Carbon tetrabromide → (2S)-4-Bromo-2-hydroxy-N-((2R)-2-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)butanamide

HRID 1864341Notes

Reaction equation

HRID 1864341 reaction equation
C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C@@H:21]([CH2:55][CH2:56]O)[C:22]([NH:24][CH2:25][C@H:26]([O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[C:31]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][C:47]3[CH:48]=[N:49][C:50]([CH3:53])=[CH:51][CH:52]=3)=[C:42]([CH3:54])[CH:41]=1)=[N:32][CH:33]=[N:34]2)[CH3:27])=[O:23].C(Br)(Br)(Br)[Br:59]>C(Cl)Cl>[Br:59][CH2:56][CH2:55][C@H:21]([OH:20])[C:22]([NH:24][CH2:25][C@H:26]([O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[C:31]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][C:47]3[CH:48]=[N:49][C:50]([CH3:53])=[CH:51][CH:52]=3)=[C:42]([CH3:54])[CH:41]=1)=[N:32][CH:33]=[N:34]2)[CH3:27])=[O:23]

Participants

5

Reactant 3

HCID 11205Carbon tetrabromideHCID 11776TriphenylphosphineHCID 57974365(2S)-2,4-Dihydroxy-N-((2R)-2-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)butanamide

Product 1

HCID 57974289(2S)-4-Bromo-2-hydroxy-N-((2R)-2-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)butanamideYield 74.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Triphenylphosphine (650 mg, 2.5 mmol) was added portion wise over 30 minutes to a solution of (2S)-2,4-dihydroxy-N-((2R)-2-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)butanamide (856 mg, 1.65 mmol, obtained as described in Example 112) and carbon tetrabromide (658 mg, 2 mmol) in DCM (10 ml). The mixture was stirred overnight at room temperature. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 2% to 5% 7N ammonia-methanol in DCM) to give the title compound (712 mg, 74%) as a solid; NMR Spectrum: (CDCl3) 1.53 (d, 3H), 2.07 (m, 1H), 2.28 (s, 3H), 2.38 (m, 1H), 2.52 (s, 3H), 3.51 (t, 2H), 3.80-3.65 (m, 2H), 4.34 (dd, 1H), 4.95 (m, 1H), 6.90 (m, 2H), 7.09 (d, 1H), 7.14 (dd, 1H), 7.28 (m, 1H), 7.50 (m, 3H), 7.63 (s, 1H), 8.23 (s, 1H), 8.44 (s, 1H); Mass spectrum: MH+ 580, 582.

Workup

  1. customAfter evaporation of the solvents
  2. customthe residue was purified by chromatography on silica gel (eluant: 2% to 5% 7N ammonia-methanol in DCM)

Sources & evidence

ORD record
ord-51dfb657a8364bbfad07d73acae67beb
Source dataset
uspto-grants-2009_12
Patent number
US07625908B2

Reaction notes

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