Tetrahydrofuran → 4-(5-chloro-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

HRID 1621911Notes

Reaction equation

HRID 1621911 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[N:20]=2)[C:15](F)=[N:16][CH:17]=1.C1COCC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[CH2:36][C:37]3[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=3)[N:20]=2)[C:15]([NH:10][C:4]2[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[N:16][CH:17]=1

Participants

5

Reactant 4

HCID 8028TetrahydrofuranHCID 2733832Lithium HexamethyldisilazideHCID 454803515-Fluoro-6-methoxypyridin-3-amineHCID 666005044-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

Product 1

HCID 666111934-(5-chloro-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amineYield 88%

Procedure

A stirred mixture of 5-fluoro-6-methoxypyridin-3-amine (Anichem, North Brunswick, N.J.; 0.834 g, 5.87 mmol) and 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.8776 g, 3.91 mmol) in THF (50.0 mL, 610 mmol) was treated dropwise with LiHMDS (1.0 M in THF, 16.74 mL, 16.74 mmol) at −15° C. (ice-salt bath) and stirred for 40 min. The reaction was then quenched with water and saturated NH4Cl(aq) (25 mL each) and diluted with EtOAc (25 mL). Organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were then washed with brine, dried over Na2SO4, and concentrated. Chromatographic purification of the residue (silica gel, 0% to 1% MeOH/DCM) followed by washing of the purified product with isopropanol gave 4-(5-chloro-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (2.07 g, 3.44 mmol, 88% yield). 1H NMR (400 MHz, CDCl3) δ 8.77 (d, J=2.54 Hz, 1H); 8.23 (d, J=2.54Hz, 1H); 7.95 (d, J=1.96 Hz, 1H); 7.90 (d, J=12.13 Hz, 1H); 7.18 (dd, J=17.41, 8.41 Hz, 4H); 6.86 (t, J=8.12 Hz, 4H); 4.86 (s, 2H); 4.82 (s, 2H); 4.01 (s, 3H); 3.81 (s, 3H); 3.79 (s, 3H); 2.60 (s, 3H).

Workup

  1. customThe reaction was then quenched with water and saturated NH4Cl(aq) (25 mL each)
  2. additiondiluted with EtOAc (25 mL)
  3. customOrganic layer was separated
  4. extractionthe aqueous layer was extracted with ethyl acetate (2×50 mL)
  5. washThe combined organic layers were then washed with brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated
  8. customChromatographic purification of the residue (silica gel, 0% to 1% MeOH/DCM)
  9. washby washing of the purified product with isopropanol

Sources & evidence

ORD record
ord-6d2aef1a898e49a0842c28030d44b8c7
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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