Trifluoroacetic acid → HCID 57797448, compound

HRID 2101194Notes

Reaction equation

HRID 2101194 reaction equation
CO[C:3](=[O:24])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:7]=[CH:6][C:5]=1[CH:19]=[CH:20]OCC.C(O)(C(F)(F)F)=O.[CH:32]1([CH:35]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]=[CH2:44])[N:38]=2)[NH2:36])[CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[CH:32]1([C@H:35]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]=[CH2:44])[N:38]=2)[N:36]2[CH2:20][CH2:19][C:5]3[C:4](=[CH:9][C:8]([O:10][C:11]4[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=4[F:18])=[CH:7][CH:6]=3)[C:3]2=[O:24])[CH2:33][CH2:34]1

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 5049666Sodium triacetoxyborohydrideHCID 57797487HCID 57797487, compoundHCID 68827789HCID 68827789, compound

Product 1

HCID 57797448HCID 57797448, compound

Reagents, catalysts & solvents 2

HCID 962WaterCatalystHCID 6344DichloromethaneSolvent3×

Procedure

To the solution of 5-(2,4-difluoro-phenoxy)-2-(2-ethoxy-vinyl)-benzoic acid methyl ester 9 (2.09 g, 6.3 mmol) in dichloromethane (20 mL) was added 2 mL of TFA and five drops of water. The reaction was stirred at room temperature for ten minutes, at which time the solvent was removed. The crude reaction mixture was re-suspended in 100 ml of dichloromethane, extracted twice with 50 ml of saturated NaHCO3. The organic layer was dried with sodium sulfate and the solvent removed. The crude intermediate was re-suspended in 100 ml of dichloroethane and added drop wise to a 100 ml solution of dichloroethane containing cyclopropyl(6-vinylpyridin-2-yl)methanamine A20 (1.2 g, 6.9 mmol) and sodium triacetoxyborohydride (3.3 g, 15.7 mmol). The mixture was stirred at 70° C. during the drop wise addition and for additional 2 hours. The reaction was diluted with 500 mL dichloromethane and extracted with saturated brine (300 mL). The organic layer was concentrated and loaded onto a silica gel column and eluted with dichloromethane followed by separation of the enatiomers (AD-H column, 10% IPA/Hex) to give 115 mg of (R)-2-(cyclopropyl(6-vinylpyridin-2-yl)methyl)-7-(2,4-difluorophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 74 as clear oil. The sterochemical configuration was assigned based on the compound 11 TLC, Rf=0.25 (CH2Cl2); Rt=20.2 min (45 min. run, AD-H chiral analalytical column, 1 ml/min, 5% IPA/Hex); 1H NMR (Methanol-D4) δ 7.69 (t, J=7.6, 1H), 7.42 (s, 1H), 7.35 (d, J=7.5, 1H), 7.29 (d, J=7.6, 1H), 7.25 (d, J=8.3, 1H), 7.09 (m, 3H), 6.97 (m, 1H), 6.78 (dd, J=10.7, 17.4, 1H), 6.18 (d, J=17.4, 1H), 5.39 (d, J=10.7, 1H), 4.99 (d, J=10.1, 1H), 3.8 (m, 2H), 2.9 (m, 2H), 1.63 (m, 1H), 0.81 (m, 1H), 0.66 (m, 1H), 0.56 (m, 1H), 0.46 (m, 1H), M+1 found 433.1; C26H22F2N2O2 requires 432.2

Workup

  1. customwas removed
  2. customThe crude reaction mixture
  3. extractionextracted twice with 50 ml of saturated NaHCO3
  4. dry with materialThe organic layer was dried with sodium sulfate
  5. customthe solvent removed
  6. additionadded drop wise to a 100 ml solution of dichloroethane
  7. stirringThe mixture was stirred at 70° C. during the drop wise addition and for additional 2 hours
  8. extractionextracted with saturated brine (300 mL)
  9. concentrationThe organic layer was concentrated
  10. washeluted with dichloromethane
  11. customfollowed by separation of the enatiomers (AD-H column, 10% IPA/Hex)

Sources & evidence

ORD record
ord-7efc990e269c435ea2653fe240b837c2
Source dataset
uspto-grants-2009_08
Patent number
US07572783B2

Reaction notes

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