2-Chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol → 4-[(5-{(1R)-2-[allyl(methyl)amino]-1-methylethoxy}quinazolin-4-yl)amino]-2-chlorophenol

HRID 1864198Notes

Reaction equation

HRID 1864198 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3F)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:20].[CH2:21]([N:24]([CH3:29])[CH2:25][C@H:26]([OH:28])[CH3:27])[CH:22]=[CH2:23]>CC(N(C)C)=O.[H-].[Na+]>[CH2:21]([N:24]([CH3:29])[CH2:25][C@@H:26]([CH3:27])[O:28][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([OH:20])=[C:2]([Cl:1])[CH:7]=1)=[N:10][CH:11]=[N:12]2)[CH:22]=[CH2:23]

Participants

5

Reactant 2

HCID 574449782-Chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenolHCID 86615686(2R)-1-[allyl(methyl)amino]propan-2-ol

Product 1

HCID 690577904-[(5-{(1R)-2-[allyl(methyl)amino]-1-methylethoxy}quinazolin-4-yl)amino]-2-chlorophenolYield 68.3%

Reagents, catalysts & solvents 2

HCID 24758Sodium hydrideSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
110 °C

Procedure

2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol (2 g) was added to a stirred solution of (2R)-1-[allyl(methyl)amino]propan-2-ol (2.24 g, prepared as described in Example 2-3) in DMA (100 ml) and sodium hydride (60% dispersion in oil, 692 mg), and the mixture heated to 110° C. for 16 hours. The mixture was concentrated in vacuo then a saturated solution of sodium bicarbonate (200 ml) was added and extracted with DCM (300 ml). The extract washed with brine, dried and concentrated in vacuo and the residue purified by chromatography using DCM—10% methanol/2N ammonia as eluent to give 4-[(5-{(1R)-2-[allyl(methyl)amino]-1-methylethoxy}quinazolin-4-yl)amino]-2-chlorophenol as a yellow solid (1.88 g, 68%); NMR spectrum (DMSO-d6) 1.43 (d, 3H), 2.17 (s, 3H), 2.54 (dd, 1H), 2.97 (m, 3H), 4.94 (m, 1H), 5.00 (dd, 1H), 5.10 (dd, 1H), 5.63 (m, 1H), 6.98 (d, 1H), 7.18 (d, 1H), 7.29 (d, 1H), 7.42 (dd, 1H), 7.69 (t, 1H), 7.84 (d, 1H), 8.44 (s, 1H), 10.01 (bs, 1H), 10.26 (s, 1H); Mass spectrum MH+ 399.

Workup

  1. concentrationThe mixture was concentrated in vacuo
  2. additiona saturated solution of sodium bicarbonate (200 ml) was added
  3. extractionextracted with DCM (300 ml)
  4. washThe extract washed with brine
  5. customdried
  6. concentrationconcentrated in vacuo
  7. customthe residue purified by chromatography

Sources & evidence

ORD record
ord-693ed1feb24c4e58adf295846318263f
Source dataset
uspto-grants-2009_12
Patent number
US07625908B2

Reaction notes

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