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

HRID 546197Notes

Reaction equation

HRID 546197 reaction equation
[NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=1.N1C(C)=CC=CC=1C.[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl: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][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[C:26]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=2)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1

Participants

5

Reactant 3

HCID 79372,6-LutidineHCID 509897073-(3-amino-1H-pyrazol-1-yl)propan-1-olHCID 866180523-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl chloride

Product 1

HCID 24889331(R)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-[1-(3-hydroxy-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 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared in Example 23, 51 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 (prepared as in Example 102, ˜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, 40% ethyl acetate/hexanes to 65% ethyl acetate/hexanes) afforded (R)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (99 mg, 74%) as a white foam: [α]30589=−27.3° (c=0.11, methylene chloride); ES-HRMS m/e calcd for C20H25N3O2Cl2 (M+H)+ 410.1397, observed 410.1398; 1H NMR (400 MHz, DMSO-d6) δ 1.10 (m, 2H, CH2), 1.35-1.78 (m, 8H, 4×CH2), 1.85 (m, 2H, CH2), 2.04 (m, 1H, CH), 3.34 (t, J=6.4 Hz, 2H, OCH2), 3.79 (m, 1H, ArCHCO), 4.02 (t, J=6.8 Hz, 2H, NCH2), 4.56 (br, 1H, OH), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.35 (dd, Jm=2.0 Hz, Jo=8.4 Hz, 1H, Ar), 7.55 (d, J=2.2 Hz, 1H, Ar), 7.59 (d, Jo=8.4 Hz, 1H, Ar), 7.59 (s, 1H, Ar), 10.71 (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, 40% ethyl acetate/hexanes to 65% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-ea46002897c64e549782bc5b8198d93f
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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