Synthesis Of Azabicyclo|3.10|Hexane Derivatives

The syntheticmethods of (1R,5S,6R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid and (1S,2S,5R)-methyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride are reviewed based on the literatures. Dueto the disadvantages in the literatures,improved methods are proposed，making itmuch more suitable for large-scale industrial production.The two intermediates are a class of molecules with biological activity, at thesame time,they are also conformationally restricted amino acids. These mimeticsshould have the ability to bind to their natural targets in the same way as the naturalpeptide sequences do, from which their structure was derived and hence shouldproduce the same biological effects. It is possible to design these molecules in such away that they show the same biological effects as their pepitide role models but withenhanced properties like a higher proteolytic stability,higher bioavailability and alsooften with improved selectivity.This artical contains improved synthetic roots ofintermediates listed above and their experiment conditions.Diethyl fumarate is choosed as the starting material,which undergos Michaeladdition reaction with ethyl chloroacetate, saponification with sodium hydroxide,intoanhydride with acetic anhydride,cyclization with benzylamine,reduction with sodiumborohydride and boron trifluoride etherate,deprotection with palladium oncarbon,protection with di-tert-butyl pyrocarbonate,oxidation with sodium chlorite togive (1R,5S,6R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acidwith a total yield of about43.8%.Caronic anhydride is choosed as the starting material,(1S,2S,5R)-methyl6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride was obtainedafter a series of chemical reactions including cyclization with benzylamine, reductionwith sodium borohydride and boron trifluoride etherate,deprotection with palladiumon carbon,chlorination with chlorosuccinimide,elimination with potassium hydroxide,addition with sodium bisulfate,nucleophilic substitution with sodiumcyanide,methyl esterification with methanol in the presence of hydrogen chloride,splitwith D-DTTA.The total yield of the entire route is11.6%.The major optimization experiment was conducted on these aspects such asaltering molar ratios,reagents,reaction time, reaction temperature,reaction solventsand so on. The target products and their intermediates are confirmed by1HNMR, GCor HPLC.There are several advantages,with improved yields,simplifiedpost-processing,reduced costs and more suitable for industrial production.