Nitrogen → 5-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde

HRID 1811983Notes

Reaction equation

HRID 1811983 reaction equation
O1CC[O:3][CH:2]1[C:6]1[CH:7]=[C:8]([C:13]2[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:14]=2)[C:9](F)=[N:10][CH:11]=1.N#N.[CH3:41][O:42][C:43]1[N:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1C=CC=CC=1.C1COCC1.C(Cl)Cl>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:20]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:15]2[N:16]=[C:17]([CH3:19])[N:18]=[C:13]([C:8]3[C:9]([NH:49][C:46]4[CH:47]=[N:48][C:43]([O:42][CH3:41])=[CH:44][CH:45]=4)=[N:10][CH:11]=[C:6]([CH:7]=3)[CH:2]=[O:3])[N:14]=2)=[CH:27][CH:26]=1

Participants

8

Reactant 4

HCID 947NitrogenHCID 811216-Methoxy-3-pyridinylamineHCID 2733832Lithium HexamethyldisilazideHCID 601549954-(5-(1,3-dioxolan-2-yl)-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

Product 1

HCID 601552675-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehydeYield 61%

Reagents, catalysts & solvents 3

HCID 241BenzeneSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

A stock solution of 4-(5-(1,3-dioxolan-2-yl)-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 143, Step 1) (5.85 g, 11.30 mmol) in benzene (50 mL) contained in a 250 mL round-bottomed flask with stir bar was frozen and lyophilized overnight (pale yellow solid obtained). The flask was opened to N2 and THF (50 mL) was added followed by 6-methoxypyridin-3-amine (1.332 mL, 12.43 mmol). The solution was cooled in an ice bath and LiHMDS (44 mL of a 1.0 M solution in THF, 44 mmol) was added. The mixture was stirred for 40 min and then quenched with water (3 mL) and concentrated to dryness. The residue was taken up in a mixture of DCM and 2 N aqueous HCl and stirred for 30 min. The product was extracted into DCM from 2 N HCl, washed with saturated aqueous NaHCO3, dried (MgSO4) and concentrated to give a brown solid. This was dissolved in DCM and purified by flash chrormatography (30% EtOAc, 10% DCM, 60% hexane) to give 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (3.98 g, 6.89 mmol, 61.0% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 12.09 (s, 1H); 9.90 (s, 1H); 9.14 (d, J=2.35 Hz, 1H); 8.77 (d, J=2.35 Hz, 1H); 8.31 (d, J=2.74 Hz, 1H); 7.87 (dd, J=8.80, 2.74 Hz, 1H); 7.28 (d, J=8.61 Hz, 2H); 7.21 (d, J=8.80 Hz, 2H); 6.87-6.94 (m, 2H); 6.78-6.87 (m, 3H); 4.83 (d, J=7.24 Hz, 4H); 3.85 (s, 3H); 3.74 (s, 3H); 3.69 (s, 3H); 2.58 (s, 3H). m/z (ESI, +ve ion) 578 (M+H)+.

Workup

  1. temperaturewas frozen
  2. custom(pale yellow solid obtained)
  3. additionwas added
  4. temperatureThe solution was cooled in an ice bath
  5. stirringThe mixture was stirred for 40 min
  6. customquenched with water (3 mL)
  7. concentrationconcentrated to dryness
  8. additionThe residue was taken up in a mixture of DCM and 2 N aqueous HCl
  9. stirringstirred for 30 min
  10. extractionThe product was extracted into DCM from 2 N HCl
  11. washwashed with saturated aqueous NaHCO3
  12. dry with materialdried (MgSO4)
  13. concentrationconcentrated
  14. customto give a brown solid
  15. custompurified by flash chrormatography (30% EtOAc, 10% DCM, 60% hexane)

Sources & evidence

ORD record
ord-2332c984cbc24d99ac7b18a56f8e97fb
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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