Benzaldehyde → 5-[(1R)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine

HRID 1864275Notes

Reaction equation

HRID 1864275 reaction equation
C(=O)C1C=CC=CC=1.[NH2:9][CH2:10][C@@H:11]([CH3:32])[O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([Cl:31])[CH:25]=1)=[N:16][CH:17]=[N:18]2.C(=O)([O-])[O-].[K+].[K+].Cl.[N:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46]Cl.O1CCOCCOCCOCCOCCOCC1>CN(C=O)C>[NH2:9][CH2:10][C@@H:11]([CH3:32])[O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:46][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][N:40]=3)=[C:26]([Cl:31])[CH:25]=1)=[N:16][CH:17]=[N:18]2

Participants

7

Reactant 5

HCID 240BenzaldehydeHCID 11430Potassium CarbonateHCID 23392Picolyl chloride hydrochlorideHCID 2855718-Crown-6HCID 575019434-({5-[(1R)-2-amino-1-methylethoxy]quinazolin-4-yl}amino)-2-chlorophenol

Product 1

HCID 690596285-[(1R)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amineYield 100%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Benzaldehyde (1.46 ml, 14.3 mmol) was added to a solution of 4-({5-[(1R)-2-amino-1-methylethoxy]quinazolin-4-yl}amino)-2-chlorophenol (obtained as described in Example 4.4, preparation of starting materials, 4.5 g, 13.08 mmol) in DMF (50 ml) and the mixture was stirred for 20 minutes. Potassium carbonate (7.23 g, 52.32 mmol), picolyl chloride hydrochloride (2.57 g, 15.70 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6/catalytic amount) were added and the reaction mixture was stirred vigorously for 16 hours. The reaction mixture was concentrated, the residue was stirred in water (250 ml) and the precipitated solid was filtered off. The solid was dissolved in 1M HCl (150 ml) and the solution washed with ethyl acetate (3×50 ml). The aqueous phase was basified with 2M NaOH and the resultant precipitate was filtered off to give 5-[(1R)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (5.69 g, 100%); NMR spectrum (DMSO-d6) 1.39 (d, 3H), 2.88-3.05 (m, 2H), 4.74-4.86 (m, 1H), 5.28 (s, 2H), 7.14-7.25 (m, 2H), 7.30 (d, 1H), 7.33-7.40 (m, 1H), 7.57 (d, 1H), 7.65 (dd, 1H), 7.70 (dt, 1H), 7.87 (dt, 1H), 8.20 (d, 1H), 8.49 (s, 1H), 8.56-8.61 (m, 1H).

Workup

  1. stirringthe reaction mixture was stirred vigorously for 16 hours
  2. concentrationThe reaction mixture was concentrated
  3. stirringthe residue was stirred in water (250 ml)
  4. filtrationthe precipitated solid was filtered off
  5. dissolutionThe solid was dissolved in 1M HCl (150 ml)
  6. washthe solution washed with ethyl acetate (3×50 ml)
  7. filtrationthe resultant precipitate was filtered off

Sources & evidence

ORD record
ord-79eaf3c60e8643d6b95f680f4cd7ab57
Source dataset
uspto-grants-2009_12
Patent number
US07625908B2

Reaction notes

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