Preparation method of pregnane derivatives 16,17-acetal (ketone)

Abstract

Disclosed is a method for preparing a pregnane derivative 16,17-acetal (ketal) compound shown in the general formula I, the method comprising the step of reacting a compound of a general formula II with a compound of a general formula III or a general formula IV in the presence of boron trifluoride, wherein the dotted line between site 1 and site 2 denotes a saturated or unsaturated bond; R is hydroxyl, halogen or -OCOR7, wherein R7 is a C1-C12 linear chain or branched alkyl, a C3-C10 cycloalkyl, a C2-C8 alkenyl or a C2-C8 alkynyl; R1 and R2 are each hydrogen, a C1-C12 linear chain or branched alkyl, a C3-C10 cycloalkyl, a C2-C8 alkenyl or a C2-C8 alkynyl, or R1, R2 and the carbon to which they are connected form a C3-C10 cycloalkyl together, with the provision that R1 and R2 are not hydrogen simultaneously; R3 is hydrogen or -OCOR8, wherein R8 is a C1-C12 linear chain or branched alkyl, or a C3-C10 cycloalkyl; R4 is hydrogen, fluorine or chlorine; R5 is hydrogen, fluorine, chlorine or methyl; and R6 is a C1-C12 linear chain or branched alkyl. Compared with current processes, the method causes little pollution to the environment, has relatively mild reaction conditions, ease of control, reduced energy consumption and low production costs.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of a class of steroid medicine for treating respiratory diseases, more specifically, the invention relates to a preparation method of pregnane derivative 16,17-acetal (ketone) compound. Background technique [0002] Steroid drugs are widely used in the field of medicine and health. Among them, a group of glucocorticoid drugs containing 16 and 17 acetal (ketone) structures represented by the Ned series have good anti-inflammatory effects and relatively Minor side effects have aroused widespread concern. For example, budesonide is mainly used for the treatment of asthma or allergic rhinitis. Clinical experiments have proved that the anti-inflammatory activity of budesonide is 1000 times that of hydrocortisone, but it rarely produces systemic side effects of corticosteroids. The 22-carbon of budesonide is R and S chiral stereoisomers, the anti-inflammatory ef...

AI Technical Summary

Problems solved by technology

For example, in U.S. Patent US3929768 and European Patent EP164636, the method for preparing budesonide by reacting 16α-hydroxyprednisolone and butyraldehyde in dioxane under the catalysis of perchloric acid is disclosed, and its main defect is that perchloric acid It is strong oxidizing agent, causes the selectivity of this step reaction to be low, and the by-product that generates is many, has increased purification difficulty; Another example discloses 16 alpha-hydroxy prednisolone and cyclohexyl formaldehyde in hydrobromic acid or hydroiodide in European patent EP2262823 React under acid catalysis, and then isobutyrylate the 21-position hydroxyl group to obtain ciclesonide. Because hydrobromic acid or hydroiodic acid are strong acids, and have strong reducibility, they are highly corrosive to the reaction equipment

[0004] In the existing disclosed methods, there are generally problems such as high requirements for reaction equipment, low yield, high cost, and large environmental pollution in the industrial production process, which is not conducive to industrial production.

Images