Ammonia → HCID 68552689, compound

A solution of 1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)-2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethanone (825 mg, 1.832 mmol) in DCM (5 mL) was treated with ammonia (9.16 mL of a 2.0 M solution in EtOH, 18.32 mmol) and stirred at RT in a sealed flask for 20 min. The flask was then charged with titanium(IV) isopropoxide (2.163 mL, 7.33 mmol) and re-sealed. The reaction mixture was stirred at RT for 16 h before being treated with sodium borohydride (0.259 mL, 7.33 mmol) in small portions. The resulting mixture was stirred at RT for 30 min, after which time the mixture had become thick and foamy. DCM (5 mL) was added to the reaction mixture in order to facilitate stirring and the reaction continued for an additional 1.5 h. After this time, the mixture was treated with concentrated ammonium hydroxide (10 mL) and DCM (15 mL), stirred vigorously at RT for 20 min and then filtered through Celite. The filtrate was placed in a separatory funnel and the phases were separated. The aqueous phase was extracted with DCM, and the combined DCM extracts were dried (Na2SO4) and concentrated on a rotary evaporator to give the crude product. The crude product was purified by flash chromatography (40 g silica gel cartridge; 40% EtOAc/Hex used to elute the less polar materials; 3% MeOH in EtOAc used to elute the amine) to afford 1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)-2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethanamine (500 mg, 1.108 mmol, 60% yield) as a clear gum. LC-MS: 451.19, [M+H]+; tR=3.07 min (b).

1. customre-sealed
2. stirringThe reaction mixture was stirred at RT for 16 h
3. stirringThe resulting mixture was stirred at RT for 30 min
4. stirringto facilitate stirring
5. waitthe reaction continued for an additional 1.5 h
6. stirringstirred vigorously at RT for 20 min
7. filtrationfiltered through Celite
8. customThe filtrate was placed in a separatory funnel
9. customthe phases were separated
10. extractionThe aqueous phase was extracted with DCM
11. dry with materialthe combined DCM extracts were dried (Na2SO4)
12. concentrationconcentrated on a rotary evaporator
13. customto give the crude product
14. customThe crude product was purified by flash chromatography (40 g silica gel cartridge
15. washto elute the less polar materials
16. washto elute the amine)

ORD record

ord-43df8a6398d549f8a95bb532b99da328

Source dataset

uspto-grants-2013_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08354432B2