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Synthesis process of phenylbutyrin

A technology of glyceryl phenylbutyrate and synthesis process, which is applied in the preparation of carboxylate, the preparation of organic compounds, organic chemistry and other directions, can solve the problems such as difficulty in controlling the reaction end point, long reaction time, complicated solvent, etc., and reduce impurities The effect of producing, improving conversion rate and high product purity

Pending Publication Date: 2021-12-28
安徽沃泰生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In view of the above-mentioned shortcomings and deficiencies of the prior art, the present invention provides a synthesis process for glycerol phenylbutyrate, which solves the defects of complex solvents, long reaction times, and difficult control of the end point of the reaction in the conventional esterification reaction process

Method used

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  • Synthesis process of phenylbutyrin
  • Synthesis process of phenylbutyrin
  • Synthesis process of phenylbutyrin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Add 187g of glycerol (2.03mol) to a 2.5L reactor, heat up to 120°C, add 1000g (6.09mol) of phenylbutyric acid in batches, stir until completely melted, and add about 20g of strong acid catalytic resin amberlyst15. Raise the temperature to 160°C, react at 0.8KPa for 2h; then rapidly raise the temperature to 220°C, continue to react at 0.8KPa for 3h, take samples to measure the impurity content of the components in the reactor, and react for 3.5h, the measured impurity content is less than 1.0 %. Cool the reactor rapidly to terminate the reaction. Let the reaction solution stand at room temperature, centrifuge at 10,000*g for 30 minutes, remove catalyst and solid impurities, and obtain the stock solution of glyceryl phenylbutyrate, which is purified by three-stage nylon 66 filter membrane with a pore size of 0.8 μm, 0.4 μm, and 0.2 μm. , to obtain the product.

[0048] Validation and analysis of the final product, including:

[0049] (1) Infrared absorption spectrum (I...

Embodiment 2

[0078] Add 187g of glycerol (2.03mol) to a 2.5L reactor, raise the temperature to 122°C, add 1000g (6.09mol) of phenylbutyric acid in batches, stir until completely melted, and add about 20g of strong acid catalytic resin amberlyst15. Raise the temperature to 150°C, react at 0.6KPa for 2.5h; then rapidly raise the temperature to 225°C, continue to react at 0.6KPa for 3h, take samples to measure the impurity content of the components in the reactor, and react for 4h, the measured impurity content is less than 1.0 %. Cool the reactor rapidly to terminate the reaction. Let the reaction solution stand at room temperature, centrifuge at 10,000*g for 30 minutes, remove catalyst and solid impurities, and obtain the stock solution of glyceryl phenylbutyrate, which is purified by three-stage nylon 66 filter membrane with a pore size of 0.8 μm, 0.4 μm, and 0.2 μm. , to obtain pure phenylbutyric acid glyceride; according to the HPLC condition test of embodiment 1, its purity reaches 98....

Embodiment 3

[0080] Add 187g of glycerol (2.03mol) to a 2.5L reactor, heat up to 120°C, add 1000g (6.09mol) of phenylbutyric acid in batches, stir until completely melted, and add about 20g of strong acid catalytic resin amberlyst15. Raise the temperature to 155°C, react at 0.4KPa for 2.5h; then rapidly raise the temperature to 220°C, continue to react at 0.4KPa for 3h, take samples to measure the impurity content of the components in the reactor, and react for 4h, the measured impurity content is less than 1.0 %. Cool the reactor rapidly to terminate the reaction. Let the reaction solution stand at room temperature, centrifuge at 10,000*g for 30 minutes, remove catalyst and solid impurities, and obtain the stock solution of glyceryl phenylbutyrate, which is purified by three-stage nylon 66 filter membrane with a pore size of 0.8 μm, 0.4 μm, and 0.2 μm. , to obtain pure glyceryl phenylbutyrate; according to the HPLC conditions of Example 1, its purity reaches 98.57%, and its purity is low...

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Abstract

The invention relates to a synthesis process of phenylbutyrin. The synthesis process is characterized in that phenylbutyric acid and glycerol are used as raw materials and subjected to two-stage esterification under the action of a catalyst, wherein the molar ratio of phenylbutyric acid to glycerol is (6-6.09): (2-2.03); in the first low-temperature reaction stage, glycerol is put into a reaction kettle firstly, then the temperature is increased to 110-130 DEG C, the phenylbutyric acid is added in batches and stirred until the phenylbutyric acid is completely dissolved, a catalyst is added and heating is performed to 140-160 DEG C, and heat preservation and reduced pressure reaction is carried out for 100-150 minutes to obtain an incompletely esterified product; in a second high-temperature reaction stage, the incompletely esterified product iscontinuously retained in the reaction kettle and heated to 215-225 DEG C, and heat preservation and pressure reduction reaction is carried out for 3.5-4.5 hours to obtain completely esterified phenylbutyrin; in the first stage and the second stage, the reaction is performed under the vacuum degree of 0.1-1KPa; and in the reaction process, extracted distillates are continuously collected and condensed. A staged heating control method is adopted, so that the problems of complex solvent, long reaction time, difficulty in control of a reaction endpoint and the like in a conventional esterification reaction process are solved.

Description

technical field [0001] The invention relates to the technical field of compound synthesis, in particular to a synthesis process of glycerol phenylbutyrate. Background technique [0002] December 31, 2018 / Bio Valley BIOON / --Horizon Pharma is a pharmaceutical company focused on the research, development and commercialization of innovative drugs for the treatment of rare diseases and rheumatic diseases. Recently, the company announced that the U.S. Food and Drug Administration (FDA) has approved Ravicti (glycerol phenylbutyrate, glycerol phenylbutyrate) oral solution to expand the applicable population to include infants with urea cycle disorder (UCD) under 2 months old. As the active ingredients of rare disease drugs, high purity can reduce the dosage and reduce toxic and side effects, so its purity is very important. For this reason, it is necessary to obtain high-purity, low-impurity products by optimizing the process flow and controlling the conditions in the synthesis pr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/08C07C69/612
CPCC07C67/08C07C69/612Y02P20/584
Inventor 李成胜周志艳张竞李丹丹王岩勃
Owner 安徽沃泰生物医药有限公司
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