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(+-)-3-Quinuclidinol → 3-({5-[(1,1-Dioxidothiomorpholin-4-yl)carbonyl]-4-(trifluoromethyl)pyrimidin-2-yl}oxy)quinuclidine fumarate

HRID 38796
Notes
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Reaction equation

HRID 38796 reaction equation
[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[H-].[Na+].Cl[C:13]1[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([N:25]2[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]2)=[O:24])=[CH:15][N:14]=1.[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37]>CN(C)C=O.[Cl-].[Na+].O.C(O)C.O>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37].[O:32]=[S:28]1(=[O:31])[CH2:29][CH2:30][N:25]([C:23]([C:16]2[C:17]([C:19]([F:22])([F:21])[F:20])=[N:18][C:13]([O:9][CH:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[N:14][CH:15]=2)=[O:24])[CH2:26][CH2:27]1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

9

Reactant 4

HCID 15381(+-)-3-QuinuclidinolHCID 24758Sodium hydrideHCID 444972Fumaric AcidHCID 581689914-{[2-Chloro-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}thiomorpholine 1,1-dioxide

Product 1

HCID 667203663-({5-[(1,1-Dioxidothiomorpholin-4-yl)carbonyl]-4-(trifluoromethyl)pyrimidin-2-yl}oxy)quinuclidine fumarateYield 50.2%

Reagents, catalysts & solvents 4

HCID 702EthanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

To a solution of quinuclidin-3-ol (127 mg) in N,N-dimethylformamide (5 mL) was added 60% sodium hydride (60 mg), and the mixture was stirred at room temperature for 20 minutes. To the reaction mixture was added 4-{[2-chloro-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}thiomorpholine 1,1-dioxide (344 mg), followed by stirring at room temperature for 1 hour, and then at 80° C. for 3 hours. To the reaction mixture were added water and saturated brine, followed by stirring and then extracting with a mixed solvent of chloroform:2-propanol=3:1. The obtained organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol:28% aqueous ammonia=10:1:0.1) to obtain a colorless oily substance (207 mg). This oily substance was dissolved in ethanol (5 mL) and then fumaric acid (58 mg) was added thereto, followed by stirring at an external temperature of 80° C. for 1 hour. The reaction mixture was cooled to room temperature under stirring, and further stirred at room temperature for 1 hour, and then the obtained colorless solid was collected by filtration, washed with ethanol, and dried to obtain 3-({5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-4-(trifluoromethyl)pyrimidin-2-yl}oxy)quinuclidine fumarate (138 mg).

Workup

  1. stirringby stirring at room temperature for 1 hour
  2. waitat 80° C. for 3 hours
  3. stirringby stirring
  4. extractionextracting with a mixed solvent of chloroform
  5. dry with materialThe obtained organic layer was dried over anhydrous magnesium sulfate
  6. customthe solvent was evaporated
  7. customThe obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol:28% aqueous ammonia=10:1:0.1)
  8. customto obtain a colorless oily substance (207 mg)
  9. stirringby stirring at an external temperature of 80° C. for 1 hour
  10. temperatureThe reaction mixture was cooled to room temperature
  11. stirringunder stirring
  12. stirringfurther stirred at room temperature for 1 hour
  13. filtrationthe obtained colorless solid was collected by filtration
  14. washwashed with ethanol
  15. customdried

Sources & evidence

ORD record
ord-ca64fe18f75141138dba77747695e57f
Source dataset
uspto-grants-2013_09
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08524727B2

Reaction notes

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