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

Participants

Reaction Conditions

Reaction Steps

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).

Provenance & Evidence