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CN-121991039-A - Rasemet-teh preparation method of herba Luo

CN121991039ACN 121991039 ACN121991039 ACN 121991039ACN-121991039-A

Abstract

The application discloses a preparation method of rismiterol, and belongs to the technical field of chemical synthesis. The application takes a compound I as an initial raw material, a compound II is produced by base catalysis, a compound III is produced by bromination reaction, a compound IV is produced by Suzuki coupling reaction of the compound III and isopropenylboronic acid pinacol ester, a key intermediate V is produced by reaction of the compound IV and 2, 6-dichloro-4-aminophenol, a compound VI is produced by diazotization coupling reaction, a compound VII is produced by ring closure reaction, and a target product of Rasemet is produced by hydrogenation reduction. The method adopts a conventional catalyst to replace a noble metal system, selects industrial easily-obtained raw materials to avoid using Grignard reagent, ensures that the yield of each step breaks through 85 percent through optimizing the reaction conditions, ensures that the purity of the final product reaches more than 99.8 percent, simultaneously realizes the reduction of the cost of the raw materials, the reduction of three wastes emission and the improvement of the operation safety, and provides a reliable technical scheme for the large-scale production of the Rasemet.

Inventors

  • JIANG RUI
  • CAO HONG
  • MA HUIJUN
  • GU WENCHAO
  • LI YUANRUI
  • LI ZEBIAO

Assignees

  • 南通常佑药业科技有限公司

Dates

Publication Date
20260508
Application Date
20251215

Claims (9)

  1. 1. The preparation method of the risperidone is characterized by comprising the following steps of: ; The method comprises the following specific steps: 1) Dissolving the compound I in the solvent A, adding alkali, and then heating and stirring to react to obtain a compound II; 2) Dissolving a compound II in a solvent B, adding a brominating reagent and a catalyst A, and reacting at a certain temperature in an inert atmosphere to obtain a compound III; 3) Dissolving a compound III and isopropenylboronic acid pinacol ester in a solvent C, and performing heating coupling under the combined action of a catalyst B, a ligand and alkali in an inert atmosphere to obtain a compound IV; 4) After a compound IV and 2, 6-dichloro-4-aminophenol are dissolved in a solvent D, heating and reacting under the catalysis of an acid binding agent in an inert atmosphere to obtain a key intermediate V; 5) Dissolving the intermediate V in a solvent E, carrying out diazotization reaction with sodium nitrite, then coupling with N-cyano-acetyl urethane, and then heating under the action of alkali to react to generate a compound VI; 6) After dissolving a compound VI in a solvent F, heating and closing a ring to react under the catalysis of alkali to obtain a compound VII; 7) And (3) dissolving the compound VII in a solvent G, pressurizing under the action of a catalyst C and a hydrogen donor for reaction, and reducing to obtain a final product of the Resimetirol, namely the compound VIII.
  2. 2. The preparation method of the rismiterol according to claim 1, wherein in the step 1), the solvent A is at least one of acetic acid and methanol, the base is at least one of sodium acetate and sodium methoxide, the molar ratio of the compound I to the base is 1:1.5-1:3.5, the heating reaction temperature is 50-115 ℃, and the heat preservation time is 6-16 h.
  3. 3. The preparation method of the rismitrol disclosed in claim 1, wherein in the step 2), the solvent B is at least one selected from acetonitrile and N, N-dimethylformamide, the catalyst A is at least one selected from methanesulfonic acid and trifluoromethanesulfonic acid, the molar ratio of the compound II to the catalyst A is 1:0.1-1:1.5, the brominating reagent is N-bromosuccinimide, the molar ratio of the compound II to the brominating reagent is 1:1-1:2, the reaction temperature is-15-5 ℃ and the reaction time is 0.5-3 h.
  4. 4. The preparation method of the rismitrol according to claim 1, wherein in the step 3), the solvent C is at least one of 1, 4-dioxane and 2-methyltetrahydrofuran, the catalyst B is at least one of palladium acetate and palladium chloride, the molar ratio of the compound III to the catalyst B is 1:0.05-1:0.3, the ligand is any one of triphenylphosphine and 2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl, the molar ratio of the compound III to the ligand is 1:0.1-1:0.5, the base is at least one of potassium carbonate, potassium phosphate, potassium acetate and triethylamine, the molar ratio of the compound III to the base is 1:0.1-1:1.5, the molar ratio of the compound III to the isopropenyl pinacol borate is 1:1.1-1:3.0, the heating reaction temperature is 80-120 ℃ and the reaction time is 4-24 h.
  5. 5. The preparation method of the rismitrol according to claim 1, wherein in the step 4), the solvent D is at least one selected from toluene, 1, 4-dioxane, N-dimethylformamide and dimethyl sulfoxide, the acid binding agent is at least one selected from potassium carbonate, potassium phosphate, N-diisopropylethylamine and triethylamine, the molar ratio of the compound IV to the acid binding agent is 1:1.5-1:3.0, the molar ratio of the compound IV to the 2, 6-dichloro-4-aminophenol is 1:1.05-1.8, the heating reaction temperature is 60-100 ℃, and the reaction time is 4-12 h.
  6. 6. The preparation method of the rismitrol according to claim 1, wherein in the step 5), the solvent E is at least one of glacial acetic acid and dilute hydrochloric acid, the molar ratio of the compound V to sodium nitrite is 1:1-1:2, the molar ratio of the compound V to N-cyanoacetyl urethane is 1:1.1-1:3.5, the coupling reaction temperature is-10 ℃, the reaction time is 0.5-2 h, the alkali is at least one of sodium acetate and potassium carbonate, the molar ratio of the compound V to the alkali is 1:2-1:5, the heating reaction temperature under the action of the alkali is 30-45 ℃, and the reaction time is 3-6 h.
  7. 7. The preparation method of the rismiterol according to claim 1, wherein in the step 6), the solvent F is at least one selected from N, N-dimethylacetamide and acetonitrile, the base is at least one selected from sodium acetate and potassium carbonate, the molar ratio of the compound VI to the base is 1:1.1-1:3.0, the heating reaction temperature is 60-120 ℃, and the reaction time is 2-5 h.
  8. 8. The preparation method of the rismitrol according to claim 1, wherein in the step 7), the solvent G is selected from at least one of methanol and tetrahydrofuran, the hydrogen donor is hydrogen, the catalyst C is selected from at least one of 10% palladium carbon and Raney nickel, the mass ratio of the compound VII to the catalyst C is 1:0.02-1:0.10, the reaction temperature is 25-55 ℃, the reaction pressure is 0.05-0.2 MPa, and the reaction time is 8-16 h.
  9. 9. A key intermediate of oseltamiol, which is characterized in that the structure of the key intermediate is shown as a formula V: ; The intermediate is used in the preparation method of the rismeterol of any one of claims 1-8.

