Method for preparing safe and effective antibechic dimimorfan phosphate

A technology of dimethylmorphine phosphate and dimethylmorphine, which is applied in the field of drug synthesis and can solve the problems of harsh reaction conditions, low product yields, and high production costs

Active Publication Date: 2014-06-04
WUHAN YAOGU BIOLOGICAL ENG
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Problems solved by technology

[0010] Although this process does not require splitting, the reaction time is long, the reaction conditions are

Method used

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Embodiment Construction

[0015] The present invention uses dextromorphan as a raw material, and only needs to go through three steps of esterification, methylation and salt formation to prepare the target product dimethylorphane phosphate, and the reaction yield of each step reaches more than 80%, and the operation Simple and economical. The method is as follows:

[0016] 1. Esterification, with dextrohydroxymorphan as raw material, under the condition of nitrogen protection, with CF 3 SO 2 Cl reacts to generate dextrohydroxymorphan trifluoromethanesulfonyl ester;

[0017] 2. Methylation, using toluene as a solvent, dextrohydroxymorphan trifluoromethanesulfonyl ester reacts with tetramethyltin under the catalysis of bistriphenylphosphine palladium dichloride to form dimethylorphane or dextrohydroxymorph Trifluoromethanesulfonyl ester reacts with methylmagnesium bromide under the action of iron acetylacetonate as a catalyst to generate dimerphane with THF as a solvent;

[0018] 3. Salt formation, d...

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Abstract

The invention relates to a method for preparing a safe and effective antibechic dimimorfan phosphate. The method comprises steps of reacting dextrorphane with trifluoro-methylsulfonyl chloride in triethylamine so as to generate dextrorphane trifluoro-methyl sulfone chloride ester; reacting the dextrorphane trifluoro-methyl sulfone chloride ester with tetramethyltin in methylbenzene so as to generate (9s, 13s, 14s)-3, 17-dimethyl morphinan (or adding the dextrorphane trifluoro-methyl sulfone chloride ester into mixed solvent of THF and N-methyl-2-pyrrolidone, adding catalyst ferric acetylacetonate and methyl magnesium bromide, stirring and heating reflux for 12 hours, so as to prepare (9s, 13s, 14s)-3, 17-dimethyl morphinan), furthermore, reacting with phosphoric acid so as to salify to prepare target product (9s, 13s, 14s)-3, 17-dimethyl morphine phosphate-dimimorfan phosphate. The method takes commercially available dextrorphane as the raw material, and prepares the target product through three steps of esterification, methylation and salification. The method has advantages of easily obtained raw materials, few synthesis steps, simple technology, low cost, high yield, high purity of the product and strong economic practicability, and is applicable to industrial production.

Description

technical field [0001] The invention relates to a method for preparing a non-addictive central antitussive drug dimethylorphin phosphate, which inhibits the medulla medulla cough center, and belongs to the technical field of drug synthesis. Background technique [0002] A cough is a sudden forceful breathing movement caused by stimulation of the respiratory center in the medulla. Antitussives are divided into central antitussives and peripheral antitussives according to their different sites of action. Centrally acting antitussives act by inhibiting the medullary cough center and are indicated for dry, nonphlegmous coughs. Peripheral antitussives exert antitussive effect by inhibiting the receptors, afferent nerves, efferent nerves or effectors in the cough reflex arc outside the cough center. [0003] Dimethylorphin phosphate was developed by Fujisawa Pharmaceutical Co., Ltd., Japan, and later merged by Yamanouchi Pharmaceuticals. The marketed product name is Astomin. Dim...

Claims

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Application Information

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IPC IPC(8): C07D221/28
CPCC07D221/28
Inventor 周利娟张琼光胡汉昆
Owner WUHAN YAOGU BIOLOGICAL ENG
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