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CN-122010961-A - Preparation method of samidofen intermediate 3-formamide naltrexone

CN122010961ACN 122010961 ACN122010961 ACN 122010961ACN-122010961-A

Abstract

The invention belongs to the technical field of medical intermediates, and provides a preparation method of a 3-formamide naltrexone serving as a saminoprofen intermediate. The preparation method comprises the steps of mixing naltrexone, ethylene glycol, paratoluenesulfonic acid and toluene, carrying out reflux reaction to obtain a compound A, mixing the compound A, organic base and dichloromethane to obtain a mixed solution, dropwise adding trifluoromethanesulfonic anhydride into the mixed solution, carrying out reaction to obtain a compound B, mixing the compound B, amine and N, N-dimethylformamide, introducing carbon monoxide under the condition of a palladium catalyst for reaction to obtain a compound C, and adding the compound C into acid for hydrolysis reaction. The preparation method does not need to use virulent zinc cyanide, adopts carbon monoxide as a carbonyl donor, has easily obtained raw materials, has the reaction pressure of 0.1-0.5 MPa and mild reaction conditions, is beneficial to industrial production, and has the total molar yield of the 3-formamide naltrexone of more than 71 percent and the purity of more than 98.0 percent.

Inventors

  • LIU JIE
  • WANG WEI
  • ZENG HUIYING
  • Jia Dengguo
  • Zhao Shiben
  • WANG XIAO
  • YU JINGBING

Assignees

  • 甘肃农垦药物碱厂有限公司
  • 兰州大学

Dates

Publication Date
20260512
Application Date
20260130

Claims (9)

  1. 1. A preparation method of a salmidafungin intermediate 3-formamide naltrexone, which is characterized by comprising the following steps: 1) Mixing naltrexone, ethylene glycol, p-toluenesulfonic acid and toluene, and carrying out reflux reaction to obtain a compound A; 2) Mixing the compound A, organic base and dichloromethane to obtain a mixed solution, and dropwise adding trifluoromethanesulfonic anhydride into the mixed solution to react to obtain a compound B; 3) Mixing a compound B, amine and N, N-dimethylformamide, and introducing carbon monoxide under the condition of a palladium catalyst to react to obtain a compound C; 4) And adding the compound C into acid to carry out hydrolysis reaction to obtain the 3-formamide naltrexone.
  2. 2. The preparation method of the 3-carboxamide naltrexone serving as a salmidafung intermediate according to claim 1, wherein the mole ratio of naltrexone, ethylene glycol and p-toluenesulfonic acid in the step 1) is 1:2.5-5:1.2-5.
  3. 3. The preparation method of the samidofen intermediate 3-carboxamide naltrexone according to claim 1 or 2, wherein the temperature of the reflux reaction in the step 1) is 95-110 ℃.
  4. 4. Process for the preparation of the 3-carboxamide naltrexone intermediate of samidofene according to claim 3, characterized in that in step 2) the organic base is triethylamine, N-diisopropylethylamine or pyridine.
  5. 5. The preparation method of the 3-carboxamide naltrexone serving as a salmidafil intermediate according to claim 4, wherein the molar ratio of the compound a to the organic base to the triflic anhydride in the step 2) is 1:1.5-2:1.2-1.5; the temperature of the reaction in the step 2) is-10-5 ℃, and the dropping speed is 9.0-15.0 mL/min.
  6. 6. Process for the preparation of the 3-carboxamide naltrexone intermediate of samidofen according to claim 4 or 5, characterized in that in step 3) the amine is hexamethyldisilazane, hexaethyldisilazane, hexaphenyldisilazane or tetramethyldiphenyldisilazane and the palladium-based catalyst is 1,1 '-bis (diphenylphosphino) ferrocene palladium dichloride dichloromethane complex, 1' -bis (diphenylphosphino) ferrocene palladium dichloride or palladium acetate.
  7. 7. The method for preparing a salmidafungin intermediate 3-carboxamide naltrexone according to claim 6, wherein the molar ratio of the compound B, the amine and the palladium catalyst in the step 3) is 1:2-8:0.007-0.01; the temperature of the reaction in the step 3) is 80-100 ℃, and the pressure of the reaction is 0.1-0.5 MPa.
  8. 8. The preparation method of the 3-formamidocaprone as a salmidocaprone intermediate according to claim 1 or 7, wherein the acid in the step 4) is hydrochloric acid, formic acid, phosphoric acid or sulfuric acid, and the concentration of the acid is 2-5 mol/L.
  9. 9. The preparation method of the salmidafungin intermediate 3-formamide naltrexone according to claim 8, wherein the dosage ratio of the compound C to the acid in the step 4) is 1 kg:7-10L, and the temperature of the hydrolysis reaction is 40-60 ℃.

