CN-117486878-B - Preparation method of ennafilat

Abstract

The invention relates to a preparation method of Enalastat in the technical field of medicine synthesis, which comprises the steps of firstly hydrolyzing a compound 2 by strong alkali to generate 7-hydroxy-5- (2-phenylethyl) - [1,2,4] triazolo [1,5-a ] pyridine-8-formic acid and pivaloyl chloride to generate mixed anhydride in situ, then carrying out condensation reaction with glycinate hydrochloride, and then directly hydrolyzing without separation to finally obtain high-quality Enalastat. The invention has the advantages of safer process, high product purity and yield, and the like, greatly reduces the raw material cost of Enalastat, and has obvious economic and social benefits.

Inventors

• QU JUN
• GAO DEHUA

Assignees

• 扬州市普林斯医药科技有限公司

Dates

Publication Date

20260505

Application Date

20231027

Claims (4)

1. 1. The preparation method of ennafilat is characterized by comprising the following steps: S1 preparation of Compound 3 from Compound 2 according to the following reaction scheme ; S2, preparing a compound 4 from the compound 3 and acyl chloride according to the following reaction formula, further adding glycine ester hydrochloride to prepare a compound 5, and further preparing a compound 1 from the compound 5 ; Wherein R 1 COCl is acyl chloride, and R 1 is selected from one of methoxy, ethoxy, isobutoxy, isopropoxy and tert-amyl; R 2 is selected from one of methyl, ethyl and isopropyl; the step S2 comprises the following sub-steps: S2-1, adding the compound 3 prepared in the step S1 into solvent tetrahydrofuran under the protection of nitrogen, stirring and cooling to 0-10 ℃, adding an acid-binding agent diisopropylethylamine, dropwise adding acyl chloride at 0-5 ℃, stirring the mixture until the reaction is completed, adding glycine ester hydrochloride, controlling the temperature to 0-10 ℃, keeping the reaction, sampling and assaying, and ending the reaction when the weight content of the compound 3/(the compound 3+the compound 4) is less than or equal to 1.0%; The acyl chloride is selected from one of methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, isopropyl chloroformate and pivaloyl chloride, and the glycine ester hydrochloride is selected from one of glycine methyl ester hydrochloride, glycine ethyl ester hydrochloride and glycine isopropyl ester hydrochloride; S2-2, dropwise adding a sodium hydroxide aqueous solution into the reaction solution, heating to 30-50 ℃, keeping the reaction, sampling and assaying, ending the reaction when the weight content of the compound 5/(the compound 5+the compound 1) is less than or equal to 1.0%, regulating the pH to 5-7 by using hydrochloric acid, cooling to 20-30 ℃, filtering and collecting solids, and washing with water and acetone in sequence to obtain a crude product; S2-3, adding the crude product prepared in the step S2-2, isopropanol and water into a reaction device under the protection of nitrogen, heating to 70-80 ℃, cooling to 20-30 ℃ after the solution is clarified, filtering and collecting solids, washing the solids with isopropanol, and drying the obtained wet solids under reduced pressure to obtain a compound 1; The compound 1 is the target product Enalastat.
2. 2. The process for the preparation of ennostat according to claim 1, characterized in that in step S1, the preparation of compound 3 is carried out in the following steps: S1-1, adding a compound 2 and a solvent under the protection of nitrogen in a reaction device, heating to 50-90 ℃, dropwise adding 50% potassium hydroxide aqueous solution, and continuously maintaining the reaction until the dropwise adding is finished, wherein when the weight content of the compound 2/(the compound 2+the compound 3) is less than or equal to 1.0%, the reaction is finished; s1-2, after the reaction, adjusting the pH of the reaction mass to be 3-5 with hydrochloric acid, adding water dropwise to the reaction mixture at 70 ℃, cooling to 20-30 ℃, collecting the precipitated crystals by filtration, washing with water, and drying the obtained solid under reduced pressure to obtain compound 3.
3. 3. The method for preparing ennostat according to claim 2, wherein the solvent in the step S1-1 is selected from 1, 4-dioxane, tetrahydrofuran, ethanol, 2-methoxyethanol, 2-propanol, 1-butanol, 2-butanol or water.
4. 4. A process for the preparation of ennostat, according to claim 3, wherein the solvent of step S1-1 is 1-butanol.

