Ethyl Acetate → 6-[2-(2-tert-Butoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy]nicotinamide

HRID 492535Notes

Reaction equation

[CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:33][CH2:34][O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=O)=O.C(OCC)(=O)C>CN(C=O)C>[C:36]([O:35][CH2:34][CH2:33][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)([CH3:39])([CH3:38])[CH3:37]

Participants

Conditions

Temperature: 70 °C

Procedure

Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 2-tert-butoxyethyl methanesulfonate (0.218 g, 1.11 mmol) in DMF (5.3 mL). Heat at 70° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1× 30 mL) and brine (1× 30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 384.2 (M+H)+, HRMS calcd for C22H30N3O3 384.2287 (M+H)+, found 384.2276, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=10.5 min, 97.7% purity.

Workup

temperatureCool the reaction mixture to room temperature
washWash with water (1× 30 mL) and brine (1× 30 mL)
dry with materialDry the organic layer over Na2SO4
filtrationfilter
concentrationconcentrate
customPurify by flash chromatography
washeluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate

Sources & evidence

ORD record: ord-e0c56e8240814511a27239dc9211526a
Source dataset: uspto-grants-2009_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07531557B2

Reaction notes

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