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CN-121990995-A - Rasemet tilo intermediate Industrial preparation method of body

CN121990995ACN 121990995 ACN121990995 ACN 121990995ACN-121990995-A

Abstract

The invention discloses an industrial preparation method of a rismiterol intermediate, and belongs to the field of medicine synthesis. In the prior art, an acetic acid/sodium acetate system is adopted to react the compound I with acetic acid at high temperature to generate an intermediate state, and the intermediate product is obtained through operations such as concentration, extraction, pH adjustment and the like and then subjected to the next hydrolysis reaction, so that the reaction time is long, the post-treatment operation is complex, and the yield is low. Compared with the prior art, the invention discloses a method for replacing acetic acid/sodium acetate system with formic acid, the purity of the generated compound II is higher, and the compound II can be directly and continuously added into the next hydrolysis reaction to prepare the compound III after most of formic acid is removed, so that the technical process is greatly simplified, the reaction time is shortened, and the product conversion rate is improved. The invention greatly improves the purity and the yield of the product by the synergistic effect of the post-treatment process of the step (1) and the solvent of the step (2), the purity of the product can reach 99 percent and the yield of the product is 85 percent without refining, and the process is also suitable for industrial production.

Inventors

  • ZHOU BUGAO
  • MA LEI
  • SUN CHAO
  • HUI JIAN

Assignees

  • 南京方生和医药科技有限公司
  • 江苏利泰尔药业有限公司

Dates

Publication Date
20260508
Application Date
20241105

Claims (8)

  1. 1. An industrialized preparation method of a Rasemet tilo intermediate, the rosuvastatin intermediate is shown as a compound III: The preparation method comprises the following steps: (1) The compound I and formic acid undergo acylation and hydrolysis reactions to generate a compound II; (2) The compound III is prepared by hydrolysis reaction of the compound II in a solvent under alkaline condition;
  2. 2. the method according to claim 1, wherein the solvent used in the reaction in the step (2) is an aqueous solution of methanol or ethanol.
  3. 3. The industrial preparation method according to claim 2, wherein the mass ratio of alcohol to water in the aqueous solution of methanol or ethanol is 1:2-1:5.
  4. 4. The industrial production method according to claim 1, wherein the reaction temperature in the step (1) is 80-100 ℃.
  5. 5. The industrial production method according to claim 1, wherein the reaction temperature in the step (2) is 60-80 ℃.
  6. 6. The method according to claim 1, wherein the alkali used in the step (2) is one of sodium hydroxide, potassium hydroxide and potassium carbonate.
  7. 7. The industrial production method according to claim 1, wherein the molar ratio of the compound II to the base in the step (2) is 1:7 to 1:10.
  8. 8. The industrial production method according to claim 1, wherein the step (1) further comprises a post-treatment process of concentrating the reaction product to a viscous state, adding water-dispersed entrainment with a feeding amount of 2-3 times of the mass, continuing concentrating to a viscous state, and repeating the operation for 1-2 times.

Description

Rasemet tilo intermediate Industrial preparation method of body Technical Field The invention belongs to the field of medicine synthesis, and particularly relates to an industrialized preparation method of a rismiterol intermediate. Background Resimitinol is a Thyroid Hormone Receptor (THR) -beta oral selective agonist, is used for treating nonalcoholic steatohepatitis (NASH) accompanied by hepatic fibrosis, is a first-pass medicament for treating nonalcoholic steatohepatitis worldwide, has high selectivity, can play a core role in liver by activating beta receptors in liver cells, regulates lipid metabolism, reduces LDL-C, triglyceride and atherogenic lipoproteins, and is inactive on THR-alpha receptors, thereby not affecting bone or heart parameters, and not affecting other hormones of thyroid hormone pathway. The prior art reports the synthesis method of the rismeterol mainly comprises the following steps: 1. Synthetic route one (refer to PCT patent WO2014043706A1 and US10894050B 2), which is a 7-step reaction, and is long in route and cumbersome in operation, wherein the preparation reaction condition of the compound 5 is severe, and commercial production is difficult. 2. The synthesis route II (refer to a synthesis route disclosed in PCT patent WO2020227549A 1) has 4 steps of reactions, but impurities similar to a parent ring structure are easy to generate during preparation of the compound 6 and the compound 7, purification is difficult, process operation is complex, yield is low, and commercial production is not facilitated. The synthesis route III (refer to the synthesis route disclosed in Chinese patent CN 101228135B) simplifies the process steps and relatively reduces the complicated degree and production cost of the process compared with the former two routes, but in the process of preparing the compound of formula 4 by using the compound of formula 3, the reaction period of the method reported in the document is longer, the reaction conversion rate is low, the post-treatment needs multiple concentration, pH adjustment and extraction washing operations, and finally the target compound is obtained by column chromatography, so that the process is complicated, the treatment period is long and the yield is low. Therefore, aiming at the problem of route three, a simple preparation method of the rivastigmine intermediate with higher economical efficiency still needs to be developed at present Disclosure of Invention The invention provides an industrialized preparation method of a rivastigmine intermediate, which aims to solve the technical problems of long single-step reaction period and complicated post-treatment operation of the industrialized preparation of the rivastigmine intermediate. In order to achieve the above purpose, the technical scheme provided by the invention is as follows: an industrialized preparation method of a Rasemet tilo intermediate, the rosuvastatin intermediate is shown as a compound III: The preparation method comprises the following steps: (1) The compound I and formic acid undergo acylation and hydrolysis reactions to generate a compound II; (2) The compound III is prepared by hydrolysis reaction of the compound II in a solvent under alkaline condition; Further, the temperature at which the reaction in the step (1) occurs is 80-100 ℃. Further, the temperature at which the reaction in the step (2) occurs is 60-80 ℃. Further, the alkali used in the step (2) is one of sodium hydroxide, potassium hydroxide and potassium carbonate. Further, the solvent used in the reaction in the step (2) is an aqueous solution of methanol or ethanol, and the mass ratio of the alcohol to the water is 1:2-1:5. Further, in the step (2), the molar ratio of the compound II to the alkali is 1:7-1:10. The compound II generated by formic acid and the compound I in the step (1) has higher purity, does not need to be obtained independently, and can be directly and continuously fed into the next hydrolysis reaction after most of formic acid is removed. However, in the industrial production, after formic acid is concentrated to a certain extent, the dispersibility of the system is poor, so that the concentration of the formic acid is incomplete, when the residual formic acid exceeds a certain limit, the next hydrolysis reaction can be inhibited, the hydrolysis of the compound II is incomplete, and the post-treatment is difficult to remove. In order to solve the technical problems, in some examples, the step (1) further comprises a post-treatment process of concentrating the reaction product to be sticky, adding water-dispersed entrainment with a feeding amount of 2-3 times of the mass, continuing concentrating to be sticky, and repeating the operation for 1-2 times. The step can remove most of formic acid in the system, and a small amount of alcohol is added in the hydrolysis reaction in the step (2), so that the alcohol can consume the formic acid in the system, thereby promoting the hydrolysis of the com