Hydrogen Peroxide → di-tert-butyl 2-[[3-({4-[(1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-4-yl)amino]quinazolin-7-yl}oxy)propyl](propyl)amino]ethyl phosphite

HRID 640023Notes

Reaction equation

HRID 640023 reaction equation
C(N(CC)[P:4]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])C.[F:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:54])[CH2:26][N:27]2[CH:31]=[C:30]([NH:32][C:33]3[C:42]4[C:37](=[CH:38][C:39]([O:43][CH2:44][CH2:45][CH2:46][N:47]([CH2:51][CH2:52][OH:53])[CH2:48][CH2:49][CH3:50])=[CH:40][CH:41]=4)[N:36]=[CH:35][N:34]=3)[CH:29]=[N:28]2)[CH:21]=[CH:22][CH:23]=1.N1C=NN=N1.OO.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].C(=O)([O-])O.[K+]>CC(N(C)C)=O.O>[P:4]([O:53][CH2:52][CH2:51][N:47]([CH2:46][CH2:45][CH2:44][O:43][C:39]1[CH:38]=[C:37]2[C:42]([C:33]([NH:32][C:30]3[CH:29]=[N:28][N:27]([CH2:26][C:25]([NH:24][C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=4)=[O:54])[CH:31]=3)=[N:34][CH:35]=[N:36]2)=[CH:41][CH:40]=1)[CH2:48][CH2:49][CH3:50])([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14]

Participants

9

Reactant 6

HCID 784Hydrogen Peroxide2×HCID 516893Potassium BicarbonateHCID 656671Sodium PyrosulfiteHCID 4251849Di-tert-butyl diethylphosphoramiditeHCID 67259961N-(3-fluorophenyl)-2-{4-[(7-{3-[(2 hydroxyethyl)(propyl)amino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-1-yl}acetamideHCID 178418441HCID 178418441, compound

Product 1

HCID 68638976di-tert-butyl 2-[[3-({4-[(1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-4-yl)amino]quinazolin-7-yl}oxy)propyl](propyl)amino]ethyl phosphite

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 31374DimethylacetamideSolvent

Procedure

Di-tert-butyl diethylphosphoramidite (747 mg, 3 mmol) was added slowly to a solution of N-(3-fluorophenyl)-2-{4-[(7-{3-[(2 hydroxyethyl)(propyl)amino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-1-yl}acetamide (390 mg, 0.75 mmol) and tetrazole (158 mg, 2.25 mmol) in dimethylacetamide (4 ml) under nitrogen. The mixture was stirred at ambient temperature for 1 hour. Hydrogen peroxide (383 μl, 3.38 mmol, 30% aqueous solution) was added slowly at 0° C. and the reaction mixture stirred for 1.5 hours at ambient temperature. An additional portion of hydrogen peroxide (42 μl, 0.37 mmol) was added to the solution to complete the oxidation. The mixture was cooled to 0° C. and a saturated solution of sodium metabisulphite (7 ml of 0.53 M solution) added slowly with vigorous stirring. The mixture was stirred at ambient temperature for 20 minutes, diluted with water and the pH adjusted to 7 with an aqueous solution of potassium hydrogen carbonate. The reaction mixture was extracted with dichloromethane (3×25 ml) and the combined organics dried and concentrated in vacuo. Purification by silica gel chromatography, eluting with dichloromethane followed by increased polarity to dichloromethane:methanol:ammonia (20:1:0.1 to 20:3:0.2) gave di-tert-butyl 2-[[3-({4-[(1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-4-yl)amino]quinazolin-7-yl}oxy)propyl](propyl)amino]ethyl phosphite as a pale yellow oil. This intermediate was dissolved in dioxane (10 ml) and a solution of 4.0 N hydrochloric acid in dioxane (1.12 ml, 4.5 mmol) added. The mixture was stirred at ambient temperature for 18 hours. The solid was filtered, washed with dichloromethane and diethyl ether and dried in vacuo for 18 hours (50° C., 0.1 mm Hg) to yield compound 255 in table 11 as the dihydrochloride salt (375 mg, 70% yield):

Workup

  1. stirringthe reaction mixture stirred for 1.5 hours at ambient temperature
  2. temperatureThe mixture was cooled to 0° C.
  3. stirringThe mixture was stirred at ambient temperature for 20 minutes
  4. extractionThe reaction mixture was extracted with dichloromethane (3×25 ml)
  5. customthe combined organics dried
  6. concentrationconcentrated in vacuo
  7. customPurification by silica gel chromatography
  8. washeluting with dichloromethane
  9. temperatureby increased polarity to dichloromethane:methanol:ammonia (20:1:0.1 to 20:3:0.2)

Sources & evidence

ORD record
ord-b3f0e430a07a4f7295010db1da018d4a
Source dataset
uspto-grants-2010_04
Patent number
US07691867B2

Reaction notes

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