1-Azabicyclo[2.2.1]heptane-2-carboxylicacid,ethylester(9CI) synthesis

Yield:646055-79-0 68.25%

Reaction Conditions:

Stage #1: methyl 2-amino-3-(tetrahydrofuran-3-yl)-propionatewith hydrogen bromide in water at 110 - 120; for 8 h;Heating in a sealed tube;
Stage #2: with ammonia in water; for 4 h;Heating / reflux;
Stage #3: with sulfuric acid;sodium hydrogencarbonatemore than 3 stages;

Steps:

6 Ethyl 1-azabicyclo[2.2.1]heptane-2-carboxylate

Methyl 3-(3-oxolanyl)-2-aminopropanoate (6.00 g, 3.46 mmol) was placed in a sealed pressure tube, then 48 % aqueous HBr (20 mL) was added and the solution was saturated with HBr gas. The tube was sealed carefully and heated at 110-120° C for 8 h. The reaction was then cooled and the contents transferred to a 250 mL round bottom flask with 20 mL of water. The excess acid was removed by rotary evaporation to give a semi solid brown mass. Then 30 % aqueous ammonium hydroxide (150 mL) was added at 0° C and the mixture was heated at gentle reflux for 4 h. The solvent was removed by rotary evaporation to give a brown solid, which then was dissolved in absolute ethanol (50 mL). Concentrated H2SO4 (10 mL) was added and the solution was refluxed for 8 h. The contents were cooled in an ice bath, and then basified with concentrated NaHCO3 solution to pH 8-9 and extracted with chloroform (4 x 40mL). The combined chloroform extracts were dried (K2CO3), filtered and concentrated to give a brown-black liquid which was distilled using a Kugelrohr apparatus (1 mm, 140° C) to afford a colorless liquid (4 g, 68.25 %) as a mixture of the exo and endo isomers of ethyl 1-azabicyclo [2.2.1]heptane-2-carboxylate.

References:

WO2004/5293,2004,A2 Location in patent:Page 71