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

HRID 2261715Notes

Reaction equation

HRID 2261715 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(Cl)(=O)C(C)(C)C.[CH2:31]([O:33][C:34]([C@@:36]1([NH2:41])[CH2:38][C@H:37]1[CH:39]=[CH2:40])=[O:35])[CH3:32]>CCOC(C)=O>[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:41][C@:36]1([C:34]([O:33][CH2:31][CH3:32])=[O:35])[CH2:38][C@H:37]1[CH:39]=[CH2:40])=[O:2])([CH3:5])([CH3:6])[CH3:7]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 62493Pivaloyl chlorideHCID 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 8857Ethyl AcetateSolvent2×

Conditions

Temperature
22.5 °C

Procedure

To a suspension of 138.8 g (600 mmol) of Boc-(2S,4R)-hydroxyproline in 890 mL of EtOAc was added 63.7 g (630 mmol) of NMM at 20-30° C. To this mixture 72.3 g (600 mmol) of pivaloyl chloride was added at 15-22° C. within 10-20 min followed by 50 mL of EtOAc. The mixture was stirred at 20-25° C. for 60-75 min. Then the emulsion of (1R,2S)-1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester prepared in example 6 was added at a temperature of 20-30° C. within 5-30 min. The dosing funnel was rinsed with 20 mL DMF and 100 mL EtOAc. The reaction mixture was stirred for 4 h at 20-25° C. After complete conversion 450 mL of aqueous HCl (IN) was added. Phases were separated and the aqueous layer was extracted with 600 mL of EtOAc. The organic phase was washed with 200 mL of water, 400 mL of aqueous NaOH (2M) and 200 mL of water. The combined organic phases were concentrated to 400 mL under reduced pressure. To the residue 1500 mL of toluene was added and the mixture was concentrated to 1000 mL under reduced pressure. To the residue 720 mL of toluene was added to yield the (2S,4R)-2-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a 12-13 wt % solution in toluene.

Workup

  1. washThe dosing funnel was rinsed with 20 mL DMF and 100 mL EtOAc
  2. stirringThe reaction mixture was stirred for 4 h at 20-25° C
  3. additionAfter complete conversion 450 mL of aqueous HCl (IN) was added
  4. customPhases were separated
  5. extractionthe aqueous layer was extracted with 600 mL of EtOAc
  6. washThe organic phase was washed with 200 mL of water, 400 mL of aqueous NaOH (2M) and 200 mL of water
  7. concentrationThe combined organic phases were concentrated to 400 mL under reduced pressure
  8. additionTo the residue 1500 mL of toluene was added
  9. concentrationthe mixture was concentrated to 1000 mL under reduced pressure
  10. additionTo the residue 720 mL of toluene was added

Sources & evidence

ORD record
ord-90c3e161b2d94539bbce5f864b1ea419
Source dataset
uspto-grants-2010_12
Patent number
US07847106B2

Reaction notes

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