Trifluoroacetic acid → methyl-(2S)-2-[(3,5-dichloroisonicotinoyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate

HRID 15420Notes

Reaction equation

HRID 15420 reaction equation
[CH3:1][O:2][C:3](=[O:32])[C@@H:4]([NH:24][C:25]([O:27]C(C)(C)C)=O)[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])[CH:10]=[CH:9]2.C(O)(C(F)(F)F)=O.[Cl:40][C:41]1[CH:49]=[N:48][CH:47]=[C:46]([Cl:50])[C:42]=1C(Cl)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:32])[C@@H:4]([NH:24][C:25](=[O:27])[C:42]1[C:41]([Cl:40])=[CH:49][N:48]=[CH:47][C:46]=1[Cl:50])[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[C:17]([Cl:23])=[CH:18][CH:19]=[CH:20][C:21]=1[Cl:22])[CH:10]=[CH:9]2

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 115720223,5-Dichloropyridine-4-carbon chlorideHCID 11784797HCID 11784797, compound

Product 1

HCID 11999284methyl-(2S)-2-[(3,5-dichloroisonicotinoyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoateYield 75%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

Methyl-(2S)-2-[(tert-butoxycarbonyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate (compound No 26, international patent application WO 03/093237) (500 mg, 1.05 mmol) was dissolved in DCM (5 ml) and a solution of TFA (0.8 ml, 10.5 mmol) in DCM (2 ml) was added drop wise over 10 minutes. After addition was complete the reaction was stirred at RT over night. The reaction was cooled to 0° C. and TEA (2.1 ml, 15.8 mmol) in DCM (2 ml) was added drop wise over 10 minutes. The reaction was cooled to −10° C. and 3,5 dichloro-isonicotinoylchloride (Bioorg. Med. Chem. Lett. 2002, 12, 1591-1594), (663 mg, 3.0 mmol) was added drop wise over 10 minutes, before allowing the reaction to warm to RT. After 1 hour the reaction was washed with aqueous HCl (1N, 10 ml), followed by washing with aqueous NaHCO3 solution (saturated, 10 ml). The DCM layer was dried over MgSO4, filtered and the solvent removed in vacuo to yield an off white solid. The solid was purified using flash chromatography (eluent EtAc) to yield the title compound as a white powder (432 mg, 75%) LCMS M+1 (552, 550, 548), Retention Time 3.82 min, 1H NMR, 300 Mz, d6-DMSO-9.50 (1H, d), 8.63 (2H, s), 8.42 (1H, d), 7.98 (1H, d), 7.94 (1H, d), 7.78 (1H, dd), 7.65 (2H, d), 7.55 (2H, m), 4.95 (1H, m), 3.74 (3H, s), 3.45 (1H, dd), 3.20 (1H, dd).

Workup

  1. additionAfter addition
  2. temperatureThe reaction was cooled to 0° C.
  3. temperatureThe reaction was cooled to −10° C.
  4. customthe reaction
  5. temperatureto warm to RT
  6. washAfter 1 hour the reaction was washed with aqueous HCl (1N, 10 ml)
  7. washby washing with aqueous NaHCO3 solution (saturated, 10 ml)
  8. dry with materialThe DCM layer was dried over MgSO4
  9. filtrationfiltered
  10. customthe solvent removed in vacuo
  11. customto yield an off white solid
  12. customThe solid was purified

Sources & evidence

ORD record
ord-9101945dc28846d1a5206ab199cd6eac
Source dataset
uspto-grants-2010_06
Patent number
US07732614B2

Reaction notes

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