2,6-Lutidine → 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(5,6-dihydro-4H-pyran-2-yl)-pyrazin-2-yl]-propionamide

HRID 719998Notes

Reaction equation

HRID 719998 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[O:28]1[CH2:33][CH2:32][CH2:31][CH:30]=[C:29]1[C:34]1[N:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:40][C:37]2[CH:36]=[N:35][C:34]([C:29]3[O:28][CH2:33][CH2:32][CH2:31][CH:30]=3)=[CH:39][N:38]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]

Participants

9

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 12067655(R)-2-(3-Chloro-4-(methylsulfonyl)phenyl)-3-cyclopentylpropanoic acidHCID 218973825-(5,6-dihydro-4H-pyran-2-yl)-pyrazin-2-ylamine

Product 1

HCID 104132552(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(5,6-dihydro-4H-pyran-2-yl)-pyrazin-2-yl]-propionamideYield 42.5%

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, 40 mg, 0.12 mmol) in methylene chloride (2 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (70 μL, 1.40 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) three times. The resulting oil was dissolved in tetrahydrofuran (1 mL) at 25° C. and then treated dropwise with a solution of 5-(5,6-dihydro-4H-pyran-2-yl)-pyrazin-2-ylamine (24 mg, 0.13 mmol) and 2,6-lutidine (17 μL, 0.15 mmol) in tetrahydrofuran (1.5 mL) via an addition funnel. The resulting cloudy solution was then stirred overnight at 25° C. for 16 h. 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 12M, Silica, 4/1 to 7/3 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(5,6-dihydro-4H-pyran-2-yl)-pyrazin-2-yl]-propionamide (25 mg, 42%) as a white foam: (ES)+-HRMS m/e calcd for C24H28ClN3O4S (M+H)+ 490.1562, found 490.1562.

Workup

  1. concentrationconcentrated in vacuo
  2. customazeotroped with methylene chloride (2 mL) three times
  3. dissolutionThe resulting oil was dissolved in tetrahydrofuran (1 mL) at 25° C.
  4. stirringThe resulting cloudy solution was then stirred overnight at 25° C. for 16 h
  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-32adfcc60d2742af82133a6810e013f5
Source dataset
uspto-grants-2006_11
Patent number
US07132425B2

Reaction notes

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