Description

Preparation method of samidofen intermediate 3-formamide naltrexone Technical Field The invention relates to the technical field of medical intermediates, in particular to a preparation method of a 3-formamide naltrexone serving as a saminoprofen intermediate. Background Samidorphan (Sa Mi Duofen) is a novel chemical substance, has a structure similar to naltrexone, can be combined with mu-opioid receptor, kappa-opioid receptor and delta-opioid receptor with high affinity, is a mu-opioid receptor antagonist, and has partial agonistic activity on kappa-opioid receptor and delta-opioid receptor. The U.S. Food and Drug Administration (FDA) has approved LYBALVI (olanzapine Ping Sami multi-fin) for the treatment of adult schizophrenia and adult bipolar I disorder, for use as maintenance monotherapy, and as monotherapy or adjuvant therapy for lithium or valproate for acute treatment of mania or mixed episodes. The preparation method of the 3-carboxamide naltrexone serving as a key intermediate of the samidofen is particularly important. US0197905A1 reports a preparation method for preparing 3-carboxamide naltrexone, which uses naltrexone as a starting material, firstly uses trifluoromethanesulfonic anhydride to protect 3-hydroxyl, then carries out substitution reaction with tetrakis (triphenylphosphine) palladium and zinc cyanide to obtain cyano intermediate, and hydrolyzes the cyano intermediate to obtain the 3-carboxamide naltrexone. The route needs to use the highly toxic zinc cyanide, has high production risk and is not beneficial to the industrial production and amplification. US10005790B2 discloses a preparation method of 3-carboxamide naltrexone, which uses naltrexone as a starting material, firstly carries out acetal protection on carbonyl, then activates 3-hydroxyl with trifluoromethanesulfonic anhydride, then carries out substitution reaction with zinc cyanide in DMF under the catalysis of palladium acetate and 1,1' -bis (diphenylphosphine) ferrocene, and finally obtains the 3-carboxamide naltrexone through hydrolysis and deprotection. The reaction route is prolonged, and the method is also used for the drastic drug zinc cyanide, which is not beneficial to industrial production. For the method of avoiding zinc cyanide, CN118027047A discloses a preparation method of 3-formamide naltrexone, which takes naltrexone as a starting material, uses trifluoro methanesulfonic anhydride or N-phenyl bis trifluoro methane sulfimide to protect 3-hydroxyl, then mixes an intermediate with palladium catalyst, organic phosphine ligand, alkali and amine in a reaction solvent, fills carbon monoxide to 20bar, and carries out high-pressure reaction to obtain the 3-formamide naltrexone. The method shortens the reaction route and avoids using zinc cyanide, but the reaction process needs to be pressurized to 20bar, the requirement on equipment is high, the production cost is high, potential safety hazards exist, and the yield of the method only reaches 56%, and is low. CN118598813a discloses a process for preparing 3-carboxamide naltrexone, which uses naltrexone as starting material, uses N, N-dimethylformamide and 3-hydroxy to react to generate amine ester intermediate, the amine ester intermediate reacts with morpholinylacetonitrile under the condition of catalyst and ligand to generate cyano intermediate, and the cyano intermediate is hydrolyzed to obtain 3-carboxamide naltrexone. The yield of the route can reach 70%, but a copper salt catalyst and nickel catalyst system is used, the catalyst consumption is large (0.05-0.2 equivalent), the production cost is improved, and the industrial production is not facilitated. Therefore, it is very necessary to develop a method for preparing 3-carboxamide naltrexone with high efficiency, low toxicity and high economical efficiency, which can avoid the use of highly toxic reagent zinc cyanide and reduce the safety risk. Disclosure of Invention The invention aims to provide a preparation method of a 3-formamide naltrexone serving as a salmidafung intermediate in order to overcome the defects of the prior art. In order to achieve the above object, the present invention provides the following technical solutions: the invention provides a preparation method of a salmidafungin intermediate 3-formamide naltrexone, which comprises the following steps: 1) Mixing naltrexone, ethylene glycol, p-toluenesulfonic acid and toluene, and carrying out reflux reaction to obtain a compound A; 2) Mixing the compound A, organic base and dichloromethane to obtain a mixed solution, and dropwise adding trifluoromethanesulfonic anhydride into the mixed solution to react to obtain a compound B; 3) Mixing a compound B, amine and N, N-dimethylformamide, and introducing carbon monoxide under the condition of a palladium catalyst to react to obtain a compound C; 4) And adding the compound C into acid to carry out hydrolysis reaction to obtain the 3-formamide naltrexone. Preferably, the mole ratio of the naltrexone t