3-Chloro-4-fluoroaniline → tert-butyl (2R)-2-[({7-(benzyloxy)-4-[3-chloro-4-fluoroanilino]quinazolin-5-yl}oxy)methyl]pyrrolidine-1-carboxylate

HRID 1442992Notes

Reaction equation

[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[C:11]([O:20][CH2:21][C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][C:41]=1[F:42])[NH2:38].C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([F:42])=[C:35]([Cl:34])[CH:36]=3)=[N:14][CH:15]=[N:16]2)=[C:11]([O:20][CH2:21][C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

Conditions

Temperature: 70 °C

Procedure

The crude tert-butyl (2R)-2-({[7-(benzyloxy)-4-chloroquinazolin-5-yl]oxy}methyl)-pyrrolidine-1-carboxylate was taken up in THF (5 ml) and 3-chloro-4-fluoroaniline (160 mg) and N,N-diisopropylethylamine (580 μl) were each added in one portion and the solution was heated at 70° C. for 18 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to leave a thick brown oil. Purification by flash chromatography, using 1.5% methanol in DCM as eluent, gave the tert-butyl (2R)-2-[({7-(benzyloxy)-4-[3-chloro-4-fluoroanilino]quinazolin-5-yl}oxy)methyl]pyrrolidine-1-carboxylate as a beige foam (350 mg, 54% over 2 steps); Mass spectrum MH+ 481.

Workup

additioneach added in one portion
temperatureThe reaction mixture was cooled to room temperature
concentrationconcentrated in vacuo
customto leave a thick brown oil
customPurification by flash chromatography

Sources & evidence

ORD record: ord-110ea862e79f4175b380aaf2573b8840
Source dataset: uspto-grants-2010_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07659279B2

Reaction notes

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