4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine → 4-(2-(5-Fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine

HRID 1812005Notes

Reaction equation

HRID 1812005 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:18]=3)=[CH:15][C:14]([CH:43]([C:45]3[CH:50]=[CH:49][C:48]([S:51]([CH3:54])(=[O:53])=[O:52])=[CH:47][CH:46]=3)[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][C:14]([CH:43]([C:45]3[CH:50]=[CH:49][C:48]([S:51]([CH3:54])(=[O:52])=[O:53])=[CH:47][CH:46]=3)[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]

Participants

3

Reactant 1

HCID 666000674-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

Product 1

HCID 595483864-(2-(5-Fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amineYield 37.1%

Reagents, catalysts & solvents 1

HCID 6422Trifluoroacetic acidSolvent

Conditions

Temperature
75 °C

Procedure

4-(2-(5-Fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (744 mg, 0.992 mmol) was dissolved in trifluoroacetic acid (Aldrich, redistilled, 99+%, 10 mL) and the flask was fitted with a reflux condenser and placed in a preheated oil bath (75° C.) and stirred overnight. Then, the reaction was cooled to room temperature, concentrated, diluted with DCM (30 mL), and treated with saturated sodium bicarbonate (30 mL) and with 5 N NaOH to raise the pH of the aqueous phase to about 7. The layers were separated, and the aqueous phase was extracted with DCM and with 10:1 DCM/MeOH). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted filter with about 2 inches of silica gel; 100:1 DCM/MeOH to 75:1 DCM/MeOH to 50:1 DCM/MeOH). The fractions with product were collected, concentrated, and purified on HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 min using a total flow rate of 100 mL/min) to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (187.7 mg 36% yield). 1H NMR (CDCl3, 400 MHZ) δ 11.60 (s, 1H), 8.73 (d, J=2.35 Hz, 1H), 8.24 (d, J=2.74 Hz, 1H), 8.06 (dd, J=11.93 Hz, 1.76 Hz, 1H), 8.01 (d, J=2.35 Hz, 1H), 7.90 (d, J=8.41 Hz, 2H), 7.45 (d, J=8.22 Hz, 2H), 4.30-4.23 (m, 1H), 4.04 (s, 3H), 2.64 (s, 3H), 1.74 (d, J=7.24 Hz, 3H). m/z (ESI, pos. ion) 510 (M+H)+.

Workup

  1. customthe flask was fitted with a reflux condenser
  2. customplaced in a preheated oil bath
  3. temperatureThen, the reaction was cooled to room temperature
  4. concentrationconcentrated
  5. additiondiluted with DCM (30 mL)
  6. additiontreated with saturated sodium bicarbonate (30 mL) and with 5 N NaOH
  7. temperatureto raise the pH of the aqueous phase to about 7
  8. customThe layers were separated
  9. extractionthe aqueous phase was extracted with DCM and with 10:1 DCM/MeOH)
  10. dry with materialdried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated
  13. custompurified on a silica gel
  14. filtrationfilter (150 mL fritted filter with about 2 inches of silica gel; 100:1 DCM/MeOH to 75:1 DCM/MeOH to 50:1 DCM/MeOH)
  15. customThe fractions with product were collected
  16. concentrationconcentrated
  17. custompurified on HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 min

Sources & evidence

ORD record
ord-d6fff3ac3673457dbbd4ceb6b0e60059
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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