Synthesis process of N-sustituent-4-piperidyl alcohol

Abstract

The synthesis process of preparing N-substituent-4-piperidyl alcohol includes the following steps: 1. adding primary amine into ethyl acrylate to react to obtain the secondary addition product; 2. adding cyclizing agent into the secondary addition product and adding concentrated hydrochloric acid after finishing cyclization to obtain N-substituent-4-piperidone hydrochloride; 3. reducing N-substituent-4-piperidone hydrochloride with NaBH4-Amberlyst-15(H+) system and regulating pH value to extract N-substituent-4-piperidyl alcohol; and 4. recovering and treating resin for reuse. The present invention has wide raw material resource, mild reaction condition, simple operation, low production cost, high yields in different steps, and excellent industrial application foreground.

Description

technical field [0001] The invention relates to a preparation method of N-substituent-4-piperidinol. These compounds are used as active ingredients for preparing medicines and belong to the technical field of pharmacy. Background technique [0002] N-substituent-4-piperidinol is an important drug intermediate, which is widely used in the synthesis of various drugs, such as loratadine, azatadine, dibenzidine, which are used more in clinical treatment for anti-skin allergies Lin, cyproheptadine, Kaisiting; anti-asthma drug ketotifen; methemoglobinemia drug propiverine hydrochloride tablets. [0003] Most of the current reports are to synthesize such compounds by reducing the corresponding piperidones. The raw material, piperidone, is mainly produced through reactions such as diester condensation, salt formation, hydrolysis, and neutralization. There are many reaction steps, complicated handling of intermediate products, high product loss, and low yield. In terms of reduction...

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Problems solved by technology

The raw material piperidone is mainly produced through reactions such as diester condensation, salt formation, hydrolysis, and neutralization. There are many reaction steps, complicated intermediate product processing, high product loss, and low yield.

In terms of reduction methods, catalytic hydrogenation reduction generally has a higher yield, but it requires catalytic hydrogenation under high temperature and high pressure conditions, which requires high equipment and certain risks in the process; using LiAlH 4 As a reducing agent, although the reaction speed is fast and the yield is high, the price is high, and it needs to be operated in an anhydrous environment, so it cannot be industrialized; the use of NaBH 4 As a reducing agent, the price is relative to LiAlH 4 Reduced a lot, the reaction conditions are milder, and the industrial operation is convenient, but the yield is low, and NaBH 4 The demand is large, which increases the production cost

[0004] Another document, Helv Chem Acta, 1966, 49 (1) 690-695, reported that pyrrolo [1,2-α] pyridone was used as raw material to obtain 4-piperidinol through reduction and then substitution reaction with iodide to obtain the corresponding For the target compound, the raw material preparation of this method is more complicated, the reduction yield is lower, and the price of the iodide used to replace it is also more expensive, so it is not suitable for industrialization

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