Acetic Acid → 8-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine

HRID 473164Notes

Reaction equation

Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[N:3]=1.[NH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[N:26](C(OC(C)(C)C)=O)[N:25]=1.CC(O)=O>CC(N(C)C)=O>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[N:3]=[C:2]2[NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1

Participants

Conditions

Temperature: 100 °C

Procedure

To 4,8-dichloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline (263 mg, 0.77 mmol) in DMA (2.0 mL) were added tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate (300 mg, 1.53 mmol) and HOAc (0.102 mL), and the mixture was heated at 100° C. for 5 h. The mixture was allowed to cool to rt and was purified by preparative reverse-phase HPLC (diphenyl column eluting over 40 mins with a gradient of 25 to 80% acetonitrile (containing 0.05% HOAc) and water (containing 0.05% HOAc) to afford 8-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine as a colorless solid (51 mg, 16%). 1H NMR (300 MHz, DMSO-d6) δ 12.23 (br s, 1H), 10.87 (br s, 1H), 8.65-8.67 (m, 2H), 8.01-8.08 (m, 3H), 7.61 (dd, J=9, 6 Hz, 1H), 5.94 (s, 1H), 2.17 (s, 3H). LCMS (ESI) m/z 405 (M+H)+.

Workup

temperatureto cool to rt
customwas purified by preparative reverse-phase HPLC (diphenyl column
washeluting over 40 mins with a gradient of 25 to 80% acetonitrile (containing 0.05% HOAc) and water (containing 0.05% HOAc)

Sources & evidence

ORD record: ord-33071eada19343b39e71ebc78babd3b0
Source dataset: uspto-grants-2014_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08633207B2

Reaction notes

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