4-Methylmorpholine → 2-[3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl]-N-[6-(trifluoromethyl)pyridin-2-yl]acetamide

HRID 1667263Notes

Reaction equation

HRID 1667263 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[F:31][C:32]([F:41])([F:40])[C:33]1[N:38]=[C:37]([NH2:39])[CH:36]=[CH:35][CH:34]=1.CN1CCOCC1>ClCCl.CN(C)C=O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:39][C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:40])([F:31])[F:41])[N:38]=3)=[O:16])[C:9]2=[O:17])=[CH:19][CH:20]=1

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 65578Oxalyl chlorideHCID 8210242-Amino-6-(trifluoromethyl)pyridineHCID 673571912-(3,3-Bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid

Product 1

HCID 674437402-[3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl]-N-[6-(trifluoromethyl)pyridin-2-yl]acetamide

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To a suspension of 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.192 g, 0.578 mmol; Example 58D) in dichloromethane (3 mL) was added a catalytic amount of N,N-dimethylformamide followed by oxalyl dichloride (2.0 Min dichloromethane) (0.578 mL, 1.157 mmol). The reaction was stirred for 30 minutes than concentrated to give an oil. After drying under high vacuum for 20 minutes, the residue was dissolved in dichloromethane (1 mL) and 6-(trifluoromethyl)pyridin-2-amine (0.075 g, 0.463 mmol) and 4-methylmorpholine (0.102 mL, 0.925 mmol) were added. After stirring for 20 minutes, the reaction was loaded onto a GraceResolv™ 40 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 35% ethyl acetate/hexanes (Flow=40 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.36 (s, 1H), 8.32 (d, J=8.5, 1H), 7.86 (t, J=8.0, 1H), 7.43 (d, J=7.3, 1H), 7.36-7.29 (m, 4H), 7.06-6.96 (m, 4H), 4.22 (s, 2H), 3.54 (t, J=6.5, 2H), 2.83 (t, J=6.5, 2H); MS (ESI+) m/z 476.1 (M+H)+.

Workup

  1. concentrationthan concentrated
  2. customto give an oil
  3. customAfter drying under high vacuum for 20 minutes
  4. dissolutionthe residue was dissolved in dichloromethane (1 mL)
  5. stirringAfter stirring for 20 minutes
  6. washthe product eluted with a gradient of 5% ethyl acetate/hexanes to 35% ethyl acetate/hexanes (Flow=40 mL/minute) over 30 minutes

Sources & evidence

ORD record
ord-6fbcbec26fe741589b9b3d2c971c25c4
Source dataset
uspto-grants-2011_10
Patent number
US08044069B2

Reaction notes

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