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

HRID 1812322Notes

Reaction equation

HRID 1812322 reaction equation
[CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:23][N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][C@H:25]4[CH3:37])[CH:19]=[N:20][C:21]=3[F:22])[N:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O.[CH3:56][S:57](Cl)(=[O:59])=[O:58]>C(Cl)Cl>[F:22][C:21]1[C:16]([C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[CH2:7][C:6]3[CH:47]=[CH:48][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=2)=[CH:17][C:18]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([S:57]([CH3:56])(=[O:59])=[O:58])[CH2:26][C@H:25]2[CH3:37])=[CH:19][N:20]=1

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 31297Methanesulfonyl chlorideHCID 66612109(R)-tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate

Product 1

HCID 66612165(R)-4-(2-fluoro-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amineYield 49%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a slightly cooled stirred solution of (R)-tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate (1.01 g, 1.535 mmol) in DCM (5.0 mL, 78 mmol) was added slowly TFA (4.00 mL, 51.9 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated and the sticky residue was taken up in a solution of DCM (10.0 mL) to which TEA (2.140 mL, 15.35 mmol) and methanesulfonyl chloride (0.598 mL, 7.68 mmol) was slowly added subsequently at 0° C. The mixture was stirred at the same temperature for 1 h, concentrated, and the crude product was partitioned between 1 N NaOH(aq) and DCM (20 mL each). The separated aqueous layer was extracted with DCM (2×20 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a crude residue which was purified by flash column chromatography (ISCO Combiflash system, 10% ethyl acetate/hexanes to 70% ethyl acetates in hexanes) to obtain the desired product (R)-4-(2-fluoro-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.4779 g, 0.752 mmol, 49.0% yield) as a pale yellow foam. m/z (ESI, +ve ion) 636 (M+H)+.

Workup

  1. temperatureTo a slightly cooled
  2. concentrationThe mixture was concentrated
  3. additionwas slowly added subsequently at 0° C
  4. stirringThe mixture was stirred at the same temperature for 1 h
  5. concentrationconcentrated
  6. customthe crude product was partitioned between 1 N NaOH(aq) and DCM (20 mL each)
  7. extractionThe separated aqueous layer was extracted with DCM (2×20 mL)
  8. washthe combined organic layers were washed with brine
  9. dry with materialdried over Na2SO4
  10. concentrationconcentrated
  11. customto give a crude residue which
  12. customwas purified by flash column chromatography (ISCO Combiflash system, 10% ethyl acetate/hexanes to 70% ethyl acetates in hexanes)

Sources & evidence

ORD record
ord-e0ff4e2df3cb40d3a477ed037b1a4f20
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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