Tetrahydrofuran → (R)-3-[(S)-(2-chloro-3,6-difluorophenoxy)phenylmethyl]pyrrolidine-1-carboxylic acid t-butyl ester

HRID 1364991Notes

Reaction equation

HRID 1364991 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=1O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@H:13]([O:20][C:23]2[C:24]([F:29])=[CH:25][CH:26]=[C:27]([F:28])[C:22]=2[Cl:21])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 5

HCID 8028TetrahydrofuranHCID 11776TriphenylphosphineHCID 27735612-Chloro-3,6-difluorophenolHCID 5363146Diisopropyl azodicarboxylateHCID 58507548(R)-3-((R)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butyl ester

Product 1

HCID 66924701(R)-3-[(S)-(2-chloro-3,6-difluorophenoxy)phenylmethyl]pyrrolidine-1-carboxylic acid t-butyl esterYield 91.5%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

A mixture of (R)-3-((R)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10 g, 36.1 mmol), 2-chloro-3,6-difluorophenol (8.9 g, 54.1 mmol) and PPh3 (9.93 g, 37.8 mmol) in THF (20.5 mL, 252 mmol) was sonicated for several minutes. While sonicating, DIAD (7.5 mL, 37.8 mmol) was slowly added dropwise to the mixture over several minutes and sonicated further for 15 minutes. The mixture was concentrated and then triturated in excess hexanes for 16 hours. The PPh3 oxide precipitate was filtered off and the organic layer was concentrated to yield a yellow oil. The crude mixture was diluted in EtOAc (300 mL), washed with 1N NaOH (2×200 mL) and saturated aqueous NaCl (100 mL). The organic layer was dried with anhydrous MgSO4, filtered, and concentrated. The organic material was purified by silica gel chromatography (330 g column, 20-50% EtOAc in hexanes) to yield 14 g of (R)-3-[(S)-(2-chloro-3,6-difluorophenoxy)phenylmethyl]pyrrolidine-1-carboxylic acid t-butyl ester as a yellow oil which was used in the next step without further purification.

Workup

  1. customwas sonicated for several minutes
  2. customWhile sonicating
  3. customsonicated further for 15 minutes
  4. concentrationThe mixture was concentrated
  5. customtriturated in excess hexanes for 16 hours
  6. filtrationThe PPh3 oxide precipitate was filtered off
  7. concentrationthe organic layer was concentrated
  8. customto yield a yellow oil
  9. washwashed with 1N NaOH (2×200 mL) and saturated aqueous NaCl (100 mL)
  10. dry with materialThe organic layer was dried with anhydrous MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customThe organic material was purified by silica gel chromatography (330 g column, 20-50% EtOAc in hexanes)

Sources & evidence

ORD record
ord-f1df725bca024055aaf94f9f2f0a797c
Source dataset
uspto-grants-2011_02
Patent number
US07888386B2

Reaction notes

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