Hydrochloric Acid → 3-Benzyloxy-carbonyl-amino-1-(4-cyanophenyl)-2-oxo-pyrrolidine

HRID 2298547Notes

Reaction equation

HRID 2298547 reaction equation
Cl.C([O:5][CH2:6][CH2:7][C@@H:8]([C:10]([OH:12])=O)[NH2:9])(=O)C.C(=O)([O-])O.[Na+].ClC([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O.C(=O)([O-])[O-].[Na+].[Na+].C([N:37]([CH2:40]C)[CH2:38][CH3:39])C.C(Cl)(=O)C(C)(C)C.NC1C=[CH:56][C:53]([C:54]#[N:55])=[CH:52][CH:51]=1.Cl.S(Cl)(C)(=O)=O.[OH-].[Na+]>O>[CH2:22]([O:21][C:8]1([NH2:9])[C:7](=[C:6]=[O:5])[CH2:40][N:37]([C:38]2[CH:39]=[CH:56][C:53]([C:54]#[N:55])=[CH:52][CH:51]=2)[C:10]1=[O:12])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1

Participants

12

Reactant 10

HCID 313Hydrochloric Acid2×HCID 8471Triethylamine2×HCID 10340Sodium CarbonateHCID 10387Benzyl chloroformateHCID 133964-AminobenzonitrileHCID 14798Sodium HydroxideHCID 31297Methanesulfonyl chlorideHCID 62493Pivaloyl chlorideHCID 516892Sodium BicarbonateHCID 45038083O-Acetyl-L-homoserine hydrochloride

Product 1

HCID 867586583-Benzyloxy-carbonyl-amino-1-(4-cyanophenyl)-2-oxo-pyrrolidineYield 49.6%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent3×

Conditions

Temperature
5 °C

Procedure

1883 g (9.52 mol) of O-acetyl-L-homoserine hydrochloride are added to a solution of 1600 g (19.04 mol) of sodium hydrogen carbonate in 9.3 litres of water, and the mixture is cooled to 5° C. 1823 g (10.47 mol) of benzyl chloro-formate are then added and the pH is maintained at 7.5 by addition of 20% sodium carbonate solution. The mixture is stirred for 2 hours at 15° C. and then extracted using 20 litres of methyl isobutyl ketone. The aqueous phase is adjusted to pH=2.0 using concentrated hydrochloric acid and extracted twice using a total of 25 litres of methyl isobutyl ketone. The combined organic phases are washed with 3.5 litres of water and concentrated in vacuo. The residue is taken up in 19.5 litres of methyl isobutyl ketone; 856 g (8.47 mol) of triethylamine are added and the mixture is cooled to 0° C. 1042 g (8.47 mol) of pivaloyl chloride are then added and stirring is carried out for 20 minutes. After the addition of 1000 g (8.47 mol) of p-aminobenzonitrile, stirring is carried out for 36 hours at room temperature. 10 litres of water are then added and the pH is adjusted to 2.0 using concentrated hydrochloric acid. The organic phase is separated off; 10 litres of water are added and the pH is adjusted to 11 using 50% sodium hydroxide solution. After washing with 3 litres of water, the organic phase is concentrated in vacuo to about 3.5 kg. The residue is dissolved in 25 litres of methanol, and 7.5 litres of 25% ammonia are added. The mixture is then heated at 60° C. for 6 hours and then concentrated in vacuo. The residue is dehydrated by removal of 3×7.5 litres of methyl isobutyl ketone by distillation, is taken up in 25 litres of tetrahydrofuran and cooled to −5° C., and 1522 g (13.28 mol) of mesyl chloride are added. 1341 g (13.28 mol) of triethylamine are then added over a period of 45 minutes and stirring is carried out for one hour; then 2300 g of 50% sodium hydroxide solution are added and stirring is carried out for one hour. 3 litres of water are then added to the reaction mixture, and the pH is adjusted to 7 using concentrated hydrochloric acid. The solid obtained after removal of the tetrahydrofuran in vacuo is stirred with 14 litres of water, filtered off with suction and washed with water. The crude product is stirred with 19 litres of methyl isobutyl ketone at 50° C. and filtered off with suction. Drying yields 1401 g (44%) of 3-benzyloxy-carbonyl-amino-1-(4-cyanophenyl)-2-oxo-pyrrolidine.

Workup

  1. extractionextracted
  2. extractionextracted twice
  3. washThe combined organic phases are washed with 3.5 litres of water
  4. concentrationconcentrated in vacuo
  5. temperaturethe mixture is cooled to 0° C
  6. stirringstirring
  7. waitis carried out for 20 minutes
  8. stirringstirring
  9. waitis carried out for 36 hours at room temperature
  10. customThe organic phase is separated off
  11. addition10 litres of water are added
  12. washAfter washing with 3 litres of water
  13. concentrationthe organic phase is concentrated in vacuo to about 3.5 kg
  14. dissolutionThe residue is dissolved in 25 litres of methanol
  15. addition7.5 litres of 25% ammonia are added
  16. temperatureThe mixture is then heated at 60° C. for 6 hours
  17. concentrationconcentrated in vacuo
  18. customThe residue is dehydrated by removal of 3×7.5 litres of methyl isobutyl ketone by distillation
  19. temperaturecooled to −5° C.
  20. stirringstirring
  21. waitis carried out for one hour
  22. stirringstirring
  23. waitis carried out for one hour
  24. customThe solid obtained
  25. customafter removal of the tetrahydrofuran in vacuo
  26. stirringis stirred with 14 litres of water
  27. filtrationfiltered off with suction
  28. washwashed with water
  29. stirringThe crude product is stirred with 19 litres of methyl isobutyl ketone at 50° C.
  30. filtrationfiltered off with suction
  31. customDrying

Sources & evidence

ORD record
ord-af57b278be8e4d75b0d3e26da1154c41
Source dataset
uspto-grants-2002_12
Patent number
US06492541B2

Reaction notes

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