1-Hydroxybenzotriazole → 5-(4-Methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazol-2-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole

HRID 517542

Reaction equation

HRID 517542 reaction equation
[CH3:1][C:2]1[N:3]=[C:4]([C:21](O)=[O:22])[S:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:9]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O[NH:47][C:48](=[NH:60])[C:49]1[CH:54]=[CH:53][C:52]([O:55][C:56]([F:59])([F:58])[F:57])=[CH:51][CH:50]=1>CN(C=O)C.O.CCOC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]([C:21]2[O:22][N:60]=[C:48]([C:49]3[CH:50]=[CH:51][C:52]([O:55][C:56]([F:57])([F:58])[F:59])=[CH:53][CH:54]=3)[N:47]=2)[S:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)[CH:9]=1

Participants

8

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27333094-(Trifluoromethoxy)benzamidoximeHCID 867114824-Methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazole-2-carboxylic acid

Product 1

HCID 733305045-(4-Methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazol-2-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazoleYield 2%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 4-methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazole-2-carboxylic acid (70 mg, 0.21 mmol), EDC.HCl (49 mg, 0.25 mmol) and HOBT (34 mmol, 0.25 mmol) in DMF (2 mL) was stirred at RT for 30 min. N-hydroxy-4-(trifluoromethoxy)benzimidamide (55 mg, 0.25 mmol) was added and the reaction mixture was stirred for 1 h at RT and then at 140° C. for another 2 h. The reaction mixture was cooled to RT, diluted with H2O (5 mL) and taken into EtOAc (10 mL). The organic layer was separated, washed with H2O (5 mL) and brine (5 mL), dried over Na2SO4, filtered and concentrated to afford the crude product, which was purified by pre-HPLC (Mobile phase: A=10 mM NH4HCO3/H2O, B=MeCN; Gradient: B=60%-95% in 18 min; Column: XBridge (C18, 5 um, 30 mm*150 mm) to give 5-(4-methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazol-2-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a yellow solid (2.0 mg, 2%). MS (ES+) C25H24F3N5O2S requires: 515, found: 516[M+H]+; 1H-NMR (500 MHz, CD3OD) δ ppm 8.24 (d, J=8.5 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 8.24 (t, J=8.0 Hz, 1H), 6.94-6.92 (m, 2H), 6.80 (d, J=8.0 Hz, 1H), 4.23 (s, 2H), 3.23 (t, J=4.5 Hz, 4H), 2.63 (t, J=4.5 Hz, 4H), 2.54 (s, 3H), 2.36 (s, 3H).

Workup

  1. stirringthe reaction mixture was stirred for 1 h at RT
  2. waitat 140° C. for another 2 h
  3. temperatureThe reaction mixture was cooled to RT
  4. customThe organic layer was separated
  5. washwashed with H2O (5 mL) and brine (5 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto afford the crude product, which
  10. customwas purified by pre-HPLC (Mobile phase
  11. waitGradient: B=60%-95% in 18 min

Sources & evidence

ORD record
ord-32fdf1582bc84236ac70a437d7a3381e
Source dataset
uspto-grants-2015_08
Patent number
US09115120B2

Linked notes

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