6-Methoxy-3-pyridinylamine → 4-(5-(Difluoromethoxy)-2-(6-methoxypyridin-3-ylamino)pyridin-3-YL)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

HRID 1812187Notes

Reaction equation

HRID 1812187 reaction equation
[F:1][CH:2]([F:37])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([N:18]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:12]=2)[C:7](F)=[N:8][CH:9]=1.[NH2:38][C:39]1[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[N:43][CH:44]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[F:37][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([N:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[N:12]=2)[C:7]([NH:38][C:39]2[CH:44]=[N:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[N:8][CH:9]=1

Participants

5

Reactant 3

HCID 811216-Methoxy-3-pyridinylamineHCID 2733832Lithium HexamethyldisilazideHCID 666114724-(5-(Difluoromethoxy)-2-fluoropyridin-3-YL)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

Product 1

HCID 666120174-(5-(Difluoromethoxy)-2-(6-methoxypyridin-3-ylamino)pyridin-3-YL)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amineYield 60.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 4-(5-(difluoromethoxy)-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.030 g, 0.059 mmol) and 5-amino-2-methoxypyridine (Aldrich) (8.06 μL, 0.065 mmol), in THF (1 mL) was cooled to 0° C. under N2 and treated with lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydriofuran (Aldrich) (0.039 mL, 0.235 mmol). The dark red mixture was stirred at 0° C. for 1 h and then partitioned between EtOAc and sat. NH4Cl. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with water, brine, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (12 g, 10% to 20% EtOAc in hexanes) to give the product as a yellow solid (0.022 g). m/z (ESI, +ve ion) 616.0 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 11.65 (s, 1H); 8.63 (br. s., 1H); 8.26 (s, 1H); 8.17 (br. s., 1H); 7.89 (d, J=8.77 Hz, 1H); 7.11-7.25 (m, 4H); 6.78-6.95 (m, 4H); 6.72 (d, J=8.77 Hz, 1H); 6.11-6.69 (m, 1H); 4.74-4.93 (m, 4H); 3.94 (s, 3H); 3.81 (d, J=8.48 Hz, 6H); 2.59 (s, 3H).

Workup

  1. custompartitioned between EtOAc and sat. NH4Cl
  2. extractionThe aqueous layer was extracted with EtOAc (2×10 mL)
  3. washThe combined organic layers were washed with water, brine
  4. dry with materialdried over MgSO4
  5. concentrationconcentrated
  6. customThe crude product was purified by column chromatography (12 g, 10% to 20% EtOAc in hexanes)

Sources & evidence

ORD record
ord-178827934c25446faccdeb60a47b4d2f
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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