Tetrahydrofuran → N-(6-methoxypyridin-3-yl)-3-(4-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-amine

HRID 1621399Notes

Reaction equation

HRID 1621399 reaction equation
[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[CH:20][N:19]=2)=[CH:16][C:15]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:28][CH2:27]2)=[CH:14][N:13]=1.[NH2:36][C:37]1[CH:38]=[N:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=1.C1COCC1>>[CH3:44][O:43][C:40]1[N:39]=[CH:38][C:37]([NH:36][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[CH:20][N:19]=3)=[CH:16][C:15]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:28][CH2:27]3)=[CH:14][N:13]=2)=[CH:42][CH:41]=1

Participants

5

Reactant 4

HCID 8028TetrahydrofuranHCID 811216-Methoxy-3-pyridinylamineHCID 2733832Lithium HexamethyldisilazideHCID 666005952-(2-Fluoro-5-((4-(methylsulfonyl)piperazin-1-YL)methyl)pyridin-3-YL)-4-methyl-1,3,5-triazine

Product 1

HCID 49784989N-(6-methoxypyridin-3-yl)-3-(4-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-amineYield 17.1%

Procedure

LiHMDS (1.0 M in THF, 557 μL, 0.557 mmol) was added to a stirred solution of 2-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-4-methyl-1,3,5-triazine (68.0 mg, 0.186 mmol) and 3-amino-6-methoxypyridine (Aldrich) (34.6 mg, 0.278 mmol) in THF (928 μL, 0.186 mmol) at 0° C. and the mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with water (10 mL) and diluted with ethyl acetate (10 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. The crude product was adsorbed onto a plug of silica gel and chromatographed through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (DCM to 5% MeOH in DCM) followed by washing with iPrOH to give N-(6-methoxypyridin-3-yl)-3-(4-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-amine (15 mg, 17%) as a yellow solid. LCMS (API-ES) m/z 471 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 11.44 (s, 1H) 9.29 (s, 1H) 8.81 (s, 1H) 8.51 (br. s., 1H) 8.29 (br. s., 1H) 8.11 (d, J=9.19 Hz, 1H) 6.85 (d, J=9.19 Hz, 1H) 3.85 (s, 3H) 3.53 (s, 2H) 3.11 (br. s., 4H) 2.87 (s, 3H) 2.75 (s, 3H) 2.34-2.49 (m, 4H).

Workup

  1. customThe reaction mixture was quenched with water (10 mL)
  2. additiondiluted with ethyl acetate (10 mL)
  3. extractionThe separated aqueous layer was extracted with ethyl acetate (2×10 mL)
  4. washthe combined organic layers were washed with brine
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated
  7. customchromatographed through a RediSep®, Teledyne ISCO, Lincoln, Nebr
  8. washby washing with iPrOH

Sources & evidence

ORD record
ord-cdd1065f2034401eb8f26e341ef91e7c
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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