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CN-121974847-A - Cabozite method for synthesizing nylon

CN121974847ACN 121974847 ACN121974847 ACN 121974847ACN-121974847-A

Abstract

The invention discloses a method for synthesizing cabotinib, which comprises the steps of placing methoxyquinoline and 4-aminophenylboronic acid pinacol ester, boric acid B (OH) 3 , a catalyst copper salt and a molecular sieve in a solvent for reaction to obtain 6, 7-dimethoxy-4- (4-aminophenoxy) quinoline, dissolving in tetrafluoroboric acid aqueous solution, adding sodium nitrite aqueous solution under the condition of ice water bath for reaction to obtain a compound 4, placing the compound 4, 1-dicyanocyclopropane and potassium phosphate in a mixed solvent of water and ethyl acetate and reacting at 60-90 ℃ under the protection of oxygen-free gas to obtain a compound 5, and placing the compound 5, p-fluorobenzene tetrafluoroborate diazonium salt and potassium phosphate in a mixed solvent of ethyl acetate and water and reacting at 60-90 ℃ under the protection of oxygen-free gas to obtain a target product cabotinib. The invention has mild reaction conditions, simple operation, high product yield, high purity and low production cost, and is suitable for industrialized production of cabotinib.

Inventors

  • LI SHOUHU
  • YAN GUOYI
  • WU MINGYUAN
  • GAO EN
  • GAO MENGLI
  • LI YIRAN
  • FENG GUIPENG
  • XIA RAN

Assignees

  • 新乡学院

Dates

Publication Date
20260505
Application Date
20251219

Claims (10)

  1. 1. The synthesis method of the cabozantinib is characterized by comprising the following specific synthesis steps: Step S1, placing methoxyquinoline, namely compound 2 and 4-aminophenylboronic acid pinacol ester, namely compound 2a, boric acid B (OH) 3 , a catalyst copper salt and a molecular sieve in a solvent for reaction to prepare 6, 7-dimethoxy-4- (4-aminophenoxy) quinoline, namely compound 3, wherein the corresponding synthetic route is as follows: Step S2, dissolving 6, 7-dimethoxy-4- (4-aminophenoxy) quinoline, namely a compound 3, in tetrafluoroboric acid water solution, and then adding sodium nitrite water solution under the ice water bath condition for reaction to prepare 6, 7-dimethoxy-4- (4-diazophenoxy) quinoline tetrafluoroborate, namely a compound 4, wherein the corresponding synthetic route is as follows: Step S3, placing 6, 7-dimethoxy-4- (4-diazophenoxy) quinoline tetrafluoroborate, namely a compound 4, 1-dicyanocyclopropane and potassium phosphate in a mixed solvent of water and ethyl acetate, and reacting at 60-90 ℃ under the protection of oxygen-free gas to prepare 1-cyano-N- (4- ((6, 7-dimethoxy-quinolin-4-yl) oxy) phenyl) cyclopropane-1-carboxamide, namely a compound 5, wherein the corresponding synthetic route is as follows: Step S4, placing 1-cyano-N- (4- ((6, 7-dimethoxy quinoline-4-yl) oxy) phenyl) cyclopropane-1-formamide, namely a compound 5, a diazonium salt of p-fluorobenzene tetrafluoroborate, namely a compound 5a and potassium phosphate in a mixed solvent of ethyl acetate and water, and reacting at 60-90 ℃ under the protection of oxygen-free gas to obtain a target product compound 1, namely cabotinib, wherein the corresponding synthetic route is as follows:
  2. 2. The method for synthesizing cabatinib according to claim 1, wherein in the step S1, the feeding molar ratio of the compound 2 to the compound 2a is 1:1-1:2, the feeding molar ratio of the compound 2 to the B (OH) 3 is 1:1.5-2.5, and the dosage of the copper salt catalyst is 20% -100% of the molar amount of the compound 2.
  3. 3. The method of claim 1, wherein the copper salt of the catalyst in step S1 is one or more of Cu (OAc) 2 、Cu(acac) 2 、CuCl 2 、CuSO 4 and Cu (NO 3 ) 2 ).
  4. 4. The method for synthesizing cabozantinib according to claim 1, wherein the solvent in the step S1 is acetonitrile, dichloromethane or tetrahydrofuran.
  5. 5. The method for synthesizing cabozantinib according to claim 1, wherein the feeding molar ratio of the compound 3 to sodium nitrite in the step S2 is 1:1-1:2.
  6. 6. The method for synthesizing cabozantinib according to claim 1, wherein in the step S3, the feeding molar ratio of the compound 4 to the 1, 1-dicyanocyclopropane is 1:1-1:2, and the feeding molar ratio of the compound 4 to the potassium phosphate is 1:1-1:2.
  7. 7. The method for synthesizing cabozantinib according to claim 1, wherein the volume ratio of ethyl acetate to water in the mixed solvent in the step S3 is 20:1-5:1.
  8. 8. The method for synthesizing cabozantinib according to claim 1, wherein in the step S4, the feeding molar ratio of the compound 5 to the compound 5a is 1:1-1:2, and the feeding molar ratio of the compound 5 to the potassium phosphate is 1:1-1:2.
  9. 9. The method for synthesizing cabozantinib according to claim 1, wherein the synthetic route is as follows:
  10. 10. The method for synthesizing cabozantinib according to claim 1, wherein the volume ratio of ethyl acetate to water in the mixed solvent in the step S4 is 20:1-5:1.

