4-(Trifluoromethyl)aniline → Methyl 3-methyl-2-(3-(4-(3-(4-(trifluoromethyl)phenyl)ureido)phenyl)isoxazole-5-carboxamido)butanoate

HRID 75830Notes

Reaction equation

[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH:15][CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.[F:24][C:25]([F:34])([F:33])[C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[C:35](C1NC=CN=1)(C1NC=CN=1)=[O:36]>C1COCC1>[CH3:22][CH:21]([CH3:23])[CH:16]([NH:15][C:13]([C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:35]([NH:30][C:29]3[CH:31]=[CH:32][C:26]([C:25]([F:33])([F:34])[F:24])=[CH:27][CH:28]=3)=[O:36])=[CH:3][CH:4]=2)[CH:12]=1)=[O:14])[C:17]([O:19][CH3:20])=[O:18]

Participants

Conditions

Temperature: 65 °C

Procedure

To Methyl 2-(3-(4-aminophenyl)isoxazole-5-carboxamido)-3-methylbutanoate (example 151, step 3, 500 mg) dissolved in THF (10 ml) were added 4-(trifluoromethyl)aniline (254 mg) and carbonyl diimidazole (283 mg) and heated to reflux at 65° C. overnight. THF was removed completely under reduced pressure to get pale brown residue which was purified by silica gel column chromatography in 3:7 EtOAc: CHCl3 to get off white solid which was crystallized from methylene chloride to yield 375 mg (47%) off white solid. MS (ES+): m/z 505 (M+1); 1HNMR (DMSO-d6, 300 MHz): δ 9.19 (s, 1H), 9.18 (d, 1H), 9.09 (s, 1H), 7.85 (d, 2H), 7.67 (s, 1H), 7.65 (d, 2H), 7.63 (d, 2H), 7.6 (d, 2H), 4.29 (m, 1H), 3.66 (s, 3H), 2.2 (m, 1H), 0.95 (d, 6H).

Workup

temperatureheated
customTHF was removed completely under reduced pressure
customto get pale brown residue which
customwas purified by silica gel column chromatography in 3:7 EtOAc
customCHCl3 to get off white solid which
customwas crystallized from methylene chloride
customto yield 375 mg (47%) off white solid

Sources & evidence

ORD record: ord-86d102d0bbe34a5fb9c6a262f2b4f278
Source dataset: uspto-grants-2014_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08835428B2

Reaction notes

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