A Preparation Method of Nabumetone-D3

Abstract

This application relates to the field of chemical synthesis technology, and specifically discloses a preparation method of nabumetone-D3. The preparation method comprises the following steps: S1: Mix 6-bromo-2-naphthol, catalyst A and an organic solvent evenly, then add deuterated iodomethane. After mixing evenly, adjust the temperature to 20-30 °C, react for 22-26 h, quench, extract, wash, dry and concentrate to obtain a first intermediate; S2: Under an inert atmosphere, mix catalyst B and tetrabutylammonium bromide evenly, heat up to 110-130 °C, react for 8-12 min, cool down to 75-85 °C, add the first intermediate, 3-buten-2-ol and sodium bicarbonate, mix evenly, then heat up to 110-130 °C, react for 22-26 h, cool, extract, wash, dry, purify and elute to obtain the product. The nabumetone-D3 prepared by this application has high purity and yield.

Description

Technical Field

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

[0002] Nabumetone-D3 is a deuterated compound of nabumetone, which is labeled by introducing deuterium atoms at specific positions in the nabumetone molecule. Usually, the sites crucial for drug metabolism or detection (such as methoxy group, etc.) are selected for isotope substitution. 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-naphthoic acid in vivo, exerting antipyretic, analgesic, and anti-inflammatory effects. As an isotope-labeled derivative of it, nabumetone-D3 retains the chemical properties of the prototype drug, and at the same time enhances the detectability in experimental studies through deuterium labeling. Through the tracer characteristics of deuterium labeling, the metabolic pathway, absorption distribution, and excretion process of the drug in vivo can be traced, providing important experimental data for drug research and development.

[0003] The patent application document with the publication number CN1982274A discloses a preparation method of nabumetone, including the following steps: using 6-methoxy-2-naphthaldehyde as the initial raw material, condensing with ethyl acetate to generate 3-alkoxycarbonyl-4-(6-methoxy-2-naphthyl)but-2-en-2-one, catalytic hydrogenation in an organic solvent to obtain 3-alkoxycarbonyl-4-(6-methoxy-2-naphthyl)butan-2-one, acidolysis to obtain the crude product of nabumetone, and recrystallizing and purifying with absolute ethanol to obtain a qualified pure product, using Raney Ni W n (n = 2 - 7), Raney Cu or Raney Co as the catalyst.

[0004] In the above technical solution, using Raney Ni Wn (n = 2 - 7), Raney Cu or Raney Co as the catalyst, these Raney-type catalysts are active towards various functional groups of the substrate. For example, the enone structure and ester group structure in the substrate are both spatially close to the active sites of the catalyst. Due to the lack of sufficient selectivity of these Raney-type catalysts, they may act on these two functional groups simultaneously, resulting in the occurrence of side reactions, thus 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 preparation method of nabumetone-D3.

[0006] The preparation method of nabumetone-D3 of the present application adopts the following technical solution:

[0007] A method for preparing nabumetone-D3 comprises the following steps:

[0008] 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;

[0009] 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.

[0010] Preferably, the catalyst A is any one of potassium carbonate and cesium carbonate;

[0011] Preferably, the catalyst B is palladium chloride.

[0012] 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.

[0013] 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.

[0014] 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.

[0015] Preferably, before use, the catalyst A is subjected to the following modification treatment, including the following steps:

[0016] Before use, the catalyst A is subjected to the following modification treatment, including the following steps:

[0017] (1) Dissolve 28.5 - 35.0 g of cesium nitrate in water, add 45 - 55 g of mesoporous material, mix evenly, let stand, perform solid-liquid separation, wash, and obtain a solid;

[0018] (2) Dissolve 28.5 - 35.0 g of sodium carbonate in water, adjust the pH to 7.5 - 8.5, then add the solid, heat to 35 - 45 °C, mix for 3.5 - 4.5 h, perform solid-liquid separation, wash, dry, and calcine to obtain the product.

[0019] Preferably, the calcination temperature in step (2) is 280 - 320 °C, and the calcination time is 2.5 - 3.5 h.

[0020] Preferably, the mesoporous material is mesoporous molecular sieve SBA-15.

[0021] In the above technical solution, by using SBA-15 with a high specific surface area and ordered mesopores, cesium carbonate is confined in the nanopores through physical confinement. At the same time, its high specific surface area provides a large number of loading points for loading cesium carbonate, enabling cesium carbonate to be highly dispersed. And Si-O-Cs bonds are formed between the surface silanol groups and cesium ions, effectively reducing the dissolution of cesium ions. After calcination treatment, Cs2SiO3 will be partially generated, further enhancing the stability of the active component.

