Tributylphosphine → 4-(4-Chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-ylmethoxy)quinazoline

HRID 1838548Notes

Reaction equation

HRID 1838548 reaction equation
N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1.[CH3:41][N:42]1[CH2:47][CH2:46][CH2:45][CH:44]([CH2:48]O)[CH2:43]1.C(P(CCCC)CCCC)CCC>C(Cl)Cl.CCOCC>[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:48][CH:44]4[CH2:45][CH2:46][CH2:47][N:42]([CH3:41])[CH2:43]4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1

Participants

7

Reactant 4

HCID 13831TributylphosphineHCID 730421,1'-(Azodicarbonyl)dipiperidineHCID 97998(1-Methyl-3-piperidyl)methanolHCID 1355137204-(4-Chloro-2-fluorophenylamino)-7-hydroxy-6-methoxyquinazoline

Product 1

HCID 224781994-(4-Chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-ylmethoxy)quinazolineYield 33%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolvent

Procedure

1,1′-(Azodicarbonyl)dipiperidine (560 mg, 2.2 mmol) was added in portions to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (240 mg, 0.75 mmol), (prepared as described for the starting material in Example 2), 1-methyl-3-piperidinemethanol (115 mg, 0.89 mmol) and tributylphosphine (440 mg, 2.2 mmol) in methylene chloride (10 ml). The mixture was stirred for 18 hours, diluted with ether and the resulting precipitate was removed by filtration. The volatiles were removed from the filtrate by evaporation, and the residue was dissolved in acetone and ethereal hydrogen chloride (1.5 ml of a 1M solution, 1.5 mmol) was added. The precipitated product was collected by filtration and purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (75/8/1). The purified solid product was triturated with ether collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-ylmethoxy)quinazoline (105 mg, 33%).

Workup

  1. custom(prepared
  2. customthe resulting precipitate was removed by filtration
  3. customThe volatiles were removed from the filtrate by evaporation
  4. dissolutionthe residue was dissolved in acetone
  5. additionethereal hydrogen chloride (1.5 ml of a 1M solution, 1.5 mmol) was added
  6. filtrationThe precipitated product was collected by filtration
  7. custompurified by column chromatography
  8. washeluting with methylene chloride/methanol/aqueous ammonia (75/8/1)
  9. customThe purified solid product was triturated with ether
  10. filtrationcollected by filtration
  11. customdried

Sources & evidence

ORD record
ord-e9ca05b953f347cc8e5aa57f7ffa90fc
Source dataset
uspto-grants-2004_01
Patent number
US06673803B2

Reaction notes

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