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CN-121974930-A - Preparation method of intermediate of Mabaluo Sha Wei

CN121974930ACN 121974930 ACN121974930 ACN 121974930ACN-121974930-A

Abstract

The invention discloses a preparation method of an intermediate of Marbalol Sha Wei, which comprises the following steps of carrying out a halogenation reaction, carrying out a second elimination reaction, carrying out a third addition reaction and carrying out a fourth ring closing reaction, wherein the selected starting materials, solvents and catalysts are industrial-grade cheap and easily available products, have the advantage of low production raw material cost, provide economic feasibility support for industrial mass production, have mild reaction conditions in each step in the reaction process, have fewer byproducts and high yield, can prepare a target product more efficiently, and simultaneously have high atom utilization rate of a synthetic route, excellent atom economy, strong stability of the used solvents and reagents, easy recycling and application, greatly reduce the production and emission of industrial three wastes, reduce environmental-friendly treatment cost, accord with the concept of green chemistry and sustainable development, and solve the problems of low yield, severe reaction conditions and high raw and auxiliary material cost in the existing method.

Inventors

  • LIAN XIONGDONG
  • Lu Xiangran
  • MA ZHIHONG

Assignees

  • 上海沃缨生物科技有限公司

Dates

Publication Date
20260505
Application Date
20260203

Claims (10)

