Ammonium Chloride → HCID 59276285, compound

Temperature

0 °C

3,3-Dimethyl-6-(5-(1-(tetrahydro-2H-pyran-4-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)indolin-2-one. (Trimethylsilylmethyl)-magnesium chloride (0.700 mL, 0.700 mmol, 1 M in diethyl ether) was added dropwise slowly to a stirred solution of tert-butyl 3,3-dimethyl-2-oxo-6-(5-(tetrahydro-2H-pyran-4-carbonyl)-[1,2,4]triazolo[1,5-c]pyridin-2-ylamino)indoline-1-carboxylate (0.118 g, 0.233 mmol) in tetrahydrofuran (10 mL) at −70° C. under nitrogen. The reaction mixture became dark red-colored upon addition of the Grignard reagent. The resulting mixture was stirred under nitrogen while slowly warming to 0° C. over 2 h. More (trimethylsilylmethyl)-magnesium chloride (0.233 mL, 0.233 mmol, 1 M in diethyl ether) was added and the resulting red solution was stirred at 0° C. under nitrogen for 35 min. More (trimethylsilylmethyl)-magnesium chloride (0.350 mL, 0.350 mmol, 1 M in diethyl ether) was added and the resulting mixture was stirred at 0° C. under nitrogen for 1.5 h. More (trimethylsilylmethyl)-magnesium chloride (0.350 mL, 0.350 mmol, 1 M in diethyl ether) was added and the resulting mixture was stirred at 0° C. under nitrogen for 1 h. Saturated aqueous ammonium chloride was added to quench the reaction. The resulting mixture was diluted with ethyl acetate and water and shaken in a separatory funnel. The layers were separated and the organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue was taken up in dichloromethane and purified using flash chromatography (Biotage) (20-100% ethyl acetate in hexane) to an impure white solid. MS (ESI) m/z 594.5 [M+H]+. To the white solids was added acetic acid (5 mL). The resulting mixture was stirred and heated at 120° C. under a reflux condenser for 85 h. The resulting mixture was filtered and purified using reverse-phase preparatory HPLC (10-60% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 30 min). Fractions containing the desired product were loaded onto a Strata X—C ion exchange column from Phenomenex. The column was washed successively with water, acetonitrile, methanol, and then a mixture of 5% ammonium hydroxide, 45% methanol, and 50% dichloromethane. The product came off with the ammonium hydroxide eluent and was concentrated on a rotary evaporator and dried under high vacuum to give the desired product (0.035 g, 0.087 mmol, 64% yield) as an off-white solid. MS (ESI) m/z 404.5 [M+1]+.

1. stirringthe resulting red solution was stirred at 0° C. under nitrogen for 35 min
2. stirringthe resulting mixture was stirred at 0° C. under nitrogen for 1.5 h
3. stirringthe resulting mixture was stirred at 0° C. under nitrogen for 1 h
4. customto quench
5. customthe reaction
6. stirringshaken in a separatory funnel
7. customThe layers were separated
8. washthe organics were washed with brine
9. dry with materialdried over magnesium sulfate
10. filtrationfiltered
11. concentrationconcentrated on a rotary evaporator
12. custompurified
13. additionTo the white solids was added acetic acid (5 mL)
14. stirringThe resulting mixture was stirred
15. temperatureheated at 120° C. under a reflux condenser for 85 h
16. filtrationThe resulting mixture was filtered
17. custompurified
18. customreverse-phase preparatory HPLC (10-60% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 30 min)
19. additionFractions containing the desired product
20. washThe column was washed successively with water, acetonitrile, methanol
21. additiona mixture of 5% ammonium hydroxide, 45% methanol, and 50% dichloromethane
22. concentrationwas concentrated on a rotary evaporator
23. customdried under high vacuum

ORD record

ord-f90c6e9eab9648df9b87bf05b7212a91

Source dataset

uspto-grants-2012_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08299056B2