反应详情

tert-Butyl N-4-[4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenylcarbamate (5.7 g, 0.011 mol), conc. ammonia solution (100 mL) and dioxan (100 mL) were heated in a pressure vessel for 20 hr at 120° C. The solvent was evaporated and the residue reconstituted in EtOAc/water (250 mL/100 mL). The organic layer was separated , dried (sodium sulphate), filtered and evaporated to give a solid which by HPLC (conditions: 5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min.) was observed to be a 2:1 mixture of tert-butyl N-4-[4-amino-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenylcarbamate and 5-(4-amino-3-methoxyphenyl)-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine. The mixture was dissolved in acetone (200 mL) and HCl (SN, 100 mL) was added dropwise over 0.5 hr. The resulting solution was stirred at room temperature overnight and the solvent was then evaporated. The acidic solution was basified with 2N NaOH (ice-cooling) and extracted with EtOAc (3×150 mL). The combined organics were washed with water (2×100 mL). During the extraction process a solid precipitated. This solid was filtered and triturated in hot EtOAc/MeOH. The insolubles were filtered, the filtrate evaporated and then resulting solid triturated with diethylether/ethyl acetate to give a yellow solid. The organic layers from the original extraction were dried (sodium sulphate), filtered and evaporated. The resulting solid was triturated with diethyl ether/ethyl acetate (5:1) and filtered to give 4-[4-amino-5-(4-amino-3-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-cyclohexanone as a yellow solid. (2.3 g, combined yield=78%). 1H NMR (d6 DMSO, 400 MHz): 8.17(1H, s), 7.32(1H, s), 6.88(1H, s), 6.77(1H, m), 6.73(1H, m), 6.71(1H, m), 6.07(2H, bs), 5.14(1H, m), 3.81 (3H, s), 2.72(2H, m), 2.35(4H, m), 2.18 (2H, m). HPLC: (5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min.) tr=11.24 min, 95%

1. customThe solvent was evaporated
2. customThe organic layer was separated
3. dry with materialdried (sodium sulphate)
4. filtrationfiltered
5. customevaporated
6. customto give a solid which by HPLC (conditions: 5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min.)
7. customthe solvent was then evaporated
8. extractionextracted with EtOAc (3×150 mL)
9. washThe combined organics were washed with water (2×100 mL)
10. customDuring the extraction process a solid precipitated
11. filtrationThis solid was filtered
12. customtriturated in hot EtOAc/MeOH
13. filtrationThe insolubles were filtered
14. customthe filtrate evaporated
15. customresulting solid
16. customtriturated with diethylether/ethyl acetate
17. customto give a yellow solid
18. extractionThe organic layers from the original extraction
19. dry with materialwere dried (sodium sulphate)
20. filtrationfiltered
21. customevaporated
22. customThe resulting solid was triturated with diethyl ether/ethyl acetate (5:1)
23. filtrationfiltered