Triphenylphosphine → (R)-4-Chloro-3-((1-methylpyrrolidin-3-yl)oxy)aniline

HRID 8631

Reaction equation

HRID 8631 reaction equation
C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([OH:15])[CH:9]=1)(C)(C)C.[CH3:17][N:18]1[CH2:22][CH2:21][C@H:20](O)[CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][C:10]=1[O:15][C@@H:20]1[CH2:21][CH2:22][N:18]([CH3:17])[CH2:19]1

Participants

6

Reactant 4

HCID 11776TriphenylphosphineHCID 6435041-Methyl-3-pyrrolidinol, (+)-HCID 5363146Diisopropyl azodicarboxylateHCID 53439113tert-Butyl (4-chloro-3-hydroxyphenyl)carbamate

Product 1

HCID 46942138(R)-4-Chloro-3-((1-methylpyrrolidin-3-yl)oxy)anilineYield 80%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a cooled (0° C.) solution of 4-chloro-3-hydroxyphenylcarbamic acid tert-butyl ester (55 g, 0.23 mol), (S)-1-methyl-pyrrolidin-3-ol (24 g, 0.24 mol), and triphenylphosphine (89 g, 0.34 mol) in THF (1.1 L) was added dropwise via addition funnel a solution of DIAD (67 mL, 0.34 mol) in THF (100 mL) over 1 h. The resultant solution was allowed to slowly warm to ambient temperature and maintained for 16 h. The THF was removed in vacuo and the residue treated with 6 N HCl (650 mL). The resultant mixture was stirred at room temperature for 4 h, at which time it was diluted with water (500 mL) and the filtered to remove the triphenylphosphine oxide. The filtrate was washed with EtOAc (3×1 L) and chloroform (5×1 L) to remove additional reaction by-products. The aqueous layer was then basified with solid NaOH pellets and extracted with ether (2×1 L) and EtOAc (2×1 L). The combined organic layers were washed with saturated NaHCO3 (2×1 L) and brine (1 L), dried (MgSO4), and concentrated to give 40 g (80%) of the title compound: MS (ES+) m/e [M+H]+ 227.

Workup

  1. temperaturemaintained for 16 h
  2. customThe THF was removed in vacuo
  3. additionthe residue treated with 6 N HCl (650 mL)
  4. additionwas diluted with water (500 mL)
  5. filtrationthe filtered
  6. customto remove the triphenylphosphine oxide
  7. washThe filtrate was washed with EtOAc (3×1 L) and chloroform (5×1 L)
  8. customto remove additional reaction by-products
  9. extractionextracted with ether (2×1 L) and EtOAc (2×1 L)
  10. washThe combined organic layers were washed with saturated NaHCO3 (2×1 L) and brine (1 L)
  11. dry with materialdried (MgSO4)
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-ccbe68207e224ea698fc109773a904a3
Source dataset
uspto-grants-2006_08
Patent number
US07091204B2

Linked notes

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