Preparation method of nabumetone-D3

Abstract

The invention relates to the technical field of chemical synthesis, and particularly discloses a preparation method of nabumetone-D3, which comprises the following steps: S1, uniformly mixing 6-bromo-2-naphthol, a catalyst A and an organic solvent, then adding deuterated iodomethane, uniformly mixing, adjusting the temperature to 20-30 DEG C, reacting for 22-26 hours, quenching, extracting, washing, drying and concentrating to obtain nabumetone-D3; a first intermediate product is obtained; s2, uniformly mixing a catalyst B and tetrabutylammonium bromide in an inert atmosphere, heating to 110-130 DEG C, reacting for 8-12 minutes, cooling to 75-85 DEG C, adding the first intermediate product, 3-butene-2-alcohol and sodium bicarbonate, uniformly mixing, heating to 110-130 DEG C, reacting for 22-26 hours, cooling, extracting, washing, drying, purifying and eluting to obtain the 3-butylammonium bromide. The nabumetone-D3 prepared by the preparation method disclosed by the invention has relatively high purity and yield.

Description

Technical Field

[0001] The present application relates to the technical field of chemical synthesis, and more specifically, to a method for preparing nabumetone-D3. Background Art

[0002] Nabumetone-D3 is a deuterated compound of nabumetone. It is labeled by introducing deuterium atoms at specific positions in the nabumetone molecule. Usually, isotope replacement is performed on key sites for drug metabolism or detection (such as methoxy groups). This labeling strategy significantly improves the detectability in experimental studies while retaining the chemical properties of the prototype drug. As a non-acidic non-steroidal anti-inflammatory drug, nabumetone itself is metabolized into the active product 6-methoxy-2-naphthylacetic acid in the body, which exerts antipyretic, analgesic and anti-inflammatory effects. As its isotope-labeled derivative, nabumetone-D3 retains the chemical properties of the prototype drug, while enhancing the detectability of experimental studies through deuterium labeling. Through the tracing characteristics of deuterium labeling, the metabolic pathways, absorption distribution and excretion processes of drugs in the body can be tracked, providing important experimental data for drug research and development.

[0003] The patent application document with publication number CN1982274A discloses a method for preparing nabumetone, comprising the following steps: using 6-methoxy-2-naphthaldehyde as an initial raw material, condensing it with ethyl acetate to generate 3-alkoxycarbonyl-4-(6-methoxy-2-naphthyl)but-2-en-2-one, catalytically hydrogenating it in an organic solvent to obtain 3-alkoxycarbonyl-4-(6-methoxy-2-naphthyl)but-2-one, acid hydrolyzing it to obtain a crude nabumetone, and purifying it by recrystallization with anhydrous ethanol to obtain a qualified pure product, and using Raney Ni W n (n=2~7), Raney Cu or Raney Co as catalyst.

[0004] In the above technical scheme, Raney Ni Wn (n=2~7), Raney Cu or Raney Co is used as a catalyst. These Raney-type catalysts are active to various functional groups of the substrate. For example, the enone structure and the ester structure in the substrate are spatially close to the active site of the catalyst. Since these Raney-type catalysts lack sufficient selectivity, they may act on these two functional groups at the same time, resulting in the occurrence of side reactions, thereby generating by-products and reducing the selectivity for the target product nabumetone. Summary of the invention

[0005] In order to improve the yield and purity of nabumetone-D3, the present application provides a method for preparing nabumetone-D3.

[0006] The preparation method of nabumetone-D3 of the present application adopts the following technical scheme: A method for preparing nabumetone-D3 comprises the following steps: S1: 9-11 g of 6-bromo-2-naphthol, 6.0-21.9 g of catalyst A and an organic solvent are mixed evenly, and then 6.0-7.0 g of deuterated iodomethane is added. After mixing evenly, the temperature is adjusted to 20-30° C., the reaction is carried out for 22-26 hours, quenching, extraction, washing, drying and concentration are carried out to obtain a first intermediate product; S2: Under an inert atmosphere, evenly mix 0.6-4.1 g of catalyst B and 55-65 g of tetrabutylammonium bromide, raise the temperature to 110-130° C., react for 8-12 min, cool to 75-85° C., add 9.5-10.5 g of the first intermediate product, 2.5-3.5 g of 3-butene-2-ol and 4-4.5 g of sodium bicarbonate, mix evenly, raise the temperature to 110-130° C., react for 22-26 h, cool, extract, wash, dry, purify and elute to obtain nabumetone-D3.

[0007] Preferably, the catalyst A is any one of potassium carbonate and cesium carbonate; Preferably, the catalyst B is palladium chloride.

[0008] In step S1, potassium carbonate or cesium carbonate reacts with deuterated iodomethane to capture iodide ions and generate highly active CD3I - Nucleophile, CD3I - The C-Br bond is attacked from the back to obtain the first intermediate product. Potassium carbonate or cesium carbonate simultaneously neutralizes the HBr generated by the reaction to maintain the alkalinity of the reaction system and ensure that the reaction proceeds in the forward direction.

