[Synthesis]
General procedure for the synthesis of 2-(4-(((benzoyloxy)carbonyl)amino)-2-oxopyrimidin-1(2H)-yl)acetic acid from diphenylmethanol and phenylmethyl 2-(4-amino-2-oxoimidopyrimidin-1(2H)-yl)acetate:
1. dissolve cytosine (10.3 g, 90 mmol, 1.0 equiv) in N,N-dimethylformamide (DMF, 90 mL).
2. Potassium tert-butoxide (11.6 g, 103.5 mmol, 1.15 eq.) was added and the reaction system was heated to 100 °C and kept for 2 hours.
3. The reaction system was cooled to 10 °C and benzyl 2-bromoacetate (16.05 mL, 101 mmol, 1.12 eq.) was added dropwise over 30 min. After completion of the dropwise addition, the reaction system was warmed to room temperature and the reaction was continued for 12 hours.
4. Acetic acid (5.9 mL, 103.5 mmol, 1.2 equiv) was added to quench the reaction and the reaction solution was rotary evaporated to dryness.
5. The residue was resuspended in water (100 mL) and stirring was continued for 4 hours, then filtered. Wash with water (4 x 150 mL) to give cytosine-1-benzylacetic acid (20.6 g).
6. Cytosine-1-benzylacetic acid (20.6 g, 82 mmol, 1.0 equiv) was dissolved in DMF (160 mL).
7. N,N'-carbonyldiimidazole (21.25 g, 131.25 mmol, 1.6 eq.) was added and the reaction system was heated to 60 °C. The reaction was carried out in two batches.
8. Diphenylmethanol (19.65 g, 106.5 mmol, 1.3 eq.) was added in two batches separated by 1 hour. The reaction was continued for 6 hours.
9. Upon completion of the reaction as detected by thin layer chromatography (TLC), the reaction was quenched by the addition of methanol (4.65 g, 115 mmol, 1.4 equiv).
10. The reaction solution was rotary evaporated and the residue was recrystallized from ethanol and then from methanol (100 mL) to give (4-N-(diphenylmethoxycarbonyl)-cytosine)-1 -acetate (29.35 g).
11. dissolve (4-N-(diphenylmethoxycarbonyl)-cytosine)-1-acetate (29.35 g, 62.5 mmol, 1.0 eq.) in a mixture of acetonitrile:methanol:water:ethanol (2:2:1:1, 350 mL), heat to dissolve the compound, and then cool to 0 °C. add lithium hydroxide monohydrate to the mixture.
12. An aqueous solution (196.8 mL) of lithium hydroxide monohydrate (LiOH-H2O, 25.5 g, 0.61 mol, 9.7 equiv) was added.
13. After completion of the reaction by TLC detection, the reaction was quenched by the addition of an aqueous solution (290 mL) of citric acid (58.5 g, 303.5 mmol, 4.9 eq.) to afford (4-N-(diphenylmethoxycarbonyl)-cytosine)-1 -acetic acid (22.1 g). |