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CN-122010848-A - Preparation method and detection method of key intermediate of dihydropyrido [4,3-d ] pyrimidinone analogue

CN122010848ACN 122010848 ACN122010848 ACN 122010848ACN-122010848-A

Abstract

The invention provides a preparation method and a detection method of a key intermediate of a dihydropyrido [4,3-d ] pyrimidinone analogue, belonging to the technical field of medicine preparation and detection, wherein the preparation method is to take 3, 6-dichloro-4-isopropyl pyridazine and 2, 6-dichloro-4-aminophenol to react under the action of fine powder potassium carbonate, and the key intermediate of the dihydropyrido [4,3-d ] pyrimidinone analogue is obtained after alcohol recrystallization after the reaction; the detection method is characterized in that a key intermediate of the dihydropyrido [4,3-d ] pyrimidinone analog is taken to prepare a sample solution, and liquid chromatography detection is carried out through gradient elution to detect impurities in the key intermediate of the dihydropyrido [4,3-d ] pyrimidinone analog. The preparation method and the refining method have the advantages of simple operation, high yield, low cost, suitability for industrial production and the like. The detection method can effectively separate, accurately detect and quantify each impurity.

Inventors

  • ZHANG XUEWEI
  • Wang Jinchong
  • MA YAJUN
  • ZHANG YUN
  • REN ZHAOXIN
  • WANG FUKUI
  • LIU TIANJIAO

Assignees

  • 河北安健成益医药科技有限公司

Dates

Publication Date
20260512
Application Date
20251216

Claims (10)

  1. 1. The preparation method of the key intermediate of the dihydropyrido [4,3-d ] pyrimidinone analogue is characterized in that 3, 6-dichloro-4-isopropyl pyridazine and 2, 6-dichloro-4-aminophenol are taken to react under the action of fine powder potassium carbonate, and the key intermediate of the dihydropyrido [4,3-d ] pyrimidinone analogue is obtained through alcohol recrystallization after the reaction is finished; The key intermediate of the dihydropyrido [4,3-d ] pyrimidinone analog is 3, 5-dichloro-4- ((6-chloro-5-isopropylpyridazin-3-yl) oxy) aniline.
  2. 2. The process for the preparation of a key intermediate of a dihydropyrido [4,3-d ] pyrimidinone analog according to claim 1, wherein the recrystallized alcohol is a C1 to C4 alcohol solvent; the amount of the alcohol is 5 to 15 times, preferably 10 times, the amount of the product obtained after the reaction.
  3. 3. The method for preparing a key intermediate of dihydropyrido [4,3-D ] pyrimidinone analogues according to claim 1 or 2, wherein the particle size D50 of the fine powder potassium carbonate is 50-200 μm.
  4. 4. The preparation method of the key intermediate of the dihydropyrido [4,3-d ] pyrimidinone analog according to claim 1 or 2, wherein the molar ratio of 3, 6-dichloro-4-isopropyl pyridazine to 2, 6-dichloro-4-aminophenol is 1:1.0-2.0, and the molar ratio of 3, 6-dichloro-4-isopropyl pyridazine to fine powder potassium carbonate is 1:2.0-5.0.
  5. 5. The method for preparing the key intermediate of the dihydropyrido [4,3-d ] pyrimidinone analog according to claim 1 or 2, wherein the reaction temperature is 80-140 ℃, and the reaction time is 6-24 hours; the solvent for the reaction is N, N-dimethylacetamide, N-dimethylformamide, N-methylpyrrolidone or 1, 3-dimethyl-2-imidazolidinone.
  6. 6. A method for detecting a key intermediate of a dihydropyrido [4,3-d ] pyrimidinone analog is characterized in that the method comprises the steps of preparing a sample solution from the key intermediate of the dihydropyrido [4,3-d ] pyrimidinone analog prepared by the preparation method according to any one of claims 1-5, adding a solvent, taking a mixed solution of phosphate buffer solution and acetonitrile with the volume ratio of 90:10 as a mobile phase A, taking a mixed solution of phosphate buffer solution and acetonitrile with the volume ratio of 20:80 as a mobile phase B, and carrying out liquid chromatography detection through gradient elution to detect impurities in the key intermediate of the dihydropyrido [4,3-d ] pyrimidinone analog; the elution conditions of the gradient elution are as follows: 0-15min, 70% -45% of mobile phase A,30% -55% of mobile phase B; 15-30 min,45% -15% of mobile phase A,55% -85% of mobile phase B; 30-48 min,15% of mobile phase A and 85% of mobile phase B; 48-50 min,15% -70% of mobile phase A,85% -30% of mobile phase B; 50-60 min,70% of mobile phase A and 30% of mobile phase B; The impurities comprise an impurity 1, an impurity 2, an impurity 5, an impurity 6, an impurity 11 and an impurity 12, and the specific structure is as follows: , 。
  7. 7. The method for detecting key intermediates of dihydropyrido [4,3-d ] pyrimidinone analogs according to claim 6, comprising the specific steps of: Adding a solvent into key intermediates of dihydropyrido [4,3-d ] pyrimidinone analogues to prepare a sample solution; Respectively preparing an impurity 1, an impurity 2, an impurity 5, an impurity 6, an impurity 11 and an impurity 12 into corresponding impurity positioning solutions; and taking a sample solution and each impurity positioning solution for liquid chromatography detection to detect each impurity in the key intermediate of the dihydropyrido [4,3-d ] pyrimidinone analog.
  8. 8. The method for detecting the key intermediate of the dihydropyrido [4,3-d ] pyrimidinone analog according to claim 7, wherein the method further comprises using a liquid chromatography to detect the obtained chromatogram, and calculating the key intermediate of the dihydropyrido [4,3-d ] pyrimidinone analog and the content of each impurity by an area normalization method or a standard curve method.
  9. 9. The method for detecting a key intermediate of a dihydropyrido [4,3-d ] azone analogue according to any one of claims 6 to 8, wherein the solvent is obtained by mixing mobile phase a and mobile phase B in a volume ratio of 70:30; The phosphate buffer solution is prepared by dissolving monoammonium phosphate in water, adding triethylamine, adjusting pH to 6.00+ -0.05 with phosphoric acid, and shaking.
  10. 10. The method for detecting the key intermediate of the dihydropyrido [4,3-d ] azone analogue, which is disclosed in any one of claims 6 to 8, is characterized in that a chromatographic column adopts octadecylsilane chemically bonded silica gel as a filler, the detection wavelength is 205 to 220nm, the flow rate is 0.8 to 1.2mL/min, and the column temperature is 25 to 35 ℃.

