1,4-Dioxane → 1-((S)-3-(4-(4-methyl-[1,4]-diazepan-1-yl)quinazolin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone

HRID 1666601Notes

Reaction equation

HRID 1666601 reaction equation
Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[NH2:21][C@H:22]1[CH2:26][CH2:25][N:24]([C:27](=[O:40])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[CH2:23]1.O1CCOCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:19][N:15]1[CH2:16][CH2:17][CH2:18][N:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH:21][C@H:22]3[CH2:26][CH2:25][N:24]([C:27](=[O:40])[CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:33][CH:34]=4)[CH2:23]3)[N:11]=2)[CH2:13][CH2:14]1

Participants

8

Reactant 4

HCID 312751,4-DioxaneHCID 23676156Sodium t-butoxideHCID 579701972-Chloro-4-(4-methyl-[1,4]-diazepan-1-yl)quinazolineHCID 86636479(S)-1-(3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride

Product 1

HCID 579701731-((S)-3-(4-(4-methyl-[1,4]-diazepan-1-yl)quinazolin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanoneYield 62.8%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

To a mixture of 2-chloro-4-(4-methyl-[1,4]-diazepan-1-yl)quinazoline (0.10 g), Pd2(dba)3 (0.017 g), (±)-BINAP (0.034 g), (S)-1-(3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (0.13 g), and 1,4-dioxane (2 mL) was added sodium t-butoxide (0.10 g) under nitrogen atmosphere, and the mixture was stirred at 80° C. for 3 h. The reaction mixture was diluted with ethyl acetate and water, then the interlayer was removed by Celite filtration, and the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate−ethyl acetate/methanol=10:1) to obtain colorless amorphous 1-((S)-3-(4-(4-methyl-[1,4]-diazepan-1-yl)quinazolin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.12 g).

Workup

  1. customthe interlayer was removed by Celite filtration
  2. washthe organic layer was washed with saturated brine
  3. dry with materialThe organic layer was dried with anhydrous magnesium sulfate
  4. customthe desiccant was removed by filtration
  5. concentrationthe filtrate was concentrated under reduced pressure
  6. customthe residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate−ethyl acetate/methanol=10:1)

Sources & evidence

ORD record
ord-6a80c4a4fdd54cd885c65615e6689943
Source dataset
uspto-grants-2011_10
Patent number
US08044068B2

Reaction notes

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