Tetrahydrofuran → Tert-butyl 4-((6-(6-methoxypyridin-3-ylamino)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyridin-3-yl)methyl)piperazine-1-carboxylate

HRID 1621407Notes

Reaction equation

HRID 1621407 reaction equation
[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:12]1[N:17]=[CH:16][C:15]([CH2:18][N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:14][C:13]=1[C:32]1[N:37]=[C:36]([CH3:38])[N:35]=[C:34]([S:39][CH3:40])[N:33]=1.[NH2:41][C:42]1[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[N:46][CH:47]=1.C1COCC1>[NH4+].[Cl-].O.C(OCC)(=O)C>[CH3:49][O:48][C:45]1[N:46]=[CH:47][C:42]([NH:41][C:12]2[N:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:14][C:13]=2[C:32]2[N:37]=[C:36]([CH3:38])[N:35]=[C:34]([S:39][CH3:40])[N:33]=2)=[CH:43][CH:44]=1

Participants

8

Reactant 4

HCID 8028TetrahydrofuranHCID 811216-Methoxy-3-pyridinylamineHCID 2733832Lithium HexamethyldisilazideHCID 59548392Tert-butyl 4-((6-fluoro-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyridin-3-yl)methyl)piperazine-1-carboxylate

Product 1

HCID 66610640Tert-butyl 4-((6-(6-methoxypyridin-3-ylamino)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyridin-3-yl)methyl)piperazine-1-carboxylateYield 49%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 25517Ammonium ChlorideSolvent

Procedure

LiHMDS (1.519 mL, 1.0 M in THF, 1.519 mmol) was added to a stirred solution of tert-butyl 4-((6-fluoro-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyridin-3-yl)methyl)piperazine-1-carboxylate (0.220 g, 0.506 mmol) and 5-amino-2-methoxypyridine (0.094 g, 0.759 mmol) in THF (3.00 mL, 36.6 mmol) at 0° 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 (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, concentrated and purified by flash column chromatography (ISCO Combiflash system, Teledyne ISCO, Lincoln, Nebr., hexanes to 50% ethyl acetates in hexanes) to give tert-butyl 4-((6-(6-methoxypyridin-3-ylamino)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyridin-3-yl)methyl)piperazine-1-carboxylate (0.133 g, 49%) as a yellow solid. LCMS (API-ES) m/z 538 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 11.42 (s, 1H) 8.81 (br. s., 1H) 8.36 (d, J=2.74 Hz, 1H) 8.27 (br. s., 1H) 8.10 (dd, J=8.71, 2.64 Hz, 1H) 6.79 (d, J=8.80 Hz, 1H) 3.95 (s, 3H) 3.50 (s, 2H) 3.43 (br. s., 4H) 2.67 (s, 3H) 2.66 (br. s., 3H) 2.42 (br. s., 4H) 1.45 (s, 9H).

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. custompurified by flash column chromatography (ISCO Combiflash system, Teledyne ISCO, Lincoln, Nebr., hexanes to 50% ethyl acetates in hexanes)

Sources & evidence

ORD record
ord-fc366333c6ed4da382a305b9af576dae
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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