Diisopropylethylamine → 3-cyclopentyl-N-[5-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-pyrazin-2-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionamide

HRID 719968Notes

Reaction equation

HRID 719968 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.[C:38]([C:40]1([OH:46])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)#[CH:39]>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:39]#[C:38][C:40]3([OH:46])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:7][N:6]=2)=[O:28])[CH2:16][CH2:15][CH2:14][CH2:13]1

Participants

7

Reactant 3

HCID 81531DiisopropylethylamineHCID 155504854-Ethynyloxan-4-olHCID 86593795N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-pheny)-propionamide

Product 1

HCID 100293663-cyclopentyl-N-[5-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-pyrazin-2-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionamideYield 55.1%

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 (prepared as in Example 57, 154 mg, 0.33 mmol), N,N-diisopropylethylamine (0.6 mL, 3.44 mmol), and 4-ethynyl-tetrahydropyran-4-ol (prepared as in Example 46, 85 mg, 0.67 mmol) in toluene (2 mL) was treated with dichlorobis(triphenylphosphine)palladium(II) (14 mg, 0.02 mmol) and copper(I) iodide (7 mg, 0.0367 mmol). The mixture was stirred at 25° C. for 17 h. The reaction mixture was then concentrated in vacuo, and the residue was partitioned with methylene chloride (50 mL) and a 0.2M aqueous hydrochloric acid solution (25 mL) and the layers were separated. The aqueous phase was back-extracted with methylene chloride (25 mL). Each organic layer was washed with a saturated aqueous sodium chloride solution (1 mL). 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 mixtures of ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[5-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-pyrazin-2-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (93 mg, 55%) as a yellow foam: (ES)+-HRMS m/e calcd for C27H33N3O5S (M+H)+ 512.2214, found 512.2219.

Workup

  1. concentrationThe reaction mixture was then concentrated in vacuo
  2. customthe residue was partitioned with methylene chloride (50 mL)
  3. customa 0.2M aqueous hydrochloric acid solution (25 mL) and the layers were separated
  4. extractionThe aqueous phase was back-extracted with methylene chloride (25 mL)
  5. washEach organic layer was washed with a saturated aqueous sodium chloride solution (1 mL)
  6. dry with materialThe combined organic layers were dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. washFlash chromatography (Merck Silica gel 60, 230–400 mesh, gradient elution with mixtures of ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-70fb94afb5ef4878aa808905758041f7
Source dataset
uspto-grants-2006_11
Patent number
US07132425B2

Reaction notes

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