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 1811986Notes

Reaction equation

HRID 1811986 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 5 N 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, 5 N 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/2 N ammonia in MeOH to 20:1 DCM/2 N ammonia in MeOH to 10:1 DCM/2 N 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 5 N 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, 5 N 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/2 N ammonia in MeOH to 20:1 DCM/2 N ammonia in MeOH to 10:1 DCM/2 N ammonia in MeOH)

Sources & evidence

ORD record
ord-3c8eb20f30c548fcbd534af974d4458a
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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