Citric Acid → [2-(7-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamic acid tert-butyl ester

HRID 1376014Notes

Reaction equation

HRID 1376014 reaction equation
Cl.Cl.[CH2:3]([N:10]1[CH2:17][CH:16]2[O:18][CH:12]([CH2:13][NH:14][CH2:15]2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].S(C1C=CC(C)=CC=1)(O[CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])(=O)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:34]([O:33][C:31](=[O:32])[NH:30][CH2:29][CH2:28][N:14]1[CH2:15][CH:16]2[O:18][CH:12]([CH2:11][N:10]([CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:17]2)[CH2:13]1)([CH3:37])([CH3:36])[CH3:35]

Participants

8

Reactant 4

HCID 311Citric AcidHCID 516892Sodium BicarbonateHCID 10781634tert-butyl N-{2-[(4-methylbenzenesulfonyl)oxy]ethyl}carbamateHCID 185403703-(Phenylmethyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane, hydrochloride (1:2)

Product 1

HCID 10144351[2-(7-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamic acid tert-butyl ester

Reagents, catalysts & solvents 3

HCID 962WaterSolvent3×HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane dihydro-chloride (see Preparation B(iv) above; 10 g, 34 mmol) in water (25 mL) was added slowly to a solution of sodium bicarbonate (10 g, 119 mmol) in water 10 mL). More water (5 mL) was added and the mixture was stirred at room temperature for 10 minutes. A solution of 2-(tert-butyloxycarbonylamino)ethyl tosylate (see Preparation A above; 11.92 g, 37 mmol) in toluene (40 mL) was added. This mixture was then heated at 65–70° C. for 7 hours before stirring at room temperature overnight. The reaction was reheated to 50° C. and the phases were separated. The aqueous layer was extracted with toluene (40 mL) at 50° C. The combined organic layers were washed with saturated sodium bicarbonate (25 mL). The solvents were evaporated under reduced pressure to yield a mixture of oil and solid (13 g, >100%). Ethyl acetate (50 mL) and citric acid (10%, 25 mL) were added to a portion of the oily solid (5 g, 138 mmol). The aqueous layer was separated and the organic layer washed again with citric acid (10%, 20 mL). The aqueous layers were combined and treated with solid sodium bicarbonate until neutral. The aqueous phase was extracted with ethyl acetate (2×50 mL), dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound as a colourless semi-solid, which solidified fully when stored in the refrigerator (4.68 g, 93%).

Workup

  1. customPreparation A above
  2. temperatureThis mixture was then heated at 65–70° C. for 7 hours
  3. stirringbefore stirring at room temperature overnight
  4. customwas reheated to 50° C.
  5. customthe phases were separated
  6. extractionThe aqueous layer was extracted with toluene (40 mL) at 50° C
  7. washThe combined organic layers were washed with saturated sodium bicarbonate (25 mL)
  8. customThe solvents were evaporated under reduced pressure
  9. customto yield
  10. customThe aqueous layer was separated
  11. washthe organic layer washed again with citric acid (10%, 20 mL)
  12. additiontreated with solid sodium bicarbonate until neutral
  13. extractionThe aqueous phase was extracted with ethyl acetate (2×50 mL)
  14. dry with materialdried over magnesium sulfate
  15. filtrationfiltered
  16. customThe filtrate was evaporated to dryness under reduced pressure

Sources & evidence

ORD record
ord-4960503c2cce4d5180193d50b84283ca
Source dataset
uspto-grants-2007_01
Patent number
US07169921B2

Reaction notes

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