Sodium Bicarbonate → 1,1-dimethylethyl 4-[2-(4-amino-5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-1-piperidinecarboxylate

温度

100 °C

To 1,1-dimethylethyl 4-[2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-1-piperidinecarboxylate (220 mg, 0.518 mmol) and 1-[(2,5-difluorophenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (290 mg, 0.726 mmol) in a 5 ml sealable vial was added 1,4-Dioxane (2 mL) and saturated NaHCO3 (1 mL). The mixture was then bubbled with N2 for 10 minutes then Pd(Ph3P)4 (59.9 mg, 0.052 mmol) was added and N2 was bubbled for 5 minutes. The mixture was then capped and heated at 100° C. After 4 hours the reaction was complete. The reaction was diluted with water (5 ml) then extracted with EtOAc (3×10 ml). The organics were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude oil was then dissolved in 3 mL of DMSO and then purified on HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 2% ACN/H2O, 0.1% TFA to 32% ACN/H2O, 0.1% TFA) with UV detection at 220 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. The water left behind was added saturated NaHCO3 and then extracted with EtOAc (3×15 mL). The organic was combined wash with saturated NaCl solution, dried over MgSO4, filtered and concentrated. Then the material was transferred to a 40 mL vial with MeCN, then water was added and it was freeze-dried to isolate 1,1-dimethylethyl 4-[2-(4-amino-5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-1-piperidinecarboxylate (151 mg, 47.2% yield) as a white powder. LC-MS (ES) m/z=617.6 [M+H]+.

1. customThe mixture was then bubbled with N2 for 10 minutes
2. customN2 was bubbled for 5 minutes
3. customThe mixture was then capped
4. additionThe reaction was diluted with water (5 ml)
5. extractionthen extracted with EtOAc (3×10 ml)
6. washwashed with brine
7. dry with materialdried over MgSO4
8. filtrationfiltered
9. concentrationconcentrated
10. dissolutionThe crude oil was then dissolved in 3 mL of DMSO
11. custompurified on HPLC
12. custom7.3-minute
13. customto remove most of the MeCN
14. waitThe water left behind
15. additionwas added saturated NaHCO3
16. extractionextracted with EtOAc (3×15 mL)
17. washThe organic was combined wash with saturated NaCl solution
18. dry with materialdried over MgSO4
19. filtrationfiltered
20. concentrationconcentrated
21. additionwater was added
22. customit was freeze-dried

ORDレコード

ord-4bdf64c5d4c64a1cbc138360498c2ee0

出典データセット

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08598156B2