Trifluoroacetic acid → 6-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amine

HRID 1812055Notes

Reaction equation

HRID 1812055 reaction equation
FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:54]=[CH:53][C:13]([CH2:14][N:15]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)[C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([C:23]3[CH:24]=[C:25]([CH2:30][N:31]4[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]4)[CH:26]=[N:27][C:28]=3[F:29])[CH:17]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH3:62][S:63](Cl)(=[O:65])=[O:64]>ClCCl>[F:29][C:28]1[C:23]([C:18]2[N:19]=[C:20]([CH3:22])[N:21]=[C:16]([N:15]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=3)[CH2:14][C:13]3[CH:53]=[CH:54][C:10]([O:9][CH3:8])=[CH:11][CH:12]=3)[CH:17]=2)=[CH:24][C:25]([CH2:30][N:31]2[CH2:36][CH2:35][N:34]([S:63]([CH3:62])(=[O:65])=[O:64])[CH2:33][CH2:32]2)=[CH:26][N:27]=1

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 66600288Tert-butyl 4-((5-(6-(bis(4-methoxybenzyl)amino)-2-methylpyrimidin-4-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate

Product 1

HCID 666001976-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amineYield 88%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

2,2,2-Trifluoroacetic acid (0.7 mL, 9.09 mmol) was added dropwise to tert-butyl 4-((5-(6-(bis(4-methoxybenzyl)amino)-2-methylpyrimidin-4-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (64.3 mg, 0.100 mmol) in dichloromethane (1.0 mL) at 25° C., and the resulting solution was stirred at 25° C. for 30 min. The reaction mixture was then concentrated in vacuo, and the residue was taken up in DCM (3.0 mL) and cooled to 0° C. Triethylamine (0.105 mL, 0.750 mmol) was added to the resulting solution, immediately followed by methanesulfonyl chloride (0.015 mL, 0.200 mmol). The resulting mixture was stirred at 0° C. for 20 min and then was concentrated onto silica gel and chromatographically purified (ISCO, 4 g, 0 to100% (10% MeOH-EtOAc)/hexanes) to provide 6-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amine (54.5 mg, 0.088 mmol, 88% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=9.39 Hz, 1H); 8.14 (s, 1H); 7.17 (d, J=6.85 Hz, 4H); 6.86 (d, J=8.80 Hz, 5H); 4.74 (br. s., 4H); 3.79 (s, 6H); 3.60 (s, 2H); 3.25 (br. s., 4H); 2.78 (s, 3H); 2.62 (s, 3H); 2.58 (br. s., 4H). 19F NMR (377 MHz, CDCl3) 6-70.62 (d, J=8.01 Hz, 1 F). m/z (ESI, +ve ion) 621.1 (M+H)+.

Workup

  1. concentrationThe reaction mixture was then concentrated in vacuo
  2. temperaturecooled to 0° C
  3. stirringThe resulting mixture was stirred at 0° C. for 20 min
  4. concentrationwas concentrated onto silica gel
  5. customchromatographically purified (ISCO, 4 g, 0 to100% (10% MeOH-EtOAc)/hexanes)

Sources & evidence

ORD record
ord-348bd530ba2b4063aa586480352f626f
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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