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CN-121990991-A - Preparation method of roflumilast impurity

CN121990991ACN 121990991 ACN121990991 ACN 121990991ACN-121990991-A

Abstract

The invention provides a preparation method of roflumilast impurities, which specifically comprises the following steps of S1, carrying out substitution reaction on a compound 14-hydroxy-7-phenoxyisoquinoline-3-methyl formate and NCS under an acidic condition to generate an impurity A, S2, carrying out methylation reaction on the impurity A and a compound 2-methylboric acid under an alkaline condition to generate an impurity B, and carrying out condensation reaction on the impurity B and a compound 3-glycine methyl ester hydrochloride to generate an impurity C. The synthesis method adopted by the invention is simple, and the obtained sample has high purity, and has great significance for Luo Shasi other process researches, impurity analysis and quality control.

Inventors

  • ZHAO MENGYUN
  • WANG KUANQI
  • LU XIANG
  • Ji Xunjin

Assignees

  • 江苏普润生物医药有限公司

Dates

Publication Date
20260508
Application Date
20260323

Claims (10)

  1. 1. A method for preparing roflumilast impurity, which is characterized by comprising the following steps: s1, carrying out substitution reaction on a compound 14-hydroxy-7-phenoxyl isoquinoline-3-methyl formate and NCS under an acidic condition to generate an impurity A; s2, carrying out methylation reaction on the impurity A and the compound 2 methyl boric acid under alkaline conditions to generate an impurity B; s3, carrying out condensation reaction on the impurity B and the compound 3 glycine methyl ester hydrochloride to generate an impurity C.
  2. 2. The preparation method of the roflumilast impurity according to claim 1 is characterized in that S1 is specifically characterized in that 14-hydroxy-7-phenoxyisoquinoline-3-methyl formate and NCS are stirred and mixed under an acidic condition, a solvent is dichloroethane, chlorination reaction is carried out at 60-70 ℃ under the protection of nitrogen, the obtained mother liquor is decompressed and concentrated, solids are collected after crystallization, column chromatography is carried out for separation, relevant components are collected, white to off-white solids are obtained, and impurity A is obtained after drying.
  3. 3. The preparation method of the roflumilast impurity according to claim 1, wherein the acidic substance adopted in the acidic condition of S1 is one or more of aluminum trichloride, ferric trichloride and trifluoro-methanesulfonate, preferably ferric trichloride, the molar ratio of the compound 1 to the acidic substance is 1:1.5-2, preferably 1:1.6-1.8, and the molar ratio of the compound 1 to NCS is 1:2.3-2.6, preferably 1:2.45-2.55.
  4. 4. The preparation method of the roflumilast impurity according to claim 1 is characterized in that S2 is specifically that impurity A, compound 2 methyl boric acid and palladium catalyst are stirred and mixed under alkaline condition, solvent is ethylene glycol methyl ether, methylation reaction is carried out under high temperature reflux under nitrogen protection, related components are collected and dried through crystallization and column chromatography separation, and off-white solid, namely impurity B, is obtained, wherein the high temperature reflux reaction temperature adopted in the methylation reaction is 105-115 ℃.
  5. 5. The method for preparing the roflumilast impurity according to claim 4, wherein the palladium catalyst in S2 is one or more of palladium acetate, tetrakis (triphenylphosphine) palladium, triphenylphosphine palladium acetate, dichloro di-tert-butyl- (4-dimethylaminophenyl) phosphine palladium, palladium acetylacetonate, (1, 3-bis (diphenylphosphine) propane) palladium chloride, [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex, and preferably [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex.
  6. 6. The method for preparing the roflumilast impurity according to claim 1, wherein the alkaline condition adopted in the step S2 is one or more of potassium phosphate, potassium carbonate, sodium phosphate and sodium carbonate, preferably the alkaline condition is sodium phosphate, and the molar ratio of the impurity A to the sodium phosphate is 1:3.5.
  7. 7. The method for preparing roflumilast impurity according to claim 1, wherein the molar ratio of impurity a to compound 2 in S2 is 1:2.5-3.5, preferably 1:3.
  8. 8. The preparation method of the roflumilast impurity according to claim 1, wherein the S3 is characterized in that the impurity B and the compound 3 are mixed with a condensing agent, a solvent is tetrahydrofuran, the condensing reaction is carried out under the condition of heat preservation and reflux, the organic phase is decompressed and concentrated, the solid is collected after crystallization and dried to obtain a light yellow solid, namely the impurity C, and the heat preservation and reflux reaction temperature is 35-45 ℃.
  9. 9. The method for preparing roflumilast impurity according to claim 1, wherein the molar ratio of impurity B to compound 3 in S3 is 1:1.1-1.3, preferably 1:1.2.
  10. 10. The preparation method of the roflumilast impurity according to claim 1, wherein the condensing agent adopted in the condensation reaction of S3 is one or more of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole, 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate, N, N, N ', N' -tetramethyl-O- (7-azabenzotriazole-1-yl) hexafluorophosphate urea, preferably 1-hydroxybenzotriazole and 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate.

