Benzoyl chloride → HCID 51354327, compound

Sodium bicarbonate (145 mg, 1.73 mmol) was added to a solution of 6-[2-amino-6-(3-amino-1-piperidinyl)-4-pyrimidinyl]-1H-indazol-3-amine trihydrochloride (150 mg, 0.346 mmol) in water (1.5 mL) with stirring. Tetrahydrofuran (THF) (1.5 mL) was added, the mixture was cooled in an ice bath, and benzoyl chloride (0.044 mL, 0.380 mmol) was added dropwise with stirring. The mixture was then warmed to room temperature and stirred for 2 hours. LCMS showed starting material remaining, product, and bis-benzoylation. An additional 40 uL of benzoyl chloride and 145 mg of NaHCO3 were added, and the mixture was stirred for 1 hour. HPLC showed complete conversion to multi-benzoylated product. The reaction was diluted with EtOAc, washed with water, dried (Na2SO4), filtered and evaporated. The crude was suspended in CH3OH (8 mL), 1 mL of concentrated aqueous HCL was added, and the mixture was stirred 3 days at 65° C. HPLC showed conversion to the desired product. The mixture was concentrated to ˜2 mL, then diluted with CH3CN (˜8 mL) and heated. Additional CH3CN was added to the hot solution until turbid. The mixture was allowed to cool slowly to room temperature with strring over 2 hours. The precipitate was collected by filtration, washed with CH3CN, then Et2O and finally hexanes. Drying afforded the title compound (156 mg) dihydrochloride as an off-white solid. A 100 mg portion was purified further by Gilson automated reverse phase HPLC (Gemini Phenomenex C18 5u, 100×300 mm), eluting with 5-90% CH3CN-water+0.1% NH4OH) to give the title compound (55 mg) as a white solid. LC-MS (ES) m/z=429 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.43-1.60 (m, 1H), 1.60-1.74 (m, 1H), 1.76-1.86 (m, 1H), 1.92-2.03 (m, 1H), 2.87-3.00 (m, 2H), 3.83-3.95 (m, 1H), 4.27-4.39 (m, 1H), 4.49 (bs, 1H), 5.38 (s, 2H), 6.12 (s, 2H), 6.64 (s, 1H), 7.46 (t, J=7.3 Hz, 2H), 7.50-7.54 (m, 1H), 7.54-7.61 (m, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.87 (d, J=7.1 Hz, 2H), 7.94 (s, 1H), 8.39 (d, J=7.6 Hz, 1H), 11.52 (s, 1H).

1. temperaturethe mixture was cooled in an ice bath
2. stirringwith stirring
3. stirringstirred for 2 hours
4. stirringthe mixture was stirred for 1 hour
5. washwashed with water
6. dry with materialdried (Na2SO4)
7. filtrationfiltered
8. customevaporated
9. addition1 mL of concentrated aqueous HCL was added
10. stirringthe mixture was stirred 3 days at 65° C
11. concentrationThe mixture was concentrated to ˜2 mL
12. additiondiluted with CH3CN (˜8 mL)
13. temperatureheated
14. additionAdditional CH3CN was added to the hot solution until turbid
15. temperatureto cool slowly to room temperature
16. filtrationThe precipitate was collected by filtration
17. washwashed with CH3CN
18. customDrying

ORD record

ord-d011367dfc744e9193dba1e0d62b10a9

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08697685B2