Cesium carbonate → 1-[(2-Isopropyl-5-methyl-phenyl)carbamothioyl]-3-[3-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]propyl]urea

HRID 573870Notes

Reaction equation

HRID 573870 reaction equation
[F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[C:27](=[O:30])(O)[O-].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:50]([C:53]1[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][C:54]=1[NH:60][C:61]([NH2:63])=[S:62])([CH3:52])[CH3:51]>ClCCl.C(OCC)(=O)C.O>[CH:50]([C:53]1[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][C:54]=1[NH:60][C:61]([NH:63][C:27]([NH:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)=[O:30])=[S:62])([CH3:52])[CH3:51]

Participants

9

Reactant 5

HCID 10796Cesium carbonateHCID 94429TriphosgeneHCID 516892Sodium BicarbonateHCID 893731681-(2-Isopropyl-5-methylphenyl)thioureaHCID 904042683-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine

Product 1

HCID 904044741-[(2-Isopropyl-5-methyl-phenyl)carbamothioyl]-3-[3-[4-[1-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]phenyl]propyl]ureaYield 38%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (C60) (0.231 g, 0.639 mmol) in a 25 mL vial equipped with a stir bar and nitrogen was added dichloromethane (4.3 mL), water (2.1 mL), and sodium bicarbonate (0.161 g, 1.92 mmol). Triphosgene (0.0760 g, 0.255 mmol) was added in one portion and the reaction was stirred vigorously until the conversion of the starting material was observed by LCMS. The reaction mixture was diluted with dichloromethane, poured through a phase separator and concentrated. The resultant solid was suspended in acetonitrile (6.0 mL) in a 100 mL round bottomed flask equipped with a stir bar and nitrogen. To this was added cesium carbonate (0.229 g, 0.702 mmol) and 1-(2-isopropyl-5-methylphenyl)thiourea (0.133 g, 0.639 mmol). The reaction was stirred overnight at room temperature. The mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by flash column chromatography using 0-30% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent provided mixed fractions. The fractions were combined and re-purified by flash column chromatography using 0-30% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and the resultant solid was dried in vacuo at 50° C. overnight to afford the title compound as a white solid (0.145 g, 38%).

Workup

  1. additionpoured through a phase separator
  2. concentrationconcentrated
  3. customThe resultant solid was suspended in acetonitrile (6.0 mL) in a 100 mL round bottomed flask
  4. customequipped with a stir bar
  5. stirringThe reaction was stirred overnight at room temperature
  6. washwashed with water
  7. extractionThe aqueous layer was extracted with ethyl acetate
  8. dry with materialThe combined organic layers were dried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customPurification by flash column chromatography
  12. customas eluent provided
  13. additionmixed fractions
  14. customre-purified by flash column chromatography
  15. customas eluent and the resultant solid was dried in vacuo at 50° C. overnight

Sources & evidence

ORD record
ord-53dadb2c57264c87be765a476f8dfaed
Source dataset
uspto-grants-2015_05
Patent number
US09029560B2

Reaction notes

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