Synthesis method for selamectin
A synthesis method for selamectin was developed, where doramectin is oxidized by manganese dioxide, oximated and de-sugared in one-step by an aqueous solution of hydroxylamine hydrochloride, and then selectively reduced in the presence of Wilkinson's catalyst and hydrogen to obtain selamectin. Doramectin is oxidized to a carbonyl group firstly, so that the generation of impurities during the subsequent reaction is reduced; t-butyl alcohol with a larger steric hindrance is used as a solvent, so that transesterification impurities are avoided; the hydrogenation is implemented in the final step, and the crude product is recrystallized before the hydrogenation reaction, so that the cost is greatly reduced. The method of the present application with an overall yield of 57%. The purity of product was 97.11%. All impurities meet the requirements of Pharmacopoeia. The present application is a simpler, more economical and more efficient synthesis method, and is suitable for industrial production.
1 . A synthesis method for selamectin, the method comprising the following steps of:
(1) reacting doramectin A with manganese dioxide at 20-30° C. for 7-14 hours to give an oxidized intermediate B;
(2) dissolving the intermediate B in tert-butyl alcohol, adding dropwise an aqueous solution of hydroxylamine hydrochloride, and reacting at 26-35° C. for 35-48 hours; neutralizing with sodium carbonate or sodium bicarbonate after the reaction, and removing the solvent under reduced pressure to obtain a yellow solid; dissolving any formed salts and residual hydroxylamine by adding water to the yellow solid, followed by suction filtration to give a yellow filter cake, and recrystallizing the yellow filter cake from a mixed solvent of acetonitrile and water to obtain an oximated and de-sugared intermediate C in one-step; and
(3) introducing hydrogen at 3-4 bar, and reacting the intermediate C in the presence of 4-8% w/w Wilkinson's catalyst at 30° C. for 8 hours to give crude selamectin D, which is then recrystallized with toluene to give pure selamectin D.
2 . The synthesis method according to claim 1 , wherein the temperature for the desugarization and oximation reaction in step (2) is 30-32° C.
3 . The synthesis method according to claim 1 , wherein the intermediate C and the mixed solvent in step (2) are mixed at a weight ratio of 1:2 to 1:4, and the water to acetonitrile in the mixed solvent are used at a weight ratio of 1:2 to 1:2.
4 . The synthesis method according to claim 3 , wherein the weight ratio of the intermediate C to the mixed solvent is 1:3, and the weight ratio of water to acetonitrile in the mixed solvent is 1:2.
5 . The synthesis method according to claim 1 , in step (2), further comprising recrystallizing the yellow filter cake by adding the mixed solvent of acetonitrile and water to the yellow filter cake, keeping the temperature at 40-80° C. and stirring for 2 hours, cooling and precipitating, carrying out suction filtration, washing the solid with the mixed solvent until white, and drying.
6 . The synthesis method according to claim 1 , wherein in step (3), the crude selamectin D is recrystallized with toluene at a weight ratio of 1:2 to 1:5.
7 . The synthesis method according to claim 6 , wherein the weight ratio of the crude selamectin D to toluene is 1:4.
8 . The synthesis method according to claim 1 , in step (3), further comprising recrystallizing crude selamectin D by adding toluene to the crude selamectin D, dissolving by heating, keeping the temperature at 40-80° C. and stirring for 2 hours, cooling and precipitating, carrying out suction filtration, washing the solid with toluene until white, and drying.