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CN-122010939-A - Enalistat impurity and preparation method thereof

CN122010939ACN 122010939 ACN122010939 ACN 122010939ACN-122010939-A

Abstract

The invention discloses Enalistat impurity and a preparation method thereof, and belongs to the technical field of pharmaceutical chemicals. The method comprises the steps of firstly carrying out nucleophilic substitution reaction on a compound 1 and a compound 2 under the action of an acid binding agent to generate a compound 4, then carrying out decarboxylation reaction on the compound 4 under an acidic condition to generate a compound 5 after hydrolyzing the compound 4 in an alkaline solution, then carrying out amide condensation reaction on the compound 5 and the compound 3 under the action of a condensing agent, a solvent and alkali to generate a compound 6, and finally carrying out hydrolysis reaction on the compound 6 in an alkaline solution and an organic solvent to generate a compound 7. The Enalafilstat impurity synthesized by the invention can be used for qualitative and quantitative analysis of the impurity in Enalafilstat production, is convenient to effectively monitor and timely reduce the impurity content by adopting necessary means, thereby improving the quality standard of Enalafilstat intermediates.

Inventors

  • YU BO
  • FAN ZIQI
  • LIN XINQIN
  • GUO LILIANG

Assignees

  • 南京联智医药科技有限公司

Dates

Publication Date
20260512
Application Date
20260313

Claims (10)

  1. 1. Enalistat impurity is characterized by having the following structural formula: 。
  2. 2. The method for preparing ennadirst impurity according to claim 1, characterized by comprising the following steps: 1) Nucleophilic substitution reaction is carried out on the compound 1 and the compound 2 under the action of an acid binding agent, so that a compound 4 is generated; 2) Hydrolyzing the compound 4 in an alkaline solution, and then carrying out decarboxylation reaction under an acidic condition to generate a compound 5; 3) Performing amide condensation reaction on the compound 5 and the compound 3 under the action of a condensing agent, a solvent and alkali to generate a compound 6; 4) Carrying out hydrolysis reaction on the compound 6 in alkaline solution and organic solvent to generate a compound 7; the reaction formula is as follows: 。
  3. 3. The method for preparing Enalidomide impurity of claim 1, wherein in step 1), the acid binding agent is one or more selected from sodium hydroxide, cesium carbonate, potassium hydroxide and sodium ethoxide.
  4. 4. The preparation method of the Ennadirst impurity according to claim 1 is characterized in that in the step 1), the molar ratio of the compound 1 to the compound 2 to the acid binding agent is 1:1.05-1.35:1.2-1.8, the temperature of nucleophilic substitution reaction is 30-40 ℃, and the time is 5-6 hours.
  5. 5. The preparation method of the Ennadirst impurity according to claim 1 is characterized in that in the step 2), the alkaline solution is selected from one or more of sodium hydroxide solution, potassium hydroxide solution and sodium ethoxide, the mass concentration of the alkaline solution is 10-30%, the temperature of the hydrolysis reaction is 40-60 ℃ and the time is 5-10 h.
  6. 6. The preparation method of the Ennadirst impurity according to claim 1, wherein in the step 2), the acidic solution is hydrochloric acid solution, the molar ratio of the compound 4 to the acidic solution is 1:4-8, the decarboxylation reaction is carried out at 50-80 ℃ for 10-12 hours.
  7. 7. The preparation method of the Enalidomide impurity according to claim 1, wherein in the step 3), the solvent is acetonitrile/water, the volume ratio of acetonitrile to water is 1:0.5-1, and the alkali is one or more selected from sodium hydroxide, triethylamine, potassium tert-butoxide and sodium carbonate.
  8. 8. The method for preparing Ennadirst impurity according to claim 1, wherein in the step 3), the condensing agent is one or more of N, N '-dicyclohexylcarbodiimide/1-hydroxybenzotriazole, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride/1-hydroxybenzotriazole, N' -diisopropylcarbodiimide/1-hydroxybenzotriazole, and the reaction temperature is 20-40 ℃ and the reaction time is 3-4 hours.
  9. 9. The preparation method of the Enalidomide impurity of claim 1, wherein in the step 4), the alkaline solution is selected from one or more of sodium hydroxide and potassium hydroxide, the mass concentration of the alkaline solution is 20-30%, and the organic solvent is selected from one or more of ethanol, methanol and 2-ethoxyethanol.
  10. 10. The method for preparing the Enalidomide impurity according to claim 1, wherein in the step 4), the reaction temperature is 70-80 ℃ and the reaction time is 9-10 h.

