The Synthesis Of Bridged Bicyclic Morpholine Amino Acid Compounds

Morpholine derivatives are widely used in drug discovery, many medicines on the market that contain morpholine fragment have already been approved by FDA and other countries in the world, for example, Linezolid, Gefinitib, Reboxetine, Timolol and so on. As the important members of morpholine family, many novel bridged bicyclic morpholine derivatives were synthesized and used. Amino acids that are the basic unit of the biological function of macromolecular protein, and also the basic material of human nutrition required protein. There are a lot of amino acids have obvious curative effect in the treatment of human diseases. with the properties of amino acid, bridged bicyclic morpholine compounds containing alpha-carboxyl group have additional effect on conformational constrains and have potential medicinal value.In this thesis, two novel bridged bicyclic morpholine amino acid compounds were synthesized in the first time:compound T1: 5-oxa-2-aza-bicyclo[2.2.1]heptane-l-carboxylic acid and compound T2: 5-oxa-2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid. The two compounds were determined by LCMS, 1H NMR,13C NMR and 13C NMR(DEPT-135). For the synthesis of compound T1, first, we adopted the strategy of construction of 5-membered ring, followed by 6-membered morpholine ring, we used the ethyl aminomalonate as starting material, and obtain compound T1 in overall yield 3.6% through 14 linear steps. In an alternative route, we used the N-Boc-trans-4-Hydroxy-L-proline methyl ester containing 5-membered ring compound as starting material, then built 6-membered morpholine ring to synthesize compound T1. This method has 8 linear steps and 5.9% overall yield, it is obvious better than the first one. For the synthesis of compound T2, we used (2R,5S)-1-tert-butyl 2,5-dimethyl 2H-pyrrole-1,2,5(5H)-tricarboxylate containing 5-membered ring as starting material, then build 6-membered morpholine ring to synthesis compound T2 in 20.8% overall yield with 8 total steps. Due to the introduction of alpha carboxyl group in the molecule, the basicity of nitrogen is reduced, the hydrophilicity of the whole molecule is increased, and the carboxyl group is also a new reactive function. all of these properties will greatly increase the application of this molecule in drug research.