Triphenylphosphine Oxide → 6-{2-Amino-6-[(3r)-3-ethyl-4-morpholinyl]-4-pyrimidinyl}-1h-indazol-3-amine

Temperature

100 °C

Into a 25 mL sealable tube under nitrogen were combined 4-chloro-6-[(3R)-3-ethyl-4-morpholinyl]-2-pyrimidinamine (140 mg, 0.58 mmol) and (4-cyano-3-fluorophenyl)boronic acid (0.114 g, 0.69 mmol) in 1,4-dioxane (9 mL). Saturated aqueous NaHCO3 (3 mL) was added, and the resulting mixture was degassed with nitrogen for 10 minutes. Pd(Ph3P)4 (0.76 g, 0.066 mmol) was added, the vessel was sealed, and the reaction mixture was stirred at 100° C. for 3 hours. The reaction was cooled to room temperature, the solids and other insoluble impurities formed during the reaction were filtered and the filtrate was concentrated. The resulting solid was partitioned between EtOAc and water, and extracted with EtOAc (2×) and CH2Cl2 (2×). The combined organic layers were washed with water and brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% CHCl3 to 90/10/1 CHCl3/CH3OH/NH4OH) afforded a mixture of the desired Suzuki product with triphenylphosphine oxide. LC-MS (ES) m/z=328 [M+H]+. In a 25 mL sealable tube under nitrogen were combined the crude containing the Suzuki product 4-{2-amino-6-[(3R)-3-ethyl-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile and hydrazine monohydrate (0.42 mL) in EtOH (6 mL). The vial was sealed, and the reaction mixture was stirred at 100° C. for 2 days. The reaction was filtered to remove some impurities and the filtrate was concentrated. The resulting solid was dissolved in a mixture of CH3CN/H2O/DMSO and purified on a Gilson RPHPLC (CH3CN/H2O w/0.1% TFA). The CH3CN was evaporated, and saturated aqueous NaHCO3 was added to the remaining water where a precipitate crashed out. The precipitate was filtered, triturated in Et2O and dried in vacuo to afford the title compound (47 mg) as a tan solid. LC-MS (ES) m/z=340 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.88 (t, J=7.5 Hz, 3H), 1.63-1.80 (m, 2H), 3.09 (td, J=12.8, 3.2 Hz, 1H), 3.37-3.46 (m, 2H), 3.51 (dd, J=11.4, 2.8 Hz, 1H), 3.80-3.91 (m, 2H), 4.30 (bs, 1H), 5.38 (s, 2H), 6.09 (bs, 2H), 6.56 (s, 1H), 7.56 (dd, J=8.6, 1.0 Hz, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.94 (s, 1H), 11.52 (s, 1H).

1. customInto a 25 mL sealable tube under nitrogen were combined
2. customthe resulting mixture was degassed with nitrogen for 10 minutes
3. customthe vessel was sealed
4. temperatureThe reaction was cooled to room temperature
5. customthe solids and other insoluble impurities formed during the reaction
6. filtrationwere filtered
7. concentrationthe filtrate was concentrated
8. customThe resulting solid was partitioned between EtOAc and water
9. extractionextracted with EtOAc (2×) and CH2Cl2 (2×)
10. washThe combined organic layers were washed with water and brine
11. dry with materialdried (MgSO4)
12. filtrationfiltered
13. concentrationconcentrated
14. customFlash chromatography on SiO2 (gradient: 100% CHCl3 to 90/10/1 CHCl3/CH3OH/NH4OH) afforded
15. customIn a 25 mL sealable tube under nitrogen were combined
16. customThe vial was sealed
17. stirringthe reaction mixture was stirred at 100° C. for 2 days
18. filtrationThe reaction was filtered
19. customto remove some impurities
20. concentrationthe filtrate was concentrated
21. dissolutionThe resulting solid was dissolved in a mixture of CH3CN/H2O/DMSO
22. custompurified on a Gilson RPHPLC (CH3CN/H2O w/0.1% TFA)
23. customThe CH3CN was evaporated
24. additionsaturated aqueous NaHCO3 was added to the remaining water where a precipitate
25. filtrationThe precipitate was filtered
26. customtriturated in Et2O
27. customdried in vacuo

ORD record

ord-e63b8e16d85e4ec7b16e973475d28121

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08697685B2