2,6-Lutidine → (I+/-R)-I+/--(Cyclopentylmethyl)-N-[1-(2-methoxyethyl)-1H-pyrazol-3-yl]-3-methyl-4-(methylsulfonyl)benzeneacetamide

HRID 546141Notes

Reaction equation

HRID 546141 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][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([CH3:39])[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]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([CH3:39])[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 866180473-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionyl chloride

Product 1

HCID 24889154(I+/-R)-I+/--(Cyclopentylmethyl)-N-[1-(2-methoxyethyl)-1H-pyrazol-3-yl]-3-methyl-4-(methylsulfonyl)benzeneacetamideYield 65%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

In a round bottom flask was placed 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared in Example 72, 30 mg, 0.21 mmol), 2,6-lutidine (34 μL, 0.29 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)-(4-methanesulfonyl-3-methyl-phenyl)-propionyl chloride in methylene chloride (0.096 M solution, 2 mL, 0.19 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction was quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and then extracted with methylene chloride (3×10 mL). The organic extracts were then combined and washed with 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, 30% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-propionamide (57 mg, 65%) as a white foam: [α]31589=−29.5° (c=0.21, methylene chloride); ES-HRMS m/e calcd for C22H31N3O4S (M+H)+ 434.2108, observed 434.2108; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.02-1.20 (m, 2H, CH2), 1.36-1.82 (m, 8H, 4×CH2), 2.03-2.20 (m, 1H, CH), 2.62 (s, 3H, ArCH3), 3.17 (s, 3H, SO2CH3), 3.19 (s, 3H, OCH3), 3.61 (t, J=5.2 Hz, 2H, OCH2), 3.82-3.94 (m, 1H, ArCH), 4.11 (t, J=5.2 Hz, 2H, NCH2), 6.41 (d, J=2.4 Hz, 1H, Ar), 7.41-7.47 (m, 2H, Ar), 7.54 (d, J=2.4 Hz, 1H, Ar), 7.84 (d, Jo=8.8 Hz, 1H, Ar), 10.75 (s, 1H, NH).

Workup

  1. customIn a round bottom flask was placed
  2. temperatureto warm up to 25° C.
  3. customAfter this time the reaction was quenched with a saturated aqueous sodium bicarbonate solution (10 mL)
  4. extractionextracted with methylene chloride (3×10 mL)
  5. washwashed with a 1 N aqueous hydrochloric acid solution (1×10 mL)
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customPurification on an AnaLogix Intelliflash system (4 g column, 30% ethyl acetate/hexanes to 75% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-26db24fb554741a88ffcba58e75c4569
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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