2,6-Lutidine → 3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2(R)-(3-trifluoromethyl-phenyl)-propionamide

HRID 546145Notes

Reaction equation

HRID 546145 reaction equation
[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6]1.N1C(C)=CC=CC=1C.[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:26](Cl)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=2)[C:26]([NH:10][C:7]2[CH:8]=[CH:9][N:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]=2)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1

Participants

5

Reactant 3

HCID 79372,6-LutidineHCID 451167281-(2-methoxyethyl)-1H-pyrazol-3-amineHCID 866180483-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionyl chloride

Product 1

HCID 248895053-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2(R)-(3-trifluoromethyl-phenyl)-propionamideYield 86%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Conditions

Temperature
0 °C

Procedure

In a round bottom flask was placed 1-(2-methoxy-ethyl)-1H-pyrazol-3-yl-amine (prepared in Example 72, 38 mg, 0.27 mmol), 2,6-lutidine (42 μL, 0.37 mmol) and methylene chloride (5 mL). This solution was then cooled to 0° C. and to it was added dropwise a solution of 3-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionyl chloride in methylene chloride (prepared in Example 83, 0.12 M solution, 2 mL, 0.24 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction was diluted with methylene chloride (5 mL). The reaction was then washed with a saturated aqueous sodium bicarbonate solution (10 mL) and a 1 N aqueous hydrochloric acid solution (1×10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 20% ethyl acetate/hexanes to 60% ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2(R)-(3-trifluoromethyl-phenyl)-propionamide (85 mg, 86%) as a colorless oil: [α]30589=−18.8° (c=0.16, methylene chloride); ES-HRMS m/e calcd for C21H26N3O2F3 (M+H)+ 410.2050, observed 410.2050; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.05-1.19 (m, 2H, CH2), 1.35-1.81 (m, 8H, 4×CH2), 2.05-2.19 (m, 1H, CH), 3.19 (s, 3H, OCH3), 3.61 (t, J=5.3 Hz, 2H, OCH2), 3.86-3.94 (m, 1H, ArCH), 4.11 (t, J=5.3 Hz, 2H, NCH2), 6.42 (d, J=2.3 Hz, 1H, Ar), 7.54 (d, J=2.3 Hz, 1H, Ar), 7.55-7.75 (m, 4H, Ar), 10.75 (s, 1H, NH).

Workup

  1. customIn a round bottom flask was placed
  2. temperatureto warm up to 25° C.
  3. washThe reaction was then washed with a saturated aqueous sodium bicarbonate solution (10 mL)
  4. dry with materiala 1 N aqueous hydrochloric acid solution (1×10 mL) and then dried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customPurification on an AnaLogix Intelliflash system (4 g column, 20% ethyl acetate/hexanes to 60% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-548479b113404313af115ad42d2142ba
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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