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CN-122010932-A - Preparation method of non-neridrone raw material

CN122010932ACN 122010932 ACN122010932 ACN 122010932ACN-122010932-A

Abstract

The invention discloses a preparation method of a non-nefarious ketone raw material, which comprises the steps of carrying out condensation reaction on ① -formyl-3-methoxybenzonitrile and 3-oxo-2-cyanoethyl butyrate to obtain a first intermediate, carrying out cyclization reaction on ② first intermediate and 4-amino-5-methylpyrrolidone to obtain a second intermediate, carrying out ethylation on ③ second intermediate to obtain a third intermediate, carrying out hydrolysis reaction on ④ third intermediate to obtain a fourth intermediate, carrying out ammonolysis reaction on ⑤ fourth intermediate to obtain a non-nefarious ketone raceme, and carrying out chiral resolution on ⑥ to obtain the non-nefarious ketone. The invention adopts a tubular reactor to carry out cyclization reaction, adopts ethylene glycol diethyl ether to replace lower alcohol as a solvent, adopts the process technologies of dynamic kinetic resolution under the catalysis of beta zeolite and ammonium iodide and the like, and greatly reduces the content of sensitive impurities in materials, thereby greatly improving the quality level of products, improving the market competitiveness of the products, improving the yield of the products and reducing the production cost of the products.

Inventors

  • HU HUAFEN
  • ZHANG PEIFENG
  • FENG ERLONG
  • XI XIAOJIN

Assignees

  • 常州市阳光药业有限公司

Dates

Publication Date
20260512
Application Date
20251231

Claims (7)

  1. 1. A preparation method of a non-nelidone raw material, which comprises the following steps: ① 4-formyl-3-methoxybenzonitrile and 3-oxo-2-cyanoethyl butyrate undergo a condensation reaction to obtain a first intermediate; ② The first intermediate and 4-amino-5-methylpyrrolidone undergo a cyclization reaction to obtain a second intermediate; ③ The second intermediate is subjected to ethylation reaction to obtain a third intermediate; ④ The third intermediate is subjected to hydrolysis reaction to obtain a fourth intermediate; ⑤ The fourth intermediate is subjected to ammonolysis reaction to obtain a non-nereidone raceme; ⑥ The chiral resolution of the step ⑥ is carried out in the presence of beta zeolite and ammonium iodide.
  2. 2. The method of claim 1, wherein the cyclization reaction of step ② is performed in a tubular reactor.
  3. 3. The method for preparing a non-nereistone raw material according to claim 2, wherein the liquid flow rate in the tubular reactor is 5-15 mL/min, the back pressure valve pressure is 0.3-0.7 MPa, the reaction temperature is 120-150 ℃, and the residence time is 200-300 s.
  4. 4. The method of claim 1, wherein the cyclization reaction of step ② is performed in an ethylene glycol diethyl ether solvent.
  5. 5. The process for preparing a raw material of non-nelidane according to claim 1 to 4, wherein the catalyst used in the ethylation reaction of step ③ is p-toluenesulfonic acid.
  6. 6. The method of claim 1 to 4, wherein the catalyst used in the hydrolysis of step ④ is lithium hydroxide.
  7. 7. The method according to any one of claims 1 to 4, wherein in the step ①, the 3-oxobutanoic acid-2-cyanoethyl ester is added dropwise.

Description

Preparation method of non-neridrone raw material Technical Field The invention belongs to the technical field of preparation of bulk drugs, and particularly relates to a preparation method of a non-neridrone bulk drug. Background Non-nelidane (english name Finerenone) is a major non-steroidal selective mineralocorticoid receptor antagonist developed by bayer corporation that blocks the deleterious effects of mineralocorticoid receptor overactivation. In diabetics, mineralocorticoid receptor overactivation is thought to lead to chronic kidney disease progression and cardiovascular impairment, possibly driven by metabolic, hemodynamic or inflammatory and fibrotic factors. On day 14 7 of 2025, bayer recently announced that U.S. FDA has approved the use of feonelet for the treatment of new indications for adult heart failure patients with Left Ventricular Ejection Fraction (LVEF) greater than or equal to 40% are marketed. With this approval, non-nefarone became the only non-steroidal aldosterone receptor antagonist approved in the united states for use in type 2 diabetes-related Chronic Kidney Disease (CKD), heart failure with a ejection fraction of > 40% (HFmrEF/HFpEF) (nsMRA). Chinese patent document CN106795155A discloses a process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide (i.e. non-nelidanone), The synthetic route is as follows: 。 The method has the defects that (1) the second step of cyclization reaction needs to be carried out for a long time under the high-temperature and high-pressure condition, so that side reactions such as hydrolysis, polymerization, decomposition and the like are easy to occur, and particularly hydrolysis impurity II is generated and has very similar physical and chemical properties with the cyclization reaction product, thereby seriously affecting the product quality. (2) Because the second step cyclization reaction is carried out in a lower alcohol solvent, the residual lower alcohol can generate an impurity III which has very similar physical and chemical properties to an ethylation product during the third step ethylation reaction, and the product quality is further influenced. (3) In the third step, concentrated sulfuric acid is used as a catalyst for ethylation, decarboxylation and hydrolysis of impurity IV are easy to generate, and in the fourth step, hydrolysis in sodium hydroxide aqueous solution also generates cyano hydrolysis impurity V, so that the product quality is also influenced. (4) the resolution yield in the last step is lower. With the expiration of the advanced patent for non-nefarious ketone and the development of new indications, the market demand for non-nefarious ketone will further increase, and there is a need to develop a process for preparing non-nefarious ketone with higher product quality and lower cost. Disclosure of Invention The invention aims to solve the problems and provide a preparation method of a non-neridrone raw material with low content of related impurities and high purity of a product. The technical scheme for realizing the aim of the invention is that the preparation method of the non-nerlidone raw material comprises the following steps: ① The 4-formyl-3-methoxybenzonitrile and 3-oxo-butyric acid-2-cyanoethyl ester undergo condensation reaction to obtain a first intermediate, wherein the reaction formula is as follows: 。 in the step ①, the 3-oxo-butyric acid-2-cyanoethyl ester is added dropwise, so that the generation of impurity I can be effectively reduced, and the product quality is improved. The structural formula of the impurity I is as follows:。 ② The first intermediate and 4-amino-5-methylpyrrolidone undergo a cyclization reaction to obtain a second intermediate, wherein the reaction formula is as follows: 。 The cyclization reaction of the step ② is carried out in a tubular reactor, so that the reaction time can be greatly shortened, side reactions such as hydrolysis, polymerization, decomposition and the like generated by long-time high-temperature reaction are reduced, and particularly, the generation of impurity II can be greatly reduced, and the product quality is further improved. The structural formula of the impurity II is as follows:。 In the tubular reactor, the flow rate of liquid is 5-15 mL/min, the back pressure valve pressure is 0.3-0.7 MPa, the reaction temperature is 120-150 ℃, and the residence time is 200-300 s. The cyclization reaction of the step ② adopts ethylene glycol diethyl ether to replace lower alcohol as a solvent, so that the possibility that residual lower alcohol and a second intermediate generate an impurity III with very similar physical and chemical properties to the third intermediate in the third-step ethylation reaction can be effectively avoided, and the product quality is further improved. The structural formula of the impurity III is as follows:。 wherein R is the residue corresponding to lower alcohol. ③ The