  1. 1. A preparation method of an intermediate of the Mabalo Sha Wei comprises the following steps of a first halogenation reaction, a second elimination reaction, a third addition reaction, a fourth ring closing reaction, and is characterized in that: in the first step, morpholine, a solvent and a halogenating reagent are mixed, and an intermediate N-halogenated morpholine is obtained through halogenation; in the second step, the intermediate N-halogenated morpholine, a solvent, alkali and a catalyst are mixed, and an imine intermediate is obtained through elimination reaction; in the third step, mixing an imine intermediate, a solvent, a nucleophilic reagent and a catalyst, and obtaining a 3-substituted morpholine intermediate through an addition reaction; in the fourth step, the 3-substituted morpholine intermediate, the solvent, the intermediate A and the pH regulator are mixed, and the Marbalol Sha Wei intermediate is obtained through ring closure reaction.
  2. 2. The method for preparing an intermediate of Marbalol Sha Wei according to claim 1, wherein in the first step, the molar ratio of morpholine to halogenated reagent is 1:1-1:2, preferably 1:1-1:1.5, the reaction temperature is 0-50 ℃, preferably 0-25 ℃, and the reaction time is 1-5 h, preferably 1-2 h; the solvent comprises polar solvent, nonpolar solvent, preferably nonpolar solvent, polar solvent comprises methanol, ethanol, isopropanol, water, dimethyl sulfoxide, N-dimethylformamide, acetonitrile, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, methyl tertiary butyl ether, nonpolar solvent comprises dichloromethane, chloroform, toluene, N-hexane and cyclohexane, halogenated reagent comprises chlorinated reagent, brominated reagent and iodinated reagent, chlorinated reagent comprises chlorine, N-chlorosuccinimide, trichloroisocyanuric acid, 1, 3-dichloro-5, 5-dimethylhydantoin, N-chlorophthalimide, trichloromelamine, sodium hypochlorite, brominated reagent comprises bromine, N-bromosuccinimide, tribromoisocyanuric acid, 1, 3-dibromo-5, 5-dimethylhydantoin, N-bromophthalimide, sodium hypobromite, iodized reagent comprises iodine, N-iodosuccinimide, triiodo isocyanuric acid and sodium hypoiodite, and intermediate N-halogenated morpholine has the following structural formula: Wherein X is one of Cl, br and I.
  3. 3. The process for preparing an intermediate of Marbazole Sha Wei according to claim 1, wherein in the second step, the molar ratio of N-halogenated morpholine to base is 1:1-1:2, preferably 1:1-1:1.5, the molar ratio of N-halogenated morpholine to catalyst is 1:0.01-1:0.2, preferably 1:0.01-1:0.1, the reaction temperature is 0-80 ℃, preferably 0-50 ℃, and the reaction time is 1h-5h, preferably 1h-2h.
  4. 4. The process for preparing an intermediate of Marba Sha Wei according to claim 1, wherein in the second step, the solvent comprises a polar solvent, preferably a polar solvent, the polar solvent comprises methanol, ethanol, isopropanol, water, dimethyl sulfoxide, N-dimethylformamide, acetonitrile, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether, the non-polar solvent comprises dichloromethane, chloroform, toluene, N-hexane, cyclohexane, the base comprises sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium phosphate, pyridine, imidazole, tetrahydropyrrole, piperidine, morpholine, methylamine, ethylamine, triethylamine, N-diisopropylethylamine, 1, 8-diazabicycloundec-7-ene, and the catalyst is a phase transfer catalyst comprising tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltriethylammonium chloride, tetraphenylphosphine chloride, triphenylphosphine bromide, 18-crown-6-ether, 15-crown-5-polyethylene glycol ether.
  5. 5. The method for preparing an intermediate of Marbalol Sha Wei according to claim 1, wherein in the third step, the molar ratio of the imine intermediate to the nucleophile is 1:1-1:2, preferably 1:1-1:1.5, the molar ratio of the imine intermediate to the catalyst is 1:1-1:2, preferably 1:1-1:1.5, the reaction temperature is 0 ℃ to 50 ℃, preferably 0 ℃ to 25 ℃, and the reaction time is 1h to 5h, preferably 1h to 2h.
  6. 6. The method for preparing an intermediate of Marbalo Sha Wei according to claim 1, wherein in the third step, the structural formula of the 3-substituted morpholine intermediate comprises the following two types: Wherein R 3 comprises H, C 1 -C 20 straight-chain alkyl, C 1 -C 20 branched-chain alkyl, C 3 -C 20 cycloalkyl and C 5 -C 20 aryl, and R 4 comprises H, na and K.
  7. 7. The method for preparing an intermediate of Marba Sha Wei according to claim 1, wherein in the third step, the solvent comprises a polar solvent, a nonpolar solvent, preferably a polar solvent, the polar solvent comprises methanol, ethanol, isopropanol, water, dimethyl sulfoxide, N-dimethylformamide, acetonitrile, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether, the nonpolar solvent comprises dichloromethane, chloroform, toluene, N-hexane, cyclohexane, the nucleophile is H 2 O、NaOR 3 、KOR 3 , sulfurous acid, sodium sulfite, sodium bisulphite, the NaOR 3 and KOR 3 , R 3 comprises H, C 1 -C 20 linear alkyl, C 1 -C 20 branched alkyl, C 3 -C 20 cycloalkyl and C 5 -C 20 aryl, the catalyst comprises an acid catalyst and a phase transfer catalyst, the acid catalyst comprises hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, benzoic acid, p-toluenesulfonic acid, aluminum trichloride, ferric trichloride, cupric chloride, cuprous chloride, boron trifluoride, diethyl ether, the phase transfer catalyst comprises tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltriethylammonium chloride, tetraphenylethyl chloride, triphenylphosphine-18-crown ether, and polyethylene glycol-5-crown ether.
  8. 8. A process for the preparation of an intermediate of Mabalo Sha Wei according to claim 1, wherein in step four the reaction temperature is from 25℃to 100℃and preferably from 50℃to 100℃and the reaction time is from 1h to 24h and preferably from 8h to 16h.
  9. 9. The method for preparing an intermediate of Marbalol Sha Wei as claimed in claim 1, wherein in the fourth step, the structural formula of the intermediate A is as follows: Wherein R 1 and R 2 are both selected from one of C 1 -C 20 linear alkyl, C 1 -C 20 branched alkyl, C 3 -C 20 cycloalkyl and C 5 -C 20 aryl, preferably one of C 1 -C 10 linear alkyl, C 1 -C 10 branched alkyl, C 3 -C 10 cycloalkyl and C 5 -C 10 aryl, and the structural formula of the Marba Sha Wei intermediate is as follows: Wherein, R 1 is one of C 1 -C 20 straight-chain alkyl, C 1 -C 20 branched-chain alkyl, C 3 -C 20 cycloalkyl and C 5 -C 20 aryl, preferably one of C 1 -C 10 straight-chain alkyl, C 1 -C 10 branched-chain alkyl, C 3 -C 10 cycloalkyl and C 5 -C 10 aryl.
  10. 10. The method for preparing an intermediate of Marba Sha Wei according to claim 1, wherein in the fourth step, the solvent comprises a polar solvent, preferably a polar solvent, the polar solvent comprises methanol, ethanol, isopropanol, water, dimethyl sulfoxide, N-dimethylformamide, acetonitrile, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether, the non-polar solvent comprises dichloromethane, chloroform, toluene, N-hexane, cyclohexane, the pH regulator comprises an acid, a base, the acid comprises hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, benzoic acid, p-toluenesulfonic acid, aluminum trichloride, ferric trichloride, cupric chloride, cuprous chloride, boron trifluoride diethyl ether, the base comprises sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium phosphate, pyridine, imidazole, tetrahydropyrrole, piperidine, morpholine, methylamine, ethylamine, triethylamine, N-diisopropylethylamine, 1, 8-diazabicycloundec-7-ene.

