Synthesis method for preparing anilino piperidine medicine by using continuous flow microchannel reactor

A channel reactor and anilinopiperidine technology, which is applied in chemical instruments and methods, chemical/physical processes, chemical/physical/physical chemical processes, etc., can solve the problem of labor hours and energy consumption, increase product production costs, Problems such as low conversion rate and selectivity, to achieve the effect of reducing material loss, improving mass transfer, conversion rate and selectivity

Pending Publication Date: 2022-04-01
YICHANG HUMANWELL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In order to solve the low conversion rate and selectivity, many side reactions, high impurity content in the traditional reactor synthesis reaction, and there are certain safety risks in repeated recrystallization under strong acid and strong alkali conditions, a large amount of waste generated will pollute the environment , the synthesis cycle is long, labor hours and energy consumption are spent, and the production cost of the product is pushed up. The technical problem to be solved by the present invention is to provide an anilinopiperidine drug with high conversion rate, strong selectivity and few side reactions. Synthetic method, reducing recrystallization operation steps, simplifying salt-forming and refining steps, and further improving product yield and purity

Method used

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  • Synthesis method for preparing anilino piperidine medicine by using continuous flow microchannel reactor
  • Synthesis method for preparing anilino piperidine medicine by using continuous flow microchannel reactor
  • Synthesis method for preparing anilino piperidine medicine by using continuous flow microchannel reactor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] 20.0 g of Compound I and 9.0 g of triethylamine, added to 200 ml of methyl isobutyl ketone, stir mixed, pumped from the feed port A of the module 1, and the flow rate was 30 mL / min; weigh 19.0 g of a compound II was added to 110 ml of methyl isobutyl ketone, stirred and mixed, pumped from the feed port B of the module 1 into the reactor, and the flow rate was 15 mL / min. The temperature of the modules 1-6 is controlled to 107 ° C, and the temperature of the module 7 is controlled to 50 ° C, the sample detection reaction conversion is 99.30%, HPLC map, see figure 1 . In the module 8, the purified water is pumped, the flow rate is 30 ml / min, and the material flows out of the module 8 is collected in the tank.

[0079] The material in the tank was discharged, and the liquid was allowed to collect organic phases; the organic phase was washed with saturated aqueous solution of sodium chloride, and then dried over anhydrous sulfate for 3 hours. 10 ml of concentrated hydrochl...

Embodiment 2

[0082] 20.0 g of a compound I and 17.0 g of potassium carbonate were weighed, and the mixture was added to 300 ml of toluene, stir mixed, pumped from the feed port A of the module 1, and the flow rate was 20 ml / min; weigh 23.0 g of Compound II to add to In 200 ml of toluene, stir mix, pumped from the feed port B of the module 1 to the reactor, and the flow rate was 13 mL / min. The temperature of the modules 1-6 is controlled to 103 ° C, and the temperature of the module 7 is controlled to 50 ° C, the sample detection reaction conversion is 97.23%, HPLC map, see image 3 . In the module 8, the purified water is pumped, the flow rate is 50 ml / min, and the material flows out of the module 8 is collected in the tank.

[0083] The material in the storage tank was released, and the liquid was allowed to collect organic phases; the organic phase was washed with saturated aqueous sodium chloride solution, and then dried in anhydrous carbon chloride for 4 hours, filtered, filtrate was ...

Embodiment 3

[0086] 20.0 g of Compound I and 10.0 g of triethylamine were weighed, and the mixture was mixed into 150 mL of ethyl acetate, stirred, pumped from the feed port A of the module 1, and the flow rate was 20 ml / min; weigh 22.0 g of Compound III added to 1000 ml of ethyl acetate, stirred and mixed, pumped from the feed port B of the module 1 into the reactor, and the flow rate was 15 mL / min. The temperature of the modules 1-6 is controlled to 68 ° C, the temperature of the module 7 is controlled to 30 ° C, the sample detection reaction conversion is 97.13%, HPLC map, see Figure 5 . In the module 8, the purified water is pumped, the flow rate is 30 ml / min, and the material flows out of the module 8 is collected in the tank.

[0087] The material in the tank was released, replaced, collected by the organic phase; the organic phase was washed with saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate for 4 hours, filtered, filtrate was concentr...

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Abstract

The invention discloses a synthesis method for preparing anilino piperidine drugs by using a continuous flow microchannel reactor. According to the method, the reaction selectivity and the conversion rate of the last-step synthesis of the anilino piperidine medicine can be effectively improved by controlling the material flow rate and the temperature of each module of the continuous flow microchannel reactor. On the basis, after the reaction liquid is subjected to simple extraction and concentration operation, the organic solvent is used for dissolving and concentrating residues, corresponding acid is added for salifying, crystallizing and filtering to obtain an acid salt crude product of the medicine, and the corresponding acid salt is obtained through decoloration and recrystallization. The method provides a way for synthesizing anilino piperidine drugs by using the continuous flow microchannel reactor, so that the conversion rate and selectivity of the reaction are improved, the impurity content is reduced, the salifying and refining steps are simplified, the product yield is improved, and meanwhile, the product purity reaches 99.8% or above.

Description

Technical field [0001] The present invention belongs to the art of drug synthesis, and in particular, a synthesis method of preparing an anilinepiperidine drugs using a continuous flow microchannel reactor. Background technique [0002] Anilinepiperidine is generally anesthetic drug acting on μ opioid receptors. At present, industrialized aniline piperidine has an Affenanini, Fentanyl, Shu Fenin, Ruitifdy, etc. drug. Such alkaline raw materials have more stable raw materials in the form of acid salts, and the process path is more than 6 steps to obtain the raw material touro alkali, and then bonded to the acid to salt to be acid type. Raw materials of the salt structure. [0003] Due to more synthetic steps, the impurity content of the resulting free base is also high, resulting in too cumbersome refining process, more material losses, and low yield. For the last step in the "Synthesis of Ruifen Tanixi", the synthesis of Hue, Ruifeni, the synthesis of Li Ziling, purified by colum...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/06C07D409/06C07D211/66B01J19/00
Inventor 张建勋舒启超魏勇周文超汪定奇陈晓轲谭政廖宗权胡雯符义刚钟丽君李莉娥
Owner YICHANG HUMANWELL PHARMA
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