Description

Preparation method of roflumilast impurity Technical Field The invention belongs to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a preparation method of roflumilast impurities. Background Luo Shasi he, chemical name [ (4-hydroxy-1-methyl-7-phenoxy isoquinoline-3-formyl) amino ] acetic acid, is a small molecule compound originally developed by the company Faboc (FibroGen). It is also the first Hypoxia Inducible Factor (HIF) -Prolyl Hydroxylase (PHD) worldwide. The medicine can promote the expression of Erythropoietin (EPO) by inhibiting Prolyl Hydroxylase (PHD) to stabilize HIF pathway under normal oxygen partial pressure condition, thereby improving iron metabolism disorder of organism. Luo Shasi he in 2018, 12, was first marketed in China under the trade name Roxadustat, and is mainly used for treating anemia associated with Chronic Kidney Disease (CKD), including dialysis and non-dialysis patients. The concrete structure is as follows: the research of medicine impurities is related to the safety, effectiveness and quality controllability of medicines. The impurity research is carried out, so that the product quality of the crude drug and the preparation of the roflumilast can be ensured, and the medication safety and the curative effect of a patient can be finally ensured. In 2016, the drug administration group reports (CN 107954931 a) that a commercial production process route of [ (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) amino ] acetic acid is obtained by taking 4-hydroxy-7-phenoxyisoquinoline-3-methyl formate as a starting material, through halogenation, methylation, condensation and hydrolysis, and is shown as follows: in Luo Shasi's preparation, multiple reaction sites are involved in the substitution reaction, and impurity A is also formed along with product a. Under the condition that the byproducts cannot be effectively removed, the impurities B and C are sequentially conducted to the API, so that the quality of the bulk drug is affected. Luo Shasi the impurity C can be used as a reference substance for qualitative research and quantitative control of impurities in the production process of the crude drug of the roflumilast, so that the method has important synthetic significance. Disclosure of Invention The invention aims to provide a preparation method of roflumilast impurities. The process has mild reaction conditions, high product yield and purity, can meet the requirements of reference substances, and has important industrial application value. The object of the invention is achieved by: a method for preparing roflumilast impurity, comprising the steps of: s1, carrying out substitution reaction on a compound 1 (4-hydroxy-7-phenoxyisoquinoline-3-methyl formate) and NCS (N-chlorosuccinimide) under an acidic condition to generate an impurity A; S2, carrying out methylation reaction on the impurity A and a compound 2 (methyl boric acid) under an alkaline condition to generate an impurity B; S3, carrying out condensation reaction on the impurity B and a compound 3 (glycine methyl ester hydrochloride) to generate an impurity C; the specific preparation process comprises the following steps: S1, stirring and mixing a compound 1 (4-hydroxy-7-phenoxyisoquinoline-3-methyl formate) and NCS under an acidic condition, wherein a solvent is dichloroethane, performing chlorination reaction at 60-70 ℃ under the protection of nitrogen, concentrating the obtained mother liquor under reduced pressure, crystallizing, collecting solids, separating by column chromatography, collecting relevant components to obtain white to off-white solids, and drying to obtain an impurity A. S2, stirring and mixing the impurity A, the compound 2 (methyl boric acid) and the palladium catalyst under an alkaline condition, wherein the solvent is ethylene glycol methyl ether, carrying out high-temperature reflux under the protection of nitrogen to carry out methylation reaction, separating by crystallization and column chromatography, collecting relevant components, and drying to obtain an off-white solid, namely the impurity B. S3, mixing the impurity B, the compound 3 (glycine methyl ester hydrochloride) and a condensing agent, performing condensation reaction under the condition of heat preservation and reflux, extracting, washing, concentrating an organic phase under reduced pressure, collecting a solid after crystallization, and drying to obtain a light yellow solid, namely the impurity C. Preferably, the acidic material adopted in the acidic condition of S1 is one or more of aluminum trichloride, ferric trichloride and trifluoromethane sulfonate, more preferably ferric trichloride, and the molar ratio of the compound 1 to the acidic material is 1:1.5-2, more preferably 1:1.6-1.8. Preferably, the molar ratio of the compound 1 to NCS in S1 is 1:2.3-2.6, preferably 1:2.45-2.55. Preferably, the alkaline condition described in S2 adopts one or more alkaline substances selected from