Tetrahydrofuran → HCID 57970126, compound

HRID 1666599Notes

Reaction equation

HRID 1666599 reaction equation
[Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([F:13])=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][N:15]([CH3:24])[C:16]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17].C(N(CC)CC)C.C1COCC1>C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+].CN(C=O)C>[CH3:14][N:15]([CH3:24])[C:16]([CH:18]1[CH2:19][CH2:20][N:21]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([F:13])=[CH:7][CH:8]=3)[N:3]=[C:2]([Cl:1])[N:11]=2)[CH2:22][CH2:23]1)=[O:17]

Participants

8

Reactant 4

HCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 411689N,N-dimethylpiperidine-4-carboxamideHCID 214739902,4-Dichloro-7-fluoroquinazoline

Product 1

HCID 57970126HCID 57970126, compoundYield 104.9%

Reagents, catalysts & solvents 3

HCID 6212ChloroformSolventHCID 6228DimethylformamideSolventHCID 516892Sodium BicarbonateSolvent

Procedure

A mixture of 2,4-dichloro-7-fluoroquinazoline (250 mg), piperidine-4-carboxylic acid dimethylamide (189 mg), triethylamine (0.24 mL), THF (6 mL), and DMF (4 mL) was stirred at room temperature for 13 h. The reaction mixture was diluted with a mixture of chloroform and saturated aqueous sodium hydrogencarbonate, and then the aqueous layer was extracted 3 times with chloroform. The organic layer was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7:3) to obtain colorless solid 1-(2-chloro-7-fluoroquinazolin-4-yl)piperidine-4-carboxylic acid dimethylamide (407 mg). (2) A mixture of 1-(2-chloro-7-fluoroquinazolin-4-yl)piperidine-4-carboxylic acid dimethylamide (250 mg), 1-((S)-3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (265 mg), N,N-diisopropylethylamine (0.32 mL), and n-butanol (1.2 mL) was heated at 120° C. for 57 h with stirring. The reaction mixture was diluted with a mixture of chloroform and saturated aqueous sodium hydrogencarbonate, and then the aqueous layer was extracted with chloroform. The organic layer was dried with anhydrous sodium 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, hexane/ethyl acetate=4:1−ethyl acetate, and silica gel, chloroform/methanol=95:5). The resulting purification product was dissolved in ethyl acetate (2.0 mL), followed by addition of a solution (0.1 mL) of 4 M HCl in ethyl acetate, and the mixture was stirred at room temperature for 3.5 h. The solvent was evaporated under reduced pressure to obtain the amorphous title compound (110 mg).

Workup

  1. extractionthe aqueous layer was extracted 3 times with chloroform
  2. dry with materialThe organic layer was dried with anhydrous sodium sulfate
  3. customthe desiccant was removed by filtration
  4. concentrationthe filtrate was concentrated under reduced pressure
  5. customthe residue was purified by silica gel column chromatography (hexane/ethyl acetate=7:3)

Sources & evidence

ORD record
ord-96e00636f0414337838fda5c5ae1aca9
Source dataset
uspto-grants-2011_10
Patent number
US08044068B2

Reaction notes

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