1-Pyrrolidinamine → HCID 86636478, compound

HRID 1666600Notes

Reaction equation

HRID 1666600 reaction equation
NN1CCCC1.[CH3:7][N:8]([CH3:29])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=3)[N:20]=[C:19]([Cl:28])[N:18]=2)[CH2:13][CH2:12]1)=[O:10].Cl.[NH2:31][C@H:32]1[CH2:36][CH2:35][N:34]([C:37](=[O:50])[CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:41][CH:40]=2)[CH2:33]1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+].C(O)CCC>[ClH:28].[CH3:7][N:8]([CH3:29])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=3)[N:20]=[C:19]([NH:31][C@H:32]3[CH2:36][CH2:35][N:34]([C:37](=[O:50])[CH2:38][C:39]4[CH:40]=[CH:41][C:42]([O:45][C:46]([F:47])([F:48])[F:49])=[CH:43][CH:44]=4)[CH2:33]3)[N:18]=2)[CH2:13][CH2:12]1)=[O:10]

Participants

8

Reactant 4

HCID 279461-PyrrolidinamineHCID 81531DiisopropylethylamineHCID 57970126HCID 57970126, compoundHCID 86636479(S)-1-(3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride

Product 1

HCID 86636478HCID 86636478, compoundYield 23.7%

Reagents, catalysts & solvents 3

HCID 2631-ButanolSolventHCID 6212ChloroformSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
120 °C

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 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 (NH silica gel, hexane/ethyl acetate=4:1−ethyl acetate, and silica gel, chloroform/methanol=95:5)
  6. customThe resulting purification product
  7. dissolutionwas dissolved in ethyl acetate (2.0 mL)
  8. additionfollowed by addition of a solution (0.1 mL) of 4 M HCl in ethyl acetate
  9. stirringthe mixture was stirred at room temperature for 3.5 h
  10. customThe solvent was evaporated under reduced pressure

Sources & evidence

ORD record
ord-c11da105693044f4b75eabd9408079ea
Source dataset
uspto-grants-2011_10
Patent number
US08044068B2

Reaction notes

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