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 1811819Notes

Reaction equation

HRID 1811819 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-fc43870691864f0293c3f60ef2ef8f8f
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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