2-Methyl-3-butyn-2-ol → 3-cyclopentyl-N-[5-(3-hydroxy-3-methyl-but-1-ynyl)-pyrazin-2-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionamide

HRID 719966Notes

Reaction equation

HRID 719966 reaction equation
Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([CH3:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[OH:38][C:39]([CH3:43])([CH3:42])[C:40]#[CH:41]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:12]1([CH2:11][C@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([CH3:27])[CH:18]=2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:41]#[C:40][C:39]([OH:38])([CH3:43])[CH3:42])=[CH:7][N:6]=2)=[O:28])[CH2:16][CH2:15][CH2:14][CH2:13]1

Participants

7

Reactant 3

HCID 82582-Methyl-3-butyn-2-olHCID 81531DiisopropylethylamineHCID 86593795N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-pheny)-propionamide

Product 1

HCID 100503603-cyclopentyl-N-[5-(3-hydroxy-3-methyl-but-1-ynyl)-pyrazin-2-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionamideYield 77.1%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 1140TolueneSolvent

Conditions

Temperature
25 °C

Procedure

A mixture of N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-pheny)-propionamide (120 mg, 0.257 mmol), N,N-diisopropylethylamine (0.5 mL, 2.87 mmol), and 3-hydroxy-3-methylbutyne (90 mg, 1.07 mmol) in toluene (2 mL) was treated with dichlorobis(triphenylphosphine)palladium(II) (11 mg, 0.0157 mmol) and copper(I) iodide (5.5 mg, 0.0288 mmol). The mixture was stirred at 25° C. for 18 h. The reaction mixture was then concentrated in vacuo, and the residue was partitioned with methylene chloride (25 mL) and a 0.2M aqueous hydrochloric acid solution (20 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL), and each aqueous phase was back-extracted with a small volume of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, gradient elution with increasing concentrations of ethyl acetate/hexanes) afforded the 3-cyclopentyl-N-[5-(3-hydroxy-3-methyl-but-1-ynyl)-pyrazin-2-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (93 mg, 77%) as a yellow foam: (ES)+-HRMS m/e calcd for C25H31N3O4S (M+H)+ 470.2108, found 470.2113.

Workup

  1. concentrationThe reaction mixture was then concentrated in vacuo
  2. customthe residue was partitioned with methylene chloride (25 mL)
  3. washThe organic layer was washed with a saturated aqueous sodium chloride solution (20 mL)
  4. extractioneach aqueous phase was back-extracted with a small volume of methylene chloride
  5. dry with materialThe combined organic layers were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. washFlash chromatography (Merck Silica gel 60, 230–400 mesh, gradient elution with increasing concentrations of ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-156be104094849faac5e4a33e4671de4
Source dataset
uspto-grants-2006_11
Patent number
US07132425B2

Reaction notes

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