Ammonia → 4-(2-(5-Methoxypyridin-3-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine

HRID 1621612Notes

Reaction equation

HRID 1621612 reaction equation
F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10](SC)[N:9]=2)=[CH:6][C:5]([CH2:17][N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]2)=[CH:4][N:3]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH2:36])[CH:33]=[N:34][CH:35]=1.C[N:38](C=O)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.N.CC(O)C>O.C(OCC)(=O)C>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:36][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:38])[N:9]=3)=[CH:6][C:5]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:25])=[O:26])[CH2:20][CH2:19]3)=[CH:4][N:3]=2)[CH:33]=[N:34][CH:35]=1

Participants

10

Reactant 7

HCID 222AmmoniaHCID 3776IsopropanolHCID 6228DimethylformamideHCID 8028TetrahydrofuranHCID 2733832Lithium HexamethyldisilazideHCID 127035955-Methoxypyridin-3-ylamineHCID 595481882-(2-Fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-4-methyl-6-(methylthio)-1,3,5-triazine

Product 1

HCID 595482214-(2-(5-Methoxypyridin-3-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amineYield 18.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

A stirred solution of 2-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-4-methyl-6-(methylthio)-1,3,5-triazine (200 mg, 0.485 mmol) and 5-methoxypyridin-3-amine (Astatech, Inc., 90 mg, 0.727 mmol) in DMF (5.00 mL, 1.000 mmol) was treated with 1.0 M LiHMDS in THF (1.939 mL, 1.939 mmol) at 0° C. and the mixture was stirred for 1 h. The reaction mixture was diluted with water (10 mL each) and ethyl acetate (15 mL). The separated aqueous layer was extracted with ethyl acetate (2×10 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude residue which was heated with 2.0 M ammonia in IPA (3.00 mL, 6.00 mmol) in a sealed tube at 90° C. overnight. After cooling, the mixture was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (pure DCM to 5% MeOH in DCM) to give 4-(2-(5-methoxypyridin-3-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (44 mg, 0.091 mmol, 18.69% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 12.13 (s, 1H); 8.74 (s, 1H); 8.55 (s, 1H); 8.31 (s, 1H); 8.19 (br. s., 1H); 7.93 (br. s., 2H); 7.78 (br. s., 1H); 3.86 (s, 3H); 3.52 (s, 2H); 3.11 (br. s., 4H); 2.87 (s, 3H); 2.46-2.50 (m, 4H); 2.46 (s, 3H). m/z (ESI, +ve ion) 486.1 (M+H)+.

Workup

  1. extractionThe separated aqueous layer was extracted with ethyl acetate (2×10 mL)
  2. washthe combined organic layers were washed with brine
  3. dry with materialdried over Na2SO4
  4. concentrationconcentrated
  5. customto give the crude residue which
  6. temperatureAfter cooling
  7. customchromatographed through a Redi-Sep pre-packed silica gel column (pure DCM to 5% MeOH in DCM)

Sources & evidence

ORD record
ord-a7f58dcd6e5e4fac9ff5c32921b5844b
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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