2,6-Lutidine → N-[5-(1-tert-butoxyimino-ethyl)-pyrazin-2-yl]-3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-propionamide

HRID 719916Notes

Reaction equation

HRID 719916 reaction equation
[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[C:27]([O:31][N:32]=[C:33]([C:35]1[CH:40]=[N:39][C:38]([NH2:41])=[CH:37][N:36]=1)[CH3:34])([CH3:30])([CH3:29])[CH3:28].N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[C:27]([O:31][N:32]=[C:33]([C:35]1[N:36]=[CH:37][C:38]([NH:41][C:8](=[O:10])[C@@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:39][CH:40]=1)[CH3:34])([CH3:28])([CH3:29])[CH3:30]

Participants

8

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 21356244(R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acidHCID 865937831-(5-amino-pyrazin-2-yl)-ethanone O-tert-butyl-oxime

Product 1

HCID 86593788N-[5-(1-tert-butoxyimino-ethyl)-pyrazin-2-yl]-3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-propionamideYield 55%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 3-cyclopentyl-2(R)-(4-methanesulfonylphenyl)-propionic acid (prepared as in Example 3, 500.0 mg, 1.687 mmol) in methylene chloride (4.2 mL) was cooled to 0° C. The reaction mixture was treated with N,N-dimethylformamide (1 drop) and oxalyl chloride (294 μL, 3.374 mmol). The reaction mixture was stirred at 0° C. for 15 min and then slowly allowed to warm to 25° C. where it was stirred for 3 h. The solution was then concentrated in vacuo. The resulting residue was dissolved in methylene chloride (8.4 mL) and then cooled to 0° C. This cooled solution was then treated dropwise with a solution of 1-(5-amino-pyrazin-2-yl)-ethanone O-tert-butyl-oxime (prepared as in Example 28, 351.4 mg, 1.687 mmol) and 2,6-lutidine (246 μL, 2.109) in tetrahydrofuran (8.4 mL). The reaction mixture was stirred at 0° C. for 30 min and then was allowed to warm to 25° C. where it was stirred overnight. The reaction mixture was then concentrated in vacuo, diluted with ethyl acetate (250 mL), and washed with a 1N aqueous hydrochloric acid solution (3×100 mL) and a saturated aqueous sodium chloride solution (1×300 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/4 ethyl acetate/hexanes) afforded the N-[5-(1-tert-butoxyimino-ethyl)-pyrazin-2-yl]-3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-propionamide (451.1 mg, 55%) as a yellow foam. This material was re-purified via Biotage chromatography (FLASH 40L, Silica, 5% ethyl acetate/methylene chloride) to afford N-[5-(1-tert-butoxyimino-ethyl)-pyrazin-2-yl]-3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-propionamide (380.4 mg, 46%) as a white foam: mp 81–83° C. (foam to gel); (ES)+-HRMS m/e calcd for C25H34N4O4S (M+H)+ 487.2374, found 487.2377.

Workup

  1. temperatureto warm to 25° C. where it
  2. stirringwas stirred for 3 h
  3. concentrationThe solution was then concentrated in vacuo
  4. dissolutionThe resulting residue was dissolved in methylene chloride (8.4 mL)
  5. temperaturecooled to 0° C
  6. stirringThe reaction mixture was stirred at 0° C. for 30 min
  7. temperatureto warm to 25° C. where it
  8. stirringwas stirred overnight
  9. concentrationThe reaction mixture was then concentrated in vacuo
  10. additiondiluted with ethyl acetate (250 mL)
  11. washwashed with a 1N aqueous hydrochloric acid solution (3×100 mL)
  12. dry with materialThe organic layer was then dried over sodium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-0dcb799996334ebd884adb9be3841d91
Source dataset
uspto-grants-2006_11
Patent number
US07132425B2

Reaction notes

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