Description

Enalistat impurity and preparation method thereof Technical Field The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to Enalistat impurities and a preparation method thereof. Background Entadalafil, chemical name N- [ 7-hydroxy-5- (2-phenethyl) [1,2,4] triazolo [1,5-a ] pyridine-8-carbonyl ] glycine, structural formula is as follows: Enalafilstat is an oral prescription drug for treating anemia in non-dialyzed adult Chronic Kidney Disease (CKD) patients, and has the trade name Enalaluo and is produced by Shenzhen Xinlitai pharmaceutical industry Co., ltd, belonging to medical insurance class B drugs. Entadalafil stabilizes hypoxia inducible factor by inhibiting prolyl hydroxylase activity, promotes the production of endogenous erythropoietin by the body, simultaneously down regulates the level of hepcidin, improves iron metabolism, and has a certain anti-inflammatory effect, thereby improving the anemia condition of CKD patients. Entadalafil belongs to a renal anemia drug, and along with the trend of younger and generalized renal diseases, the Entadalafil gradually pays attention to and pays attention to renal anemia in various countries, and has very broad market prospects under the promotion of hope and market demands of huge patients. In chinese patent application CN110214139B a process for the production of triazolopyridine compounds is disclosed, which details specific preparation steps of ennadirst, wherein step 8 (CN 110214139B, [00421] - [00423] paragraph) is disclosed, the synthetic route being: To a suspension of methyl 2- ({ [ 7-chloro-5- (2-phenylethyl) - [1,2,4] triazolo [1,5-a ] pyridin-8-yl ] carbonyl } amino) acetate (compound (3)) (29.3 kg,78.6 mol) in 2-ethoxyethanol (150L) was added 5mol/L aqueous sodium hydroxide solution (88L, 440 mol), and the mixture was stirred at 87℃for 9.5 hours. After the completion of the reaction, a mixed solution of ethanol (146.5L) and water (14.5L) was added dropwise to the reaction mixture at 70 ℃. The mixture was cooled to room temperature and stirred at the same temperature for 9 hours. The precipitated crystals were collected by filtration and washed with a mixed solution of ethanol (78.3L) and water (11.7L). The wet crystals obtained were dried under reduced pressure to give disodium 2- ({ [ 7-hydroxy-5- (2-phenylethyl) - [1,2,4] triazolo [1,5-a ] pyridin-8-yl ] carbonyl } amino) acetate (compound (2), a salt of compound (1) (32.9 kg,85.6 mol, yield 109%). The present inventors have found the following impurity compounds when reproducing the above synthesis steps: The impurity compound belongs to impurities generated by side reaction in the reaction process, has obvious influence on the activity of finished Enalafilstat products and toxic and side effects of human bodies, needs to establish scientific detection and monitoring means, has great significance on qualitative and quantitative analysis of the impurities and improves the quality of Enalafilstat. However, no related compound is described and researched in the prior art, and on the basis of the related compound, preparation, identification and research are needed, so that the related compound has great significance for improving the quality of Ennadirst. Disclosure of Invention The invention aims to provide the Entadalastat impurity, which can be used for qualitative and quantitative analysis of the impurities in Entadalastat production, is convenient to effectively monitor and timely reduce the impurity content by adopting necessary means so as to improve the quality standard of the Entadalastat intermediate, and aims to provide the preparation method of the Entadalastat impurity, which is simple and convenient to operate, mild in reaction condition and high in atomic economy. In order to solve the technical problems, the invention adopts the following technical scheme: Enalistat impurity has the structural formula shown as follows: 。 further, the preparation method of the Enalistat impurity comprises the following steps: 1) Nucleophilic substitution reaction is carried out on the compound 1 and the compound 2 under the action of an acid binding agent, so that a compound 4 is generated; 2) Hydrolyzing the compound 4 in an alkaline solution, and then carrying out decarboxylation reaction under an acidic condition to generate a compound 5; 3) Performing amide condensation reaction on the compound 5 and the compound 3 under the action of a condensing agent, a solvent and alkali to generate a compound 6; 4) Carrying out hydrolysis reaction on the compound 6 in alkaline solution and organic solvent to generate a compound 7; the reaction formula is as follows: 。 further, in the step 1), the acid binding agent is one or more selected from sodium hydroxide, cesium carbonate, potassium hydroxide and sodium ethoxide. Further, in the step 1), the molar ratio of the compound 1 to the compound 2 to the acid binding agent is 1:1.05-1.35:1.2-1.8, the temperature o