Sodium Iodide → HCID 56597870, compound

Temperature

90 °C

To a 10 mL microwave vial were sequentially added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.125 g, 0.334 mmol), sodium iodide (10.02 mg, 0.067 mmol) and zinc (4.37 mg, 0.067 mmol), DMSO(2.5 mL), triethylamine (0.093 mL, 0.669 mmol) and DBU (0.101 mL, 0.669 mmol). The stirring suspension was degassed with nitrogen for 5 min., wherein an emulsion had formed. Added next were phenylacetylene (0.110 mL, 1.003 mmol) and Pd(Ph3P)4 (0.039 g, 0.033 mmol). The sealed reaction mixture was placed onto a heat block, stirred at 90° C. for 3 hr, and then allowed to cool to room temperature overnight. The contents were poured onto water and 20% THF/EtOAc, stirred, and the layers separated. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The filter pad was washed with additional EtOAc. The combined filtrates were concentrated in vacuo to a yellow/orange residue that was dried on hi-vac pump. The crude solid was then pre-adsorbed onto silica gel and purified by silica gel chromatography (dry loaded, eluent: 5-80% gradient of DCM and chloroform containing 10% 2M Ammonia (in methanol)). The isolated product was obtained as a yellow solid which was then further purified by reverse phase HPLC (mobile phase: 20-90% ACN in H2O, 0.1% TFA, Gradient time: 8 min). The isolated solid was dissolved in 10% MeOH/CH2Cl2 and treated with 0.6 g of Silicycle carbonate resin for 30 min. The contents were filtered through Celite and the filter pad washed with additional 10% MeOH/CH2Cl2. The combined filtrates were concentrated in vacuo to afford a solid which was dried in vacuum oven for 18 hr. The final product was collected as 0.045 g (30%). LCMS E-S (M+H)=440.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (d, J=6.82 Hz, 6 H), 2.13 (s, 3 H), 2.21 (s, 3 H), 4.37 (d, J=4.80 Hz, 2 H), 5.18-5.33 (m, 1 H), 5.90 (s, 1 H), 7.45-7.56 (m, 3 H), 7.64-7.73 (m, 2 H), 7.86 (s, 1 H), 8.42 (s, 1 H), 8.92 (t, J=4.80 Hz, 1 H), 11.55 (br. s., 1 H).

1. customThe stirring suspension was degassed with nitrogen for 5 min.
2. customwherein an emulsion had formed
3. additionAdded next
4. customThe sealed reaction mixture
5. temperatureto cool to room temperature overnight
6. stirringstirred
7. customthe layers separated
8. washThe organic layer was washed with brine
9. dry with materialdried over MgSO4
10. filtrationfiltered
11. concentrationconcentrated in vacuo
12. washThe filter pad was washed with additional EtOAc
13. concentrationThe combined filtrates were concentrated in vacuo to a yellow/orange residue that
14. customwas dried on hi-vac pump
15. custompre-adsorbed onto silica gel and purified by silica gel chromatography (dry loaded, eluent: 5-80% gradient of DCM and chloroform containing 10% 2M Ammonia (in methanol))
16. customThe isolated product was obtained as a yellow solid which
17. customwas then further purified by reverse phase HPLC (mobile phase: 20-90% ACN in H2O, 0.1% TFA, Gradient time: 8 min)
18. dissolutionThe isolated solid was dissolved in 10% MeOH/CH2Cl2
19. additiontreated with 0.6 g of Silicycle carbonate resin for 30 min
20. filtrationThe contents were filtered through Celite
21. washthe filter pad washed with additional 10% MeOH/CH2Cl2
22. concentrationThe combined filtrates were concentrated in vacuo
23. customto afford a solid which
24. customwas dried in vacuum oven for 18 hr
25. customThe final product was collected as 0.045 g (30%)

ORD record

ord-9828d34130e748c19c689a84e8cd8366

Source dataset

uspto-grants-2015_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09073924B2