4-Aminoacetanilide → N-(4-(3-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-YL)-5-((4-(methylsulfonyl)piperazin-1-YL)methyl)pyridin-2-ylamino)phenyl)acetamide

HRID 1621792Notes

Reaction equation

HRID 1621792 reaction equation
[NH2:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:23]1[C:28]([C:29]2[N:34]=[C:33]([CH3:35])[N:32]=[C:31]([N:36]([CH2:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)[CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[N:30]=2)=[CH:27][C:26]([CH2:55][N:56]2[CH2:61][CH2:60][N:59]([S:62]([CH3:65])(=[O:64])=[O:63])[CH2:58][CH2:57]2)=[CH:25][N:24]=1>C1COCC1>[CH3:54][O:53][C:50]1[CH:49]=[CH:48][C:47]([CH2:46][N:36]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[C:31]2[N:32]=[C:33]([CH3:35])[N:34]=[C:29]([C:28]3[C:23]([NH:1][C:2]4[CH:3]=[CH:4][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[CH:10][CH:11]=4)=[N:24][CH:25]=[C:26]([CH2:55][N:56]4[CH2:61][CH2:60][N:59]([S:62]([CH3:65])(=[O:64])=[O:63])[CH2:58][CH2:57]4)[CH:27]=3)[N:30]=2)=[CH:52][CH:51]=1

Participants

5

Reactant 3

HCID 312304-AminoacetanilideHCID 2733832Lithium HexamethyldisilazideHCID 666116314-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

Product 1

HCID 66612119N-(4-(3-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-YL)-5-((4-(methylsulfonyl)piperazin-1-YL)methyl)pyridin-2-ylamino)phenyl)acetamideYield 57.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution of 4′-aminoacetanilide (0.097 g, 0.643 mmol) in THF (5 mL) was cooled to 0° C. under N2. Lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran (Aldrich) (0.313 mL, 1.608 mmol) was added and the mixture was stirred at 0° C. for 30 min before 4-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.200 g, 0.322 mmol) was added. The resulting mixture was stirred at 0° C. for 10 min, and then the ice bath was removed and stirring was continued for 2 h. The reaction was quenched with sat. NH4Cl. The resulting mixture was partitioned between pH 7 buffer (1 M TRIS-HCl) and CHCl3. The aqueous layer was extracted with CHCl3 (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, 3% MeOH and 12% EtOAc in DCM) to give the product as a yellow solid (0.140 g). m/z (ESI, +ve ion) 752.0 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 11.82 (s, 1H); 8.72 (s, 1H); 8.24 (s, 1H); 7.54 (d, J=8.48 Hz, 2H); 7.40 (d, J=8.62 Hz, 2H); 7.22 (d, J=7.75 Hz, 4H); 7.07 (br. s., 1H); 6.87 (dd, J=8.18, 4.09 Hz, 4H); 4.85 (d, J=4.68 Hz, 4H); 3.81 (d, J=3.95 Hz, 6H); 3.51 (s, 2H); 3.19 (br. s., 4H); 2.71 (s, 3H); 2.60 (s, 3H); 2.44-2.58 (m, 4H); 2.18 (s, 3H).

Workup

  1. additionwas added
  2. customthe ice bath was removed
  3. stirringstirring
  4. waitwas continued for 2 h
  5. customThe reaction was quenched with sat. NH4Cl
  6. customThe resulting mixture was partitioned between pH 7 buffer (1 M TRIS-HCl) and CHCl3
  7. extractionThe aqueous layer was extracted with CHCl3 (2×10 mL)
  8. dry with materialThe combined organic layers were dried over MgSO4
  9. concentrationconcentrated
  10. customThe crude product was purified by column chromatography (40 g, 3% MeOH and 12% EtOAc in DCM)

Sources & evidence

ORD record
ord-4772c9dc988f450ba3fbf13d0762476e
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

Loading…