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CN-121990951-A - In Ballon Sha Wei Process for the preparation of intermediates

CN121990951ACN 121990951 ACN121990951 ACN 121990951ACN-121990951-A

Abstract

The invention relates to a preparation method of a balo Sha Wei intermediate, belonging to the technical field of drug synthesis. The preparation method comprises the steps of reacting a compound 02 with 2-fluorobenzaldehyde in the presence of an alkaline reagent, and performing post-treatment to obtain a compound 03. The compound 03 undergoes a cyclization reaction in the presence of an acid to give a compound 04. The preparation method provided by the invention has the advantages of short reaction time, mild reaction, easily available reagents, safe operation, high product yield and high product purity, can reduce cost and is beneficial to industrial implementation.

Inventors

  • KOU JINGPING
  • WU ZEYI
  • QIU MEIYAN
  • LU HUIXIONG
  • WANG ZHONGQING
  • Lin Jidi
  • XU GUOBIN
  • ZENG JIEBIN
  • LIU YUTING
  • LIAO SHOUZHU
  • ZHANG CHENXIA

Assignees

  • 广东东阳光药业股份有限公司

Dates

Publication Date
20260508
Application Date
20241105

Claims (10)

  1. 1. A method for producing a compound 03, comprising: And (3) carrying out coupling reaction on the compound 02 and 2-fluorobenzaldehyde in a solvent in the presence of an alkaline reagent to obtain a compound 03, wherein the alkaline reagent comprises at least one of sodium hydroxide, sodium carbonate and potassium carbonate.
  2. 2. The method according to claim 1, wherein the alkaline agent is potassium carbonate.
  3. 3. The production method according to any one of claims 1 to 2, wherein the solvent in the coupling reaction comprises at least one of methanol, ethanol, N-dimethylformamide; optionally, the reaction temperature of the coupling reaction is 15 ℃ to 100 ℃, preferably 30 ℃ to 80 ℃, more preferably 60 ℃.
  4. 4. The preparation method according to any one of claims 1 to 3, wherein the molar ratio of the compound 02 to the 2-fluorobenzaldehyde is 1.0 (1.0-2.0); Optionally, the molar ratio of the compound 02 to the alkaline reagent is 1.0 (0.5-2.5), preferably 1.0 (1.0-2.0), and more preferably 1.0:1.5.
  5. 5. The preparation method of the compound 03, according to claim 1, further comprises a post-treatment step after the coupling reaction is completed, wherein the post-treatment step comprises the steps of spin drying under reduced pressure, water adding crystallization, filtering and drying a filter cake.
  6. 6. A method for producing compound 04, comprising: In the presence of acid, the compound 03 undergoes a cyclization reaction in a solvent to obtain a compound 04.
  7. 7. The production method according to claim 6, wherein the acid comprises at least one of trifluoroacetic acid and trifluoromethanesulfonic acid; optionally, the solvent for the cyclization reaction comprises trifluoroacetic acid; Optionally, the reaction temperature of the cyclization reaction is 40-80 ℃; Optionally, the feeding molar ratio of the compound 03 to the acid is 1.0 (0.5-1.5); optionally, the preparation method of the compound 04 further comprises a post-treatment step, wherein the post-treatment step comprises the steps of cooling, crystallizing and pulping by using an ice water bath, filtering and drying.
  8. 8. The process for the preparation of compound 04 according to any one of claims 6 to 7 further comprises the preparation of compound 03, said compound 03 being prepared according to the process for the preparation according to any one of claims 1 to 5.
  9. 9. The preparation method according to any one of claim 1 to 8, wherein the preparation method of the compound 03 further comprises a synthesis method of a compound 02, Under the condition of nitrogen or inert gas atmosphere, the compound 01 reacts with potassium thioacetate in a solvent to obtain a compound 02, and optionally, the feeding mole ratio of the compound 01 to the potassium thioacetate is 1.0 (1.1-2.0); Optionally, the solvent comprises at least one of N, N-dimethylformamide, acetone, methanol, ethanol, preferably N, N- Dimethylformamide; optionally, the reaction temperature of the reaction of the synthesis method of the compound 02 is 15 ℃ to 35 ℃; Optionally, the synthesis method of the compound 02 further comprises a post-treatment step, wherein the post-treatment step comprises adding water and ethyl acetate, extracting, separating liquid, washing the obtained ethyl acetate layer by using sodium chloride aqueous solution, and drying under reduced pressure.
  10. 10. A compound which is a compound represented by formula 03 or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound represented by formula 03,

