ClC1C=CC(C([O:8][C@H:9]2[C@:13]([F:15])([CH3:14])[C@H:12]([N:16]3[CH:24]=[N:23][C:22]4[C:17]3=[N:18][C:19]([NH2:26])=[N:20][C:21]=4Cl)[O:11][C@@H:10]2[CH2:27][O:28]C(=O)C2C=CC(Cl)=CC=2)=O)=CC=1.[Na].[CH3:41][O-:42].Cl>CO.ClCCl>[NH2:26][C:19]1[N:18]=[C:17]2[C:22]([N:23]=[CH:24][N:16]2[C@@H:12]2[O:11][C@H:10]([CH2:27][OH:28])[C@@H:9]([OH:8])[C@:13]2([F:15])[CH3:14])=[C:21]([O:42][CH3:41])[N:20]=1
To a dry 5 L three-necked round flask fitted with a mechanical stirrer and an addition funnel was loaded (2R,3R,4R,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-(((4-chlorobenzoyl)oxy)methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl 4-chlorobenzoate (6b, 313.2 g, 526.5 mmol). The solid was suspended in anhydrous methanol (2.1 L) and cooled in an ice-water bath under an atmosphere of nitrogen. A solution of sodium 25 wt. % methoxide in methanol (361 mL, 1.58 mol) was added via an additional funnel over 20 min to give a clear solution. The reaction was allowed to warm to room temperature for 6 hours to form a turbid solution. The completion of the reaction was confirmed by LC/MS by the lack of any remaining 6-chloro deprotected nucleoside. The reaction solution was acidified with con. HCl (132 mL, 1.58 mol). After standing at room temperature (1 h), the solution was filtered to remove a white precipitate. The precipitate was washed with methanol (3×50 mL). The combined filtrate was concentrated under reduced pressure to afford a sticky solid residue. The residue was mixed with 420 mL of 2 N HCl (420 mL) and dichloromethane (1 L). The organic layer was separated and the aqueous layer was extracted with additional dichloromethane (3×500 mL). To the aqueous layer, ethyl acetate (1.4 L) was added and solid sodium carbonate (86 g) was added portion-wise to neutralize the aqueous layer to ca pH 8 (caution: foaming). After separation of the organic layer, the solid in aqueous layer was dissolved by adding more water (200 mL). The aqueous layer was extracted with ethyl acetate (3×700 mL and 400 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to a light yellow color solid that was redissolved in acetone (820 mL) at 50° C. and stirred until new solid formation initiated. The saturated solution was cooled in a freezer and product was collected by filtration. The white solid was rinsed with acetone (2×150 mL) and ethyl ether (3×80 mL) and dried (0.2 mm Hg, 50° C., 4H) to a white crystalline solid, 151.6 g (92%) of material with NMR and HPLC matching material purified by chromatography.
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