Trifluoromethanesulfonic acid → (R)-4-(2-(5-isopropyl-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine

HRID 1621872Notes

Reaction equation

HRID 1621872 reaction equation
[CH:1]([C:4]1[CH:5]=[C:6]([NH:12][C:13]2[C:18]([C:19]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:20]=3)=[CH:17][C:16]([C@H:45]([N:47]3[CH2:52][CH2:51][N:50]([S:53]([CH3:56])(=[O:55])=[O:54])[CH2:49][CH2:48]3)[CH3:46])=[CH:15][N:14]=2)[CH:7]=[N:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2].FC(F)(F)S(O)(=O)=O>C(O)(C(F)(F)F)=O>[CH:1]([C:4]1[CH:5]=[C:6]([NH:12][C:13]2[C:18]([C:19]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH2:26])[N:20]=3)=[CH:17][C:16]([C@H:45]([N:47]3[CH2:52][CH2:51][N:50]([S:53]([CH3:56])(=[O:55])=[O:54])[CH2:49][CH2:48]3)[CH3:46])=[CH:15][N:14]=2)[CH:7]=[N:8][C:9]=1[O:10][CH3:11])([CH3:2])[CH3:3]

Participants

4

Reactant 2

HCID 62406Trifluoromethanesulfonic acidHCID 66612093(R)-4-(2-(5-isopropyl-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

Product 1

HCID 59548369(R)-4-(2-(5-isopropyl-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amineYield 31.5%

Reagents, catalysts & solvents 1

HCID 6422Trifluoroacetic acidSolvent

Conditions

Temperature
80 °C

Procedure

A dark red solution of (R)-4-(2-(5-isopropyl-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.097 g, 0.124 mmol) and trifluoromethanesulfonic acid (0.055 mL, 0.620 mmol) in 1 mL TFA was sealed and heated to 80° C. for 30 min. The reaction was cooled with ice, then quenched with 10N NaOH until basic, and partitioned between water and DCM. The aqueous layer was extracted with DCM 2 times, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. This material was dissolved in DMSO (plus a few drops TFA) and purified by RPHPLC, 10-80% ACN/H2O (plus 0.1% TFA); product-containing fractions were concentrated to dryness, then treated with sat'd aq. NaHCO3 and DCM. The aq. layer was extracted 3×DCM and combined organics dried over sodium sulfate, filtered, and concentrated in vacuo to give (R)-4-(2-(5-isopropyl-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine as a yellow solid (0.021 g, 0.039 mmol, 31% yield). m/z (ESI, +ve ion) 542 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.58 (br. s., 1H), 8.69 (br. s., 1H), 8.17-8.34 (m, 2H), 7.92 (br. s., 1H), 5.38 (br. s., 2H), 3.97 (s, 3H), 3.47-3.62 (m, 1H), 3.11-3.31 (m, 5H), 2.77 (br. s., 3H), 2.49-2.68 (m, 7H), 1.44 (d, J=6.1 Hz, 3H), 1.27 (d, J=6.8Hz, 6H).

Workup

  1. temperatureThe reaction was cooled with ice
  2. customquenched with 10N NaOH until basic, and
  3. custompartitioned between water and DCM
  4. extractionThe aqueous layer was extracted with DCM 2 times
  5. dry with materialthe combined organics were dried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. dissolutionThis material was dissolved in DMSO (plus a few drops TFA)
  9. custompurified by RPHPLC, 10-80% ACN/H2O (plus 0.1% TFA)
  10. concentrationproduct-containing fractions were concentrated to dryness
  11. additiontreated with sat'd aq. NaHCO3 and DCM
  12. extractionThe aq. layer was extracted 3×DCM
  13. dry with materialcombined organics dried over sodium sulfate
  14. filtrationfiltered
  15. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-e2276e8c05a8499ea310441e90017efb
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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