反应详情

温度

40 °C

(4-oxo-2-thioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid (20.0 g, 1.0 eq) was slurried in a mixture of water (112 mL) and isopropyl alcohol (20 mL). NaOH solution (50.9% aqueous, 13.82 g, 1.99 eq) was added followed by a water line wash (10 mL) resulting in a solution. Then Na2CO3 (1.50 g, 0.16 eq) was charged and the solution was heated to 40±3° C. Thereafter 4-fluorobenzyl chloride (13.4 g, 1.05 eq) was added, followed by a line wash of isopropyl alcohol (12 mL) and the reaction mixture was stirred at 40±3° C. until the reaction was deemed complete (˜2.5 hours). The reaction mixture was cooled to 20±3° C. and formic acid (2.4 g, 0.6 eq) was added resulting in crystallisation of the product within 30 minutes. A second charge of formic acid (6.9 g, 1.7 eq) was added over 1 hour and the slurry was stirred at 20±3° C. for at least one hour. The slurry was filtered to isolate the product, which was washed twice with a mixture of water (32 mL) and isopropyl alcohol (8 mL), then with isopropyl alcohol (40 mL) and dried in vacuo at 50° C. to yield the title compound as an off-white solid (28.6 g, 97% th). 1H NMR (d6 DMSO) δ 1.95 (2H, m), 2.57 (2H, t), 2.85 (2H, t), 4.4 (2H, s), 4.7 (2H, s), 7.15 (2H, dd), 7.45 (2H, dd), ˜13.6 (1H, vbrs).

1. washwash (10 mL)
2. customresulting in a solution
3. washwash of isopropyl alcohol (12 mL)
4. custom(˜2.5 hours)
5. temperatureThe reaction mixture was cooled to 20±3° C.
6. customresulting in crystallisation of the product within 30 minutes
7. additionwas added over 1 hour
8. stirringthe slurry was stirred at 20±3° C. for at least one hour
9. filtrationThe slurry was filtered
10. customto isolate the product, which
11. washwas washed twice with a mixture of water (32 mL) and isopropyl alcohol (8 mL)
12. dry with materialwith isopropyl alcohol (40 mL) and dried in vacuo at 50° C.