1,4-Dioxane → HCID 68501953, compound

HRID 1712002Notes

Reaction equation

HRID 1712002 reaction equation
Cl.Cl[C:3]1[N:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[F:21])[C:10]2[C:5](=[CH:6][C:7]([O:24][CH3:25])=[C:8]([O:22][CH3:23])[CH:9]=2)[N:4]=1.Cl.Cl.[CH3:28][N:29]([CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[C:30](=[O:37])[C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[CH3:36].N12CCCN=C1CCCCC2.O1CCOCC1>O.C(OCC)(=O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:24][CH3:25])=[C:8]([O:22][CH3:23])[CH:9]=3)[N:4]=[C:3]([N:41]3[CH2:40][CH2:39][CH:38]([N:29]([CH3:28])[C:30](=[O:37])[C@@H:31]4[CH2:35][CH2:34][CH2:33][N:32]4[CH3:36])[CH2:43][CH2:42]3)[N:12]=2)=[C:15]([F:21])[CH:16]=1

Participants

7

Reactant 4

HCID 312751,4-DioxaneHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 68508375HCID 68508375, compoundHCID 86630491HCID 86630491, compound

Product 1

HCID 68501953HCID 68501953, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

2-Chloro-N-(4-chloro-2-fluorophenyl)-6,7-dimethoxyquinazoline-4-amine hydrochloride (405 mg), N,1-dimethyl-N-piperidin-4-yl-L-prolinamide dihydrochloride (447 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (608 mg) were added to 1,4-dioxane (20 mL), followed by heating under reflux for 24 hours. After concentration of the reaction solution, ethyl acetate and water were added to the residue, the organic layer was separated, and the water layer was further extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over magnesium sulfate and then filtered. The solvent was evaporated under a reduced pressure. By purifying the residue by silica gel flash column chromatography (chloroform-MeOH), N-(1-{4-[(4-chloro-2-fluorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}piperidin-4-yl)-N,1-dimethyl-L-prolinamide was obtained. This was dissolved in ethyl acetate (10 mL), and 4 M HCl/ethyl acetate solution (0.5 mL) was added thereto. By evaporating the solvent under a reduced pressure and recrystallizing the resulting residue from EtOH-diethyl ether, N-(1-{4-[(4-chloro-2-fluorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}piperidin-4-yl)-N,1-dimethyl-L-prolinamide dihydrochloride (155 mg) was obtained as pale yellow powder.

Workup

  1. temperatureby heating
  2. temperatureunder reflux for 24 hours
  3. customthe organic layer was separated
  4. extractionthe water layer was further extracted with ethyl acetate
  5. washThe combined organic layer was washed with saturated brine
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. customThe solvent was evaporated under a reduced pressure
  9. customBy purifying the residue by silica gel flash column chromatography (chloroform-MeOH)

Sources & evidence

ORD record
ord-6955480a7c434f00ad99bd8c214057aa
Source dataset
uspto-grants-2010_09
Patent number
US07790884B2

Reaction notes

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