Triethylamine → 1-(Cyclopropylmethyl)-3-(4-(4-((5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-2-yl)methyl)piperazine-1-carbonyl)phenyl)urea

HRID 1807809Notes

Reaction equation

HRID 1807809 reaction equation
[F:1][C:2]([F:17])([F:16])[C:3]([C:9]1[S:13][C:12]([CH2:14]O)=[N:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH:30]1([CH2:33][NH:34][C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]([N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)=[O:45])=[CH:40][CH:39]=2)=[O:36])[CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH:30]1([CH2:33][NH:34][C:35]([NH:37][C:38]2[CH:39]=[CH:40][C:41]([C:44]([N:46]3[CH2:51][CH2:50][N:49]([CH2:14][C:12]4[S:13][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:17])([F:16])[F:1])=[CH:10][N:11]=4)[CH2:48][CH2:47]3)=[O:45])=[CH:42][CH:43]=2)=[O:36])[CH2:31][CH2:32]1

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 11430Potassium CarbonateHCID 31297Methanesulfonyl chlorideHCID 580558061-(Cyclopropylmethyl)-3-(4-(Piperazine-1-carbonyl)phenyl)ureaHCID 866385861,1,1,3,3,3-Hexafluoro-2-(2-(hydroxymethyl)thiazol-5-yl)propan-2-ol

Product 1

HCID 591758311-(Cyclopropylmethyl)-3-(4-(4-((5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)thiazol-2-yl)methyl)piperazine-1-carbonyl)phenyl)ureaYield 0.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Conditions

Temperature
0 °C

Procedure

To a stirring solution of 1,1,1,3,3,3-hexafluoro-2-(2-(hydroxymethyl)thiazol-5-yl)propan-2-ol (0.533 mmol, 150 mg) and triethylamine (1.600 mmol, 162 mg) in dichloromethane (4 mL) at 0° C. was added methanesulfonyl chloride (0.533 mmol, 61.1 mg). The mixture was stirred at 0° C. for 1 hour before warming to room temperature and stirring for 1 hour. The reaction mixture was diluted with dichloromethane (50 mL) and washed with water (2×20 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (4 mL) and 1-(cyclopropylmethyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea (0.635 mmol, 192 mg) was added followed by potassium carbonate (1.905 mmol, 263 mg). The mixture was heated to reflux for 6 hours then was cooled, diluted with dichloromethane (75 mL) and washed with water (2×20 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC, strong cation exchange column chromatography and silica gel column chromatography (10% methanol/90% dichloromethane) to afford the title compound (1.5 mg).

Workup

  1. temperaturebefore warming to room temperature
  2. stirringstirring for 1 hour
  3. washwashed with water (2×20 mL)
  4. dry with materialThe organic phase was dried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationthe filtrate was concentrated under reduced pressure
  7. dissolutionThe resulting residue was dissolved in acetonitrile (4 mL)
  8. temperatureThe mixture was heated
  9. temperatureto reflux for 6 hours
  10. temperaturethen was cooled
  11. washwashed with water (2×20 mL)
  12. dry with materialThe organic phase was dried over magnesium sulfate
  13. filtrationfiltered
  14. concentrationthe filtrate was concentrated under reduced pressure
  15. customThe resulting residue was purified by HPLC, strong cation exchange column chromatography and silica gel column chromatography (10% methanol/90% dichloromethane)

Sources & evidence

ORD record
ord-d4d7aa8a96d74f858c9ee605621a66da
Source dataset
uspto-grants-2013_01
Patent number
US08357679B2

Reaction notes

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