The Synthesis Of Selamectin And (R)-4-cyano-3-hydroxybutyric Acid Ethyl Ester

The first part of this paper was focused on the synthesis of selamectin(Revolution) in AVMs. Selamectin was invented by Pfizer and first to be launched to market in UK in July of 1999. It is a kind of endectocide especially against fleas, filariae and scalls on cats and dogs, which is much safer and with good effects by oral use and injection use.Selamectin was synthesized from doramectin in three steps. The first step, hydrogenization, give intermediateⅠ(95.8%). And meanwhile the best reaction condition (T=40~45℃, P=0.3~0.4MPa) was obtained by the change of pressure and temperature. The second step was oxidation by oxidant A addition method and oxidant A bottoming method to give intermediateⅡ(93.4%), and the most suitable amount of oxidant A (3.0aq) also came out by research between the two methods. The third step was occurred simultaneously with oximation and monosaccharide separation to give crude product (75.5%). And I also found the best condition (triethyllamine addition at 45℃) through triethyllamine addition, disodic phosphate addition, changing solution concentration and room temperature reaction. At last selamectin was gained with purity of 98.5% above and yield of 55% by crystallization in solution A for two times.In the second part, we carried our work on the synthesis of (R)-4-cyano-3-hydroxybutyric acid ethyl ester which is a key intermediate of statins. Statin is a new-generation lipid-lowering medicines with reducing LDL-C and enhancing HDL-C developed in 1980s and the effect is the best by contrasting to others of the same types on market. (R)-4-cyano-3-hydroxybutyric acid esters have always been a key scientific subject both in China and aboard.Four synthetic routes were conceived from L-malic acid to (R)-4-cyano-3-hydroxybutyric acid ethyl ester. Firstly (S)-3,4-dihydroxybutyric acid ethyl ester was synthesized from L-malic acid by esterification and reduction, which was then bromized, cyclized, methylsulfonylated, and sulfinylcylized to give bromide, ether, and sulfolipins respectively. At last all the intermediates from last step were treated by cyanation to give (R)-4-cyano-3-hydroxybutyric acid ethyl ester with yields of 56.7%, 30.3%, 16.5% and 24.0% respectively. A relatively cheap-cost method with an overall yield of 56.7% and optical rotation value of [α]25D=-31.02(c 1.0,CDCl3) was obtained through lab-commonly-used reagents instead of expensive metal ligand and enzyme.The structure of all the intermediates and final product were identified by spectral data 1H-NMR or MS.