Trifluoroacetic acid → HCID 59548245, compound

HRID 1812211Notes

Reaction equation

HRID 1812211 reaction equation
COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C@@H:32]([N:34]4[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][C@@H:35]4[CH3:47])[CH3:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=CC=1.C(O)(C(F)(F)F)=O.CCN(CC)CC.[CH3:73][S:74](Cl)(=[O:76])=[O:75]>C(Cl)Cl>[F:29][C:27]1[CH:28]=[C:23]([NH:22][C:21]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=3)=[CH:17][C:18]([C@@H:32]([N:34]3[CH2:39][CH2:38][N:37]([S:74]([CH3:73])(=[O:76])=[O:75])[CH2:36][C@@H:35]3[CH3:47])[CH3:33])=[CH:19][N:20]=2)[CH:24]=[N:25][C:26]=1[O:30][CH3:31]

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 66611667HCID 66611667, compound

Product 1

HCID 59548245HCID 59548245, compoundYield 43.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A solution of (S)-tert-butyl 4-((S)-1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate (0.101 g, 0.127 mmol) (the first-eluting diastereomer from Example 271, Step 4) in DCM (3.00 mL, 46.6 mmol) was treated with TFA (3.00 mL, 38.9 mmol) and the resulting mixture was stirred at room temperature for 30 min before being concentrated to give a brown oil. This oil was re-dissolved in DCM (3.00 mL) and sequentially treated with Et3N (0.089 mL, 0.636 mmol) and methanesulfonyl chloride (0.030 mL, 0.382 mmol) (slow addition) at −15° C., and the resulting mixture was stirred for 1 h. The reaction mixture was then quenched with saturated aqueous NaHCO3 and water. The separated aqueous layer was extracted with DCM (2×) and the combined organic layers were dried over Na2SO4 and concentrated. The crude product was treated with TFA (2.00 mL) and heated at 80° C. overnight. The resulting mixture was allowed to cool to room temperature and was then concentrated in vacuo. The crude product was adsorbed onto silica gel and chromatographically purified (silica gel, 0% to 5% MeOH/DCM) to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((S)-1-((S)-2-methyl-4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (29 mg, 0.055 mmol, 42.9% yield) as a yellow solid. m/z (ESI, +ve ion) 532 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.95 (s, 1H); 8.74 (d, J=2.54 Hz, 1H); 8.27-8.46 (m, 3H); 7.90 (br. s., 1H); 7.77 (br. s., 1H); 3.99-4.09 (m, 1H); 3.93 (s, 3H); 3.20-3.30 (m, 1H); 2.94-3.11 (m, 2H); 2.84 (s, 3H); 2.75-2.84 (m, 2H); 2.45 (s, 3H); 2.40 (dd, 1H); 2.29-2.35 (m, 1H); 1.28 (d, J=6.65 Hz, 3H); 1.15 (d, J=6.26 Hz, 3H).

Workup

  1. concentrationbefore being concentrated
  2. customto give a brown oil
  3. stirringthe resulting mixture was stirred for 1 h
  4. customThe reaction mixture was then quenched with saturated aqueous NaHCO3 and water
  5. extractionThe separated aqueous layer was extracted with DCM (2×)
  6. dry with materialthe combined organic layers were dried over Na2SO4
  7. concentrationconcentrated
  8. additionThe crude product was treated with TFA (2.00 mL)
  9. temperatureheated at 80° C. overnight
  10. temperatureto cool to room temperature
  11. concentrationwas then concentrated in vacuo
  12. customchromatographically purified (silica gel, 0% to 5% MeOH/DCM)

Sources & evidence

ORD record
ord-ef8832b01a844a3a9a06ae7ba9867d4a
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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