[0009] In step S2, tetrabutylammonium bromide is used as a phase transfer catalyst to promote the dispersion of palladium chloride in the system and assist ion transport. Under high temperature conditions, PdCl2 may dissociate or react with a ligand to generate an active palladium intermediate. The bromine atom in the first intermediate undergoes oxidative addition under palladium catalysis and combines with the active palladium intermediate to form a Pd-aryl intermediate. Sodium bicarbonate provides an alkaline environment to promote the deprotonation of the hydroxyl group of 3-butene-2-ol to generate an enolate anion. The anion acts as a nucleophile and migrates and inserts with the Pd-aryl intermediate to form a new carbon-carbon bond. The intermediate undergoes a reduction elimination step to release palladium chloride and simultaneously generates nabumetone-D3.

[0010] Preferably, in step S2, after adding the first intermediate product, 3-butene-2-ol and sodium bicarbonate and mixing evenly, the temperature is maintained at 75-85° C., hydrogen is introduced, and the hydrogen partial pressure is controlled between 10-40 kPa. After treating for 40-60 minutes, the pressure is released and an inert gas is introduced.

[0011] Preferably, the catalyst A is subjected to the following modification treatment before use, comprising the following steps: The catalyst A is subjected to the following modification treatment before use, comprising the following steps: (1) Dissolve 28.5-35.0 g of cesium nitrate in water, add 45-55 g of mesoporous material, mix well, let stand, separate solid and liquid, wash, and obtain a solid; (2) Dissolve 28.5-35.0 g of sodium carbonate in water, adjust the pH to 7.5-8.5, then add the solid, raise the temperature to 35-45°C, mix for 3.5-4.5 hours, separate the solid and liquid, wash, dry, and calcine to obtain the product.

[0012] Preferably, the calcination temperature in step (2) is 280-320° C., and the calcination time is 2.5-3.5 h.

[0013] Preferably, the mesoporous material is mesoporous molecular sieve SBA-15.

[0014] In the above technical solution, by using SBA-15 with high specific surface area and ordered mesopores, cesium carbonate is confined in nanopores through physical confinement. At the same time, its high specific surface area provides a large number of loading points for loading cesium carbonate, so that cesium carbonate can be highly dispersed. And through the surface silanol groups and cesium ions to form Si-O-Cs bonds, the dissolution of cesium ions is effectively reduced. After calcination, Cs2SiO3 is partially generated, further enhancing the stability of the active component.

[0015] Preferably, the catalyst B is subjected to a modification treatment before use, comprising the following steps: (a) Under an inert atmosphere, 9-11 g of the magnetic mesoporous material is dispersed in toluene, and then 4-6 mL of 3-chloropropyltrimethoxysilane is added and mixed evenly, and refluxed for 22-26 h, and solid-liquid separation is performed, and the mixture is washed and dried to obtain a pretreated product; (b) dispersing the pretreated product in an ethanol solution, then adding 4-6 g of cysteamine and 4-6 g of sodium carbonate and mixing evenly, adjusting the temperature to 20-30° C., reacting for 22-26 h, solid-liquid separation, washing, and drying to obtain a pre-modified product; (c) dispersing 4-6 g of the pre-modified product in an ethanol solution, then adding 1-2 g of palladium chloride and mixing evenly, adjusting the temperature to 20-30° C., immersing for 22-26 h, solid-liquid separation, washing, and drying to obtain a pre-loaded catalyst; (d) In a mixed atmosphere, the temperature is raised to 60-80° C., the preloaded catalyst is subjected to reduction treatment for 40-60 min, and then cooled to obtain; The mixed atmosphere is formed by mixing hydrogen and nitrogen in a volume ratio of (0.5-1.5):(8.5-9.5).

[0016] Preferably, the magnetic mesoporous material is a magnetic SBA-15 mesoporous molecular sieve.

[0017] Preferably, in the mixed atmosphere, the flow rate of the mixed gas is 100-150 mL / min.

[0018] Preferably, in step S1, after adding catalyst A, the process further comprises adding 0.3-0.4 g potassium iodide.

[0019] In S1, 6-bromo-2-naphthol undergoes a methylation reaction with deuterated iodomethane. On the one hand, the iodide ion of potassium iodide can combine with the iodine atom in deuterated iodomethane to form a more active intermediate, accelerating the transfer of methyl to the phenolic hydroxyl group of 6-bromo-2-naphthol, thereby increasing the reaction rate and yield. On the other hand, catalyst A cooperates with potassium iodide to activate the reaction substrate through coordination or electronic effects, thereby promoting the reaction.

[0020] Preferably, in step S2, the step of adding 0.3-0.4 g of potassium iodide is also included while adding sodium bicarbonate.

[0021] In S2, on the one hand, the iodide ion of potassium iodide can activate the hydroxyl group of 3-butene-2-ol, making it easier to deprotonate to form a nucleophile, or by coordinating with the intermediate, reduce the reaction energy barrier and accelerate the reaction process. On the other hand, the iodide ion of potassium iodide cooperates with the alkaline environment to stabilize the reaction intermediates, reduce the occurrence of side reactions, and promote the formation of nucleophiles, thereby improving the synthesis efficiency and product purity.