Description

Preparation method and detection method of key intermediate of dihydropyrido [4,3-d ] pyrimidinone analogue Technical Field The invention relates to a medicine preparation and detection technology, in particular to a preparation method and a detection method of a key intermediate of a dihydropyrido [4,3-d ] pyrimidinone analogue. Background Resimiterol, originally developed by Roche, and marketed under the chemical name 2- (3, 5-dichloro-4- ((5-isopropyl-6-oxo-1, 6-dihydropyridazin-3-yl) oxy) phenyl) -3, 5-dioxo-2, 3,4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile, english name Resmetirom, was approved by the FDA for the treatment of non-alcoholic steatohepatitis (MASH) accompanied by liver fibrosis, month 3 of 2024, and has the following structural formula: , the prevalence of MASH in 10-30% of the total number of common adult MASLD patients is on an annual rising trend, and therefore, the demand for this drug will be increasing in the future. Chinese patent CN101228135B discloses a process for preparing rosuvastatin, wherein compound 7 reacts with 2, 6-dichloro-4-aminophenol to form compound 24, which is hydrolyzed to compound 25, and (2-cyanoacetyl) carbamic acid ethyl ester reacts with metal nitrite in the presence of alkali to form compound 30, compound 30 is cyclized in acidic environment to obtain crude product, and the crude product is refined to obtain rosuvastatin. , The crude product obtained by the method is dissolved by acetonitrile, decolorized by active carbon, filtered, concentrated, and then refined by hot acetonitrile twice to obtain the Rasemet with the yield of 61%. The above route uses a key intermediate 24, namelyThe chemical name is 3, 5-dichloro-4- ((6-chloro-5-isopropyl pyridazin-3-yl) oxo) aniline, and cas number is 920509-27-9. The current main routes for preparing the compound are roughly divided into the following four types according to different acid binding agents: Route 1, CN109574995, US2021/292304, CN111592528, WO2019/240938 and other documents report that the preparation method of the compound comprises the steps of heating up and reacting cuprous iodide and potassium carbonate serving as acid binding agents in dimethyl sulfoxide, and purifying by column chromatography, wherein the yield is 52-67%, and the method is not suitable for technical production, and patent CN119504714A reports that the yield is increased to 78.5% by using ethanol for recrystallization, but the price of the cuprous iodide is higher, so that the material cost is higher, and the method is still not suitable for industrial production. In scheme 2, WO2007/9913 reports that the potassium tert-butoxide is used as an acid binding agent for preparing the compound, and the compound is not purified in the operation but is directly used in the next step, so that the quality control of an intermediate is not facilitated, and the compound is not suitable for industrial production. In the scheme 3, CN111909137 and US2025/206725 report that cesium carbonate is used as an acid binding agent to prepare the compound, the yields are 69% and 32%, respectively, and the method has lower yield, uses expensive cesium carbonate, has higher cost and is not suitable for industrial production. Scheme 4, CN117843621 reports the preparation of the compound using potassium carbonate as an acid binding agent, but the method still requires column chromatography purification for post-treatment, which is not suitable for technical production. In view of the good market prospect of the Racemeterol, it is necessary to find a method for preparing a key intermediate which is green, environment-friendly, simple to operate, high in yield and low in cost, and to develop a method for detecting impurities in the key intermediate so as to better control the quality of the intermediate. Disclosure of Invention Aiming at the problems, the invention provides a preparation method and a detection method of a key intermediate of a dihydropyrido [4,3-d ] pyrimidinone analogue. In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: the preparation method comprises the steps of taking 3, 6-dichloro-4-isopropyl pyridazine and 2, 6-dichloro-4-aminophenol to react under the action of fine powder potassium carbonate, and recrystallizing the obtained product through alcohol after the reaction is finished to obtain the key intermediate of the dihydropyrido [4,3-d ] pyrimidinone analogue; The key intermediate of the dihydropyrido [4,3-d ] pyrimidinone analog is 3, 5-dichloro-4- ((6-chloro-5-isopropylpyridazin-3-yl) oxy) aniline. Further, the recrystallized alcohol is a C1 to C4 alcohol solvent, in particular methanol, ethanol, isopropanol or tert-butanol; the amount of the alcohol is 5 to 15 times, preferably 10 times, the amount of the product obtained after the reaction. Further, the particle diameter D50 of the fine powder potassium carbonate is 50-200 mu m. Further, the molar ratio of 3, 6-dichloro-4-isopropy