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

HRID 546144Notes

Reaction equation

HRID 546144 reaction equation
[NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])[N:3]=1.N1C(C)=CC=CC=1C.[CH:20]1([CH2:25][C@H:26]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)[C:27](Cl)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[CH:20]1([CH2:25][C@H:26]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=2)[C:27]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][C:8]([OH:10])([CH3:11])[CH3:9])[N:3]=2)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1

Participants

5

Reactant 3

HCID 79372,6-LutidineHCID 593449381-(3-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol2×HCID 866180483-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionyl chloride

Product 1

HCID 248891553-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2(R)-(3-trifluoromethyl-phenyl)-propionamideYield 81%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Conditions

Temperature
0 °C

Procedure

In a round bottom flask was placed 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in Example 80 42 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 (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-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2(R)-(3-trifluoromethyl-phenyl)-propionamide (83 mg, 81%) as a white foam: [α]31589=−25.0° (c=0.14, methylene chloride); ES-HRMS m/e calcd for C22H28N3O2F3 (M+H)+ 424.2207, observed 424.2207; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.05-1.19 (m, 2H, CH2), 1.32-1.80 (m, 8 H, 4×CH2), 2.01-2.21 (m, 1H, CH), 3.86 (s, 2H, NCH2), 3.82-3.94 (m, 1H, ArCH), 4.64 (s, 1H, OH), 6.46 (d, J=2.3 Hz, 1H, Ar), 7.50 (d, J=2.3 Hz, 1H, Ar), 7.52-7.74 (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-a33ffb8119dc4287b17d37537b5ed172
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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