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

HRID 2261711Notes

Reaction equation

HRID 2261711 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].C1COCC1.CN1CCOCC1.[CH2:29]([O:31][C:32]([C@@:34]1([NH2:39])[CH2:36][C@H:35]1[CH:37]=[CH2:38])=[O:33])[CH3:30]>>[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:39][C@:34]1([C:32]([O:31][CH2:29][CH3:30])=[O:33])[CH2:36][C@H:35]1[CH:37]=[CH2:38])=[O:2])([CH3:5])([CH3:6])[CH3:7]

Participants

5

Reactant 4

HCID 79724-Methylmorpholine2×HCID 8028TetrahydrofuranHCID 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

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 2.03 mL (20.0 mmol) of NMM was added. A suspension was formed. The mixture was cooled to −23° C. and 2.85 g (20.0 mmol) of isobutylchloroformiate was added. After stirring for 10 min additional 4.25 g (42.0 mmol) of NMM was added. To this mixture the solution of (1R,2S)-1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester prepared in example 1 was added at a temperature of −15° C. within 5 min. The reaction mixture was stirred for 2.5 h at 0° C. 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 EtOAc. The extract was washed with 40 mL of water and 40 mL of aqueous Na2CO3 solution (10 wt %), 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 was formed
  2. addition2.85 g (20.0 mmol) of isobutylchloroformiate was added
  3. additionwas added
  4. filtrationSalts were filtered off
  5. additionthe filtrate was treated with 20 mL of aqueous HCl (0.5 N)
  6. customThe solvents were removed at 50° C. under reduced pressure
  7. customa rotary evaporator
  8. extractionthe residue was extracted twice with 50 mL of EtOAc
  9. washThe extract was washed with 40 mL of water and 40 mL of aqueous Na2CO3 solution (10 wt %)
  10. dry with materialdried over sodium sulfate
  11. customFinally the solvent was removed completely

Sources & evidence

ORD record
ord-ec8ec69e6d2449e4a7df5976b157b2ca
Source dataset
uspto-grants-2010_12
Patent number
US07847106B2

Reaction notes

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