Trifluoroacetic acid → HCID 59548467, compound

HRID 1812275Notes

Reaction equation

HRID 1812275 reaction equation
COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=C(C)[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:32][CH3:33])=[C:29]([F:31])[CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[C:21]#[N:22])[N:10]=2)=CC=1.[CH2:45]([Mg]Br)[CH3:46].B(F)(F)F.[CH3:53][CH2:54]OCC.[C:58](O)([C:60](F)(F)F)=O.OS(C(F)(F)F)(=O)=O.[OH-].[Na+]>C1COCC1.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[NH2:22][C:21]([C:20]1[CH:23]=[C:16]([C:11]2[N:12]=[C:45]([CH3:46])[N:14]=[C:9]([NH2:8])[N:10]=2)[C:17]([NH:24][C:25]2[CH:26]=[N:27][C:28]([O:32][CH3:33])=[C:29]([F:31])[CH:30]=2)=[N:18][CH:19]=1)([CH2:58][CH3:60])[CH2:53][CH3:54]

Participants

9

Reactant 6

HCID 6422Trifluoroacetic acidHCID 8000Boron trifluoride etherateHCID 14798Sodium HydroxideHCID 62406Trifluoromethanesulfonic acidHCID 66611143HCID 66611143, compoundHCID 178418443HCID 178418443, compound

Product 1

HCID 59548467HCID 59548467, compoundYield 12.62%

Reagents, catalysts & solvents 2

HCID 178460666HCID 178460666, compoundCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

To a slurry of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinonitrile (Example 143, 0.205 g, 0.346 mmol) in 7 mL THF at 0° C. was added tetraisopropoxytitanium (0.122 mL, 0.415 mmol) followed by ethylmagnesium bromide 1.0 M in THF (2.214 mL, 2.214 mmol). The reaction became dark brown. After 30 min, boron trifluoride diethyl etherate (0.210 mL, 1.660 mmol) was added. The reaction was warmed to ambient temperature, and after 15 min, quenched with 10 N NaOH. The aqueous was extracted 3× EtOAc. The combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give 0.234 g. This material treated with 2 mL TFA and triflicacid (0.154 mL, 1.730 mmol). The reaction was sealed, and heated to 80° C. for 30 min. The reaction was cooled and pour onto ice, basified with 10 N NaOH and extracted 3×DCM. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting material was treated with DMSO and TFA purified by RPHPLC, 10-60% ACN/H2O (+0.1% TFA); Product-containing fractions were concentrated and treated with sat'd aq. NaHCO3 and DCM. The aqueous layer was extracted 3×10% IPA/DCM and combined organics dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-(5-(3-aminopentan-3-yl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.018 g, 0.044 mmol, 12.62% yield) as a yellow solid. m/z (ESI, +ve ion) 413 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.92 (s, 1H), 8.88 (d, J=2.5 Hz, 1H), 8.35-8.46 (m, 3H), 7.88 (br. s., 1H), 7.72 (br. s., 1H), 3.93 (s, 3H), 2.44 (s, 3H), 1.53-1.84 (m, 4H), 0.69 (t, J=7.3 Hz, 6H).

Workup

  1. waitafter 15 min
  2. customquenched with 10 N NaOH
  3. extractionThe aqueous was extracted 3× EtOAc
  4. dry with materialThe combined extracts were dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customto give 0.234 g
  8. customThe reaction was sealed
  9. temperatureheated to 80° C. for 30 min
  10. temperatureThe reaction was cooled
  11. additionpour onto ice
  12. extractionextracted 3×DCM
  13. dry with materialThe combined organics were dried over anhydrous sodium sulfate
  14. filtrationfiltered
  15. concentrationconcentrated
  16. additionThe resulting material was treated with DMSO and TFA
  17. custompurified by RPHPLC, 10-60% ACN/H2O (+0.1% TFA)
  18. concentrationProduct-containing fractions were concentrated
  19. additiontreated with sat'd aq. NaHCO3 and DCM
  20. extractionThe aqueous layer was extracted 3×10% IPA/DCM
  21. dry with materialcombined organics dried over sodium sulfate
  22. filtrationfiltered
  23. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-db4bf79eed9b4b6aa5700824fb947e53
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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