Citric Acid → (2S,4R,5R)-4-Isopropenyl-5-[4-methoxy-3-(3-methoxy-propoxy)-phenyl]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester

HRID 1009830Notes

Reaction equation

HRID 1009830 reaction equation
[H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([C@@H:8]1[CH2:12][C@H:11]([C:13](=O)[CH3:14])[C@H:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[N:9]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:7].[C:37](O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OC)(C)(C)C>[CH3:3][CH2:4][O:5][C:6]([C@@H:8]1[CH2:12][C@H:11]([C:13]([CH3:37])=[CH2:14])[C@H:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[N:9]1[C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])=[O:7]

Participants

7

Reactant 3

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 16124434HCID 16124434, compound

Product 1

HCID 16124546(2S,4R,5R)-4-Isopropenyl-5-[4-methoxy-3-(3-methoxy-propoxy)-phenyl]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester

Reagents, catalysts & solvents 3

HCID 74505Methyltriphenyliphosphonium bromideCatalystHCID 8028TetrahydrofuranSolvent2×HCID 15413tert-Butyl methyl etherSolvent

Conditions

Temperature
50 °C

Procedure

A suspension of 0.104 g (0.0026 mol) of a 60% suspension of sodium hydride in mineral oil in 20 mL of tetrahydrofuran is treated with 0.89 g (0.0025 mol) of methyltriphenylphosphonium bromide. The white suspension is heated to 50° C. and stirred for 7 hours at this temperature. The red suspension is cooled to 0° C. and a solution of (2S,4S,5R)-4-Acetyl-5-[4-methoxy-3-(3-methoxy-propoxy)-phenyl]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (0.60 g, 0.00125 mol) dissolved in 5 mL of tetrahydrofuran is added. The mixture is stirred for 1.5 hours at 0° C. and diluted with 20 mL of tert-butylmethyl ether. A 10% aqueous solution of citric acid (25 mL) is added and the mixture extracted. The aqueous phase is re-extracted with a further 20 mL of tert-butyl methyl ether and the organic phases combined. The combined organic phases are washed with 20 mL of water containing 10 mL of saturated aqueous sodium hydrogen carbonate followed by 30 mL of water. The organic phase is dried and the solvent removed in vacuum at 30° C. to give the crude product as an oil. This oil is chromatographed over silica-gel, eluting with heptane/ethyl acetate (4/1) to give the desired product.

Workup

  1. temperatureThe red suspension is cooled to 0° C.
  2. additionis added
  3. stirringThe mixture is stirred for 1.5 hours at 0° C.
  4. extractionthe mixture extracted
  5. extractionThe aqueous phase is re-extracted with a further 20 mL of tert-butyl methyl ether
  6. washThe combined organic phases are washed with 20 mL of water containing 10 mL of saturated aqueous sodium hydrogen carbonate
  7. customThe organic phase is dried
  8. customthe solvent removed in vacuum at 30° C.
  9. customto give the crude product as an oil
  10. customThis oil is chromatographed over silica-gel
  11. washeluting with heptane/ethyl acetate (4/1)

Sources & evidence

ORD record
ord-8184bf449958489b8c9a656b47bf1a51
Source dataset
uspto-grants-2011_07
Patent number
US07973175B2

Reaction notes

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