Water → 4-(2-fluoro-5-(morpholinomethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

HRID 1621546Notes

Reaction equation

HRID 1621546 reaction equation
Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[F:28][C:29]1[C:34](B(O)O)=[CH:33][C:32]([CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:31][N:30]=1.C([O-])(=O)C.[K+].O>O1CCOCC1.C(=O)(O)[O-].[Na+]>[F:28][C:29]1[C:34]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:3]=2)=[CH:33][C:32]([CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:31][N:30]=1

Participants

7

Reactant 4

HCID 962WaterHCID 517044Potassium AcetateHCID 595482094-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amineHCID 66600372HCID 66600372, compound

Product 1

HCID 666111724-(2-fluoro-5-(morpholinomethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amineYield 23%

Reagents, catalysts & solvents 2

HCID 312751,4-DioxaneSolventHCID 516892Sodium BicarbonateSolvent

Procedure

A mixture of 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (8.82 g, 22.91 mmol), 2-fluoro-5-(morpholinomethyl)pyridin-3-ylboronic acid (5.000 g, 20.83 mmol), potassium acetate (6.28 g, 63.9 mmol), and Am-Phos (1.036 g, 1.666 mmol) in dioxane (40 mL) and water (3.00 mL, 167 mmol) was heated in a CEM Voyager Microwave (Large-Scale Unit) for 25 min at 120° C. while 100 Watts of energy was supplied via Powermax (Simultaneous heating while cooling technology). The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with CHCl3 (3×100 mL). The organic extracts were combined and dried over Na2SO4. The solution was filtered and concentrated to give crude product as a yellow oil. This was purified by chromatography through a SiliCycle SiliaSep pre-packed silica gel column (330 gram) using a gradient of 0-100% ethyl acetate/hexanes over 40 min, followed by a gradient of 1-20% methanol/dichloromethane over 30 min to give a tan oil. This was triturated with DCM and diethyl ether and the mixture was filtered. The filtrate was concentrated to give 4-(2-fluoro-5-(morpholinomethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (2.615 g, 4.80 mmol, 23% yield) as a light-yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J=1.56 Hz, 1H); 7.79 (td, J=7.97, 2.05 Hz, 1H); 7.22 (dd, J=8.61, 7.04 Hz, 4H); 6.81-6.92 (m, 4H); 4.82 (d, J=3.33 Hz, 2H); 3.76-3.86 (m, 4H); 3.70 (ddd, J=9.54, 4.99, 4.84 Hz, 4H); 3.45-3.57 (m, 6H); 2.55 (s, 3H); 2.46 (dq, J=12.79, 4.41 Hz, 4H). m/z (ESI, +ve ion) 545.2 (M+H)+.

Workup

  1. temperaturewas supplied via Powermax (Simultaneous heating while cooling technology)
  2. extractionextracted with CHCl3 (3×100 mL)
  3. dry with materialdried over Na2SO4
  4. filtrationThe solution was filtered
  5. concentrationconcentrated
  6. customto give crude product as a yellow oil
  7. customThis was purified by chromatography through a SiliCycle SiliaSep pre-packed silica gel column (330 gram)
  8. customover 40 min
  9. customto give a tan oil
  10. customThis was triturated with DCM and diethyl ether
  11. filtrationthe mixture was filtered
  12. concentrationThe filtrate was concentrated

Sources & evidence

ORD record
ord-502be22071594d75b84b62a6290b502f
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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