Description

Rasemet-teh preparation method of herba Luo Technical Field The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of a rismiterol. Background Resimetirol (Resmetirom), 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, its structural formula is as follows: ; Ralset is a thyroid hormone receptor beta (THR-beta) selective agonist developed by the company Madrigal Pharmaceuticals of America. The drug was approved by the U.S. Food and Drug Administration (FDA) for marketing at month 2024 under the trade designation Rezdiffra, and its indications cover non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD) and related dyslipidemia. As a NASH oral therapeutic drug which is marketed in the first worldwide lot, the successful marketing of the Ralset not only fills the blank of clinical treatment in the field, but also marks the new era of accurate targeted intervention of NASH treatment from traditional symptomatic management, and has remarkable clinical value and broad market prospect. As a breakthrough innovative drug, the research and development of the synthesis process of the rismiterol is always the focus of industry. Although numerous documents and patents disclose preparation methods, the prior art generally faces multiple challenges in industrial production, including problems of complex reaction steps, low yield, high raw material cost, outstanding environmental protection pressure and the like, and is difficult to meet the comprehensive requirements of large-scale production on high efficiency, economy and sustainability. The synthetic route using 3, 6-dichloropyridazine as starting material is disclosed by the original research company in patent WO 2007009913: The method comprises the steps of constructing a target molecular skeleton through three-step core reaction, namely, preparing an intermediate a through free radical reaction with isobutyric acid under the catalysis of silver nitrate in the first step, performing coupling reaction with 4-amino-2, 6-dichlorophenol under the catalysis of cuprous iodide in the alkaline condition in the second step to obtain an intermediate b, hydrolyzing with an acetic acid/sodium acetate system to obtain an intermediate c, and sequentially performing diazotization, coupling with N-cyano-acetyl urethane and ring closing reaction to finally obtain the Rasemet (VIII). The method can prepare target products, but has a plurality of industrial bottlenecks, the core defects are concentrated on the aspects of cost, purification and environmental protection, namely, depending on noble metal or heavy metal catalysts such as silver nitrate, cuprous iodide and the like, the method has the advantages of greatly increasing the production cost due to high reagent price and large consumption, causing environmental pollution easily caused by heavy metal residues, being not in line with the green production requirement, generating a large number of isomer impurities with similar structures due to poor selectivity of the coupling reaction in the second step, having great purification difficulty, needing depending on complex purification means such as column chromatography and the like, being difficult to adapt to large-scale production, having low economy of hydrolysis reaction atoms, complicated reaction condition control and post-treatment operation in each step, and further limiting the industrialized application of the method due to low total yield of the route. Another related patent WO2014043706 discloses another synthetic strategy starting from 3, 6-dichloropyridazine: the scheme integrally adopts a route of substitution-protection-format reaction-reduction deprotection-coupling-ring closure, wherein a raw material I and 4-amino-2, 6-dichlorophenol undergo substitution reaction under alkaline conditions to obtain an intermediate g, an amino group of the intermediate g is protected by benzoic anhydride to generate an intermediate h, the intermediate h is hydrolyzed under an acetic acid/sodium acetate system to obtain an intermediate j, the intermediate j and isopropenyl magnesium chloride (or magnesium bromide) undergo format reaction to introduce isopropenyl to obtain an intermediate k, double bond reduction and amino deprotection are carried out to obtain an intermediate m, and finally the target product is obtained through diazotization coupling and ring closure reaction. The main problems of the route are that the reaction condition is strict, the format reaction condition is severe, the purchase cost is high, the reaction system is extremely sensitive to moisture and temperature, the post-treatment process is complicated, the generated solid waste and salt-containing wastewater have great harm to the environment, the large-scale use of the format reagent has obvious safety risks