Acetone cardice → Di-tert-butyl 3,3'-carbonylbis(azetidine-1-carboxylate)

HRID 926652Notes

Reaction equation

HRID 926652 reaction equation
[Li]CCCC.ClC1C2C(=CC=C(C(C3C(C)=NC(C)=CC=3)O)C=2)N=C(OC)C=1CC1C=CC(C(F)(F)F)=CC=1.C(=O)=O.CC(C)=O.[Cl:47][C:48]1[C:57]2[C:52](=[CH:53][CH:54]=[C:55]([C:58]([OH:81])([CH:70]3[CH2:73][N:72]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:71]3)[CH:59]3[CH2:62][N:61]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:60]3)[CH:56]=2)[N:51]=[C:50]([O:82][CH3:83])[C:49]=1[CH2:84][C:85]1[CH:90]=[CH:89][C:88]([C:91]([F:94])([F:93])[F:92])=[CH:87][CH:86]=1>C(OCC)C.C1(C)C=CC=CC=1>[Cl:47][C:48]1[C:57]2[C:52](=[CH:53][CH:54]=[C:55]([C:58]([OH:81])([CH:59]3[CH2:60][N:61]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:62]3)[CH:70]3[CH2:71][N:72]([C:74]([O:76][C:77]([CH3:78])([CH3:79])[CH3:80])=[O:75])[CH2:73]3)[CH:56]=2)[N:51]=[C:50]([O:82][CH3:83])[C:49]=1[CH2:84][C:85]1[CH:86]=[CH:87][C:88]([C:91]([F:93])([F:92])[F:94])=[CH:89][CH:90]=1.[C:58]([CH:59]1[CH2:62][N:61]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:60]1)([CH:70]1[CH2:71][N:72]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:73]1)=[O:81]

Participants

8

Reactant 4

HCID 18522661Acetone cardiceHCID 86715629(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanol2×HCID 118006442Di-tert-butyl 3,3'-((4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(hydroxy)methylene)bis(azetidine-1-carboxylate)2×HCID 178418339Butyllithium

Product 2

HCID 118006144Di-tert-butyl 3,3'-carbonylbis(azetidine-1-carboxylate)HCID 118006442Di-tert-butyl 3,3'-((4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(hydroxy)methylene)bis(azetidine-1-carboxylate)

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 3283Diethyl EtherSolvent

Procedure

n-BuLi (1.60 M in hexane, 0.752 mL, 0.12 mmol) was added dropwise under argon to a slurry of 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (51.8 mg, 0.12 mmol, Intermediate 12: step d) in diethyl ether (0.8 mL) at ˜−70° C. with stirring. The grey slurry was immediately transferred to an ice bath for ˜30 seconds at which point a homogeneous dark amber solution formed. The reaction was then immediately transferred back to the dry ice/acetone bath and after stirring for 2 minutes was treated with a solution of di-tert-butyl 3,3′-carbonylbis(azetidine-1-carboxylate) (42.7 mg, 0.125 mmol, Intermediate 85: step b) in toluene (0.4 mL) over 50 seconds. After 5 minutes stirring at ˜−70° C., the reaction was removed from the cold bath and stirred under ambient conditions for 1 minute and then transferred to an ice bath and stirred for 30 minutes. The homogeneous yellow reaction was then quenched with 5 M aqueous NH4Cl (0.035 mL), diluted with EtOAc (3 mL), dried (Na2SO4), filtered, and concentrated. The residue was flash chromatographed (0-100% EtOAc in heptane over 16 column volumes) to provide a 65/35 mol fraction ratio of the title compound/di-tert-butyl 3,3′-carbonylbis(azetidine-1-carboxylate) as a thick yellow oil. This mixture was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=2.02 Hz, 1H), 7.83 (d, J=8.59 Hz, 1H), 7.58 (dd, J=2.02, 9.09 Hz, 1H), 7.51 (d, J=8.59 Hz, 2H), 7.40 (d, J=8.08 Hz, 2H), 4.36 (s, 2H), 4.03-4.16 (m, 5H), 3.92 (t, J=8.59 Hz, 2H), 3.54-3.67 (m, 4H), 3.11-3.21 (m, 2H), 1.39 (s, 18H); MS m/e 692.2 [M+H]+.

Workup

  1. customa homogeneous dark amber solution formed
  2. stirringafter stirring for 2 minutes
  3. stirringAfter 5 minutes stirring at ˜−70° C.
  4. customthe reaction was removed from the cold bath
  5. stirringstirred under ambient conditions for 1 minute
  6. customtransferred to an ice bath
  7. stirringstirred for 30 minutes
  8. customThe homogeneous yellow reaction
  9. customwas then quenched with 5 M aqueous NH4Cl (0.035 mL)
  10. additiondiluted with EtOAc (3 mL)
  11. dry with materialdried (Na2SO4)
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customchromatographed (0-100% EtOAc in heptane over 16 column volumes)

Sources & evidence

ORD record
ord-4a549d0af57e432c9e69d93e5bbe27f9
Source dataset
uspto-grants-2016_03
Patent number
US09284308B2

Reaction notes

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