4-Methylmorpholine → (2R)-4-[4-(4-chloro-2,3-difluorophenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

HRID 84268Notes

Reaction equation

HRID 84268 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C@@:16]([CH3:24])([S:20]([CH3:23])(=[O:22])=[O:21])[C:17](O)=[O:18])[C:10](=[O:25])[CH:9]=2)=[C:4]([F:26])[C:3]=1[F:27].CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[O:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH:47]1[O:52][NH2:53]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C@@:16]([CH3:24])([S:20]([CH3:23])(=[O:21])=[O:22])[C:17]([NH:53][O:52][CH:47]3[CH2:48][CH2:49][CH2:50][CH2:51][O:46]3)=[O:18])[C:10](=[O:25])[CH:9]=2)=[C:4]([F:26])[C:3]=1[F:27]

Participants

5

Reactant 4

HCID 79724-MethylmorpholineHCID 184502-Chloro-4,6-dimethoxy-1,3,5-triazineHCID 5142091O-(Tetrahydropyran-2-yl)hydroxylamineHCID 67250147(2R)-4-[4-(4-chloro-2,3-difluorophenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid

Product 1

HCID 86671949(2R)-4-[4-(4-chloro-2,3-difluorophenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

Procedure

To a suspension of (2R)-4-[4-(4-chloro-2,3-difluorophenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (4500 mg, 10.7 mmol) in Me-THF (450 mL) was added N-methyl morpholine (1.80 mL, 16.1 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (2520 mg, 13.9 mmol). The reaction mixture was stirred at room temperature for 1 h. To the mixture was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (1630 mg, 13.9 mmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was washed with water and passed through pad of sodium sulfate, celite and silica gel. The pad was washed with ethyl acetate. The combined organic solution was concentrated under reduced pressure to give the title compound as a solid in quantitative yield. LCMS m/z 519.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-1.57 (m, 3 H) 1.59 (d, J=3.90 Hz, 3 H) 1.64-1.74 (m, 3 H) 2.15-2.26 (m, 1 H) 2.39-2.49 (m, 1 H) 3.10 (d, J=6.44 Hz, 3 H) 3.46-3.58 (m, 1 H) 3.70-3.83 (m, 1 H) 4.03 (d, J=7.02 Hz, 1 H) 4.07-4.21 (m, 1 H) 4.95-5.01 (m, 1 H) 6.48-6.53 (m, 1 H) 6.61-6.64 (m, 1 H) 7.42-7.49 (m, 1 H) 7.51-7.59 (m, 1 H) 7.79 (dd, J=10.83, 7.12 Hz, 1 H), H—N wasn't observed. 19F NMR (376 MHz, DMSO-d6) δ ppm −138.09 (dd, J=22.56, 7.52 Hz) −139.10 (dd, J=22.56, 7.52 Hz)

Workup

  1. stirringthe resulting mixture was stirred at room temperature for 1 h
  2. washThe reaction mixture was washed with water
  3. washThe pad was washed with ethyl acetate
  4. concentrationThe combined organic solution was concentrated under reduced pressure

Sources & evidence

ORD record
ord-e8375b5eef574a13a8101f70016c7c7b
Source dataset
uspto-grants-2014_09
Patent number
US08846933B2

Reaction notes

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