Tetrahydrofuran → HCID 66881939, compound

HRID 1820701Notes

Reaction equation

HRID 1820701 reaction equation
CCOC(/[N:6]=N/C(OCC)=O)=O.[C:13]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:18]=CC=C[CH:14]=1.[O:32]([C:39]1[CH:40]=[C:41]([OH:45])[CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[CH2:46]1[CH2:50]O[CH2:48][CH2:47]1>>[O:32]([C:39]1[CH:40]=[C:41]([CH:42]=[CH:43][CH:44]=1)[O:45][CH:46]1[CH2:50][CH:18]2[NH:6][CH:48]([CH2:14][CH2:13]2)[CH2:47]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1

Participants

5

Reactant 4

HCID 8028TetrahydrofuranHCID 11776TriphenylphosphineHCID 128423-PhenoxyphenolHCID 5462977Diethyl azodicarboxylate

Product 1

HCID 66881939HCID 66881939, compound

Procedure

Diethylazodicarboxylate (1.89 mL, 12 mmol) was added dropwise to a solution of 3-endo-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.27 g, 10 mmol), triphenylphosphine (3.15 g, 12 mmol) and 3-phenoxyphenol (1.93 mL, 12 mmol) in THF (60 mL). The reaction mixture was stirred under a nitrogen atmosphere for 72 h at ambient temperature. Volatiles were removed under reduced pressure. The resultant material was dissolved in DCM (50 mL) and TFA (5 mL) added. The reaction mixture was stirred at ambient temperature for 12 h. Volatiles were removed under reduced pressure, the crude product dissolved in methanol (40 mL) and the solution loaded onto a SCX cartridge (20 g). The cartridge was eluted with methanol (40 mL) to remove triphenylphosphine oxide. Elution with ammonia in methanol (2M, 40 mL) followed by evaporation in vacuo afforded crude 3-(3-phenoxyphenoxy)-8-azabicyclo[3.2.1]octane as an oil. The crude material was then purified by chromatography on silica gel. Elution with 98:2 DCM:MeOH with a gradient to 90:10:0.5 DCM:MeOH:ammonia, afforded the product as an oil. The product was dissolved in methanol (5 mL) and treated with hydrochloric acid in methanol until the solution was acidic. The solution was concentrated in vacuo and diethyl ether was added to precipitate the product. The precipitate was collected by filtration and recrystallised from methanol/diethyl ether to afford 3-exo-(3-phenoxyphenoxy)-8-azabicyclo[3.2.1]octane as the hydrochoride salt (1.08 g, 3.26 mmol, 33%). M.S. (ESI) (m/z): 296 [M+H]+.

Workup

  1. customVolatiles were removed under reduced pressure
  2. dissolutionThe resultant material was dissolved in DCM (50 mL)
  3. additionTFA (5 mL) added
  4. stirringThe reaction mixture was stirred at ambient temperature for 12 h
  5. customVolatiles were removed under reduced pressure
  6. dissolutionthe crude product dissolved in methanol (40 mL)
  7. washThe cartridge was eluted with methanol (40 mL)
  8. customto remove triphenylphosphine oxide
  9. washElution with ammonia in methanol (2M, 40 mL)
  10. customfollowed by evaporation in vacuo

Sources & evidence

ORD record
ord-f59330da87154b03bd14fe5efe67bb1e
Source dataset
uspto-grants-2009_10
Patent number
US07605170B2

Reaction notes

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