Trifluoroacetic acid → HCID 86643295, compound

HRID 218060Notes

Reaction equation

HRID 218060 reaction equation
C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH:12]([C:16](=[O:19])[CH2:17]Br)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.[F-].[K+].C1OCCOCCOCCOCCOCCOC1.[F:40][C:41]([F:46])([F:45])[C:42]([O-:44])=[O:43].[F:47]C(F)(F)C(O)=O>C1C=CC=CC=1.ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH:10]12[CH2:11][CH:12]([C:16](=[O:19])[CH2:17][F:47])[CH2:13][CH:14]1[CH2:15][NH:8][CH2:9]2

Participants

8

Reactant 5

HCID 6422Trifluoroacetic acidHCID 2855718-Crown-6HCID 84468TrifluoroacetateHCID 522689Potassium FluorideHCID 86643296HCID 86643296, compound

Product 1

HCID 86643295HCID 86643295, compound

Reagents, catalysts & solvents 2

HCID 241BenzeneSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of 1-(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-7-yl)-2-bromo-1-ethanone (0.126 g, 0.380 mmol), potassium fluoride (0.067 g, 1.15 mmol) and 18-crown-6 (0.050 g, 0.19 mmol) in benzene (10 mL) was heated at reflux overnight. The mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography, eluting with 20-30% ethyl acetate in hexanes, to obtain the cis isomer (0.022 g), trans isomer (0.030 g), and a mixture of cis/trans 1-(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-7-yl)-2-fluoro-1-ethanone (0.040 g), as oils. The separated isomers were de-protected and converted into their trifluoroacetate salts by reaction with trifluoroacetic acid in dichloromethane (5 mL) (ambient temperature, 1 h). The solvent was evaporated, and the products were dried by vacuum to obtain 1-(3-azabicyclo[3.3.0]oct-7-yl)-2-fluoro-1-ethanone trifluoroacetate as cis and trans isomers (0.025 g and 0.032 g, respectively) (1H NMR of trans isomer (CD3OD, 300 MHz): δ 5.08 (s, 1H), 4.93 (s, 1H), 3.37-3.29 (m, 2H), 3.24-3.16 (m, 3H), 3.00-2.95 9m, 2H), 2.34-2.22 (m, 2H), 1.69-1.58 (m, 2H); MS (m/z): 172 (M+1); 1H-NMR of cis isomer (CD3OD, 300 MHz): δ 5.13 (s, 1H), 4.98 (s, 1H), 3.60-3.52 (m, 2H), 3.78-3.67 (m, 2H), 3.12-2.96 (m, 3H), 2.38-2.15 (m, 2H), 1.91-1.64 (m, 2H); MS (m/z): 172 (M+1)). The cis isomer exhibited Ki values at rat and human α4β2 of 6.8 nM and 6.3 nM respectively and did not pass HTS for α7. The trans isomer exhibited a Ki value at rat and human α4β2 of 154 nM and 176 nM respectively and exhibited a Ki value at α7 of >10.000 nM.

Workup

  1. temperaturewas heated
  2. temperatureat reflux overnight
  3. filtrationThe mixture was filtered
  4. concentrationthe filtrate was concentrated
  5. custompurified by silica gel column chromatography
  6. washeluting with 20-30% ethyl acetate in hexanes
  7. customto obtain the cis isomer (0.022 g)
  8. customThe solvent was evaporated
  9. customthe products were dried by vacuum

Sources & evidence

ORD record
ord-924b2179552c4b18886c8f946925e814
Source dataset
uspto-grants-2012_06
Patent number
US08198296B2

Reaction notes

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