Nicergoline bulk drug and synthesis process thereof

Abstract

The present invention discloses a nicergoline bulk drug synthesis process, and relates to the technical field of chemical products, the process comprises the following steps: 1, methanol is dropwise added into concentrated sulfuric acid, ergol is added, and an ultraviolet lamp is adopted to irradiate the reaction liquid; adding into a micro-channel reactor, and adding ammonia water; and recrystallizing by using acetonitrile to obtain the 10 alpha-methoxy ergol. Step 2, adding potassium hydroxide and dimethyl sulfoxide into a micro-channel reactor, and adding 10 alpha-methoxy ergol and methyl iodide for reaction; drying is carried out, such that 1-N-methyl-10alpha-methoxy ergol is obtained; and step 3, sequentially adding 1-N-methyl-10alpha-methoxy ergol, 5-bromonicotinic acid, tetrahydrofuran and dicyclohexyl carbodiimide into the micro-channel reactor, carrying out a reaction, and cooling a reaction solution after the reaction is completed, so as to obtain nicergoline. According to the method, an optimized raw material medicine production process is adopted, the nicergoline preparation period is short, the cost is low, and the production efficiency and the yield are greatly improved.

Description

technical field [0001] The invention relates to the technical field of chemical products, in particular to a nicergoline crude drug and a synthesis process thereof. Background technique [0002] Nicergoline, whose chemical name is 10α-methoxy-1,6-dimethylergoline-8β-methanol-5′-bromonicotinate, is a semi-synthetic ergot alkaloid derivative with α-receptor blocking. vasodilator and vasodilator. It can strengthen the metabolism of brain cell energy, increase the utilization of oxygen and glucose, promote the conversion of the neurotransmitter dopamine and enhance nerve conduction, strengthen the biosynthesis of brain proteins, and improve brain function. It is rapidly absorbed after oral administration, and the absolute bioavailability is less than 5%. [0003] There are four kinds of synthetic methods of Nicergoline: [0004] Route 1: Take lysergic acid as the starting material, add 10α-methoxy lysergic acid methyl ester in methanol-concentrated sulfuric acid solution unde...

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Problems solved by technology

[0007] Among them, route 1: using lysergic acid as the starting material, since the reduction of lysergic acid ester C-8 ester group to ergot alcohol with lithium aluminum hydride may bring about the impact of optical isomers, and lysergic acid is not easy to buy

Route 2: Using 1-N-methyl-10α-methoxyergool as the starting material, phosphorus oxychloride was used for chlorination, and 5-bromonicotinic acid and 5-bromonicotinic acid were chlorinated Bromonicotinic acid chloride has the possibility of side reactions with chlorinating reagents, and the product is not easy to purify

Route 3 and Route 4 are not easy to control and have low efficiency during the synthesis reaction

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