Description

Cabozite method for synthesizing nylon Technical Field The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a synthesis method of cabatinib. Background Cabozantinib (XL 184) is a novel small molecule, multi-target tyrosine kinase inhibitor developed by the company Exelixis biopharmaceutical in the united states, and its structural formula is shown below. Chinese name N- [4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] phenyl ] -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide. The molecular structure of the recombinant strain is composed of four parts of substituted quinoline, 4-oxybenzene imine, 1-diacyl cyclopropane and 4-fluorobenzene imine, and can inhibit rearranged genes (RET), hepatocyte growth factor receptor (MET), vascular Endothelial Growth Factor Receptor (VEGFR), stem cell growth factor receptor (KIT), tyrosine kinase receptor (TRKB) and the like during transfection. Is approved by the FDA in the united states for use in the treatment of metastatic medullary thyroid carcinoma, advanced MTC (medullarythyroidcarcinoma) and advanced renal clear cell carcinoma in 2012. The symptoms of treatment currently undergoing clinical trials include different cancer types for patients with prostate cancer, bladder cancer, ovarian cancer, brain, melanoma, breast cancer, non-small cell lung cancer, pancreatic cancer, and hepatocellular carcinoma. Regarding the synthesis of cabotinib, various documents or patents have been reported, and the original research company (Exelixis) discloses a synthesis method in patent WO2005030140, and the synthesis route is as follows: the synthetic route takes 3, 4-dimethoxy acetophenone as a starting material, 2-amino-4, 5-dimethoxy acetophenone is prepared through nitration and reduction, 6, 7-dimethoxy-4-hydroxy-quinoline is prepared through cyclization with ethyl formate under the alkaline condition of sodium methoxide, and then the key intermediate is obtained through reaction with trifluoro methanesulfonyl chloride under the catalysis of DMAP. In addition, cyclopropyl dicarboxylic acid is used as an initial raw material, and then the cyclopropyl dicarboxylic acid and para-fluoroaniline are subjected to amidation reaction respectively to obtain an intermediate, namely the formula III. And finally, reacting the intermediate shown in the formula II with the intermediate shown in the formula III at high temperature to obtain the cabozantinib. The method needs to adopt high temperature, has harsh process conditions, has more byproducts under the high temperature conditions, has high purification difficulty, is difficult to obtain high-quality products, and is not convenient for industrialized production. Patent literature of CN201711475163.5 reports that 6, 7-dimethoxy-4-quinolinone is prepared by taking 3, 4-dimethoxy acetophenone as a starting material, then 6, 7-dimethoxy-4- (4-aminophenoxy) quinoline is prepared by chlorination and substitution, and then the final product of cabotinib is obtained by condensation with cyclopropyl-1, 1-dicarboxylic acid and 4-fluoroaniline. The synthetic route uses corrosive acyl chloride reagents such as phosphorus oxychloride, thionyl chloride, oxalyl chloride and the like, is unfavorable for the environment and the health of human bodies, and is not favorable for industrialized production. Patent literature of CN 20161119931.1 reports that starting from malonic acid, 3- (4-fluorophenylamino) -3-oxopropionic acid is prepared by monoamidation with p-fluoroaniline, then N- (4- (6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -N ' - (4-fluorophenyl) malonamide is prepared by condensation with 4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] aniline, and finally cabotinib is synthesized by reaction with 1, 2-dibromoethane under the condition of K 2CO3. In the reaction scheme, condensing agents such as HATU and the like are required, and the problems of difficulty in post-treatment and the like are accompanied with the generation of byproducts. Patent literature CN 201910763341.7 reports that 1, 1-dicyanocyclopropane is used as a starting material to prepare 1, 1-dicarboxamido cyclopropane through alkaline hydrolysis, then the 1, 1-dicyanocyclopropane is reacted with 4-substituted fluorobenzene compound (r=cl, br, I or B (OH) 2) to prepare N- (4-fluorophenyl) -1, 1-dicarboxamide cyclopropane, and finally the 4- ((6, 7-dimethyl-quinolin-4-yl) oxy) substituted benzene (r=cl, br, I or B (OH) 2) is reacted to prepare cabatinib. In the route, the 1, 1-dicarboxamide cyclopropane is easy to generate byproducts due to structural symmetry and 4-substituted fluorobenzene compound, so that the problems of difficult post-treatment and the like are caused. In summary, the prior art for synthesizing the cabozantinib still has more problems, and the research and the search of a synthetic route of the cabozantinib which is suitable for industrial production and has the advantages of mild reaction conditions, simple operation, high