Triethylamine → tert-Butyl 2-[(3R*,4S*)-1-{[2-chloro-6-(trifluoromethyl)phenyl]methyl}-3-{[1-(cyclohex-1-en-1-ylmethyl)piperidin-4-yl]carbamoyl}-4-methylpyrrolidin-3-yl]acetate

HRID 446016Notes

Reaction equation

HRID 446016 reaction equation
[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:55]([O:59][C:60](=[O:71])[CH2:61][C@@:62]1([C:68]([OH:70])=O)[C@H:66]([CH3:67])[CH2:65][NH:64][CH2:63]1)([CH3:58])([CH3:57])[CH3:56].Br[CH2:73][C:74]1[C:79]([C:80]([F:83])([F:82])[F:81])=[CH:78][CH:77]=[CH:76][C:75]=1[Cl:84].C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O>[Cl:84][C:75]1[CH:76]=[CH:77][CH:78]=[C:79]([C:80]([F:81])([F:82])[F:83])[C:74]=1[CH2:73][N:64]1[CH2:65][C@@H:66]([CH3:67])[C@@:62]([CH2:61][C:60]([O:59][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:71])([C:68](=[O:70])[NH:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=3)[CH2:9][CH2:10]2)[CH2:63]1

Participants

9

Reactant 6

HCID 8471TriethylamineHCID 11430Potassium CarbonateHCID 2724699PyBOPHCID 177506812-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzeneHCID 71293641(3R,4S)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-3-carboxylic acidHCID 866782451-[(Cyclohex-1-en-1-yl)methyl]piperidin-4-amine

Product 1

HCID 71293811tert-Butyl 2-[(3R*,4S*)-1-{[2-chloro-6-(trifluoromethyl)phenyl]methyl}-3-{[1-(cyclohex-1-en-1-ylmethyl)piperidin-4-yl]carbamoyl}-4-methylpyrrolidin-3-yl]acetateYield 70.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
45 °C

Procedure

1-(Cyclohex-1-en-1-ylmethyl)piperidin-4-amine obtained in Example 4b (240 mg, 1.24 mmol), N,N-dimethylformamide (3 ml), triethylamine (344 μl, 2.47 mmol) and PyBOP (856 mg, 1.64 mmol) were added to (3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-3-carboxylic acid obtained in Example 4h (200 mg, 0.822 mmol), followed by stirring with heating in a 45° C. oil bath for 1.5 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. 2-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzene (247 mg, 0.903 mmol), potassium carbonate (170 mg, 1.23 mmol) and N,N-dimethylformamide (1 ml) were added thereto, followed by heating with stirring in a 45° C. oil bath for three hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over magnesium sulfate. The resulting crude product was purified by column chromatography twice (NH silica gel, elution solvent: ethyl acetate/heptane and silica gel, elution solvent: ethyl acetate/heptane) to give the title compound (353 mg, yield 70.1%).

Workup

  1. extractionwas extracted with ethyl acetate
  2. dry with materialThe organic layer was dried over magnesium sulfate
  3. concentrationconcentrated
  4. temperatureby heating
  5. stirringwith stirring in a 45° C. oil bath for three hours
  6. extractionwas extracted with ethyl acetate
  7. washThe organic layer was washed with water and brine
  8. dry with materialdried over magnesium sulfate
  9. customThe resulting crude product was purified by column chromatography twice (NH silica gel, elution solvent: ethyl acetate/heptane and silica gel, elution solvent: ethyl acetate/heptane)

Sources & evidence

ORD record
ord-73f8b43ea6a9465db9bcfdd6657cd9dc
Source dataset
uspto-grants-2013_07
Patent number
US08476301B2

Reaction notes

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