Sodium methanethiolate → 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfanylmethyl-pyrazin-2-yl)-propionamide

HRID 719905Notes

Reaction equation

HRID 719905 reaction equation
Br[CH2:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:29])[C@@H:11]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([Cl:28])[CH:19]=2)[CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:7][CH:8]=1.[CH3:30][S-:31].[Na+]>CC(C)=O.C(OCC)(=O)C>[Cl:28][C:20]1[CH:19]=[C:18]([CH:11]([CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[C:10]([NH:9][C:6]2[CH:5]=[N:4][C:3]([CH2:2][S:31][CH3:30])=[CH:8][N:7]=2)=[O:29])[CH:23]=[CH:22][C:21]=1[S:24]([CH3:27])(=[O:26])=[O:25]

Participants

5

Reactant 2

HCID 4378561Sodium methanethiolate3×HCID 67482634N-(5-bromomethyl-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide

Product 1

HCID 100048072-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfanylmethyl-pyrazin-2-yl)-propionamideYield 61.6%

Reagents, catalysts & solvents 2

HCID 180AcetoneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

A solution of N-(5-bromomethyl-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (95.1 mg, 0.19 mmol) in acetone (1 mL) was cooled to 0° C. and then treated with sodium thiomethoxide (12.9 mg, 0.18 mmol). The reaction stirred at 0° C. for 1.5 h and then was treated with a second aliquot of sodium thiomethoxide (3.6 mg, 0.051 mmol). The reaction was stirred at 0° C. and then slowly warmed to 25° C. over 1.5 h. A third aliquot of sodium thiomethoxide (3–4 mg, 0.042–0.057 mmol) was added, and the reaction mixture was stirred at 25° C. for 1.5 h, at which point, APCI-LRMS indicated the reaction had gone to completion. The reaction was then diluted with ethyl acetate (50 mL), washed with water (2×25 mL) and a saturated aqueous sodium chloride solution (25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/2 ethyl acetate/hexanes) afforded racemized 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfanylmethyl-pyrazin-2-yl)-propionamide (51.9 mg, 58%) as a white foam: mp 70–75° C. (foam to gel); (ES)+-HRMS m/e calcd for C21H26ClN3O3S2 (M+H)+ 468.1177, found 468.1179.

Workup

  1. stirringThe reaction was stirred at 0° C.
  2. temperatureslowly warmed to 25° C. over 1.5 h
  3. stirringthe reaction mixture was stirred at 25° C. for 1.5 h, at which point, APCI-LRMS
  4. washwashed with water (2×25 mL)
  5. dry with materiala saturated aqueous sodium chloride solution (25 mL), dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-40dc3329bdc843ba8e3c783abc0ce3ac
Source dataset
uspto-grants-2006_11
Patent number
US07132425B2

Reaction notes

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