Description

In Ballon Sha Wei Process for the preparation of intermediates Technical Field The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of a baluo Sha Wei intermediate. Background Balo Sha Wei (Baloxavir marboxil, BAL) is a novel anti-influenza chemical, a new drug developed by the original company in japan for salt wild-type pharmacy (shimogi) and co-developed by it with Roche for influenza a and B viruses, including tamiflu (oseltamivir) resistant influenza strains and avian influenza strains (H7N 9, H5N 1), and balo Sha Wei acts by inhibiting cap-dependent endonucleases in influenza viruses. The molecular structure of baluo Sha Wei is shown below: patent application JP6212678B1 discloses a process for preparing balo Sha Wei by means of compound a: Wherein the synthetic route of compound a is as follows: In the synthetic route, the first step reaction is applied to n-butyllithium, the n-butyllithium is sensitive to air and water, can react with the n-butyllithium and can even cause combustion or explosion, the whole system is ensured to be anhydrous and oxygen-free during experimental operation, the reaction condition is harsh, great potential safety hazards exist, malodorous and highly toxic thiophenol is also used in the whole synthetic process, and the compound belongs to a tubular product in China and is not suitable for industrial scale-up production. Later, there is a patent report on an improvement method of the route, for example, chinese patent application CN115677656A reports that 7, 8-difluoro dibenzo [ b, e ] thiazepine-11 (6H) -alcohol is prepared from 6-bromo-2, 3-difluoro toluene as a raw material through three steps, and the synthetic route is as follows: The preparation method discloses that 6-bromo-2, 3-difluorotoluene is taken as a raw material to carry out bromination reaction under the condition of bromine and an initiator to obtain 6-bromo-2, 3-difluorobenzyl bromide, the 6-bromo-2, 3-difluorobenzyl bromide is subjected to substitution reaction under the condition of alkali and 2-mercaptobenzaldehyde to obtain 3, 4-difluoro-2- (((2-benzaldehyde)) thio) methyl) -benzyl bromide, and the 3, 4-difluoro-2- (((2-benzaldehyde)) thio) methyl) -benzyl bromide is subjected to nucleophilic addition reaction under the condition of alkali to realize the baluo Sha Wei intermediate 7, 8-difluoro dibenzo [ b, e ] thiaheptacyclo-11 (6H) -alcohol. The preparation method of the first two steps needs to carry out reaction at reflux temperature, the reaction temperature is high, and the reaction time is too long. The preparation method in the third step requires specific low-temperature conditions, has high requirements on equipment, increases the complexity of operation and is not beneficial to industrial mass production. Therefore, a preparation method of the baluo Sha Wei intermediate is still needed to be researched, so that the method is simple and convenient to operate, easy to implement, high in yield, high in purity, low in cost and environment-friendly. Disclosure of Invention In order to solve the technical problems, the invention provides a preparation method of a baluo Sha Wei intermediate, In a first aspect, the present invention provides a process for the preparation of compound 03 comprising: In the presence of an alkaline reagent, performing a coupling reaction on the compound 02 and 2-fluorobenzaldehyde in a solvent to obtain a compound 03; Wherein the alkaline reagent comprises at least one of sodium hydroxide (NaOH), sodium carbonate (Na 2CO3) and potassium carbonate (K 2CO3). In some embodiments, the alkaline agent is potassium carbonate (K 2CO3). In some embodiments, the solvent in the coupling reaction comprises at least one of methanol, ethanol, N-Dimethylformamide (DMF). In some embodiments, the reaction temperature of the coupling reaction is 15 ℃ to 100 ℃. In some embodiments, the reaction temperature of the coupling reaction is 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃,60 ℃, 65 ℃, 70 ℃, 75 ℃,80 ℃, 85 ℃, 90 ℃, 95 ℃, or 100 ℃. In some preferred embodiments, the reaction temperature of the coupling reaction is 30 ℃ to 80 ℃. In some more preferred embodiments, the reaction temperature of the coupling reaction is 60 ℃. In some embodiments, the molar ratio of the compound 02 to the 2-fluorobenzaldehyde is 1.0 (1.0-2.0). In some embodiments, the molar ratio of compound 02 to 2-fluorobenzaldehyde charge is 1.0:1.0, 1.0:1.5, or 1.0:2.0. In some embodiments, the molar ratio of the compound 02 to the alkaline reagent is 1.0 (0.5-2.5). In some embodiments, the molar ratio of compound 02 to alkaline reagent charge is 1.0:0.5, 1.0:1.0, 1.0:1.5, 1.0:2.0, or 1.0:2.5. In some preferred embodiments, the molar ratio of the compound 02 to the alkaline reagent is 1.0 (1.0-2.0). In some more preferred embodiments, the molar ratio of compound 02 to alkaline reagent charge is 1.0:1.5. In some embodiments, the preparation method of the compound 03