4-Methylmorpholine → (2S,4R)-tert-butyl 2-((1R,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate

HRID 604810Notes

Reaction equation

HRID 604810 reaction equation
[C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:32]([O:34][C:35]([C@@:37]1([NH2:42])[CH2:39][C@H:38]1[CH:40]=[CH2:41])=[O:36])[CH3:33]>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10](=[O:12])[NH:42][C@:37]1([C:35]([O:34][CH2:32][CH3:33])=[O:36])[CH2:39][C@H:38]1[CH:40]=[CH2:41])=[O:2])([CH3:5])([CH3:6])[CH3:7]

Participants

6

Reactant 4

HCID 79724-Methylmorpholine2×HCID 62365Isobutyl chloroformateHCID 88804(2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acidHCID 10820795rac-ethyl (1R,2S)-1-amino-2-ethenylcyclopropane-1-carboxylate

Product 1

HCID 57892908(2S,4R)-tert-butyl 2-((1R,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-23 °C

Procedure

To a solution of 4.87 g (21.0 mmol) of Boc-(2S,4R)-hydroxyproline in 25 mL of THF was added 2.03 mL (20.0 mmol) of N-methylmorpholine. A suspension formed. The mixture was cooled to −23° C. and 2.85 g (20.0 mmol) of isobutylchloroformate was added. After stirring for 10 min additional 4.25 g (42.0 mmol) of N-methylmorpholine was added. To this mixture was added the solution of (1R,2S)-1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester prepared in example 1 at a temperature of −15° C. within 5 min. The reaction mixture was stirred for 2.5 h at 0° C. The salts were filtered off and the filtrate was treated with 20 mL of aqueous HCl (0.5 N). The solvents were removed at 50° C. under reduced pressure using a rotary evaporator and the residue was extracted twice with 50 mL of ethyl acetate. The extract was washed with 40 mL of water and 40 mL of aqueous sodium carbonate solution (10% w/w), and dried over sodium sulfate. Finally the solvent was removed completely to give 8.19 g of (2S,4R)-2-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil. The product was used in the next step without further purification.

Workup

  1. customA suspension formed
  2. additionwas added
  3. filtrationThe salts were filtered off
  4. additionthe filtrate was treated with 20 mL of aqueous HCl (0.5 N)
  5. customThe solvents were removed at 50° C. under reduced pressure
  6. customa rotary evaporator
  7. extractionthe residue was extracted twice with 50 mL of ethyl acetate
  8. washThe extract was washed with 40 mL of water and 40 mL of aqueous sodium carbonate solution (10% w/w)
  9. dry with materialdried over sodium sulfate
  10. customFinally the solvent was removed completely

Sources & evidence

ORD record
ord-934fb5e7eb1b4223a14cfae8562eeac6
Source dataset
uspto-grants-2011_03
Patent number
US07910728B2

Reaction notes

Loading…