Tetrahydrofuran → 6-chloro-N-cyclohexyl-2-[2-(4-fluorophenyl)ethoxy]nicotinamide

HRID 1187367Notes

Reaction equation

Cl[C:2]1[C:7]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])=[CH:6][CH:5]=[C:4]([Cl:17])[N:3]=1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24][OH:25])=[CH:21][CH:20]=1.C1COCC1>O1CCOCC1>[Cl:17][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])=[C:2]([O:25][CH2:24][CH2:23][C:22]2[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=2)[N:3]=1

Participants

Conditions

Temperature: 150 °C

Procedure

2,6-dichloro-N-cyclohexylnicotinamide (Intermediate 1, 273 mg, 1 mmol) was stirred in 1,4-dioxane (4 ml). To this solution was added 4-fluorophenethyl alcohol (154 mg, 1.1 mmol) followed by bis-sodium hexamethyldisilylamide 1.0M in THF (1.1 ml, 1.1 mmol). The tube was sealed and subjected to microwave heating 150° C. (Biotage Initiator 300 W) for 2 hours. The solvent was evaporated and the residue was diluted with water (15 ml) and extracted with dichloromethane (2×20 ml). The combined extract was washed with brine (20 ml) dried over MgSO4, filtered and evaporated. The crude product was purified on SiO2 (40 g) eluting with ethyl acetate/isohexane 0-40% and gave 6-chloro-N-cyclohexyl-2-[2-(4-fluorophenyl)ethoxy]nicotinamide (153 mg, 40%) as a white solid

Workup

customThe tube was sealed
customThe solvent was evaporated
additionthe residue was diluted with water (15 ml)
extractionextracted with dichloromethane (2×20 ml)
extractionThe combined extract
washwas washed with brine (20 ml)
dry with materialdried over MgSO4
filtrationfiltered
customevaporated
customThe crude product was purified on SiO2 (40 g)
washeluting with ethyl acetate/isohexane 0-40%

Sources & evidence

ORD record: ord-4e93512bae9640d5acd6a18aef349882
Source dataset: uspto-grants-2014_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08673938B2

Reaction notes

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