[0022] In summary, this application has the following beneficial effects: 1. The present application uses 6-bromo-2-naphthol as the starting material. Under the action of catalyst A and the high reactivity of deuterated iodomethane, the efficient introduction of deuterium atoms is ensured, laying the foundation for the synthesis of high isotopic abundance products. In the synergistic catalytic system formed by palladium chloride, tetrabutylammonium bromide and sodium bicarbonate, the subsequent reaction is efficiently carried out under a nitrogen atmosphere, thereby improving the selectivity of the target product nabumetone-D3 and greatly reducing the generation of by-products.

[0023] 2. The preferred modification treatment of catalyst A and catalyst B in the present application provides a stable dispersion environment for the active ingredients, improves the exposure of the catalytic active sites, and thus accelerates the reaction rate. At the same time, the confinement effect of the carrier can also regulate the reaction path, reduce the generation of by-products, and simplify the separation and recovery process, thereby improving the purity and yield of nabumetone-D3. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 is the mass spectrum of nabumetone-D3 obtained in Example 1; Figure 2 This is the H NMR spectrum of commercially available nabumetone (purity > 99%); Figure 3 The hydrogen nuclear magnetic resonance spectrum of nabumetone-D3 prepared in Example 1 is shown in FIG. DETAILED DESCRIPTION

[0025] The present application is further described in detail below with reference to embodiments.

[0026] Unless otherwise specified, the raw materials used in the examples and comparative examples of the present application are all commercially available.

[0027] 6-bromo-2-naphthol, purity not less than 98%; deuterated iodomethane, deuterated rate not less than 99%; The specific surface area of ​​mesoporous molecular sieve SBA-15 (abbreviated as SBA-15) is 600-1000m 2 / g, pore size distribution is 6~10nm, particle size distribution is 1~10μm; magnetic SBA-15 mesoporous molecular sieve (abbreviated as Fe3O4-SBA-15) has a specific surface area of ​​500-800m 2 / g, pore size distribution is 5~8nm; particle size distribution is 5~15μm.

[0028] Preparation Examples 1-3 Modified Cesium Carbonate Preparation Example 1 The preparation method of the modified cesium carbonate of this preparation example comprises the following steps: (1) Dissolve 28.5 g of cesium nitrate in 500 mL of deionized water, add 45.0 g of SBA-15, treat with an ultrasonic frequency of 30 kHz for 30 min, let stand for 12 h, filter, rinse with 0°C deionized water for 3 times, and then wash with anhydrous ethanol for 2 times to obtain a solid; (2) Dissolve 28.5 g of sodium carbonate in 500 mL of deionized water, adjust the pH to 7.5 with 0.1 mol / L dilute hydrochloric acid, then add the solid, raise the temperature to 35°C, stir and mix for 3.5 h, filter, wash 4 times with deionized water, then wash 2 times with anhydrous ethanol, dry at 60°C, and calcine at 280°C for 3.5 h to obtain modified cesium carbonate.

[0029] Among them, the heating rate is 3℃ / min; The test shows that the loading amount of cesium carbonate in the modified cesium carbonate is about 31.1%.

[0030] Preparation Example 2 The preparation method of the modified cesium carbonate of this preparation example comprises the following steps: (1) Dissolve 35.0 g of cesium nitrate in 500 mL of deionized water, add 55.0 g of SBA-15, treat with an ultrasonic frequency of 30 kHz for 30 min, let stand for 12 h, filter, rinse with 0°C deionized water for 3 times, and then wash with anhydrous ethanol for 2 times to obtain a solid; (2) Dissolve 35.0 g of sodium carbonate in 500 mL of deionized water, adjust the pH to 8.5 with 0.1 mol / L dilute hydrochloric acid, then add the solid, heat to 45°C, stir and mix for 4.5 h, filter, wash 4 times with deionized water, then wash twice with anhydrous ethanol, dry at 60°C, and calcine at 320°C for 2.5 h to obtain modified cesium carbonate.

[0031] Among them, the heating rate is 1℃ / min; The test shows that the loading amount of cesium carbonate in the modified cesium carbonate is 31.4%.

[0032] Preparation Example 3 The preparation method of the modified cesium carbonate of this preparation example comprises the following steps: (1) Dissolve 31.8 g of cesium nitrate in 500 mL of deionized water, add 50.0 g of SBA-15, treat with an ultrasonic frequency of 30 kHz for 30 min, let stand for 12 h, filter, rinse with 0°C deionized water for 3 times, and then wash with anhydrous ethanol for 2 times to obtain a solid; (2) Dissolve 31.8 g of sodium carbonate in 500 mL of deionized water, adjust the pH to 8 with 0.1 mol / L dilute hydrochloric acid, then add the solid, heat to 40°C, stir and mix for 4 h, filter, wash 4 times with deionized water, then wash twice with anhydrous ethanol, dry at 60°C, and calcine at 300°C for 3 h to obtain modified cesium carbonate.

[0033] Among them, the heating rate is 2℃ / min; The test shows that the loading amount of cesium carbonate in the modified cesium carbonate is 31.2%.

