Benzeneethanamine, alpha-methyl-, phosphate (1:1) → 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

HRID 1621752Notes

Reaction equation

HRID 1621752 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[C:5]([F:8])=[N:6][CH:7]=1.Cl[C:13]1[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:14]=1.CC(N)CC1C=CC=CC=1.OP(O)(O)=O.C([O-])(=O)C.[K+]>CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[N:14]=2)[C:5]([F:8])=[N:6][CH:7]=1

Participants

7

Reactant 4

HCID 62885Benzeneethanamine, alpha-methyl-, phosphate (1:1)HCID 517044Potassium AcetateHCID 249017795-Chloro-2-fluoropyridine-3-boronic AcidHCID 595482094-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

Product 1

HCID 666005044-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amineYield 77.1%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 5-chloro-2-fluoropyridin-3-ylboronic acid (454 mg, 2.59 mmol) (Combi-Blocks Inc.), 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (950 mg, 2.468 mmol), Amphos 2 (87 mg, 0.123 mmol) and potassium acetate (744 mg, 7.58 mmol) (Aldrich) in EtOH (15 mL) and water (1.5 mL) was purged with argon and heated in a microwave reactor at 100° C. for 30 min. The reaction mixture was concentrated to remove the EtOH and partitioned between water (20 mL) and EtOAc (20 mL). The aqueous phase was further extracted with EtOAc (20 mL). The combined organic phases were washed with saturated aqueous sodium chloride (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified on the ISCO (40 g column, eluent: 30-80% EtOAc in hexanes) to give 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (913 mg, 1.902 mmol, 77% yield) as a pale yellow sticky solid. The material was used in the next step without further purification. m/z (ESI, +ve ion) 480.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.53 (1H, dd, J=7.9, 2.6 Hz); 8.25 (1H, dd, J=2.6, 1.3 Hz); 7.21 (4H, d, J=8.6 Hz); 6.80-6.90 (4H, m); 4.82 (2H, s); 4.80 (2H, s); 3.81 (3H, s); 3.80 (3H, s); 2.54 (3H, s).

Workup

  1. customwas purged with argon
  2. concentrationThe reaction mixture was concentrated
  3. customto remove the EtOH
  4. custompartitioned between water (20 mL) and EtOAc (20 mL)
  5. extractionThe aqueous phase was further extracted with EtOAc (20 mL)
  6. washThe combined organic phases were washed with saturated aqueous sodium chloride (40 mL)
  7. dry with materialThe organic phase was dried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe crude product was purified on the ISCO (40 g column, eluent: 30-80% EtOAc in hexanes)

Sources & evidence

ORD record
ord-d53f28d83bb34077a020cb861a4c230c
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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