Ammonia → HCID 86666898, compound

Temperature

60 °C

Titanium tetraisopropoxide (3.0 mL, 10 mmol) was added to a mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propan-1-one (2.5 g, 8.6 mmol) and 2.0 M ammonia in ethanol (21.4 mL) at 0° C. The reaction was heated and stirred at 60° C. under nitrogen for 3 hours. The reaction was allowed to cool to room temperature, cooled in an ice bath and the sodium tetrahydroborate (0.486 g, 12.9 mmol) was added, the solution was stirred at room temperature for another 2 hours. The reaction mixture was quenched with 2 M ammonia in water, and was stirred to form the precipitate. The slurry was filtered, the solids were washed with EtOAc and the organic layer was concentrated in vacuo. The residue was diluted with methylene chloride, washed with sat'd NaHCO3, water, brine, dried over MgSO4, filtered and concentrated to give 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propan-1-amine as an oil. This was diluted with 1,4-dioxane (48 mL) and DIPEA (5.0 mL) and the di-tert-butyldicarbonate (2.81 g, 12.9 mmol) was added. The reaction was allowed to stir at room temperature overnight. The reaction was complete by LC/MS, and the reaction mixture was diluted with EtOAc and washed with 1 N HCl, brine, dried over magnesium sulfate and concentrated to give the crude product as an oil. The product was purified by chromatography on silica gel eluting with a hexane: EtOAc gradient to give tert-butyl [1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propyl]carbamate as a semisolid (2.0 g, 80%). LCMS calculated for C11H13BrClO (M+H)+: m/z=274.9, 276.9. found: 274.9, 276.8. This racemic material was separated by chiral column HPLC: ChiralPak AD-H 20×250 mm, 3% ethanol:hexane, 18 mL/min, loading 10 mg/mL, to give the separated enantiomers. Peak 2 tert-butyl [1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propyl]carbamate was used further in synthesis.

1. temperatureThe reaction was heated
2. temperatureto cool to room temperature
3. temperaturecooled in an ice bath
4. stirringthe solution was stirred at room temperature for another 2 hours
5. customThe reaction mixture was quenched with 2 M ammonia in water
6. stirringwas stirred
7. customto form the precipitate
8. filtrationThe slurry was filtered
9. washthe solids were washed with EtOAc
10. concentrationthe organic layer was concentrated in vacuo
11. additionThe residue was diluted with methylene chloride
12. washwashed with sat'd NaHCO3, water, brine
13. dry with materialdried over MgSO4
14. filtrationfiltered
15. concentrationconcentrated

ORD record

ord-fa6448d2d6c04816954bebb1d3068f30

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09096600B2