2,6-Lutidine → (S)-N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide

HRID 2365729Notes

Reaction equation

HRID 2365729 reaction equation
[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Br:31][C:32]1[N:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[Br:31][C:32]1[N:33]=[CH:34][C:35]([NH:38][C:8](=[O:10])[C@@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:36][CH:37]=1

Participants

7

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 5995392-Amino-5-bromopyrazineHCID 70945341(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid

Product 1

HCID 70674569(S)-N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamideYield 51.3%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent3×

Procedure

A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 1, 100 mg, 0.29 mmol) in methylene chloride (4 mL) and N,N-dimethylformamide (4 drops) was treated with a solution of oxalyl chloride in methylene chloride (2.0 M, 150 μL, 0.30 mmol) and stirred for 15 min at room temperature. After this time, the reaction mixture was then concentrated in vacuo and the resulting residue was dissolved in methylene chloride (4 mL) and then added dropwise to a separate reaction flask containing a mixture of 5-bromo-pyrazin-2-ylamine (76 mg, 0.44 mmol) and 2,6-lutidine (100 μL, 0.87 mmol) in methylene chloride (3 mL) at room temperature. The resulting reaction mixture was the stirred room temperature for 1.5 h. The reaction mixture was quenched by the addition of methanol and then diluted with methylene chloride and the organic layer was washed with a 1N aqueous hydrochloric acid solution. The organic layer was then dried, filtered and the filtrate concentrated in vacuo. The crude material was purified via Biotage flash column chromatography (40 S silica gel column, 25% ethyl acetate/hexanes) to afford (S)—N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (74 mg, 51%) as a white foam: HR-ES(+) m/e calcd for C21H20N4O2F3Br [M+H]+ 497.0795, observed 497.0796; 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (s, 1H), 9.09 (d, J=1.07 Hz, 1H), 8.65 (d, J=1.28 Hz, 1H), 8.02 (dd, J=7.88, 10.44 Hz, 2H), 7.77 (t, J=7.67 Hz, 1H), 5.22 (dd, J=4.90, 10.66 Hz, 1H), 5.04 (d, J=18.33 Hz, 1H), 4.76 (d, J=18.11 Hz, 1H), 1.04-2.19 (m, 11H).

Workup

  1. concentrationAfter this time, the reaction mixture was then concentrated in vacuo
  2. dissolutionthe resulting residue was dissolved in methylene chloride (4 mL)
  3. additionadded dropwise to a separate reaction flask
  4. additioncontaining
  5. customThe resulting reaction mixture
  6. customthe stirred room temperature
  7. customfor 1.5 h
  8. customThe reaction mixture was quenched by the addition of methanol
  9. additiondiluted with methylene chloride
  10. washthe organic layer was washed with a 1N aqueous hydrochloric acid solution
  11. customThe organic layer was then dried
  12. filtrationfiltered
  13. concentrationthe filtrate concentrated in vacuo
  14. customThe crude material was purified via Biotage flash column chromatography (40 S silica gel column, 25% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-0d7441861cf84e54837d16f5326e804d
Source dataset
uspto-grants-2014_04
Patent number
US08697705B2

Reaction notes

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