p-Toluenesulphonyl cyanide → 2,4-Dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

Temperature

-78 °C

To a solution of LiCl (dry, 5.3 g, 126 mmol) in THF (150 mL) was added iPrMgCl (63 mL of 2 M in THF, 126 mmol). After stirring for 15 min, the mixture was cooled to −78° C. and 2,4-dichloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (31 g, 4.5 mmol) was added dropwise as a solution in THF (50 mL). After stirring for 20 min, a solution of tosyl cyanide (19.8 g, 100 mmol) in THF (50 mL) was added dropwise. The mixture was stirred at −78° C. for 30 min. The reaction was quenched with HOAc (20 mL) and after stirring at −78° C. for 15 min, water (200 mL) and EtOAc (200 mL) were added. The organic layer was separated, and the aqueous layer was further extracted with EtOAc (two×150 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give the crude product. After sitting as a concentrate in EtOAc overnight, crystals formed which were collected to afford 3.8 grams 90% purity by 1H NMR. The filtrate was purified via flash chromatography to afford the title compound (12 g). The combined yield was 15.8 grams (66% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) 0.00 (s, 9H), 0.91-1.01 (m, 2H), 3.53-3.66 (m, 2H), 5.65 (s, 2H), 7.94 (s, 1H).

1. stirringAfter stirring for 20 min
2. stirringThe mixture was stirred at −78° C. for 30 min
3. customThe reaction was quenched with HOAc (20 mL)
4. stirringafter stirring at −78° C. for 15 min
5. additionwater (200 mL) and EtOAc (200 mL) were added
6. customThe organic layer was separated
7. extractionthe aqueous layer was further extracted with EtOAc (two×150 mL)
8. washThe combined organic extracts were washed with brine
9. dry with materialdried over MgSO4
10. concentrationconcentrated in vacuo
11. customto give the crude product
12. concentrationa concentrate in EtOAc overnight
13. customcrystals formed which
14. customwere collected
15. customto afford 3.8 grams 90% purity by 1H NMR
16. customThe filtrate was purified via flash chromatography

ORD record

ord-8a3a82d5ddd4428291c1b43141704daa

Source dataset

uspto-grants-2015_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09040547B2