Sodium bis(trimethylsilyl)amide → N-(2-Chloro-5-(3-(2-methyl-6-(methylthio)pyrimidin-4-YL)-5-(1-morpholinoethyl)pyridin-2-ylamino)pyridin-3-YL)methanesulfonamide

HRID 1622026Notes

Reaction equation

HRID 1622026 reaction equation
F[C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH3:9])=[CH:4][C:3]=1[C:16]1[CH:21]=[C:20]([S:22][CH3:23])[N:19]=[C:18]([CH3:24])[N:17]=1.[NH2:25][C:26]1[CH:27]=[C:28]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:29]([Cl:32])=[N:30][CH:31]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:32][C:29]1[C:28]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:27][C:26]([NH:25][C:2]2[C:3]([C:16]3[CH:21]=[C:20]([S:22][CH3:23])[N:19]=[C:18]([CH3:24])[N:17]=3)=[CH:4][C:5]([CH:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH3:9])=[CH:6][N:7]=2)=[CH:31][N:30]=1

Participants

5

Reactant 3

HCID 2724254Sodium bis(trimethylsilyl)amideHCID 666008374-(1-(6-Fluoro-5-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyridin-3-yl)ethyl)morpholineHCID 71480920N-(5-amino-2-chloro-3-pyridinyl)methanesulfonamide

Product 1

HCID 86647090N-(2-Chloro-5-(3-(2-methyl-6-(methylthio)pyrimidin-4-YL)-5-(1-morpholinoethyl)pyridin-2-ylamino)pyridin-3-YL)methanesulfonamideYield 69.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a flame dry 15 mL round-bottom flask was added 4-(1-(6-fluoro-5-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyridin-3-yl)ethyl)morpholine (0.160 g, 0.459 mmol), N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (0.122 g, 0.551 mmol), and THF (4.0 mL). The mixture was cooled to 0° C. under N2. Sodium bis(trimethylsilyl)amide, 1.0 m in THF (Aldrich) (1.837 mL, 1.837 mmol) was then added to the solution in one portion. The now dark burgundy color mixture was stirred at 0° C. for 10 min then warmed up to rt and stirred for 1 h. The reaction mixture was quenched with sat. NH4Cl. The reaction mixture was partitioned between water and CHCl3. The aqueous layer was extracted with CHCl3 (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, DCM:EtOAc:MeOH=65%:32%:3%) to afford the product as a yellow solid (175 mg). MS (ESI pos. ion) m/z: 550.0. 1H NMR (300 MHz, CDCl3) 8 ppm 1.41 (d, J=6.58 Hz, 3H) 2.34-2.48 (m, 2H) 2.49-2.60 (m, 2H) 2.66 (s, 3H) 2.81 (s, 3H) 3.13 (s, 3H) 3.39 (d, J=6.58 Hz, 1H) 3.72 (t, J=4.38 Hz, 4H) 6.75 (br. s., 1H) 7.45 (s, 1H) 8.01 (d, J=1.90 Hz, 1H) 8.30 (d, J=1.90 Hz, 1H) 8.52 (d, J=2.48 Hz, 1H) 8.76 (d, J=2.48 Hz, 1H) 12.43 (s, 1H).

Workup

  1. customTo a flame dry 15 mL round-bottom flask
  2. temperaturethen warmed up to rt
  3. stirringstirred for 1 h
  4. customThe reaction mixture was quenched with sat. NH4Cl
  5. customThe reaction mixture was partitioned between water and CHCl3
  6. extractionThe aqueous layer was extracted with CHCl3 (2×10 mL)
  7. dry with materialThe combined organic layers were dried over MgSO4
  8. concentrationconcentrated
  9. customThe crude product was purified by column chromatography (40 g, DCM:EtOAc:MeOH=65%:32%:3%)

Sources & evidence

ORD record
ord-981ad2d23ae0408e9cb32b2fa097ab60
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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