HCID 131736819, compound → HCID 102196131, compound

HRID 1486809Notes

Reaction equation

HRID 1486809 reaction equation
[F:1][C:2]1[N:7]=[CH:6][C:5]([C@H:8]2[CH2:14][C@H:13]3[NH:15][C@@H:9]2[CH2:10][CH2:11][CH2:12]3)=[CH:4][CH:3]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:14][C@@H:13]3[NH:15][C@H:9]2[CH2:10][CH2:11][CH2:12]3)=[CH:4][CH:3]=1

Participants

3

Reactant 1

HCID 131736819HCID 131736819, compound

Product 1

HCID 102196131HCID 102196131, compoundYield 43%

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent

Procedure

Resolution of racemates is done by semi-preparative chiral HPLC such as e.g. with a 250×20 mm, 5 μL, CHIRALPAK® IA column. 5.2 g (25.2 mmol) of (+/−)-exo-6-(6-fluoro-pyridine-3-yl)-8-aza-bicyclo-[3.2.1]octane-8-carboxylic acid benzyl ester (III) are dissolved in 42 ml of a mobile solvent (MeCN/0.1% diethylamine). The injection volume is 1 ml. Separation was done under isocratic conditions with a flow of 20 ml/min. Detection is performed by means of a UV detector at a wavelength of 280 nm. The retention time of the (+)-enantiomer (VI) is approx. 8-13 min, that of the (−)-enantiomer (V) approx. 19-38 min. Both enantiomers are separately collected, after chiral HPLC the mobile solvent is removed by means of the rotary evaporator. The enantiomeric purity is determined by analytic chiral HPLC by means of a 250×4.6 mm, 5 μL, CHIRALPAK® IA column. 1 mg of the respective enantiomer is dissolved in 1 ml of a mobile solvent (MeOH/0.1% TEA). The injection volume is 10 μL. Separation was done under isocratic conditions with a flow of 1 ml/min. Detection is done at 280 nm. The retention time of the (+)-enantiomer (VI) is 11.5 min, that of the (−)-enantiomer (V) 17.5 min. 2.24 g (10.86 mmol, 43%, >99% ee, [α]D20 (CHCl3, c=0.5)=−30.9°) of (−)-(1R,5S,6S)-6-(6-fluoro-pyridine-3-yl)-8-aza-bicyclo[3.2.1]octane (V) and 2.2 g (10.67 mmol, 42%, >99% ee, [α]D20 (CHCl3, c=0.5)=)+29.0° of (+)-(1S,5R,6R)-6-(6-fluoro-pyridine-3-yl)-8-aza-bicyclo[3.2.1]octane (VI), respectively, is isolated as a colorless solid.

Workup

  1. customSeparation
  2. customBoth enantiomers are separately collected
  3. customafter chiral HPLC the mobile solvent is removed by means of the rotary evaporator
  4. dissolution1 mg of the respective enantiomer is dissolved in 1 ml of a mobile solvent (MeOH/0.1% TEA)
  5. customSeparation
  6. waitThe retention time of the (+)-enantiomer (VI) is 11.5 min, that of the (−)-enantiomer (V) 17.5 min

Sources & evidence

ORD record
ord-fd514c0e6ddc4322a87045439a655d2f
Source dataset
uspto-grants-2016_08
Patent number
US09428497B2

Reaction notes

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