Tetrahydrofuran → (S)-3-((S)-cyclopropylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester

HRID 1671382Notes

Reaction equation

HRID 1671382 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]1[CH2:19]OC[CH2:16]1.[CH:20]1([Mg]Br)[CH2:22][CH2:21]1>[NH4+].[Cl-]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([CH:16]2[CH2:15][CH2:19]2)[OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([CH:20]2[CH2:22][CH2:21]2)[OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 3

HCID 8028Tetrahydrofuran2×HCID 1514343(S)-tert-butyl 3-formylpyrrolidine-1-carboxylateHCID 178418630HCID 178418630, compound

Product 2

HCID 66890044(S)-3-((S)-cyclopropylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl esterHCID 66891333(S)-3-((R)-cyclopropylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester

Reagents, catalysts & solvents 1

HCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
-78 °C

Procedure

(S)-3-Formyl-pyrrolidine-1-carboxylic acid t-butyl ester (1.0 g, 5 mmol) and THF (10 mL, 100 mmol) were combined under nitrogen, and the resulting solution was cooled to −78° C. 0.5M Cyclopropylmagnesium bromide in THF (15 mL, 7.5 mmol) was then added dropwise over 10 minutes. The mixture was allowed to warm to room temperature slowly overnight. Then aqueous saturated NH4Cl (30 mL) was added dropwise to quench the reaction. The resulting mixture was extracted with EtOAc (2×30 mL), and the combined organic layers were washed with saturated aqueous NaHCO3 (1×30 mL) and saturated aqueous NaCl (1×30 mL), then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (15-55% MeCN:H2O+0.05% TFA over 80 minutes) on a 2″ column to yield (S)-3-((R)-cyclopropylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester (520 mg, 2nd eluting peak) and (S)-3-((S)-cyclopropylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester (418 mg, 1st eluting peak). The lyophilized solids were dissolved in EtOAc and washed with saturated aqueous NH4CO3, the organics were separated, dried over Na2SO4 and the solvent was removed under reduced pressure.

Workup

  1. temperatureto warm to room temperature slowly overnight
  2. customto quench
  3. customthe reaction
  4. extractionThe resulting mixture was extracted with EtOAc (2×30 mL)
  5. washthe combined organic layers were washed with saturated aqueous NaHCO3 (1×30 mL) and saturated aqueous NaCl (1×30 mL)
  6. dry with materialdried over anhydrous MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude product was purified by preparative HPLC (15-55% MeCN:H2O+0.05% TFA over 80 minutes) on a 2″ column

Sources & evidence

ORD record
ord-dfcfa302ee044eb48899fc2ea6d32cd1
Source dataset
uspto-grants-2011_08
Patent number
US07994209B2

Reaction notes

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