Description

Preparation method of intermediate of Mabaluo Sha Wei Technical Field The invention relates to the technical field of preparation of pharmaceutical intermediates, in particular to a preparation method of an intermediate of Marbalol Sha Wei. Background Marbalo Sha Wei (Baloxavir Marboxil) is a novel anti-influenza virus drug developed by Japanese salt wild pharmaceutical company together with Swiss and has the trade name Xofluza. The drug can inhibit the transcription of the virus self mRNA by inhibiting Cap dependent endonuclease in the replication process of influenza virus and blocking the CAP structure of the virus from obtaining host mRNA from host cells. Compared with the traditional anti-influenza drug oseltamivir, the marbalo Sha Wei has the advantages of single-dose oral administration, quicker curative effect, smaller adverse reaction and the like, and becomes an important breakthrough in the field of anti-influenza drugs. In the prior art, the method I is disclosed in patent WO2016175224, as shown in figure 1, 3-morpholinone is used as a starting material, DIBAL-H is reduced to carbonyl after a protecting group is added, intermediate 5 is obtained through methylation, 7 is obtained through esterification of carboxylic acid compound 6 and Boc-protected hydrazine is reacted to be converted into 8, boc protecting group is removed to obtain intermediate 9, compound 9 and compound 5 are coupled under the condition of stannic chloride, compound 10 is obtained through ring closure after deprotection, and racemic compound 1A is obtained. The second method is disclosed in patent WO2017221869, as shown in figure 2, the substitution reaction is carried out on the compound 11 and the acetal 12 to obtain 13, then the hydrazine is used for deprotection to obtain an intermediate 14, the methyl esterification of the carboxylic acid intermediate 6 is carried out to obtain 15,15 and the hydrazine protected by Boc are reacted to generate an intermediate 16,16 and 14, the ammonolysis reaction is carried out to obtain 17, then the acid catalytic deprotection is carried out to obtain a racemized compound 1A, compared with the first method, the synthetic steps of the route are relatively shorter, the reaction conditions are milder, the low-temperature reaction in the route I is avoided, the cost of the used raw materials is relatively lower, but the atom economy of the route in the process of preparing the intermediate 14 is lower, the stability of the intermediate 13 is poor, the amplification preparation is not facilitated, the third method disclosed in patent WO2019070059, as shown in figure 3, the L-serine 18 protected by Boc is used as a starting material, the carboxyl methyl esterification is carried out after the substitution with the acetal 12, then the Boc is carried out to obtain the compound 21, the compound 6 is reacted by the two steps of debenzylation and substitution reaction to obtain 22,22 and the hydrazine protected by Boc are carried out to obtain 23, the method four is as shown in figure 4, intermediate 28 is obtained after methylation by taking morpholone as a raw material, intermediate 29 is formed by ring closure of intermediate 28 and intermediate 9 under acid catalysis, intermediate 1A is obtained by reduction of sodium borohydride, the route is relatively short, but the selectivity in the reduction reaction of intermediate 29 is poor, lactam reduction byproducts are easy to generate, the total reaction yield is low, and the method is mainly carried out in a laboratory scale at present. Disclosure of Invention The invention aims to provide a preparation method of an intermediate of Marbalol Sha Wei, which aims to solve the problems in the background technology. The preparation method of the intermediate of the Ma Ballon Sha Wei comprises the following steps of first halogenating reaction, second eliminating reaction, third adding reaction, fourth closing ring reaction; in the first step, morpholine, a solvent and a halogenating reagent are mixed, and an intermediate N-halogenated morpholine is obtained through halogenation; in the second step, the intermediate N-halogenated morpholine, a solvent, alkali and a catalyst are mixed, and an imine intermediate is obtained through elimination reaction; in the third step, mixing an imine intermediate, a solvent, a nucleophilic reagent and a catalyst, and obtaining a 3-substituted morpholine intermediate through an addition reaction; in the fourth step, the 3-substituted morpholine intermediate, the solvent, the intermediate A and the pH regulator are mixed, and the Marbalol Sha Wei intermediate is obtained through ring closure reaction. Preferably, in the first step, the molar ratio of the morpholine to the halogenated reagent is 1:1-1:2, preferably 1:1-1:1.5, the reaction temperature is 0-50 ℃, preferably 0-25 ℃, and the reaction time is 1h-5h, preferably 1h-2h; the solvent comprises polar solvent, nonpolar solvent, preferably nonpolar solvent, polar s