Hydrochloric Acid → 7H-Pyrrolo(2,3-d)pyrimidine, 4-chloro-

Temperature

60 °C

4-Hydroxy-7H-pyrrolo[2,3-d]pyrimidine (7, 306 g, 2.25 mol) was added in portions over 20 min to phosphorus oxychloride (1050 ml, 1727 g, 11.26 mol, 5.0 equiv). Stirring was continued at room temperature for 15 min then this suspension was slowly heated to reflux and the evolving hydrochloric acid was scrubbed through 20% sodium hydroxide solution. Reflux was continued for 30 min after all material went in solution. The reaction mixture was allowed to cool to 60° C. and it was poured onto ice (5 Kg) with stirring. Stirring was continued for 20 min and potassium carbonate was slowly added in portions to adjust pH to 7.5. Ice was added as needed to keep the temperature below 20° C. The precipitate was collected by filtration, washed well with water and dried in a vacuum oven (30° C.). The crude material was taken in ethyl acetate and stirred at 50° C. for 1.5 hrs. This solution was treated with charcoal, stirred at 50° C. for an additional 20 min and filtered hot through celite. The resulting solution was concentrated to 900 ml and cooled in an ice bath with stirring. The precipitate was collected by filtration, washed with small volume of cold ethyl acetate and dried in a vacuum oven (40° C.) to afford 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 227g, 334.8 g theoretical, 67.8%) as yellow to brown crystalline solids. Further concentration of the mother liquor produces an additional crop of the desired product (5-10%) as yellow to brown crystals of less purity. For 1: 1H NMR (DMSO-d6, 400 MHz) δ ppm 12.58 (bs, 1H), 8.58 (s,1H), 7.69 (d,1H, J=3.5 Hz), 6.59 (d, 1H, J=3.5 Hz); C6H4ClN3 (MW, 153.57), LCMS (EI) m/e 154/156 (M++H).

1. temperaturethis suspension was slowly heated
2. temperatureto reflux
3. temperatureReflux
4. waitwas continued for 30 min
5. additionit was poured onto ice (5 Kg)
6. stirringwith stirring
7. stirringStirring
8. waitwas continued for 20 min
9. additionIce was added
10. customthe temperature below 20° C
11. filtrationThe precipitate was collected by filtration
12. washwashed well with water
13. customdried in a vacuum oven (30° C.)
14. stirringstirred at 50° C. for 1.5 hrs
15. additionThis solution was treated with charcoal
16. stirringstirred at 50° C. for an additional 20 min
17. filtrationfiltered hot through celite
18. concentrationThe resulting solution was concentrated to 900 ml
19. temperaturecooled in an ice bath
20. stirringwith stirring
21. filtrationThe precipitate was collected by filtration
22. washwashed with small volume of cold ethyl acetate
23. customdried in a vacuum oven (40° C.)

ORD record

ord-2f3b6de7422944959b891ef4d0f16c15

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08410265B2