 7.26 (m, 3H), 4.93 ( dt, J = 12.5, 6.2, 1H), 4.01 (m, 1H), 1.32 (m, 3H), 1.19 (t, J = 5.9 Hz, 6H).
[0234] - Step 2: Coupling compound 8 with compound 6 to provide ((((3aR,4R,6R,6aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-2, 2-Dimethyltetrahydrofuro[3,4-d][1,3]dioxolan-4-yl)methoxy)(...
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