Hydrochloric Acid → (-)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt

HRID 637057Notes

Reaction equation

HRID 637057 reaction equation
[C:1]([C@:11]([C:28]([OH:30])=[O:29])([OH:27])[C@:12]([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)([OH:16])[C:13]([OH:15])=[O:14])(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.Cl.[F:32][C:33]1[CH:34]=[C:35]([C:40]2([CH2:45][CH2:46][OH:47])[CH2:44][CH2:43][NH:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[F:39]>O.CO.CO>[C:17]([C@:12]([C:13]([OH:15])=[O:14])([OH:16])[C@:11]([C:1](=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)([OH:27])[C:28]([OH:30])=[O:29])(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[F:32][C:33]1[CH:34]=[C:35]([C:40]2([CH2:45][CH2:46][OH:47])[CH2:44][CH2:43][NH:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[F:39]

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 184645443-(3,4-Difluorophenyl)-3-(2-hydroxyethyl)pyrrolidineHCID 66875417(R, R)-di-p-anisoyltartaric acid

Product 1

HCID 131720893(-)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 22242641Methanol--water (1/1)Solvent

Procedure

Combine (R,R)-di-p-anisoyltartaric acid (0.93 g, 2.2 mmol) and aqueous 12 M hydrochloric acid solution (0.19 mL, 2.28 mmol) in water/methanol (10 mL)/(10 mL). Heat to reflux. Add dropwise, a solution of 3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine (1.0 g, 4.4 mmol) in methanol (10 mL). After 15 minutes, slowly cool to ambient temperature. Filter the solid that forms and rinse with water to give (−)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt. [α]2D0=−25.1 (c=1.02, dimethylsulfoxide). Analysis on HPLC, on an analytical sample of the free amine obtained by extraction, using a CHIRALPAK AD 25 cm×0.46 cm column eluting with pentane/methanol/triethylamine (80/10/0.1) with a flow rate of 1.0 mL/minute indicates an enantiomeric excess of 97.8%, (97.8% ee), retention time 19.0 minutes for the 3,4,5-trimethoxybenzamide prepared from the (−)-isomer of the (R,R)-di-p-anisoyltartaric acid salt, retention time 12.5 minutes for the 3,4,5-trimethoxybenzamide prepared from the (+)-isomer of the (R,R)-di-p-anisoyltartaric acid salt.

Workup

  1. temperatureHeat to reflux
  2. additionAdd dropwise
  3. filtrationFilter the solid that forms
  4. washrinse with water

Sources & evidence

ORD record
ord-3fd707d3c2bf4f05a464756421268b9e
Source dataset
uspto-grants-2001_02
Patent number
US06194406B1

Reaction notes

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