1-Pyrrolidinamine → 1-(3-(4,6-Dimethylpyridin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone

HRID 1666616Notes

Reaction equation

HRID 1666616 reaction equation
NN1CCCC1.[CH3:7][C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][CH:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[CH:9]=1.[F:21][C:22]([F:35])([F:34])[O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(Cl)(Cl)Cl.O>[CH3:7][C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][CH:16]2[CH2:20][CH2:19][N:18]([C:31](=[O:32])[CH2:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][C:22]([F:34])([F:21])[F:35])=[CH:25][CH:26]=3)[CH2:17]2)[CH:9]=1

Participants

8

Reactant 5

HCID 279461-PyrrolidinamineHCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27773192-[4-(Trifluoromethoxy)phenyl]acetic acidHCID 579701123-(4,6-Dimethylpyridin-2-ylamino)pyrrolidine

Product 1

HCID 579702121-(3-(4,6-Dimethylpyridin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanoneYield 65.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6212ChloroformSolvent2×

Procedure

A mixture of 2-amino-4,6-dimethylpyridine (2.0 g), 1-benzylpyrrolidin-3-one (2.9 g), acetic acid (2.9 mL), and chloroform (34 mL) was ice-cooled, followed by addition of sodium triacetoxyborohydride (4.9 g), and the mixture was stirred for 18 h while heating slowly to room temperature. To the reaction mixture was added 1 M aqueous sodium hydroxide to make it basic, and then the mixture was extracted with chloroform. 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 purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=65:35) to obtain 1-benzyl-3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (1.3 g). (2) 1-Benzyl-3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (1.3 g) was dissolved in methanol (13 mL), followed by addition of 20% Pd(OH)2/C (0.26 g), and the mixture was stirred at room temperature for 20 h under hydrogen atmosphere. The catalyst was removed by Celite filtration, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, chloroform/methanol=19:1) to obtain 3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (0.10 g). (3) A mixture solution of 3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (0.73 g), 4-trifluoromethoxyphenylacetic acid (0.12 g), EDC.HCl (0.12 g), HOBt.H2O (0.12 g), and chloroform (1.0 mL) was stirred at room temperature. After completion of the reaction, the reaction mixture was diluted with chloroform and washed with 1 M aqueous sodium hydroxide and brine. 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 purified by silica gel column chromatography (chloroform/methanol=19:1) and then crystallized with hexane and diethyl ether to obtain the title compound (0.14 g).

Workup

  1. customAfter completion of the reaction
  2. washwashed with 1 M aqueous sodium hydroxide and 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 (chloroform/methanol=19:1)
  7. customcrystallized with hexane and diethyl ether

Sources & evidence

ORD record
ord-9ae2df6ffd1745d8beaf14b415da8dba
Source dataset
uspto-grants-2011_10
Patent number
US08044068B2

Reaction notes

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