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

HRID 719990Notes

Reaction equation

HRID 719990 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.[CH3:28][O:29][CH2:30][CH2:31][NH:32][C:33]1[CH:38]=[N:37][C:36]([NH2:39])=[CH:35][N:34]=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:39][C:36]2[CH:35]=[N:34][C:33]([NH:32][CH2:31][CH2:30][O:29][CH3:28])=[CH:38][N:37]=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 21897315N-(2-methoxy-ethyl)-pyrazine-2,5-diamine

Product 1

HCID 104353072(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-methoxy-ethylamino)-pyrazin-2-yl]-propionamideYield 185.8%

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, 325 mg, 0.33 mmol) in methylene chloride (15 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (565 μL, 1.13 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 N-(2-methoxy-ethyl)-pyrazine-2,5-diamine (182 mg, 1.08 mmol) and 2,6-lutidine (137 μL, 1.18 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, 2/3 to 1/4 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-methoxy-ethylamino)-pyrazin-2-yl]-propionamide (295 mg, 62%) as a white foam: (ES)+-HRMS m/e calcd for C22H29ClN4O4S (M+H)+ 481.1671, found 481.1678.

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-d178ea79ae964070bc0739f313617510
Source dataset
uspto-grants-2006_11
Patent number
US07132425B2

Reaction notes

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