(S)-tert-butyl 3-formylpyrrolidine-1-carboxylate → HCID 58104612, compound

HRID 588008Notes

Reaction equation

HRID 588008 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].[CH:15]1([Mg]Cl)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C1COCC1.O.CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]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:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 2

HCID 1514343(S)-tert-butyl 3-formylpyrrolidine-1-carboxylateHCID 178478990HCID 178478990, compound

Product 2

HCID 58104612HCID 58104612, compoundHCID 66892172HCID 66892172, compound

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

(S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl ester (2.8 g, 13.8 mmol) was dissolved in THF (50 mL) under nitrogen and cooled at −78° C. Cyclohexylmagnesium chloride (2.0M in ether; 10.0 mL, 20.0 mmol, 1.4 eq) was added via syringe over approximately 10 minutes. The resulting mixture was stirred at −78° C. for 20 minutes, then placed in an ice bath for 30 minutes. The reaction was quenched with saturated aqueous NH4Cl (15 mL). THF was removed under reduced pressure, and the remaining material was extracted with EtOAc (3×30 mL). The organics were washed with water (25 mL) and saturated aqueous NaCl (25 mL), dried over Na2SO4, and concentrated to yield the crude product. This material was dissolved in McCN (10 mL), water (8 mL), and MeOH (11 mL). The material was purified by preparative HPLC in 3 portions (2″ C18 column; 20-50% MeCN over 1 hour; the desired compound was recovered at ˜46%). The fractions were collected from the first eluting and second eluting, separately, and the MeCN was removed. Each fraction was extracted with DCM (3×125 mL), dried over Na2SO4, and concentrated to yield (S)-3-((S)-cyclohexylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester (1.1 g; 1st eluting peak) and (S)-3-((R)-cyclohexylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester (1.7 g; 2nd eluting peak).

Workup

  1. waitplaced in an ice bath for 30 minutes
  2. customThe reaction was quenched with saturated aqueous NH4Cl (15 mL)
  3. customTHF was removed under reduced pressure
  4. extractionthe remaining material was extracted with EtOAc (3×30 mL)
  5. washThe organics were washed with water (25 mL) and saturated aqueous NaCl (25 mL)
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated
  8. customto yield the crude product
  9. customThe material was purified by preparative HPLC in 3 portions (2″ C18 column
  10. wait20-50% MeCN over 1 hour
  11. customthe desired compound was recovered at ˜46%)
  12. customThe fractions were collected from the
  13. washfirst eluting
  14. customsecond eluting, separately, and the MeCN was removed
  15. extractionEach fraction was extracted with DCM (3×125 mL)
  16. dry with materialdried over Na2SO4
  17. concentrationconcentrated

Sources & evidence

ORD record
ord-f03df4aa097b483bb7940d6fcf1cb9d8
Source dataset
uspto-grants-2016_01
Patent number
US09227933B2

Reaction notes

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