Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate

A solution of ethyl 1 -(2-chloroethyl)-4-piperidine-4-carboxylate (II) (5.0 g, 22.76 mmol) in tetrahydrofuran (THF, 147.0 mL) was cooled down to -50°C under nitrogen. LDA (2.0 in heptane THF/ethyl benzene, 17.0 mL, 34.0 mmol) was added to the solution at -50°C over 25 mins. The reaction mixture was allowed to warm up to room temperature over 16h. The reaction was quenched with saturated aqueous K2CO3 (122.0 mL) and extracted with diethyl ether (3 x 120.0 mL). The combined organic layers were dried with Mgs04, filtered and concentrated under vacuum. The resulting orange liquid was co-evaporated three times with dichloromethane to remove excess ethyl benzene, resulting in an orange oil (4.15g, 99.4percent). Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (III): Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate Ethyll-azabicyclo[2.2.2 Joctane-4-carboxylate; A solution of ethyl 1-(2-chloroethyl)-4-piperidinecarboxylate (20.42 g, 92.9 mmol) in THF (600 mL) was cooled to-50 °C under Ar. LDA (2.0 M in heptane/THF/ethyl benzene, 70 mL, 140 mmol) was slowly added to the solution at -50 °C over 25 min. The reaction was allowed to warm up to room temperature overnight. The reaction was quenched with K2C03 (saturated aqueous) (500 mL) and extracted with Et20 (3 x 500 mL). The combined organic layers were dried over MgS04, filtered, and concentrated under vacuum. The resulting orange oil was co-evaporated three times with CH2C12 to remove excess ethyl benzene, resulting in the title compound (16.29 g, 95.7percent). EI-MS m/z 184 (M+H+) Rt (1.08 min).In a 500 mL three-necked flask, potassium bis(trimethylsilyl)amide (150 mL, 1 M in tetrahydrofuran) Was added dropwise to a solution of compound 1-3 (21.55 g, 0 mol) in toluene (220 mL) at 40 ° C, Stir overnight at 40 ° C under nitrogen. The reaction was quenched with acetic acid (28 mL) and ethanol (14 mL) Stirred at 40 ° C for 20 min, adjusted to pH> 7 with aqueous potassium carbonate, extracted with ethyl acetate (500 mL) The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give 11g (yield 60.11percent) of a brown oil.Ethyl quinuclidine-4-carboxylate (900 mg, 4.91 mmol) was hydrolyzed in a mixture of ethanol (2 mL) and sodium hydroxide (aq) (2M, 7.5 mL) at 50 C. The reaction was followed by TLC (methanol/diethylamine 20/1). After 3 hours the mixture was neutralized with HC1 (2 M) to pH=5 and evaporated. The residue was extracted with methanol which however also extracted NaCl. The extract was evaporated and the solid was extracted with ethanol which was not very effective in extracting the desired zwitterionic amino acid. All extracts and solids were combined and HC1 (2 M) was added to pH< 1 and the mixture was evaporated until it was completely dry. The solid residue was suspended in dichioromethane (10 mL) and oxalyl chloride (25 mmol, 2.3 mL) was added followed by two drops of N, N-dimethylformamide. The mixture was refluxed for 6 hours and then evaporated to dryness. To the residue was added N, N-dimethylformamide (10 mL) and sodium azide (10.4 mmol, 680 mg) and the mixture was stirred at 50 C for 20 h, then partitioned between saturated sodium carbonate and toluene. A three phase liquid system was formed. The toluene phase (on top) was collected, dried, and heated at reflux for 1 hours (visible gas formation occurred before reaching the reflux temperature), then cooled and extracted three times with HC1 (SM, 3 x 20 mL). The aqueous phases were combined and heated at reflux for 1 h, then evaporated to almost dryness and triturated with abs. ethanol. The precipitate was collected and gave the desired 4-aminoquinuclidine as the dihydrochloride (173 mg, 0.87 mmol, 18% yield). 'H NMR (400 MHz, deuterium oxide) 3.68- 3.52 (m, 4H), 2.37-2.23 (m, 4H).

Molecular Weight:183.25
XLogP3:0.9
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:183.125928785
Monoisotopic Mass:183.125928785
Topological Polar Surface Area:29.5
Heavy Atom Count:13
Complexity:193
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes