Toluene → N-Cyclopropylmethyl-6-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinamide

HRID 1514682Notes

Reaction equation

C[Al](C)C.[NH2:5][CH2:6][CH:7]1[CH2:9][CH2:8]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[C:22]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[N:23][O:24][C:25]=2[CH2:26][OH:27])=[N:15][CH:14]=1.C1(C)C=CC=CC=1>O1CCOCC1>[CH:7]1([CH2:6][NH:5][C:12](=[O:11])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:22]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)=[N:23][O:24][C:25]=3[CH2:26][OH:27])=[N:15][CH:14]=2)[CH2:9][CH2:8]1

Participants

Conditions

Temperature: 85 °C

Procedure

A trimethylaluminium solution (2 M in toluene, 418 μL, 0.84 mmol) was added to a solution of aminomethylcyclopropane (61.3 mg, 0.84 mmol) in dioxane (3.75 mL). 6-[3-(4-Fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (75.0 mg, 0.21 mmol) in dioxane (3.75 mL) was added after 1 h at 50° C. The reaction mixture was stirred at 85° C. overnight. Again trimethylaluminium solution in toluene (2 M in toluene, 418 μL, 0.84 mmol) was added and stirring was continued for 3 h at 85° C. The solvent was removed by distillation. The residue was purified by chromatography (silica, ethyl acetate:heptane=4:6 to 8:2) to yield the title compound (30 mg, 36%) as a light yellow solid. MS: m/e=398.2 [M+H]+.

Workup

stirringstirring
waitwas continued for 3 h at 85° C
customThe solvent was removed by distillation
customThe residue was purified by chromatography (silica, ethyl acetate:heptane=4:6 to 8:2)

Sources & evidence

ORD record: ord-e2fc6d0b65dd4829981749bbd6395fa5
Source dataset: uspto-grants-2012_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08222246B2

Reaction notes

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