1,1'-Carbonyldiimidazole → HCID 59527753, compound

HRID 2189987Notes

Reaction equation

HRID 2189987 reaction equation
C1N=CN([C:6]([N:8]2[CH:12]=N[CH:10]=[CH:9]2)=[O:7])C=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.[CH2:26]([O:28][C:29]([C:31]1([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)CCNC[CH2:32]1)=[O:30])[CH3:27]>CC#N>[CH2:26]([O:28][C:29]([C:31]1([C:37]2[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=2)[CH2:10][CH2:9][N:8]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=3)[CH2:21][CH2:22]2)=[O:7])[CH2:12][CH2:32]1)=[O:30])[CH3:27]

Participants

5

Reactant 3

HCID 682631,1'-Carbonyldiimidazole2×HCID 752601-(4-Fluorophenyl)piperazineHCID 22028818Ethyl 4-(4-fluorophenyl)piperidine-4-carboxylate

Product 1

HCID 59527753HCID 59527753, compoundYield 29.6%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent3×

Conditions

Temperature
20 °C

Procedure

Under inert conditions a 100 mL four necked flask with a magnetic stirrer bar was charged with 0.89 g (5.5 mmol) of CDI in 10 mL MeCN. At 0-5° C. a solution of 0.99 g (5.5 mmol) 1-(4-fluorophenyl)piperazine in 10 mL MeCN was added drop wise during 15 min. The light yellow solution was stirred for 15 min at 0-5° C. and 3 h at 20° C. After 90 min an additional 70 mg CDI was added. 1.2 g (4.8 mmol) 4-(4-fluoro-phenyl)-piperidine-4-carboxylic acid ethyl ester (WO2000071517) in 5 ml MeCN was added. The mixture was heated for in total 5 days to reflux. The reaction mixture was concentrated under vacuum. The residue was dissolved in 15 ml N,N-dimethylacetamide and heated twice for 30 min at 200° C. under micro wave irradiations. The dark brown reaction solution was concentrated under high vacuum. The residue was taken up between 100 mL water and 100 mL ethyl acetate and extracted. The aqueous layers were extracted once with 100 mL ethyl acetate and the organic layers were washed once with 100 mL brine, dried over Na2SO4, filtered off, concentrated under vacuum and purified through column chromatography over silica eluting with a gradient formed from i-propanol and heptane. The product containing fractions were evaporated to yield 0.65 g (29%) of the title compound as light yellow viscous oil. MS ISP (m/e): 458.3 [(M+H)+].

Workup

  1. temperatureThe mixture was heated for in total 5 days
  2. temperatureto reflux
  3. concentrationThe reaction mixture was concentrated under vacuum
  4. dissolutionThe residue was dissolved in 15 ml N,N-dimethylacetamide
  5. temperatureheated twice for 30 min at 200° C. under micro wave irradiations
  6. concentrationThe dark brown reaction solution was concentrated under high vacuum
  7. extractionextracted
  8. extractionThe aqueous layers were extracted once with 100 mL ethyl acetate
  9. washthe organic layers were washed once with 100 mL brine
  10. dry with materialdried over Na2SO4
  11. filtrationfiltered off
  12. concentrationconcentrated under vacuum
  13. custompurified through column chromatography over silica eluting with a gradient
  14. customformed from i-propanol and heptane
  15. additionThe product containing fractions
  16. customwere evaporated

Sources & evidence

ORD record
ord-3682fda8dfee428281c9714d760df95c
Source dataset
uspto-grants-2012_12
Patent number
US08324250B2

Reaction notes

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