Hydrochloric Acid → HCID 86622859, compound

Temperature

95 °C

Place 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (prepared essentially as described in Preparation 1) (3 g, 7.08 mmol) in toluene (60 mL) with 3-(2-methyl-[1,3]dioxolan-2-yl)-propylamine (prepared essentially as described in Preparation 38) (3.08 g, 21.24 mmol), tris(dibenzylideneacetone)dipalladium (1.3 g, 1.42 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binapthyl (1.77 g, 2.84 mmol), and cesium carbonate (3.3 g, 9.91 mmol) and heat for 16 h at 95° C. in a sealed tube. Cool the reaction to RT, dilute with EtOAc (600 mL) and filter. Concentrate the filtrate and purify (silica gel chromatography, eluting with 10:90 to 25:75 EtOAc:hexanes) to give the crude product as an orange oil (1.72 g). Dissolve 7-chloro-3-(2,2,2-trifluoroacetyl)-6-[3-(2-methyl[1,3]dioxolan-2-yl)-propylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.72 g, 4.09 mmol) in DCM (20 mL) and add methanol (2 mL) and 2 N HCl in diethyl ether (20 mL) and stir at RT for 3 h. Concentrate and dissolve the residue in acetic acid (30 mL) and add sodium cyanoborohydride (1.28 g, 20.43 mmol). Stir the reaction at RT for 0.5 h then concentrate to remove the acetic acid. Dissolve the residue in DCM (200 mL) and extract with saturated aqueous sodium bicarbonate solution (400 mL), Extract the aqueous layer with DCM (100 mL) and combine the organic fractions, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 10:90 EtOAc:hexanes) to give the title compound as a foam (1.2 g, 81%).

1. customprepared essentially
2. temperatureCool
3. customthe reaction to RT
4. filtrationfilter
5. concentrationConcentrate the filtrate
6. custompurify
7. wash(silica gel chromatography, eluting with 10:90 to 25:75 EtOAc:hexanes)
8. customto give the crude product as an orange oil (1.72 g)
9. concentrationConcentrate
10. dissolutiondissolve the residue in acetic acid (30 mL)
11. stirringStir
12. customthe reaction at RT for 0.5 h
13. concentrationthen concentrate
14. customto remove the acetic acid
15. dissolutionDissolve the residue in DCM (200 mL)
16. extractionextract with saturated aqueous sodium bicarbonate solution (400 mL)
17. extractionExtract the aqueous layer with DCM (100 mL)
18. dry with materialdry (sodium sulfate)
19. concentrationconcentrate
20. custompurify
21. wash(silica gel chromatography, eluting with 10:90 EtOAc:hexanes)

ORD record

ord-c22474ca54ec40f59dfcd8a782ea4786

Source dataset

uspto-grants-2011_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07981882B2