Hydrogen Bromide → (1S,2S,4R)-4-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentan-1-ol

Temperature

85 °C

To a slurry of 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (10.0 g, 0.0377 mol) and (1S,2S,4R)-4-amino-2-(hydroxymethyl)cyclopentanol.HBr (800 g) in isopropyl alcohol (82 mL, 1.1 mol) and water (11 mL, 0.59 mol), triethylamine (13 mL, 0.094 mol) was added. This mixture was then heated to 85° C. for 23 hours. The mixture was cooled to 50° C., at which point 4M hydrochloric acid in water (20 mL) was added slowly. The resulting mixture was then stirred at 50° C. for 3 hours. HPLC indicated that the reaction was complete. The reaction mixture was cooled to ambient temperature and sodium bicarbonate (10 g, 0.1 mol) was added portionwise. Excess solids were filtered; the bed washed with isopropyl alcohol (20 mL) and the filtrate concentrated to ˜70 mL. Ethyl acetate (150 mL) was added followed by a mixture of saturated NaHCO3 aq (35 mL) and water (35 mL). The layers were separated and the aqueous phases extracted with ethyl acetate (2×50 mL) and filtered. The organic layers were combined and washed with saturated NaCl aq (50 mL) and then concentrated to afford the title compound (90.3 g) as a brown solid. 1H NMR (300 MHz, CD3OD, δ): 8.56 (s, 1H), 7.67 (d, 1H), 6.65 (d, 1H), 5.52 (m, 1H), 4.50 (m, 1H), 3.79 (m, 1H), 3.66 (m, 1H), 2.63 (m, 1H), 2.25 (m, 3H) and 2.02 (m, 1H).

1. additionwas added slowly
2. temperatureThe reaction mixture was cooled to ambient temperature
3. filtrationExcess solids were filtered
4. washthe bed washed with isopropyl alcohol (20 mL)
5. concentrationthe filtrate concentrated to ˜70 mL
6. additionEthyl acetate (150 mL) was added
7. additionfollowed by a mixture of saturated NaHCO3 aq (35 mL) and water (35 mL)
8. customThe layers were separated
9. extractionthe aqueous phases extracted with ethyl acetate (2×50 mL)
10. filtrationfiltered
11. washwashed with saturated NaCl aq (50 mL)
12. concentrationconcentrated

ORD record

ord-afd3eb4783c64c25a46c59677d93e850

Source dataset

uspto-grants-2015_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08933225B2