2,6-Lutidine → (R)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

HRID 546195Notes

Reaction equation

HRID 546195 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][C:33]([Cl:36])=[C:32]([Cl: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][C:33]([Cl:36])=[C:32]([Cl:37])[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-olHCID 866180523-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl chloride

Product 1

HCID 24889501(R)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamideYield 74%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Conditions

Temperature
25 °C

Procedure

In a round bottom flask was placed 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 56 mg, 0.36 mmol), 2,6-lutidine (57 μL, 0.49 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl chloride in methylene chloride (˜0.16 M solution, 2 mL, 0.33 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (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 45% ethyl acetate/hexanes) afforded (R)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (102 mg, 74%) as a white foam: [α]30589=−13.3° (c=0.12, methylene chloride); ES-HRMS m/e calcd for C21H27N3O2Cl2 (M+H)+ 424.1553, observed 454.1553; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (s, 6H, 2×CH3), 1.09 (m, 2H, CH2), 1.34-1.79 (m, 8H, 4×CH2), 2.03 (m, 1H, CH), 3.80 (m, 1H, ArCHCO), 3.86 (s, 2H, NCH2), 4.65 (s, 1H, OH), 6.45 (s, 1H, Ar), 7.35 (brd, 1H, Ar), 7.51 (s, 1H, Ar), 7.58 (m, 2H, Ar), 10.73 (s, 1H, NH).

Workup

  1. customIn a round bottom flask was placed
  2. customtransferred to a separatory funnel
  3. washwashed with a saturated aqueous sodium bicarbonate solution (10 mL)
  4. dry with materiala 1 N aqueous hydrochloric acid solution (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 45% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-7d8b0b65ee3a41e690a7dcdb6ed95f6e
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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