Methylprednisolone intermediate, preparation method therefor and application thereof

Abstract

The invention discloses a preparation method for a methylprednisolone intermediate, wherein the methylprednisolone intermediate is obtained by carrying out a cyano substitution reaction, a silanyloxy protection reaction, an intramolecular nucleophilic substitution reaction and a substitution reaction on a compound I. The method specifically comprises the following steps: by taking the compound I as a raw material, a compound II is obtained by adding a cyanidation reagent into the compound I and carrying out the cyano substitution reaction; a compound III is obtained by carrying out the silanyloxy protection reaction on the compound II and a silanyloxy reagent under an alkaline environment; a compound IV is obtained by carrying out the intramolecular nucleophilic substitution reaction on the compound III and an amino alkali metal reagent; and the methylprednisolone intermediate is obtained by carrying out the substitution reaction on the compound IV and organic carboxylate under the alkaline environment. The method has the advantages that the raw materials are cheap, the yield is high and stable and the like.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a methylprednisolone intermediate and a preparation method thereof. Background technique [0002] Methylprednisolone is an adrenal glucocorticoid drug, because of its strong anti-inflammatory effect, less dosage, slight sodium retention effect, and can reduce the pathological response of body tissues to damaging stimuli, it is widely used in clinical practice . [0003] In the current preparation process of methylprednisolone intermediates, the difficulty of synthesis lies in the preparation method of the side chain, and there are three major problems: 1. Derivation of the 21-position side chain; 2. Dehydrogenation of the 1-2 position Reaction; Three, 6α-methyl synthesis. Among them, the 21-position side chain is derived. The prior art is mainly the synthesis method of iodine substitution. This method has two disadvantages. The price of iodine reagent is high, result...

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Problems solved by technology

Among them, the 21-position side chain is derived. The existing technology is mainly the synthesis method of iodine replacement. This method has two disadvantages. The price of iodine reagent is high, resulting in high single-step cost.

In addition, in the production process of this method, a large amount of low-concentration iodine-containing wastewater is produced, the recovery value is low, the treatment is troublesome, and the environmental pollution is relatively serious

1-2 position dehydrogenation, generally use DDQ (dichlorodicyanobenzoquinone) dehydrogenation, DDQ is highly toxic, the production operation is more dangerous, the production process produces a large amount of cyanide-containing wastewater, the treatment is very difficult, and the discharge

6α-methyl synthesis, the raw material usually used is hydrocortisone, this raw material is expensive, using this raw material to directly do 6α-methylation reaction, there is a selectivity problem: 6β-methyl and 6(7)-ene bond Impurities are difficult to remove in subsequent refining

[0004] Patent application CN200710201633.9 adopts the iodine obtained by the iodination reaction of 6α-methylpregnant intermediate as raw material, and uses glacial acetic acid and triethylamine as reaction reagents in acetone solvent to obtain the preparation method, mainly because the price of iodine is expensive , leading to high cost and large amount of waste water

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