Preparation method of difenidol hydrochloride intermediate

Abstract

The invention discloses a preparation method of a difenidol hydrochloride intermediate. The preparation method comprises the following steps: S1, taking 1,3-bromochloropropane as a raw material, controlling the temperature to be 12-15 DEG C, dropwise adding hexahydropyridine, maintaining the temperature to be 30-45 DEG C in the dropwise adding process, and carrying out a reaction for 1-3 h under the condition that the temperature is 30-45 DEG C; S2, adding alkali liquor into the system, and carrying out heat preservation for 1-3 h at the temperature of 30-35 DEG C; and cooling to 17 DEG C or less, dropwise adding a hydrochloric acid solution, stirring until the pH value of the reaction system is 2-3, maintaining the temperature of the system at 12-16 DEG C, and carrying out a reaction for0.5-1.5 h; S3, carrying out centrifugal treatment on the reaction solution to obtain a solid product, dissolving the solid product in an organic solvent, and stirring for 1-3 h at the temperature of 3-6 DEG C; and finally, carrying out centrifugal treatment to obtain a solid product, and drying to obtain N-(3-chloropropyl)piperidine hydrochloride; and S4, dissolving the product obtained in the S3into tetrahydrofuran, adding an acid-binding agent triethylamine, stirring for 1 h, and then carrying out centrifugal separation, so as to obtain a filtrate, namely an N-(3-chloropropyl)piperidine solution. The preparation method disclosed by the invention is simple, low in time consumption and high in production efficiency.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical chemical intermediate substances, and more specifically, relates to a preparation method of a difenidol hydrochloride intermediate. Background technique [0002] The chemical name of Diphenidol Hydrochloride is 1,1-diphenyl-4-(1-piperidinyl)-1-butanol hydrochloride, which is the main component of Vertigo, and Diphenidol Hydrochloride can improve vertebral base Insufficient arterial blood supply, expansion and spasm of blood vessels, adjustment of vestibular nervous system, inhibition of abnormal impulse of vestibular nervous system, inhibition of vomiting center and medullary emetic chemoreceptor area, with peripheral weak anticholinergic effect, difenidol hydrochloride is widely used in Anti-vertigo and anti-emetic, can be used to treat Meniere's disease, after ear surgery (labyrinthitis) and motion sickness, can improve nystagmus, and can also prevent and treat dizziness or n...

AI Technical Summary

Problems solved by technology

[0007] The preparation process steps of the intermediate N-(3-chloropropyl)piperidine product in the above scheme are time-consuming and inefficient, and it is necessary to repeat the technology of acid-dissolving and alkali-precipitating for many times to remove impurities

Due to the mainstream process of synthesizing intermediate N-(3-chloropropyl)piperidine, in the process of acid adjustment and base adjustment, it needs to stand for many times before the subsequent operation can be carried out after the organic phase and the aqueous phase are completely separated. It takes a lot of time to wait for its standing and stratification (separation and standing time before acidification is not less than 1h, separation and standing time after acidification: 1 hour; after alkalization and before separation, standing time: 10 to 20 hours); in addition, the most important What is because the next step Grignard reaction is quite strict to the dry requirement of intermediate (N-(3-chloropropyl) piperidine) (Grignard reaction meeting water can be quenched thereby termination reaction), and adopt such technique to obtain The intermediate (N-(3-chloropropyl) piperidine) will inevitably need to greatly prolong the drying time (drying time: not less than 4 days) to remove the moisture therein. Therefore, the process for producing qualified intermediate products The steps are quite time consuming and less efficient

[0008] Therefore, the current preparation process is difficult to prepare high-purity N-(3-chloropropyl)piperidine quickly and easily, which eventually leads to great difficulties in the preparation of difenidol hydrochloride.

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