2,6-Lutidine → (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid pyrazin-2-ylamide

HRID 1261512Notes

Reaction equation

HRID 1261512 reaction equation
[CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:17]([F:20])([F:19])[F:18])[C:9]1=[O:21])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:35]=[N:34][CH:33]=[CH:32][N:31]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.CO>[N:31]1[CH:32]=[CH:33][N:34]=[CH:35][C:30]=1[NH:29][C:5](=[O:7])[C@@H:4]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:17]([F:19])([F:18])[F:20])[C:9]1=[O:21])[CH2:3][CH:2]([CH3:22])[CH3:1]

Participants

8

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 78747AminopyrazineHCID 70945056(S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid

Product 1

HCID 70674572(S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid pyrazin-2-ylamideYield 12%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 887MethanolSolventHCID 6344DichloromethaneSolvent3×

Procedure

A solution of (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid (95 mg, 0.30 mmol) in methylene chloride (5 mL) and N,N-dimethylformamide (5 drops) at room temperature was treated with a solution of oxalyl chloride (2.0M in methylene chloride, 200 μL, 0.36 mmol) and stirred for 15 min. After this time, the reaction mixture was concentrated in vacuo and then diluted with methylene chloride (5 mL) and added to a flask containing a solution of 2-aminopyrazine (Aldrich, 57 mg, 0.60 mmol), 2,6-lutidine (250 μL) in methylene chloride (2.5 mL) at 0° C. The reaction mixture was then stirred at room temperature for a period of 30 min After this time, the reaction mixture was treated with methanol and then diluted with methylene chloride. The reaction mixture was then transferred to a separatory funnel and washed with a 1N aqueous hydrochloric acid solution. The organic layer was then dried over magnesium sulfate, filtered to remove the drying agent and the filtrate was concentrated with silica gel (2 g). The silica gel with absorbed material was placed in a SIM and purified via Biotage flash column chromatography (40 S silica gel column, 25%-40% ethyl acetate/hexanes) to afford (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid pyrazin-2-ylamide (14 mg, 12%): HR-ES(+) m/e calcd for C19H19N4O2F3 [M+H]+ 393.1533, observed 393.1532; 1H NMR (400 MHz, CHLOROFORM-d) δ 9.49 (s, 1H), 9.03 (br. s., 1H), 8.29-8.38 (m, 2H), 8.10 (d, J=7.67 Hz, 1H), 7.84 (d, J=7.88 Hz, 1H), 7.65 (t, J=7.67 Hz, 1H), 5.14 (dd, J=6.93, 8.84 Hz, 1H), 4.69-4.82 (m, 1H), 4.58-4.67 (m, 1H), 1.88-2.15 (m, 2H), 1.62 (td, J=6.87, 13.96 Hz, 1H), 1.01-1.10 (m, 6H).

Workup

  1. concentrationAfter this time, the reaction mixture was concentrated in vacuo
  2. additiondiluted with methylene chloride (5 mL)
  3. additionadded to a flask
  4. stirringThe reaction mixture was then stirred at room temperature for a period of 30 min After this time
  5. customThe reaction mixture was then transferred to a separatory funnel
  6. washwashed with a 1N aqueous hydrochloric acid solution
  7. dry with materialThe organic layer was then dried over magnesium sulfate
  8. filtrationfiltered
  9. customto remove the drying agent
  10. concentrationthe filtrate was concentrated with silica gel (2 g)
  11. custompurified via Biotage flash column chromatography (40 S silica gel column, 25%-40% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-3a1418819c9048148b28cb5bf506fad1
Source dataset
uspto-grants-2013_06
Patent number
US08470866B2

Reaction notes

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