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

HRID 1811812Notes

Reaction equation

HRID 1811812 reaction equation
[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.F[C:17]1[C:22]([C:23]2[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([S:30][CH3:31])[N:24]=2)=[CH:21][C:20]([CH2:32][N:33]2[CH2:38][CH2:37][N:36]([S:39]([CH3:42])(=[O:41])=[O:40])[CH2:35][CH2:34]2)=[CH:19][N:18]=1.[NH2:43][C:44]1[CH:45]=[N:46][C:47]([O:50][CH3:51])=[CH:48][CH:49]=1>[NH4+].[Cl-].O.C(OCC)(=O)C>[CH3:51][O:50][C:47]1[N:46]=[CH:45][C:44]([NH:43][C:17]2[C:22]([C:23]3[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([S:30][CH3:31])[N:24]=3)=[CH:21][C:20]([CH2:32][N:33]3[CH2:38][CH2:37][N:36]([S:39]([CH3:42])(=[O:40])=[O:41])[CH2:35][CH2:34]3)=[CH:19][N:18]=2)=[CH:49][CH:48]=1

Participants

8

Reactant 4

HCID 8028Tetrahydrofuran2×HCID 811216-Methoxy-3-pyridinylamineHCID 2733832Lithium HexamethyldisilazideHCID 595481882-(2-Fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-4-methyl-6-(methylthio)-1,3,5-triazine

Product 1

HCID 66599816N-(6-methoxypyridin-3-yl)-3-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-amineYield 60.9%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 25517Ammonium ChlorideSolvent

Procedure

LiHMDS, 1.0 M in THF (0.754 mL, 0.754 mmol) was added dropwise to 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 (0.311 g, 0.754 mmol) (Example 34, Step 5) and 3-amino-6-methoxypyridine (0.094 g, 0.754 mmol) in tetrahydrofuran (10 mL, 0.754 mmol) at −10° C. and the mixture was stirred at the same temperature for 1 h. The reaction mixture was diluted with NH4Cl (aq) and water (10 mL each) and diluted with ethyl acetate (20 mL). The separated aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatography (ISCO Combiflash system, Teledyne ISCO, Lincoln, Nebr., DCM to 5% MeOH in DCM) to give N-(6-methoxypyridin-3-yl)-3-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-amine (237 mg, 0.459 mmol, 60.8% yield) as a yellow solid.

Workup

  1. extractionThe separated aqueous layer was extracted with ethyl acetate (2×20 mL)
  2. washthe combined organic layers were washed with brine
  3. dry with materialdried over Na2SO4
  4. concentrationconcentrated
  5. custompurified by flash column chromatography (ISCO Combiflash system, Teledyne ISCO, Lincoln, Nebr., DCM to 5% MeOH in DCM)

Sources & evidence

ORD record
ord-75ae2794721344f4ad69e8d582274e13
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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