2,6-Lutidine → 2(R)-(3-chloro-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-methoxy-phenyl)-pyrazin-2-yl]-propionamide

HRID 719987Notes

Reaction equation

HRID 719987 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C@@H](CC2CCCC2)C(O)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:22](Cl)(=[O:26])[C:23](Cl)=O.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([C:36]2[N:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)[CH:33]=[CH:34][CH:35]=1.N1[C:48](C)=[CH:47][CH:46]=[CH:45][C:44]=1[CH3:50]>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:6]([C@@H:23]([CH2:50][CH:44]2[CH2:45][CH2:46][CH2:47][CH2:48]2)[C:22]([NH:42][C:39]2[CH:38]=[N:37][C:36]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=3)=[CH:41][N:40]=2)=[O:26])[CH:5]=[CH:4][CH:3]=1

Participants

9

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 12067655(R)-2-(3-Chloro-4-(methylsulfonyl)phenyl)-3-cyclopentylpropanoic acidHCID 218973522-Pyrazinamine, 5-(3-methoxyphenyl)-

Product 1

HCID 674829962(R)-(3-chloro-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-methoxy-phenyl)-pyrazin-2-yl]-propionamideYield 83%

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 300 mg, 0.91 mmol) in methylene chloride (15 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (522 μL, 1.04 mmol) and N,N-dimethylformamide (1 drop). The reaction mixture was stirred at 0° C. for 30 min, concentrated in vacuo, and azeotroped with methylene chloride (2 mL) two times. The resulting oil was dissolved in tetrahydrofuran (5 mL) at 25° C. and then treated dropwise with a solution of 5-(3-methoxy-phenyl)-pyrazin-2-ylamine (201 mg, 1.00 mmol) and 2,6-lutidine (126 μL, 1.09 mmol) in tetrahydrofuran (6 mL) via an addition funnel. The resulting cloudy solution was then stirred overnight for 16 h at 25° C. After this time, the reaction was diluted with water (10 mL) and then extracted with methylene chloride (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/1 to 3/2 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-methoxy-phenyl)-pyrazin-2-yl]-propionamide (388 mg, 83%) as a light yellow foam: (ES)+-HRMS m/e calcd for C26H28ClN3O4S (M+H)+ 514.1562, found 514.1567.

Workup

  1. concentrationconcentrated in vacuo
  2. customazeotroped with methylene chloride (2 mL) two times
  3. dissolutionThe resulting oil was dissolved in tetrahydrofuran (5 mL) at 25° C.
  4. stirringThe resulting cloudy solution was then stirred overnight for 16 h at 25° C
  5. extractionextracted with methylene chloride (3×25 mL)
  6. dry with materialThe combined organic layers were dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-920751443db64348b83b815028f0e25e
Source dataset
uspto-grants-2006_11
Patent number
US07132425B2

Reaction notes

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