Trifluoroacetic acid → 4-(2-(6-Methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine

HRID 1621573Notes

Reaction equation

HRID 1621573 reaction equation
COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:33][C:34]4[CH:35]=[N:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=4)=[N:17][CH:18]=[C:19]([CH:21]([N:23]4[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]4)[CH3:22])[CH:20]=3)[N:12]=[C:11]([CH3:42])[N:10]=2)=CC=1.FC(F)(F)C(O)=O>>[CH3:41][O:40][C:37]1[N:36]=[CH:35][C:34]([NH:33][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:42])[N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:20][C:19]([CH:21]([N:23]3[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:25][CH2:24]3)[CH3:22])=[CH:18][N:17]=2)=[CH:39][CH:38]=1

Participants

3

Reactant 2

HCID 6422Trifluoroacetic acidHCID 66610489N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine

Product 1

HCID 595484284-(2-(6-Methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amineYield 72%

Conditions

Temperature
75 °C

Procedure

N,N-Bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (499.0 mg, 0.6744 mmol) was dissolved in trifluoroacetic acid (10.4 mL, 140 mmol) and the flask was fitted with a reflux condenser, placed in a preheated oil bath (75° C.) and stirred overnight. Then, the reaction was cooled to room temperature, concentrated, diluted with DCM (40 mL) and treated with saturated sodium bicarbonate, water, and 5N NaOH until the pH of the aqueous phase was about 7. Then, the layers were separated, and the aqueous phase was extracted with DCM and 10:1 DCM/MeOH. During these extractions, 5N NaOH was added to the aqueous phase to raise the pH from about 5 to about 11. 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; 75:1 DCM/MeOH to 50:1 DCM/MeOH to 35:1 DCM/2N ammonia in MeOH to 20:1 DCM/2N ammonia in MeOH to 10:1 DCM/2N ammonia in MeOH) to give 4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (241.9 mg, 72% yield) as a yellow powder. 1H NMR (CDCl3, 400 MHz) δ 11.68 (s, 1H), 8.71 (s, 1H), 8.36 (d, J=2.74 Hz, 1H), 8.27 (d, J=2.35 Hz, 1H), 8.13 (dd, J=8.80 Hz, 2.74 Hz, 1H), 6.79 (d, J=8.80 Hz, 1H), 5.42 (br s, 2H), 3.95 (s, 3H), 3.60-3.52 (m, 1H), 3.30-3.20 (m, 4H), 2.77 (s, 3H), 2.70-2.53 (m, 7H), 1.45 (d, J=6.06 Hz, 3H). m/z (ESI, +ve ion) 500 (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 (40 mL)
  6. additiontreated with saturated sodium bicarbonate, water, and 5N NaOH until the pH of the aqueous phase
  7. customThen, the layers were separated
  8. extractionthe aqueous phase was extracted with DCM and 10:1 DCM/MeOH
  9. extractionDuring these extractions, 5N NaOH
  10. additionwas added to the aqueous phase
  11. temperatureto raise the pH from about 5 to about 11
  12. dry with materialdried over sodium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated
  15. custompurified on a silica gel
  16. filtrationfilter (150 mL fritted filter with about 2 inches of silica gel; 75:1 DCM/MeOH to 50:1 DCM/MeOH to 35:1 DCM/2N ammonia in MeOH to 20:1 DCM/2N ammonia in MeOH to 10:1 DCM/2N ammonia in MeOH)

Sources & evidence

ORD record
ord-ac2183d841904410a3d040dfbe6dfdf7
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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