[0034] Preparation Example 4~6 Modified Palladium Chloride Preparation Example 4 The preparation method of the modified palladium chloride of this preparation example comprises the following steps: (a) Under nitrogen atmosphere, 9 g of Fe3O4-SBA-15 was added to 200 mL of toluene and treated with an ultrasonic frequency of 30 kHz for 30 min, then 4 mL of 3-chloropropyltrimethoxysilane was added, stirred and mixed evenly, and refluxed for 22 h. The product was separated by a magnet, and washed alternately with toluene and anhydrous ethanol for 3 times each, and dried in a vacuum drying oven at 60 ° C to constant weight to obtain a pretreated product; (b) adding the pretreated product to 200 mL of ethanol solution, treating it with an ultrasonic frequency of 30 kHz for 30 min, then adding 4 g of cysteamine and 4 g of sodium carbonate, reacting at 20° C. for 26 h, separating the product with a magnet, washing it with anhydrous ethanol for 3 times, and drying it in a vacuum drying oven at 60° C. to constant weight to obtain a premodified product; (c) Add 4 g of the pre-modified product to 500 mL of ethanol solution, then add 1 g of palladium chloride, stir and mix evenly, adjust the temperature to 20°C, stir and immerse for 22 hours, separate the product with a magnet, wash it with anhydrous ethanol for 3 times, and dry it in a vacuum drying oven at 60°C to constant weight to obtain a pre-loaded catalyst; (d) The Fe3O4-SBA-15 catalyst loaded with palladium chloride was placed in a tubular furnace, replaced with high-purity nitrogen three times, and then heated to 60°C. The mixed gas was introduced at a flow rate of 150 mL / min for 60 min. After the mixture was cooled to room temperature by nitrogen, the modified palladium chloride was obtained.

[0035] In step (b) and step (c), the ethanol solution is prepared by mixing ethanol and deionized water in a volume ratio of 7:3; The mixed gas is a mixture of hydrogen and nitrogen in a volume ratio of 0.5:0.95.

[0036] The test shows that the loading amount of palladium chloride in the modified palladium chloride is 18.2%.

[0037] Preparation Example 5 The preparation method of the modified palladium chloride of this preparation example comprises the following steps: (a) Under nitrogen atmosphere, 11 g of Fe3O4-SBA-15 was added to 200 mL of toluene and treated with an ultrasonic frequency of 30 kHz for 30 min. Then, 6 mL of 3-chloropropyltrimethoxysilane was added and stirred to mix evenly. After reflux reaction for 26 h, the product was separated by a magnet, and washed alternately with toluene and anhydrous ethanol for 3 times each, and dried in a vacuum drying oven at 60 °C to constant weight to obtain a pretreated product; (b) adding the pretreated product to 200 mL of ethanol solution, treating it with an ultrasonic frequency of 30 kHz for 30 min, then adding 6 g of cysteamine and 6 g of sodium carbonate, reacting at 30° C. for 22 h, separating the product with a magnet, washing it with anhydrous ethanol for 3 times, and drying it in a vacuum drying oven at 60° C. to constant weight to obtain a premodified product; (c) Add 6 g of the pre-modified product to 500 mL of ethanol solution, then add 2 g of palladium chloride, stir and mix evenly, adjust the temperature to 30°C, stir and immerse for 26 hours, separate the product with a magnet, wash it with anhydrous ethanol for 3 times, and dry it in a vacuum drying oven at 60°C to constant weight to obtain a pre-loaded catalyst; (d) The Fe3O4-SBA-15 catalyst loaded with palladium chloride was placed in a tubular furnace, replaced with high-purity nitrogen three times, and then heated to 80°C. The mixed gas was introduced at a flow rate of 100 mL / min for 40 min. After the mixture was cooled to room temperature, nitrogen was continued to be introduced to obtain modified palladium chloride.

[0038] In step (b) and step (c), the ethanol solution is prepared by mixing ethanol and deionized water in a volume ratio of 1:1; The mixed gas is a mixture of hydrogen and nitrogen in a volume ratio of 0.15:0.85.

[0039] The test shows that the loading amount of palladium chloride in the modified palladium chloride is 22.5%.

[0040] Preparation Example 6 The preparation method of the modified palladium chloride of this preparation example comprises the following steps: (a) Under nitrogen atmosphere, 10 g of Fe3O4-SBA-15 was added to 200 mL of toluene, and the mixture was treated with an ultrasonic frequency of 30 kHz for 30 min. Then, 5 mL of 3-chloropropyltrimethoxysilane was added, and the mixture was stirred and mixed evenly. After reflux reaction for 24 h, the product was separated by a magnet, and washed alternately with toluene and anhydrous ethanol for 3 times each, and dried in a vacuum drying oven at 60 °C to constant weight to obtain a pretreated product; (b) adding the pretreated product to 200 mL of ethanol solution, treating it with an ultrasonic frequency of 30 kHz for 30 min, then adding 5 g of cysteamine and 5 g of sodium carbonate, reacting at 25° C. for 24 h, separating the product with a magnet, washing it with anhydrous ethanol for 3 times, and drying it in a vacuum drying oven at 60° C. to constant weight to obtain a premodified product; (c) Add 5 g of the pre-modified product to 500 mL of ethanol solution, then add 1.5 g of palladium chloride, stir and mix evenly, adjust the temperature to 25°C, stir and immerse for 24 hours, separate the product with a magnet, wash it with anhydrous ethanol for 3 times, and dry it in a vacuum drying oven at 60°C to constant weight to obtain a pre-loaded catalyst; (d) The Fe3O4-SBA-15 catalyst loaded with palladium chloride was placed in a tubular furnace, replaced with high-purity nitrogen three times, and then heated to 70°C. The mixed gas was introduced at a flow rate of 120 mL / min for 50 min. After the mixture was cooled to room temperature, nitrogen was continued to be introduced to obtain modified palladium chloride.

