CN-121991040-A - Preparation method of deuterium-celecoxib

Abstract

The invention discloses a preparation method of deuterium-celecoxib, and belongs to the technical field of chemical synthesis. According to the scheme, 4, 6-dichloropyridazine-3-carboxylic acid methyl ester is used as a starting material, a target product is efficiently synthesized through nucleophilic substitution, ammonolysis/hydrolysis, amide condensation and targeted condensation, a noble metal catalyst is not needed to participate, a key carbon-nitrogen bond is built through a high-selectivity nucleophilic substitution process, deuterated methylamine hydrochloride is accurately introduced in a final step, reaction stability and selectivity are improved, the process condition is mild, the operation is simple and convenient, the yield of the final product is more than 85%, the product purity is more than 99.8%, the used solvent and reagent are environment-friendly, no heavy metal residue exists, waste liquid and waste residues are few and are easy to treat, the environment-friendly chemical concept is completely met, and an efficient, economical and safe industrial path is provided for the large-scale production of deuterium-alexitinib.

Inventors

• GE WENJIE
• MA HUIJUN
• SU CHENLIANG
• LI ZEBIAO
• LI KEYING
• LIN YANFENG

Assignees

• 南通常佑药业科技有限公司

Dates

Publication Date

20260508

Application Date

20251224

Claims (5)

1. 1. The preparation method of the deuterium-celecoxib is characterized by comprising the following steps of: ; The method comprises the following specific steps: 1) Adding a compound I and 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazole-3-yl) aniline into a solvent A, stirring and dissolving, adding an alkali reagent, and heating under an inert atmosphere to carry out nucleophilic substitution reaction to obtain an intermediate II; 2) Dissolving the intermediate II in a solvent B, adding an ammonolysis reagent, heating to perform ammonolysis reaction to replace chlorine atoms on a pyridazine ring, dissolving an ammonolysis product in the solvent C, and adding an aqueous solution of alkali to perform ester group hydrolysis reaction to obtain an intermediate III; 3) Adding cyclopropanecarboxylic acid, a condensing agent and alkali into the solvent D, uniformly stirring, then controlling Wen Di to add the solvent D solution of the intermediate III, and heating to perform amide condensation reaction after the dripping is finished to obtain an intermediate IV; 4) And (3) dissolving the intermediate IV in a solvent E, and performing condensation reaction with deuterated methylamine hydrochloride under the action of alkali and a condensing agent in an inert atmosphere to obtain the target product deuterium-celecoxib.
2. 2. The method for preparing deuterium cocoa xitinib according to claim 1, characterized in that in step 1): The solvent A is at least one selected from water, dioxane, ethylene glycol dimethyl ether, tetrahydrofuran, methyl ethyl ketone, acetonitrile and isopropanol; The heating reaction temperature is 50-100 ℃ and the reaction time is 16-24 hours; The alkali reagent is selected from any one of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium phosphate, dipotassium hydrogen phosphate and potassium acetate; The molar ratio of the compound I to the 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazole-3-yl) aniline is 1:1.1-1.5; The molar ratio of the compound I to the alkali reagent is 1:0.3-2.0.
3. 3. The preparation method of deuterium-cocoa-xitinib as defined in claim 1, wherein in the step 2), the solvent B is at least one selected from dimethyl sulfoxide, dimethylformamide, dioxane, water, methanol and ethanol; The ammonolysis reagent is selected from any one of concentrated ammonia water, ammonia/methanol solution and ammonia/ethanol solution; the molar ratio of the intermediate II to the ammonolysis reagent is 1:2.5-7.0; The ammonolysis reaction is carried out by heating at 60-80 ℃ for 6-8 hours; The solvent C is at least one selected from water, methanol, ethanol, acetonitrile and tetrahydrofuran; the alkali is selected from any one of lithium hydroxide, sodium hydroxide and potassium hydroxide; the molar ratio of the intermediate II to the alkali is 1:1.1-4.0; The temperature of the ester group hydrolysis reaction is 20-30 ℃ and the reaction time is 2-4 h.
4. 4. The preparation method of deuterium-cocoa-xitinib according to claim 1, wherein in the step 3), the solvent D is at least one selected from toluene, acetonitrile, dichloromethane, acetone, ethanol and dioxane; the condensing agent is selected from any one of N, N, N ', N' -tetramethyl-O- (7-azabenzotriazole-1-yl) hexafluorophosphate, benzotriazole-N, N, N ', N' -tetramethyl urea hexafluorophosphate and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; The mol ratio of the intermediate III to the condensing agent is 1:1.1-1.5; the base is at least one of triethylamine and N, N-diisopropylethylamine; The molar ratio of the intermediate III to the alkali is 1:1-3; the mol ratio of the intermediate III to the cyclopropanecarboxylic acid is 1:1.1-1.5; the temperature in the process of dripping the intermediate III is controlled to be 10-15 ℃; the temperature of the amide condensation reaction is 20-40 ℃ and the heat preservation time is 4-10 h.
5. 5. The preparation method of deuterium cocoa xitinib according to claim 1, wherein in the step 4), the solvent E is at least one selected from methanol, ethanol, acetonitrile, tetrahydrofuran, acetone and N-methylpyrrolidone; The condensing agent is at least one selected from N, N, N ', N' -tetramethyl-O- (7-azabenzotriazole-1-yl) hexafluorophosphate, benzotriazole-N, N, N ', N' -tetramethyl urea hexafluorophosphate, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole; the molar ratio of the intermediate IV to the condensing agent is 1:0.4-2.2; The alkali is at least one of triethylamine, N-diisopropylethylamine, N-methylimidazole and N-methylmorpholine; The molar ratio of the intermediate IV to the alkali is 1:0.6-5; the mol ratio of the intermediate IV to the deuterated methylamine hydrochloride is 1:1.1-1.5; the temperature of the condensation reaction is 30-50 ℃ and the reaction time is 1-4 h.

