Formaldehyde → (R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butylester

HRID 924329Notes

Reaction equation

HRID 924329 reaction equation
[C:1]([C@@H:9]1[CH2:13][CH:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[N:11](/C=C/C2C=CC=CC=2)[C:10]1=[O:35])(=O)C1C=CC=CC=1.[CH2:36]=O.[OH-].C([N+](C[CH2:53][CH2:54][CH3:55])(CCCC)CCCC)CCC.[C:56]([O-:59])([O-])=[O:57].[K+].[K+]>O1CCCC1.[Cl-].[Na+].O>[C:54]([O:59][C:56]([N:11]1[C@H:12]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:19][CH:20]=2)[CH2:13][C:9](=[CH2:1])[C:10]1=[O:35])=[O:57])([CH3:53])([CH3:55])[CH3:36]

Participants

7

Reactant 4

HCID 712FormaldehydeHCID 11430Potassium CarbonateHCID 2723671Tetrabutylammonium HydroxideHCID 86673650HCID 86673650, compound

Product 1

HCID 46193438(R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butylester

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
50 °C

Procedure

The mixture of (R/S)-3-Benzoyl-(S)-5-biphenyl-4-ylmethyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4a, R1=t-butoxycarbonyl, R4=phenyl) (0.455 g, 1 mmol), formaldehyde (37% in water, 0.24 g, 3 mmol), tetrabutyl ammonium hydroxide (6.5 mg, 0.01 mmol) and K2CO3 (0.28 g, 1.3 mmol, dissolved in 1 mL water) in 5 mL dry tetrahydrofuran was heated to 50° C. and stirred for 2 hours. Then the reaction mixture is diluted with 5 mL brine and stirred for 15 min, stop stirring, and remove the lower aqueous layer. the organic phase is then concentrated in vacuo. ethyl acetate 10 mL is added, filtered and the filtrate concentrated and purified by column chromatography eluting with 5:1 heptane/ethyl acetate to afford (R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butylester (1a, R1=t-butoxycarbonyl). Spectroscopic data as reported in WO2009/090251 (Example 23, Method 1).

Workup

  1. stirringstirred for 15 min
  2. stirringstop stirring
  3. customremove the lower aqueous layer
  4. concentrationthe organic phase is then concentrated in vacuo
  5. additionethyl acetate 10 mL is added
  6. filtrationfiltered
  7. concentrationthe filtrate concentrated
  8. custompurified by column chromatography
  9. washeluting with 5:1 heptane/ethyl acetate

Sources & evidence

ORD record
ord-e2bb3e5cf32f419297c0afac01f29844
Source dataset
uspto-grants-2016_03
Patent number
US09278908B2

Reaction notes

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