Trifluoroacetic acid → N-Methyl-6-[5-(3-phenoxymethylazetidin-1-yl)-[1,2,4]oxadiazol-3-yl]-N-phenyl-[1,3,5]triazine-2,4-diamine

HRID 341463Notes

Reaction equation

HRID 341463 reaction equation
[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([N:21]3[CH2:24][CH:23](O)[CH2:22]3)[O:18][N:17]=2)[N:3]=1.CCN(C(C)C)C(C)C.CN([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)C1N=C(N)N=C(C2N=C(C(Cl)(Cl)Cl)ON=2)N=1.FC(F)(F)[C:61](O)=[O:62]>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[CH3:15][N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([C:16]2[N:20]=[C:19]([N:21]3[CH2:24][CH:23]([CH2:61][O:62][C:53]4[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=4)[CH2:22]3)[O:18][N:17]=2)[N:5]=1

Participants

8

Reactant 4

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 66802564N-methyl-N-phenyl-6-(5-trichloromethyl-[1,2,4]oxadiazol-3-yl)-[1,3,5]triazine-2,4-diamine2×HCID 668028881-{3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazol-5-yl}-azetidin-3-ol2×

Product 1

HCID 56942418N-Methyl-6-[5-(3-phenoxymethylazetidin-1-yl)-[1,2,4]oxadiazol-3-yl]-N-phenyl-[1,3,5]triazine-2,4-diamineYield 7%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

3-Phenoxymethyl-azetidine-1-carboxylic acid tert-butyl ester (Intermediate 166, 50 mg, 0.189 mmol) was stirred in a mixture of DCM (1 mL) and trifluoroacetic acid (0.25 mL) at room temperature for 30 min. The mixture was evaporated under vacuum and the residue was dissolved in anhydrous DMF (0.5 mL). DIPEA (165 μL, 0.945 mmol) was added, followed by a solution of N-methyl-N-phenyl-6-(5-trichloromethyl-[1,2,4]oxadiazol-3-yl)-[1,3,5]triazine-2,4-diamine (prepared in an analogous manner to Intermediate 60, 37 mg, 0.095 mmol) in DMF (1.5 mL). The reaction was stirred at room temperature for approximately 42 h. The mixture was diluted with EtOAc (15 mL) then washed with saturated aq. ammonium chloride (3×5 mL), saturated aq. sodium carbonate (3×5 mL), brine (5 mL), dried over sodium sulfate and evaporated under vacuum. The crude residue was purified by flash chromatography (0-2% MeOH in DCM) and then further purified by preparative HPLC, Method D, to afford the title compound (6 mg, 7%).

Workup

  1. customThe mixture was evaporated under vacuum
  2. dissolutionthe residue was dissolved in anhydrous DMF (0.5 mL)
  3. washthen washed with saturated aq. ammonium chloride (3×5 mL), saturated aq. sodium carbonate (3×5 mL), brine (5 mL)
  4. dry with materialdried over sodium sulfate
  5. customevaporated under vacuum
  6. customThe crude residue was purified by flash chromatography (0-2% MeOH in DCM)
  7. customfurther purified by preparative HPLC, Method D

Sources & evidence

ORD record
ord-4cc54296c9ce43ce81184b76c7d37952
Source dataset
uspto-grants-2014_11
Patent number
US08895733B2

Reaction notes

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