Buagafuran active pharmaceutical ingredient, preparation method and application thereof
A method suitable for large-scale production of buagafuran active pharmaceutical ingredient. A buagafuran active pharmaceutical ingredient (API) with a high purity prepared by the method includes an active ingredient of buagafuran, an impurity A, and an impurity B. In the buagafuran API, a content of the active ingredient of buagafuran is higher than 97.5%, and a total content of the impurity A and the impurity B is less than 0.04%. The buagafuran API can be applied to new drug development processes such as clinical research, pharmaceutical research and quality control research.
1. A method of preparing a buagafuran active pharmaceutical ingredient (API) comprising the following steps:
Step i: reducing a compound 1 to form a compound 2;
Step ii: oxidizing the compound 2 to form a compound 3;
Step iii: reacting methyl vinyl ketone with the compound 3 in a cyclization reaction to form a compound 4;
wherein structures of the compound 1, the compound 2, the compound 3, and the compound 4 are:
and further comprising:
Step a: adding the compound 4 to a potassium hydroxide aqueous solution, heating and stirring, then cooling after a reaction is completed to obtain a first mixture, and adding a concentrated hydrochloric acid to adjust a pH of the first mixture to near-neutral and then performing extraction drying, filtration and filtrate concentration to form a compound 5; and
Step b: dissolving the compound 5 in tert-butanol to obtain a second mixture, adding the second mixture to a potassium hydroxide aqueous solution, heating and stirring, adding bromobutane to obtain a third mixture, adjusting a pH of the third mixture to near-neutral, filtering the third mixture to obtain a first filtrate, concentrating the first filtrate to obtain a concentrate, dissolving the concentrate in methanol, adding sodium borohydride, stirring to obtain a fourth mixture, adding: n-hexane and water to adjust a pH of the fourth mixture to acidity, separating out a n-hexane layer, and concentrating to obtain a crude buagafuran;
wherein, structures of the compound 4, the compound 5 and the buagafuran are:
2. The method according to claim 1 , further comprising, after the step b, dissolving the crude buagafuran in ethanol, filtering to obtain a filtrate, cooling the filtrate to 10° C. to −20° C., performing a suction filtration to obtain a wet product of refined buagafuran, and drying the wet product to obtain a refined buagafuran API.