Quinuclidine, 3-amino-, dihydrochloride → 1-(1-Azabicyclo[2.2.2]oct-3-yl)-3-(5-phenyl-1,3-thiazol-4-yl) urea hydrochloride

HRID 383954

Reaction equation

HRID 383954 reaction equation
[C:1]1([C:7]2[S:11][CH:10]=[N:9][C:8]=2C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC(P([N:29]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[ClH:32].Cl.[NH2:34][CH:35]1[CH:40]2[CH2:41][CH2:42][N:37]([CH2:38][CH2:39]2)[CH2:36]1.Cl.[CH3:44][OH:45]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.O.CN(C=O)C>[ClH:32].[N:37]12[CH2:42][CH2:41][CH:40]([CH2:39][CH2:38]1)[CH:35]([NH:34][C:44]([NH:29][C:8]1[N:9]=[CH:10][S:11][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:45])[CH2:36]2

Participants

10

Reactant 4

HCID 197853Quinuclidine, 3-amino-, dihydrochlorideHCID 199401P,P-Diphenylphosphinic azideHCID 9448135-phenyl-1,3-thiazole-4-carboxylic AcidHCID 21893726Hydrochloride methanol

Product 1

HCID 685931721-(1-Azabicyclo[2.2.2]oct-3-yl)-3-(5-phenyl-1,3-thiazol-4-yl) urea hydrochloride

Reagents, catalysts & solvents 5

HCID 702EthanolSolvent2×HCID 962WaterSolventHCID 1140TolueneSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 5-phenyl-1,3-thiazole-4-carboxylic acid (300 mg) in toluene (6 mL) were added dropwise TEA (672 μL) and DPPA (409 μL) at room temperature, followed by stirring at the same temperature for 20 minutes. Next, after stirring at 90° C. for 5 minutes, a mixture of 3-aminoquinuclidine dihydrochloride (407 mg) and DMF (2 mL) was added thereto, followed by heating under reflux for 1 hour. To the reaction liquid was added water, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (YAMAZEN YFLC WPrep2XY, eluent; CHCl3:MeOH:28% aqueous ammonia=80:10:1) to obtain an oily substance. This was dissolved in EtOH, followed by addition of 10% HCl/MeOH at room temperature and concentration under reduced pressure. The residue obtained was added with EtOH and EtOAc, and left to stand, and the solid precipitated was collected by filtration, and washed with EtOAc to obtain 1-(1-azabicyclo[2.2.2]oct-3-yl)-3-(5-phenyl-1,3-thiazol-4-yl) urea hydrochloride (15 mg) as a white solid.

Workup

  1. stirringNext, after stirring at 90° C. for 5 minutes
  2. additionwas added
  3. temperatureby heating
  4. temperatureunder reflux for 1 hour
  5. customTo the reaction liquid
  6. extractionfollowed by extraction with EtOAc
  7. washThe organic layer was washed with water and brine in this order
  8. dry with materialdried over MgSO4
  9. concentrationconcentrated under reduced pressure
  10. customThe residue was purified by medium-pressure preparative liquid chromatography (YAMAZEN YFLC WPrep2XY, eluent; CHCl3:MeOH:28% aqueous ammonia=80:10:1)
  11. customto obtain an oily substance
  12. concentrationconcentration under reduced pressure
  13. customThe residue obtained
  14. waitleft
  15. customthe solid precipitated
  16. filtrationwas collected by filtration
  17. washwashed with EtOAc

Sources & evidence

ORD record
ord-34117598542c4a71b319b48357d0a8c1
Source dataset
uspto-grants-2013_02
Patent number
US08367696B2

Linked notes

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