Water → HCID 66611854, compound

HRID 1812096Notes

Reaction equation

HRID 1812096 reaction equation
[CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][N:8]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.CCN(CC)CC.Cl[C:50]([O:52][CH3:53])=[O:51].O>C(Cl)Cl>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH:30][C:50](=[O:51])[O:52][CH3:53])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:37][CH:36]=1

Participants

6

Reactant 4

HCID 962WaterHCID 6586Methyl chloroformateHCID 8471TriethylamineHCID 66612096HCID 66612096, compound

Product 1

HCID 66611854HCID 66611854, compoundYield 7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A solution of N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-yl)pyridine-2,5-diamine (Example 194, Step 2, 0.152 g, 0.266 mmol) and Et3N (0.111 mL, 0.799 mmol) in DCM (3 mL) was treated with methyl chloroformate (Aldrich) (0.025 mL, 0.319 mmol) and the mixture was stirred at rt for 2 days during which time solvent was lost due to evaporation. The residue was taken into the mixed solvent (1:1 DCM/THF, 5 mL) and Et3N (0.5 mL) and methyl chloroformate (0.1 mL) were added. The mixture was stirred at rt for 2 h. The resulting solid was collected and transferred to an Erlenmeyer flask using MeOH and DMSO. Water was added and the mixture was sonicated. The resulting orange solid was collected and this mixture was heated in TFA (2 mL) in the presence of trifluoromethanesulfonic acid (TCI) (0.2 mL) at rt for 30 min, then at 60° C. overnight. Solid sodium carbonate was added until effervescence subsided. Sodium bicarbonate was added slowly until no more effervescence was observed. The resulting solid was collected by filtration. The crude product was purified by preparative HPLC using Phenomenex, Gemni 5 micron C18 100×30mm column (1%-90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 15 min). The fractions containing product were collected and lyophilized to give an orange fluffy solid, which was taken into water and the resulting yellow precopitate was collected, washed with water and dried to give methyl 5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-ylamino)pyridin-2-ylcarbamate (0.0074 g, 7% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 11.84 (s, 1H); 10.10 (s, 1H); 8.74 (d, J=2.74 Hz, 1H); 8.64 (d, J=2.54 Hz, 1H); 8.37 (d, J=2.74 Hz, 1H); 8.19 (dd, J=9.00, 2.74 Hz, 1H); 7.98 (br. s., 1H); 7.82-7.90 (m, 1H); 7.80 (d, J=8.80 Hz, 1H); 3.68 (s, 3H); 2.45 (s, 3H). m/z (ESI, +ve ion) 386.9 (M+H)+.

Workup

  1. customwas lost due to evaporation
  2. additionwere added
  3. stirringThe mixture was stirred at rt for 2 h
  4. customThe resulting solid was collected
  5. additionWater was added
  6. customthe mixture was sonicated
  7. customThe resulting orange solid was collected
  8. temperaturethis mixture was heated in TFA (2 mL) in the presence of trifluoromethanesulfonic acid (TCI) (0.2 mL) at rt for 30 min
  9. customat 60° C.
  10. customovernight
  11. additionSolid sodium carbonate was added until effervescence
  12. additionSodium bicarbonate was added slowly until no more effervescence
  13. filtrationThe resulting solid was collected by filtration
  14. customThe crude product was purified by preparative HPLC
  15. customC18 100×30mm column (1%-90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 15 min)
  16. additionThe fractions containing product
  17. customwere collected
  18. customto give an orange fluffy solid, which
  19. customthe resulting yellow precopitate was collected
  20. washwashed with water
  21. customdried

Sources & evidence

ORD record
ord-9b3d6b195d6b47a8881de40e80cc505e
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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