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N,N-Dimethylaniline → 4-Chloro-2-(chloromethyl)quinazoline

HRID 1876106
Notes
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Reaction equation

HRID 1876106 reaction equation
[Cl:1][CH2:2][C:3]1[N:12]=[C:11](N(C2C=CC(OC)=CC=2)C)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Cl:23]CC1NC(=O)C2C(=CC=CC=2)N=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:23][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([CH2:2][Cl:1])[N:12]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 949N,N-DimethylanilineHCID 24813Phosphorus oxychlorideHCID 11358914(2-Chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amineHCID 1354173742-(Chloromethyl)-4(3H)-quinazolinone

Product 1

HCID 131575204-Chloro-2-(chloromethyl)quinazoline

Reagents, catalysts & solvents 1

HCID 6212
Chloroform
Solvent

Procedure

(2-Chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: A mixture of 2-chloromethyl-quinazolin-4(3H)-one (256 mg, 1.32 mmol), phosphoryl chloride (1.23 ml, 13.2 mmol) and N,N-dimethylaniline (0.34 ml, 2.64 mmol) in chloroform (10 ml) was heated under reflux for 4 h. The reaction mixture was poured onto ice and extracted by ethyl acetate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel with acetate and hexane (1:1) as eluent, yielding 180 mg of 4-chloro-2-chloromethyl-quinazoline. The intermediate (170 mg, 0.80 mmol) and (4-methoxy-phenyl)-methylamine (131.7 mg, 0.96 mmol) in isopropyl alcohol (5 ml) with concentrated HCl (0.05 ml) was stirred at room temperature overnight. The precipitation was formed and collected by filtration, then washed and dried to give 231 mg (92%) of the title compound. 1H NMR (CDCl3): 7.82 (d, J=8.7 Hz, 1H), 7.59-7.53 (m, 1H), 7.15-7.12 (m, 2H), 7.03-7.00 (m, 2H), 6.95-6.91 (m, 2H), 4.73 (s, 2H), 3.85 (s, 3H), 3.62 (s, 3H).

Workup

  1. temperaturewas heated
  2. temperatureunder reflux for 4 h
  3. additionThe reaction mixture was poured onto ice
  4. extractionextracted by ethyl acetate
  5. customThe solvent was evaporated
  6. customthe residue was purified by column chromatography on silica gel with acetate and hexane (1:1) as eluent

Sources & evidence

ORD record
ord-789aa56febab460b9585b7b8796cd6f8
Source dataset
uspto-grants-2012_11
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08309562B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes