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

HRID 1621404Notes

Reaction equation

HRID 1621404 reaction equation
[CH3:1][O:2][C:3]1[CH:47]=[CH:46][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:23][N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[CH:19]=[N:20][C:21]=3F)[N:10]=2)=[CH:5][CH:4]=1.[F:48][C:49]1[CH:50]=[C:51]([NH2:57])[CH:52]=[N:53][C:54]=1[O:55][CH3:56].O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>>[CH3:1][O:2][C:3]1[CH:47]=[CH:46][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:23][N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[CH:19]=[N:20][C:21]=3[NH:57][C:51]3[CH:52]=[N:53][C:54]([O:55][CH3:56])=[C:49]([F:48])[CH:50]=3)[N:10]=2)=[CH:5][CH:4]=1

Participants

5

Reactant 4

HCID 8028Tetrahydrofuran2×HCID 2733832Lithium HexamethyldisilazideHCID 454803515-Fluoro-6-methoxypyridin-3-amineHCID 60156087Tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate

Product 1

HCID 66600044Tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)piperazine-1-carboxylateYield 90.2%

Procedure

A solution of tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (25 g, 38.8 mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem LLC, Monmouth N.J.) (8.28 g, 58.3 mmol) in tetrahydrofuran (400 mL, 38.8 mmol) contained in an oven dried 1 L 3-neck round-bottomed flask equipped with N2 inlet was stirred at a temperature between −5° C. and −10° C. and treated dropwise with a 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (117 mL, 117 mmol). The dark pink solution was stirred between −5° C. and −10° C. for 1 h. The reaction was quenched with water (100 mL) and NH4Cl (100 mL) and diluted with EtOAc (350 mL). The separated aqueous layer was extracted with EtOAc (2×300 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give the crude product which was adsorbed onto silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (Teledyne ISCO, Lincoln, Nebr.) (330 g) eluting with a gradient of 10% to 50% EtOAc in hexane to give tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)piperazine-1-carboxylate (26.8 g, 35.0 mmol, 90% yield). m/z (ESI, positive ion) m/z 766 (M+H)+.

Workup

  1. customdried 1 L
  2. customround-bottomed flask equipped with N2 inlet
  3. stirringThe dark pink solution was stirred between −5° C. and −10° C. for 1 h
  4. customThe reaction was quenched with water (100 mL) and NH4Cl (100 mL)
  5. additiondiluted with EtOAc (350 mL)
  6. extractionThe separated aqueous layer was extracted with EtOAc (2×300 mL)
  7. dry with materialthe combined organic extracts were dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customto give the crude product which
  11. customchromatographed through a Redi-Sep® pre-packed silica gel column (Teledyne ISCO, Lincoln, Nebr.) (330 g)
  12. washeluting with a gradient of 10% to 50% EtOAc in hexane

Sources & evidence

ORD record
ord-4529e5e57b414dc4af07de0ab13a71dd
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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