Description

Preparation method of deuterium-celecoxib Technical Field The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of deuterium-celecoxib. Background Deuterated celecoxib (Deucravacitinib), chemical name 6- [ (cyclopropylcarbonyl) amino ] -4- [ [ 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl ] amino ] -N- (methyl-D3) -3-pyridazinecarboxamide, is the first and only approved allosteric inhibitor of tyrosine kinase 2 (TYK 2) worldwide. The structural formula is as follows: ; The drug was approved by the U.S. FDA at month 2022 (trade name: sotyktu) for the treatment of moderate to severe plaque psoriasis adult patients suitable for systemic or phototherapy, followed by approval in Europe, china at month 2023, and 10. The method has the core advantages of accurately targeting the psoriasis pathogenic nuclear spindle, having good safety and tolerance, having no 'black frame warning', obtaining the consistent recommendation of domestic and foreign authoritative guidelines, and opening up a brand new field of psoriasis targeting oral treatment. From the market prospect, the commercial value of the deuterium-celecoxib is remarkable, the global total sales of 2024 reaches 2.46 hundred million dollars, the 44.7% is increased by the same ratio, the clinical accessibility is further improved as the deuterium-celecoxib is brought into the medical insurance catalogue of China, and the future sales and market scale are expected to be continuously enlarged. Therefore, the development of the high-efficiency, stable and economic preparation method of the deuterium-celecoxib has important practical significance for promoting the large-scale production and meeting the clinical demands. Despite the outstanding clinical value and market potential of deuterium-celecoxib, the prior art synthesis technology still has a number of bottlenecks. The first synthetic route disclosed by the original research company in patent WO2014/074661A is as follows: ; The route takes 4, 6-dihydroxypyridazine-3-ethyl formate as an initial raw material, and the target product is prepared through five steps of reaction of ester hydrolysis, phosphorus oxychloride mediated chlorination, condensation with deuterated methylamine, buchwald-Hartwig coupling and aromatic nucleophilic substitution. The route has the obvious defects that firstly, the overall yield is low, the stability of the generated trichloro intermediate (4, 6-dichloropyrazine-3-carboxylic acid chloride) is extremely poor in the key chlorination and condensation steps, the degradation phenomenon is aggravated after the post-treatment process is amplified, the combined yield of the two steps is only 15-45%, the industrial amplification is seriously limited, secondly, the synthesis cost is high, expensive deuteration reagent is input in the early reaction stage, the consumption is large and the loss is high, meanwhile, a noble metal palladium catalyst is required for Buchwald-Hartwig coupling, thirdly, the product quality and the environmental friendliness are insufficient, palladium catalyst residues are difficult to thoroughly remove, the quality of raw materials is influenced, heavy metal residues pollute the environment, and the subsequent treatment process is complicated and the yield is low. Patent CN117756729a discloses another synthetic route for deuterium-celecoxib: The route takes 3-amino-6-chloropyridazine as a starting material, and the product is prepared through six steps of reaction of bromination, diazotization-cyanidation, cyclopropylamide substitution, buchwald-Hartwig coupling, acid hydrolysis and condensation. The method has the advantages that the method is simple in process, low in cost, high in energy consumption and harsh in operation, and low in cost, the method is easy to decompose when being heated, side reactions and potential safety hazards are easy to cause, and the method still depends on a noble metal palladium catalyst, so that the preparation cost is increased, the environmental protection and quality problems of heavy metal residues are caused, and the method is not in line with the green chemical idea. In summary, the existing deuterium-celecoxib synthesis method has common technical defects, severely restricts the industrial application of the existing deuterium-celecoxib synthesis method, and can be specifically summarized into four points, namely low process efficiency, long synthesis route, complicated steps and low total yield, high preparation cost, dependence on a noble metal catalyst and a large amount of deuterated reagent added in the early stage, poor economy, poor safety controllability, insufficient stability of a key intermediate, harsh reaction conditions, obvious amplification effect and higher safety risks, environmental protection and hidden danger of quality, residual pollution of the noble metal catalyst, difficulty in removal and influence on the quality of raw material