Description

Preparation method of ennafilat Technical Field The invention relates to the technical field of medicine synthesis, in particular to a preparation method of ennacirst. Background On 9 months 25 of 2020, the new drug Enalastat ENAROY (enarodustat) is approved by Japan for oral administration to treat anemia associated with Chronic Kidney Disease (CKD). The new medicine for anemia oral administration comprises Enalastat ENAROY (enarodustat), basic information of the medicine: Chemical Names:enarodustat,JTZ-951 CAS Registry Number(s):1262132-81-9 Molecular Formula:C17H16N4O4 Molecular Weight:340.338 The chemical structural formula is as follows: ENAROY is an orally active HIF-PH inhibitor that promotes erythropoiesis by promoting endogenous production of erythropoietin and controlling expression of molecules responsible for iron metabolism. Phase 3 clinical study demonstrated Effectiveness and safety in anemic CKD patients without dialysis, peritoneal dialysis and hemodialysis. In the global market, the current HIF-PHI medicine field is not crowded no matter the medicines are marketed or the products are researched, but the continuously rising sales and the wide market prospect lead each medicine enterprise to lay out the development of the HIF-PHI innovative medicines in a dispute way. In the prior art, the synthetic route of Enalastat has the following two routes: 1. Japanese tobacco Co of original research manufacturer discloses a commercial production process of the compound in US2020/339563, which adopts the following preparation method, wherein 5, 7-dichloro- [1,2,4] triazolo [1,5-a ] pyridin-8-yl) methyl formate 2 is taken as a reaction key compound, the reaction product is reacted with a compound 3, 7-chloro-5- (2-phenylethyl) - [1,2,4] triazolo [1,5-a ] pyridine-8-formic acid (compound 5) is obtained by hydrolysis, then the amidation reaction is carried out on the compound 5 and glycine methyl ester hydrochloride by using HOBt and EDCI condensing agents, so as to obtain a compound 6, and finally the final hydrolysis reaction is carried out to synthesize the target product Ennastat. The thermal stability analysis of 45 common amide condensing agents is described by the sciences scientist Org.Process.Res.Dev, DOI:10.1021/acs.oprd.8b00193, high Energy Functional Group (HEFG) -containing molecules such as 1-hydroxybenzotriazole (HOBt), a known dry explosive material, and 1-hydroxyazabenzotriazole (HOAt), the large scale use of which often requires extensive safety testing to ensure process safety. Meanwhile, the 1-hydroxybenzotriazole is easy to degrade to generate hydrazine structure impurities, and the initial material chloronitrobenzene of the hydrazine structure impurities has potential genetic toxicity. From a process safety point of view, this commercial production method has some drawbacks, requiring further effort for process improvement. The reaction equation: 2. In U.S. patent 2011/77267 and journal literature [ ACS MEDICINAL CHEMISTRY LETTERS,2017, vol.8, #12, p1320-1325], a preparation method of a compound discovery stage is reported, wherein 7- (benzyloxy) -5-iodo- [1,2,4] triazole [1,5-a ] pyridine-8-carboxylic acid tert-butyl ester 25 is taken as a raw material, and phenylacetylene is subjected to Sonogashira coupling reaction and ester hydrolysis to obtain a compound 26, the compound 26 and glycine methyl ester hydrochloride are subjected to amidation reaction by using HOBt and EDCI condensing agents to obtain SI-4, benzyl is then released in palladium-hydrocarbon to obtain SI-5, and finally the target product Ennasstat is synthesized through hydrolysis reaction. Compound 26 is a salt of methanesulfonic acid, which is readily produced as a potential carcinogen using methanol or ethanol as a solvent in later process steps. At the same time, the use of metal palladium-carbon catalyst in the final step of the API increases the process operation of removing palladium from the product, and these potential process defects and risks result in the method being eliminated by the original manufacturer and unsuitable for commercial production. The reaction equation: In summary, finding a preparation method of Enalastat with the advantages of safer process, low raw material cost, high product purity and yield becomes a technical problem to be solved in the current commercial production. Disclosure of Invention The invention aims to provide a preparation method of Enalastat, which has safer process, high product purity and yield, and can reduce the production cost, thereby being more suitable for commercial production. Therefore, the preparation method of Enalastat provided by the invention comprises the following steps: S1 preparation of Compound 3 from Compound 2 according to the following reaction scheme S2, preparing a compound 4 from the compound 3 and acyl chloride according to the following reaction formula, further adding glycine ester hydrochloride to prepare a compound 5, and further preparin