[0041] In step (b) and step (c), the ethanol solution is prepared by mixing ethanol and deionized water in a volume ratio of 3:2; The mixed gas is a mixture of hydrogen and nitrogen in a volume ratio of 0.1:0.9.

[0042] The test shows that the loading amount of palladium chloride in the modified palladium chloride is 20.8%.

[0043] Example 1 The present embodiment provides a method for preparing nabumetone-D3, comprising the following steps: S1: 10.0 g of 6-bromo-2-naphthol and 6.8 g of catalyst A were added to a three-necked flask, and then 150 mL of anhydrous N,N-dimethylformamide was added, and the mixture was stirred and mixed evenly. Then 6.76 g of deuterated iodomethane was added and mixed evenly. The mixture was heated to 25°C, and the reaction was continued for 24 hours. Then 1000 mL of deionized water was added for quenching. The amount of deionized water can be appropriately increased according to the situation. The total amount generally does not exceed 2000 mL. Then, ethyl acetate was used for extraction 3 times, and the volume ratio of ethyl acetate to water phase was 1:1 each time. The organic phases were combined, and then washed with saturated brine of the same volume as the organic phase, and then dried with anhydrous sodium sulfate, filtered, and the organic phase was rotary evaporated to remove ethyl acetate to obtain the first intermediate product; S2: Under a nitrogen atmosphere, 0.74 g of catalyst B and 60 g of tetrabutylammonium bromide were stirred and mixed evenly, the temperature was raised to 120° C., the mixture was reacted for 10 min, the temperature was lowered to 80° C., 10 g of the first intermediate product, 3 g of 3-butene-2-ol and 4.2 g of sodium bicarbonate were added, the mixture was stirred and mixed evenly, the temperature was raised to 120° C., the mixture was reacted for 24 h, the mixture was cooled to room temperature, the reaction solution was extracted 3 times with ethyl acetate having an equal volume to the reaction solution each time, the organic phases were combined, and then the mixture was washed 3 times with saturated brine having an amount of half the volume of the organic phase each time, the mixture was dried with anhydrous sodium sulfate, the mixture was filtered, and the organic phase was rotary evaporated to obtain a crude product; A mixed solvent consisting of petroleum ether and ethyl acetate in a volume ratio of 20:1 was added to a silica gel chromatography column for filling and balancing until the solvent flowed out at a uniform rate. The crude product was dissolved in 23 mL of ethyl acetate, and 10 mL of petroleum ether was added for dilution. After mixing evenly, the column was loaded and eluted with a mixed solvent consisting of petroleum ether and ethyl acetate in a volume ratio of 20:1 until there was no impurity. The column was switched to a mixed solvent consisting of petroleum ether and ethyl acetate in a volume ratio of 10:1 for elution. The eluate was collected in sections, the eluate containing the target product was combined, and the solvent was removed by rotary evaporation to obtain nabumetone-D3.

[0044] Wherein, catalyst A is potassium carbonate, and catalyst B is palladium chloride.

[0045] After detection, the yield of nabumetone-D3 was 91.5%, the isotopic abundance was 98.71%, and the HPLC purity was ≥98.0%.

[0046] Example 2 The present embodiment provides a method for preparing nabumetone-D3, comprising the following steps: S1: 11.0 g of 6-bromo-2-naphthol and 7.0 g of catalyst A were added to a three-necked flask, and then 150 mL of anhydrous N,N-dimethylformamide was added, and the mixture was stirred and mixed evenly. Then, 7.0 g of deuterated iodomethane was added and mixed evenly. The mixture was heated to 30°C, and the reaction was continued for 26 hours. Then, 1000 mL of deionized water was added for quenching. The amount of deionized water can be appropriately increased according to the situation. The total amount generally does not exceed 2000 mL. Then, ethyl acetate was used for extraction 3 times, and the volume ratio of ethyl acetate to water phase was 1:1 each time. The organic phases were combined, and then washed with saturated brine of the same volume as the organic phase, and then dried with anhydrous sodium sulfate, filtered, and the organic phase was rotary evaporated to remove ethyl acetate to obtain the first intermediate product; S2: Under a nitrogen atmosphere, 7.0 g of catalyst B and 65 g of tetrabutylammonium bromide were stirred and mixed evenly, the temperature was raised to 130° C., the mixture was reacted for 12 min, the temperature was lowered to 85° C., 10.5 g of the first intermediate product, 3.5 g of 3-butene-2-ol and 4.5 g of sodium bicarbonate were added, the mixture was stirred and mixed evenly, the temperature was raised to 130° C., the mixture was reacted for 26 h, the mixture was cooled to room temperature, the reaction solution was extracted 3 times with ethyl acetate having an equal volume to the reaction solution each time, the organic phases were combined, and then the mixture was washed 3 times with saturated brine having a volume of half the organic phase each time, the mixture was dried with anhydrous sodium sulfate, the mixture was filtered, and the organic phase was rotary evaporated to obtain a crude product; A mixed solvent consisting of petroleum ether and ethyl acetate in a volume ratio of 20:1 was added to a silica gel chromatography column for filling and balancing until the solvent flowed out at a uniform rate. The crude product was dissolved in 23 mL of ethyl acetate, and 10 mL of petroleum ether was added for dilution. After mixing evenly, the column was loaded and eluted with a mixed solvent consisting of petroleum ether and ethyl acetate in a volume ratio of 20:1 until there was no impurity. The column was switched to a mixed solvent consisting of petroleum ether and ethyl acetate in a volume ratio of 10:1 for elution. The eluate was collected in sections, the eluate containing the target product was combined, and the solvent was removed by rotary evaporation to obtain nabumetone-D3.

