1-Pyrrolidinamine → (S)-1-(3-(4-dimethylaminothieno[3,2-d]pyrimidin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone

HRID 1666626Notes

Reaction equation

HRID 1666626 reaction equation
NN1CCCC1.Cl[C:8]1[N:9]=[C:10]([N:17]([CH3:19])[CH3:18])[C:11]2[S:16][CH:15]=[CH:14][C:12]=2[N:13]=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.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl.O.C(O)CO>[CH3:18][N:17]([CH3:19])[C:10]1[C:11]2[S:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:8]([NH:21][C@H:22]2[CH2:26][CH2:25][N:24]([C:27](=[O:40])[CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:33][CH:34]=3)[CH2:23]2)[N:9]=1

Participants

8

Reactant 4

HCID 279461-PyrrolidinamineHCID 81531DiisopropylethylamineHCID 202849982-chloro-N,N-dimethylthieno[3,2-d]pyrimidin-4-amineHCID 86636479952435-26-6

Product 1

HCID 57970137(S)-1-(3-(4-dimethylaminothieno[3,2-d]pyrimidin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanoneYield 12.2%

Reagents, catalysts & solvents 3

HCID 174Ethylene GlycolSolventHCID 962WaterSolventHCID 6212ChloroformSolvent

Conditions

Temperature
110 °C

Procedure

To a solution of 50% aqueous dimethyl amine (0.77 g) in ethanol (30 mL) was added 2,4-dichlorothieno[3,2-d]pyrimidine (1.00 g) with ice cooling, and the mixture was stirred for 12 h while heating to room temperature. The reaction mixture was concentrated under reduced pressure and diluted with chloroform and water, and then the aqueous layer was extracted with chloroform. The organic layer was washed with 1 M hydrochloric acid and saturated brine, then the organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was crystallized with diethyl ether to obtain 2-chloro-N,N-dimethylthieno[3,2-d]pyrimidin-4-amine (0.90 g). (2) A mixture of 2-chloro-N,N-dimethylthieno[3,2-d]pyrimidin-4-amine (0.60 g), (S)-1-(3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (2.70 g), N,N-diisopropylethylamine (1.80 g), and ethylene glycol (18 mL) was heated at 110° C. for 20 h with stirring. The reaction mixture was diluted with chloroform and water, and then the aqueous layer was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol, and NH silica gel, chloroform/methanol) and crystallized with diethyl ether to obtain white solid (S)-1-(3-(4-dimethylaminothieno[3,2-d]pyrimidin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.16 g).

Workup

  1. extractionthe aqueous layer was extracted with chloroform
  2. concentrationThe organic layer was concentrated under reduced pressure
  3. customthe residue was purified by silica gel column chromatography (silica gel, chloroform/methanol, and NH silica gel, chloroform/methanol)
  4. customcrystallized with diethyl ether

Sources & evidence

ORD record
ord-631e1545ec5a473981c7983645a21b8f
Source dataset
uspto-grants-2011_10
Patent number
US08044068B2

Reaction notes

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