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

HRID 1621706Notes

Reaction equation

HRID 1621706 reaction equation
C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[CH:62]=[CH:61][C:13]([CH2:14][N:15]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)[C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([C:23]3[CH:24]=[C:25]([CH2:38][N:39]4[CH2:44][CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41][CH2:40]4)[CH:26]=[N:27][C:28]=3[NH:29][C:30]3[CH:31]=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=3)[N:17]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH3:70][S:71](Cl)(=[O:73])=[O:72]>ClCCl>[CH3:8][O:9][C:10]1[CH:62]=[CH:61][C:13]([CH2:14][N:15]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)[C:16]2[N:17]=[C:18]([C:23]3[C:28]([NH:29][C:30]4[CH:31]=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=4)=[N:27][CH:26]=[C:25]([CH2:38][N:39]4[CH2:44][CH2:43][N:42]([S:71]([CH3:70])(=[O:73])=[O:72])[CH2:41][CH2:40]4)[CH:24]=3)[N:19]=[C:20]([CH3:22])[N:21]=2)=[CH:12][CH:11]=1

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 59548319Tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(2-methoxypyrimidin-5-ylamino)pyridin-3-yl)methyl)piperazine-1-carboxylate

Product 1

HCID 59548317N,N-bis(4-methoxybenzyl)-4-(2-(2-methoxypyrimidin-5-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amineYield 69.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

TFA (4.00 mL, 51.9 mmol) was added slowly to an ice-bath cooled stirred solution of tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(2-methoxypyrimidin-5-ylamino)pyridin-3-yl)methyl)piperazine-1-carboxylate (413 mg, 0.551 mmol) in dichloromethane (5.00 mL, 78 mmol) and the resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuum to remove as much TFA as possible. The sticky residue was taken up in dichloromethane (5.00 mL) to which triethylamine (0.384 mL, 2.76 mmol) and methanesulfonyl chloride (0.129 mL, 1.654 mmol) were slowly added at 0° C. The mixture was stirred at 0° C. for 1 h and concentrated. The crude product was partitioned between 1 N NaOH(aq) and dichloromethane (20 mL each), and the separated aqueous layer was extracted with dichloromethane (2×20 mL) The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product which was purified by flash column chromatography (ISCO Combiflash system, pure DCM to 3% MeOH in DCM w/NH3) to give N,N-bis(4-methoxybenzyl)-4-(2-(2-methoxypyrimidin-5-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (277 mg, 0.381 mmol, 69.1% yield) as a brown foam. m/z (ESI, +ve ion) 727.2 (M+H)+.

Workup

  1. temperaturecooled
  2. concentrationThe mixture was concentrated under vacuum
  3. customto remove as much TFA as possible
  4. additionwere slowly added at 0° C
  5. stirringThe mixture was stirred at 0° C. for 1 h
  6. concentrationconcentrated
  7. customThe crude product was partitioned between 1 N NaOH(aq) and dichloromethane (20 mL each)
  8. extractionthe separated aqueous layer was extracted with dichloromethane (2×20 mL) The combined organic layers
  9. washwere washed with brine
  10. dry with materialdried over Na2SO4
  11. concentrationconcentrated
  12. customto give the crude product which
  13. customwas purified by flash column chromatography (ISCO Combiflash system, pure DCM to 3% MeOH in DCM w/NH3)

Sources & evidence

ORD record
ord-770355f005d14a5bb2208ea3779128a0
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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