[0047] Wherein, catalyst A is cesium carbonate, and catalyst B is palladium chloride.

[0048] After detection, the yield of nabumetone-D3 was 91.7% and the HPLC purity was ≥98.0%.

[0049] Example 3 The present embodiment provides a method for preparing nabumetone-D3, comprising the following steps: S1: 9.0 g of 6-bromo-2-naphthol and 6.0 g of catalyst A were added to a three-necked flask, and then 150 mL of anhydrous N,N-dimethylformamide was added, and the mixture was stirred and mixed evenly. Then, 6.0 g of deuterated iodomethane was added and mixed evenly. The mixture was heated to 20°C, and the reaction was continued for 22 hours. Then, 1000 mL of deionized water was added for quenching. The amount of deionized water can be appropriately increased according to the situation. The total amount generally does not exceed 2000 mL. Then, ethyl acetate was used for extraction 3 times, and the volume ratio of ethyl acetate to aqueous phase was 1:1 each time. The organic phases were combined, and then washed with saturated brine of the same volume as the organic phase, and then dried with anhydrous sodium sulfate, filtered, and the organic phase was rotary evaporated to remove ethyl acetate to obtain the first intermediate product; S2: Under a nitrogen atmosphere, 0.6 g of catalyst B and 55 g of tetrabutylammonium bromide were stirred and mixed evenly, the temperature was raised to 110° C., the mixture was reacted for 8 min, the temperature was lowered to 75° C., 9.5 g of the first intermediate product, 2.5 g of 3-butene-2-ol and 4.0 g of sodium bicarbonate were added and stirred and mixed evenly, the temperature was raised to 110° C., the mixture was reacted for 22 h, the mixture was cooled to room temperature, the reaction solution was extracted 3 times with ethyl acetate having an equal volume to the reaction solution each time, the organic phases were combined, and then the mixture was washed 3 times with saturated brine having a volume of half the organic phase each time, the mixture was dried with anhydrous sodium sulfate, the mixture was filtered, and the organic phase was rotary evaporated to obtain a crude product; A mixed solvent consisting of petroleum ether and ethyl acetate in a volume ratio of 20:1 was added to a silica gel chromatography column for filling and balancing until the solvent flowed out at a uniform rate. The crude product was dissolved in 23 mL of ethyl acetate, and 10 mL of petroleum ether was added for dilution. After mixing evenly, the column was loaded and eluted with a mixed solvent consisting of petroleum ether and ethyl acetate in a volume ratio of 20:1 until there was no impurity. The column was switched to a mixed solvent consisting of petroleum ether and ethyl acetate in a volume ratio of 10:1 for elution. The eluate was collected in sections, the eluate containing the target product was combined, and the solvent was removed by rotary evaporation to obtain nabumetone-D3.

[0050] Wherein, catalyst A is potassium carbonate, and catalyst B is palladium chloride.

[0051] After detection, the yield of nabumetone-D3 was 91.1% and the HPLC purity was ≥98.0%.

[0052] Example 4 The difference between this embodiment and embodiment 1 is that: S2: Under a nitrogen atmosphere, 0.74 g of catalyst B and 60 g of tetrabutylammonium bromide were stirred and mixed uniformly, the temperature was raised to 120° C., the reaction was carried out for 10 min, the temperature was lowered to 75° C., 10 g of the first intermediate product, 3 g of 3-butene-2-ol and 4.2 g of sodium bicarbonate were added and stirred and mixed uniformly, hydrogen was slowly introduced, and the hydrogen partial pressure was controlled to be between 10 and 20 kPa. The mixture was treated for 40 min, the introduction of hydrogen was stopped, and the pressure in the system was slowly released. After the pressure stabilized, nitrogen was introduced to restore the pressure to 1 standard atmospheric pressure, the temperature was raised to 120° C., the reaction was carried out for 24 h, and the mixture was cooled to room temperature. The reaction solution was extracted 3 times with ethyl acetate having an equal volume to the reaction solution each time, the organic phases were combined, and then washed 3 times with saturated brine having a volume of half the organic phase each time, and then dried with anhydrous sodium sulfate, filtered, and the organic phase was rotary evaporated to obtain a crude product; A mixed solvent consisting of petroleum ether and ethyl acetate in a volume ratio of 10:1 was added to a silica gel chromatography column for development, and the crude product was then dissolved in 15 mL of ethyl acetate, loaded onto a silica gel chromatography column, and eluted with an eluent consisting of petroleum ether and ethyl acetate in a volume ratio of 20:1, the eluate containing the target product was collected, and the solvent was removed by rotary evaporation to obtain nabumetone-D3.

