4-Methylmorpholine → (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine

HRID 323225Notes

Reaction equation

HRID 323225 reaction equation
C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=O)C1C=CC(OC)=CC=1.[Cl:31][C:32]1[CH:33]=[C:34]([C@@:39]2([CH2:44][CH2:45][OH:46])[CH2:43][CH2:42][NH:41][CH2:40]2)[CH:35]=[CH:36][C:37]=1[Cl:38].C(=O)([O-])[O-].[K+].[K+].[CH3:53][O:54][C:55]1[CH:56]=[C:57]([CH:61]=[C:62]([O:66][CH3:67])[C:63]=1[O:64][CH3:65])[C:58](Cl)=[O:59].CN1CCOCC1.[CH3:75][S:76](Cl)(=[O:78])=[O:77]>CC(C)=O.C1(C)C=CC=CC=1.O>[CH3:53][O:54][C:55]1[CH:56]=[C:57]([CH:61]=[C:62]([O:66][CH3:67])[C:63]=1[O:64][CH3:65])[C:58]([N:41]1[CH2:42][CH2:43][C@@:39]([C:34]2[CH:35]=[CH:36][C:37]([Cl:38])=[C:32]([Cl:31])[CH:33]=2)([CH2:44][CH2:45][O:46][S:76]([CH3:75])(=[O:78])=[O:77])[CH2:40]1)=[O:59]

Participants

9

Reactant 5

HCID 79724-MethylmorpholineHCID 11430Potassium CarbonateHCID 31297Methanesulfonyl chlorideHCID 78282Benzoyl chloride, 3,4,5-trimethoxy-HCID 131720896(S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid

Product 1

HCID 10896745(S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine

Reagents, catalysts & solvents 3

HCID 180AcetoneSolventHCID 962WaterSolvent2×HCID 1140TolueneSolvent

Conditions

Temperature
5 °C

Procedure

Combine (S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt (9.05 kg, 13.3 mol), potassium carbonate (6.42 kg) in acetone (27.2 kg). Cool to about 5° C. and add water (8.3 gal). Cool to about 3° C. and slowly add a solution of 3,4,5-trimethoxybenzoyl chloride (14.0 kg, 26.9%, in 1,2-dimethoxethane, 16.3 mol) over about 25 minutes. When the reaction is complete, warm to 25° C. Dilute the reaction mixture with toluene (36.35 kg). Separate the layers and extract the organic layer with a solution of water (2 gal) and 3 M aqueous hydrochloric acid solution (2 kg) and then brine. Concentrate the organic layer in vacuo until about 5 gallons remains. Add toluene (18.2 kg) and again concentrate in vacuo until about 5 gallons remain. Add toluene (36.15 kg) and cool to about −3° C. Add N-methylmorpholine (6.85 kg, 67.7 mol) and then methanesulfonyl chloride (3.40 kg, 29.7 mol). When the reaction s complete, add water (4.8 gal) and warm to about 25° C. Separate the layers and extract the organic layer with a 3 M aqueous hydrochloric acid solution (18.1 kg). Separate the layers to give a solution of (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine.

Workup

  1. temperatureCool to about 3° C.
  2. temperaturewarm to 25° C
  3. customSeparate the layers
  4. extractionextract the organic layer with a solution of water (2 gal) and 3 M aqueous hydrochloric acid solution (2 kg)
  5. concentrationConcentrate the organic layer in vacuo until about 5 gallons
  6. concentrationAdd toluene (18.2 kg) and again concentrate in vacuo until about 5 gallons
  7. temperatureAdd toluene (36.15 kg) and cool to about −3° C
  8. temperaturewarm to about 25° C
  9. customSeparate the layers
  10. extractionextract the organic layer with a 3 M aqueous hydrochloric acid solution (18.1 kg)
  11. customSeparate the layers

Sources & evidence

ORD record
ord-7d8034ea03ee4457a245645fd8acc520
Source dataset
uspto-grants-2001_04
Patent number
US06211199B1

Reaction notes

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