Azetidine → 2-Fluoro-4-(3-(1-(7-fluoroquinolin-2-YL)azetidin-3-YL)pyrazin-2-YL)-N-methylbenzamide

HRID 2364580Notes

Reaction equation

HRID 2364580 reaction equation
FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:22]1[CH2:25][CH:24]([C:26]2[C:27]([C:32]3[CH:41]=[CH:40][C:35]([C:36]([NH:38][CH3:39])=[O:37])=[C:34]([F:42])[CH:33]=3)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:23]1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[C:55]1[CH:64]=[CH:63][C:62]2[C:57](=[CH:58][C:59]([F:65])=[CH:60][CH:61]=2)[N:56]=1)(=O)=O.N1CCC1>O.CS(C)=O>[F:42][C:34]1[CH:33]=[C:32]([C:27]2[C:26]([CH:24]3[CH2:23][N:22]([C:55]4[CH:64]=[CH:63][C:62]5[C:57](=[CH:58][C:59]([F:65])=[CH:60][CH:61]=5)[N:56]=4)[CH2:25]3)=[N:31][CH:30]=[CH:29][N:28]=2)[CH:41]=[CH:40][C:35]=1[C:36]([NH:38][CH3:39])=[O:37]

Participants

7

Reactant 4

HCID 10422AzetidineHCID 11430Potassium CarbonateHCID 866941337-Fluoroquinolin-2-yl trifluoromethanesulfonateHCID 867054064-(3-(Azetidin-3-YL)pyrazin-2-YL)-2-fluoro-N-methylbenzamide tris(2,2,2-trifluoroacetate)

Product 1

HCID 726942252-Fluoro-4-(3-(1-(7-fluoroquinolin-2-YL)azetidin-3-YL)pyrazin-2-YL)-N-methylbenzamideYield 78%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent

Conditions

Temperature
50 °C

Procedure

A mixture of 4-(3-(azetidin-3-yl)pyrazin-2-yl)-2-fluoro-N-methylbenzamide tris(2,2,2-trifluoroacetate) (0.953 g, 1.517 mmol), potassium carbonate (0.839 g, 6.070 mmol), 7-fluoroquinolin-2-yl trifluoromethanesulfonate (0.537 g, 1.821 mmol, prepared according to Step 3 of Example 2), and DMSO (10 mL) was stirred at 50° C. for 1 h. LCMS showed the product and no more azetidine starting material. The mixture was diluted with water and extracted with CH2Cl2 three times. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude was purified by silica gel chromatography: 40 g, 5-100% EtOAc-hexane. The impurity 2-hydroxyquinoline was further removed by trituration with CH2Cl2 and hexane twice. The product was obtained as a white solid (510 mg, 78%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.09 (d, J=4.50 Hz, 3H) 4.33-4.50 (m, 5H) 6.56 (d, J=9.00 Hz, 1H) 6.81 (d, J=7.04 Hz, 1H) 6.98 (td, J=8.61, 2.54 Hz, 1H) 7.31-7.45 (m, 3H) 7.56 (dd, J=8.71, 6.36 Hz, 1H) 7.84 (d, J=9.00 Hz, 1H) 8.28 (t, J=8.02 Hz, 1H) 8.57 (d, J=2.15 Hz, 1H) 8.64 (d, J=2.35 Hz, 1H). m/z=432 (M+1).

Workup

  1. extractionextracted with CH2Cl2 three times
  2. dry with materialThe organic layer was dried over Na2SO4
  3. concentrationconcentrated in vacuo
  4. customThe crude was purified by silica gel chromatography
  5. customThe impurity 2-hydroxyquinoline was further removed by trituration with CH2Cl2 and hexane twice

Sources & evidence

ORD record
ord-0fe2812ff6f5491e88be4534a8f6b7a1
Source dataset
uspto-grants-2014_04
Patent number
US08691986B2

Reaction notes

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