[0053] Wherein, catalyst A is potassium carbonate, and catalyst B is palladium chloride.

[0054] The rest is the same as in Example 1.

[0055] After detection, the yield of nabumetone-D3 was 91.7% and the HPLC purity was ≥98.0%.

[0056] Example 5 The difference between this embodiment and embodiment 4 is that: S2: Under a nitrogen atmosphere, 0.74 g of catalyst B and 60 g of tetrabutylammonium bromide were stirred and mixed uniformly, the temperature was raised to 120° C., the reaction was carried out for 10 min, the temperature was lowered to 85° C., 10 g of the first intermediate product, 3 g of 3-butene-2-ol and 4.2 g of sodium bicarbonate were added and stirred and mixed uniformly, hydrogen was slowly introduced, and the hydrogen partial pressure was controlled to be between 20 and 40 kPa. The mixture was treated for 60 min, the introduction of hydrogen was stopped, and the pressure in the system was slowly released. After the pressure stabilized, nitrogen was introduced to restore the pressure to 1 standard atmosphere, the temperature was raised to 120° C., the reaction was carried out for 24 h, and the mixture was cooled to room temperature. The reaction solution was extracted 3 times with ethyl acetate having an equal volume to the reaction solution each time, the organic phases were combined, and then washed 3 times with saturated brine having a volume of half the organic phase each time, and then dried with anhydrous sodium sulfate, filtered, and the organic phase was rotary evaporated to obtain a crude product; A mixed solvent consisting of petroleum ether and ethyl acetate in a volume ratio of 10:1 was added to a silica gel chromatography column for development, and the crude product was then dissolved in 15 mL of ethyl acetate, loaded onto a silica gel chromatography column, and eluted with an eluent consisting of petroleum ether and ethyl acetate in a volume ratio of 20:1, the eluate containing the target product was collected, and the solvent was removed by rotary evaporation to obtain nabumetone-D3.

[0057] The rest is the same as Example 4.

[0058] After detection, the yield of nabumetone-D3 was 91.9% and the HPLC purity was ≥98.0%.

[0059] Example 6 The difference between this embodiment and embodiment 1 is that: Catalyst A is modified cesium carbonate from Preparation Example 1, and catalyst B is modified palladium chloride from Preparation Example 4; The amount of catalyst A used was 21.86 g; the amount of catalyst B used was 4.07 g; The rest is the same as in Example 1.

[0060] After detection, the yield of nabumetone-D3 was 92.6% and the HPLC purity was ≥99.0%.

[0061] Example 7 The difference between this embodiment and embodiment 1 is that: Catalyst A is modified cesium carbonate from Preparation Example 2, and catalyst B is modified palladium chloride from Preparation Example 5; The amount of catalyst A used was 17.33 g; the amount of catalyst B used was 2.63 g; The rest is the same as in Example 1.

[0062] After detection, the yield of nabumetone-D3 was 92.3% and the HPLC purity was ≥99.0%.

[0063] Example 8 The difference between this embodiment and embodiment 1 is that: Catalyst A is modified cesium carbonate from Preparation Example 3, and catalyst B is modified palladium chloride from Preparation Example 6; The amount of catalyst A used was 13.08 g; the amount of catalyst B used was 2.14 g; The rest is the same as in Example 1.

[0064] After detection, the yield of nabumetone-D3 was 92.1% and the HPLC purity was ≥99.0%.

[0065] Example 9 The difference between this embodiment and embodiment 8 is that: In step S1, after adding catalyst A, the step of adding 0.3 g of potassium iodide is also included; In step S2, the step of adding 0.3 g of potassium iodide is also included while adding sodium bicarbonate.

[0066] The rest is the same as Example 8.

[0067] After detection, the yield of nabumetone-D3 was 92.7% and the HPLC purity was ≥99.0%.

[0068] Example 10 The difference between this embodiment and embodiment 9 is that: In step S1, after adding catalyst A, the step of adding 0.4 g of potassium iodide is also included; In step S2, the step of adding 0.4 g of potassium iodide is also included while adding sodium bicarbonate.

[0069] The rest is the same as Example 9.

[0070] After detection, the yield of nabumetone-D3 was 92.8% and the HPLC purity was ≥99.0%.

[0071] Comparative Example 1 The difference between this comparative example and Example 1 is: No sodium bicarbonate is added in step S2; The rest is the same as in Example 1.

[0072] The yield of nabumetone-D3 was 83% and the HPLC purity was 92.8%.

[0073] Analyze Example 1 and combine Figure 1 It can be seen that the strongest peak in the figure corresponds to the molecular ion peak of the deuterated product, and its mass-to-charge ratio is consistent with the theoretical molecular weight of nabumetone-D3 (the molecular formula of nabumetone-D3 is C 15 H 13 D3O2, theoretical molecular weight is 231.3, plus H + The mass-to-charge ratio of the product is about 332.3, and although there is a slight deviation, it can still prove that the product has successfully introduced deuterium atoms, verifying the correctness of the deuterated structure. This is consistent with the high deuterated rate result of 98.71% isotope abundance in Example 1, and there are no significant impurity peaks in the mass spectrum except for the related ion peaks of nabumetone-D3, and the impurity content in the surface product is extremely low, indicating that the nabumetone-D3 prepared in Example 1 has a high purity.

