2-Chloroethyl isocyanate → N-(2-Chloroethyl)-N'-((2R)-2-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)urea

HRID 1864342Notes

Reaction equation

[Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[NH2:7][CH2:8][C@@H:9]([CH3:37])[O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[C:24]([CH3:36])[CH:23]=1)=[N:14][CH:15]=[N:16]2>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][C@H:9]([O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[C:24]([CH3:36])[CH:23]=1)=[N:14][CH:15]=[N:16]2)[CH3:37])=[O:6]

Participants

Conditions

Temperature: 0 °C

Procedure

Chloroethylisocyanate (116 μl, 1.36 mmol) was added drop wise to an ice-cooled solution of 5-[(1R)-2-amino-1-methylethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (516 mg, 1.24 mmol, obtained as described in Example 112, preparation of starting materials) in DCM (10 ml). The mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 3% to 5% 7N ammonia-methanol in DCM) to give the title compound (584 mg, 74%); NMR Spectrum: (CDCl3) 1.46 (d, 3H), 2.28 (s, 3H), 2.52 (s, 3H), 3.46 (m, 1H), 3.57 (m, 4H), 4.00 (m, 1H), 4.76 (m, 1H), 6.40 (m, 1H), 6.62 (m, 1H), 6.67 (d, 1H), 6.91 (d, 1H), 7.08 (d, 1H), 7.12 (dd, 1H), 7.18 (d, 1H), 7.34 (t, 1H), 7.53 (dd, 1H), 7.67 (s, 1H), 8.27 (s, 1H), 8.34 (s, 1H), 9.82 (s, 1H); Mass spectrum: MH+ 521.

Workup

customAfter evaporation of the solvents
customthe residue was purified by chromatography on silica gel (eluant: 3% to 5% 7N ammonia-methanol in DCM)

Sources & evidence

ORD record: ord-e2794eb4c745451fb53b15026113e5ae
Source dataset: uspto-grants-2009_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07625908B2

Reaction notes

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