[0074] Analyze Example 1 and combine Figure 2~Figure 3 It can be seen that: contrast Figure 2 It is known that in Figure 3The hydrogen atom signal corresponding to the deuterated site marked in nabumetone-D3 disappears, indicating that the deuterium atom successfully replaces the target hydrogen atom in nabumetone-D3 prepared in Example 1. In addition to the target molecular hydrogen signal, there are no significant impurity peaks in the two figures, indicating that the impurity content in the synthetic product is extremely low.

[0075] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make modifications to the present embodiment without any creative contribution as needed, but such modifications are protected by the patent law as long as they are within the scope of the claims of the present application.

Claims

1. A method for preparing nabumetone-D3, characterized in that, The steps include: S1: 9-11 g of 6-bromo-2-naphthol, 6.0-21.9 g of catalyst A and an organic solvent are mixed evenly, and then 6.0-7.0 g of deuterated iodomethane is added. After mixing evenly, the temperature is adjusted to 20-30° C., the reaction is carried out for 22-26 hours, quenching, extraction, washing, drying and concentration are carried out to obtain a first intermediate product; S2: Under an inert atmosphere, evenly mix 0.6-4.1 g of catalyst B and 55-65 g of tetrabutylammonium bromide, raise the temperature to 110-130° C., react for 8-12 min, cool to 75-85° C., add 9.5-10.5 g of the first intermediate product, 2.5-3.5 g of 3-butene-2-ol and 4-4.5 g of sodium bicarbonate, mix evenly, raise the temperature to 110-130° C., react for 22-26 h, cool, extract, wash, dry, purify and elute to obtain nabumetone-D3.

2. The method for preparing nabumetone-D3 according to claim 1, wherein The catalyst A is any one of potassium carbonate and cesium carbonate.

3. The preparation method of nabumetone-D3 according to claim 1, characterized in that, The catalyst B is palladium chloride.

4. The method for preparing nabumetone-D3 according to claim 1, wherein In step S2, after the first intermediate product, 3-butene-2-ol and sodium bicarbonate are added and mixed evenly, the temperature is maintained at 75-85° C., hydrogen is introduced, and the hydrogen partial pressure is controlled between 10-40 kPa. After treating for 40-60 minutes, the pressure is released and an inert gas is introduced.

5. The method for preparing nabumetone-D3 according to claim 2, wherein The catalyst A is subjected to the following modification treatment before use, comprising the following steps: (1) Dissolve 28.5-35.0 g of cesium nitrate in water, add 45-55 g of mesoporous material, mix well, let stand, separate solid and liquid, wash, and obtain a solid; (2) Dissolve 28.5-35.0 g of sodium carbonate in water, adjust the pH to 7.5-8.5, then add the solid, raise the temperature to 35-45°C, mix for 3.5-4.5 hours, separate the solid and liquid, wash, dry, and calcine to obtain the product.

6. The method for preparing nabumetone-D3 according to claim 5, characterized in that: The calcination temperature in step (2) is 280-320° C., and the calcination time is 2.5-3.5 h.

7. The method for preparing nabumetone-D3 according to claim 3, characterized in that: The catalyst B is subjected to a modification treatment before use, comprising the following steps: (a) Under an inert atmosphere, 9-11 g of the magnetic mesoporous material is dispersed in toluene, and then 4-6 mL of 3-chloropropyltrimethoxysilane is added and mixed evenly, and refluxed for 22-26 h, and solid-liquid separation is performed, and the mixture is washed and dried to obtain a pretreated product; (b) dispersing the pretreated product in an ethanol solution, then adding 4-6 g of cysteamine and 4-6 g of sodium carbonate and mixing evenly, adjusting the temperature to 20-30° C., reacting for 22-26 h, solid-liquid separation, washing, and drying to obtain a pre-modified product; (c) dispersing 4-6 g of the pre-modified product in an ethanol solution, then adding 1-2 g of palladium chloride and mixing evenly, adjusting the temperature to 20-30° C., immersing for 22-26 h, solid-liquid separation, washing, and drying to obtain a pre-loaded catalyst; (d) In a mixed atmosphere, the temperature is raised to 60-80° C., the preloaded catalyst is subjected to reduction treatment for 40-60 min, and then cooled to obtain; The mixed atmosphere is formed by mixing hydrogen and nitrogen in a volume ratio of (0.5-1.5):(8.5-9.5).

8. The method for preparing nabumetone-D3 according to claim 7, characterized in that: In the mixed atmosphere, the flow rate of the mixed gas is 100-150 mL / min.

9. The method for preparing nabumetone-D3 according to claim 1, wherein In step S1, after adding catalyst A, the step of adding 0.3-0.4 g of potassium iodide is also included.

10. The method for preparing nabumetone-D3 according to claim 1, characterized in that: In step S2, the step of adding 0.3-0.4 g of potassium iodide is also included while adding sodium bicarbonate.

Images