[0022] Preferably, before use, the catalyst B is subjected to modification treatment, including the following steps:

[0023] (a) Under an inert atmosphere, disperse 9 - 11 g of magnetic mesoporous material in toluene, then add 4 - 6 mL of 3-chloropropyltrimethoxysilane and mix evenly. Carry out a reflux reaction for 22 - 26 h, perform solid-liquid separation, wash, and dry to obtain a pretreated product;

[0024] (b) Disperse the pretreated product in an ethanol solution, then add 4 - 6 g of cysteamine and 4 - 6 g of sodium carbonate and mix evenly. Adjust the temperature to 20 - 30 °C and react for 22 - 26 h. Perform solid-liquid separation, wash, and dry to obtain a pre-modified product;

[0025] (c) Disperse 4 - 6 g of the pre-modified product in an ethanol solution, then add 1 - 2 g of palladium chloride and mix evenly. Adjust the temperature to 20 - 30 °C and impregnate for 22 - 26 h. Perform solid-liquid separation, wash, and dry to obtain a pre-loaded catalyst;

[0026] (d) Under a mixed atmosphere, heat up to 60 - 80 °C, reduce the pre-loaded catalyst for 40 - 60 min, and then cool to obtain the product;

[0027] The mixed atmosphere is composed of hydrogen and nitrogen mixed according to a volume ratio of (0.5 - 1.5) : (8.5 - 9.5).

[0028] Preferably, the magnetic mesoporous material is magnetic SBA-15 mesoporous molecular sieve.

[0029] Preferably, in the mixed atmosphere, the flow rate of the mixed gas is 100 - 150 mL / min.

[0030] Preferably, in step S1, after adding catalyst A, it further includes the step of adding 0.3 - 0.4 g of potassium iodide.

[0031] 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 the methyl group to the phenolic hydroxyl group of 6-bromo-2-naphthol, thereby increasing the reaction rate and yield. On the other hand, catalyst A and potassium iodide cooperate to activate the reaction substrate through coordination or electronic effects, promoting the progress of the reaction.

[0032] Preferably, in step S2, when adding sodium bicarbonate, it further includes the step of adding 0.3 - 0.4 g of potassium iodide.

[0033] In S2, on the one hand, the iodide ion of potassium iodide can activate the hydroxyl group of 3-buten-2-ol, making it more likely to deprotonate to form a nucleophile, or by coordinating with the intermediate, reducing the reaction energy barrier and accelerating the reaction process. On the other hand, the iodide ion of potassium iodide cooperates with the alkaline environment to stabilize the reaction intermediate, reduce the occurrence of side reactions, and at the same time promote the formation of nucleophiles, thereby improving the synthesis efficiency and product purity.

[0034] In summary, the present application has the following beneficial effects:

[0035] 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, it ensures the efficient introduction of deuterium atoms, laying a foundation for the synthesis of high-isotope-abundance products. And 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, improving the selectivity of the target product nabumetone-D3 and greatly reducing the generation of by-products.

[0036] 2. Preferably, the catalysts A and B in this application are modified to provide a stable dispersion environment for the active ingredients, increase the exposure degree of their catalytic active sites, thereby accelerating 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, improving the purity and yield of nabumetone-D3. Description of the Drawings

[0037] Figure 1 It is the mass spectrum of nabumetone-D3 prepared in Example 1;

[0038] Figure 2 It is the 1H NMR spectrum of commercially available nabumetone (purity > 99%);

[0039] Figure 3 It is the 1H NMR spectrum of nabumetone-D3 prepared in Example 1. Detailed Description of the Invention

[0040] The following further describes this application in detail with reference to examples.

[0041] The raw materials in the examples and comparative examples of this application are all ordinary commercially available products unless otherwise specified.

[0042] 6-bromo-2-naphthol, purity not less than 98%; deuterated iodomethane, deuterium substitution rate not less than 99%;

[0043] The specific surface area of mesoporous molecular sieve SBA-15 (abbreviated as SBA-15) is 600 - 1000 m 2 / g, the pore size distribution is 6 - 10 nm, and the particle size distribution is 1 - 10 μm; the specific surface area of magnetic SBA-15 mesoporous molecular sieve (abbreviated as Fe3O4-SBA-15) is 500 - 800 m 2 / g, the pore size distribution is 5 - 8 nm; the particle size distribution is 5 - 15 μm.

[0044] Preparation Examples 1 - 3 Modified Cesium Carbonate

[0045] Preparation Example 1

[0046] The preparation method of the modified cesium carbonate in this preparation example includes the following steps:

[0047] (1) Dissolve 28.5 g of cesium nitrate in 500 mL of deionized water, add 45.0 g of SBA-15, treat it with an ultrasonic frequency of 30 kHz for 30 min, then let it stand for 12 h, filter, wash it 3 times with deionized water at 0 °C, and then wash it 2 times with absolute ethanol to obtain a solid;

[0048] (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, heat up to 35 °C, stir and mix for 3.5 h. After filtration, wash 4 times with deionized water first, then wash 2 times with absolute ethanol, dry at 60 °C, and calcine at 280 °C for 3.5 h to obtain modified cesium carbonate.

[0049] Among them, the heating rate is 3 °C / min;

[0050] Detection shows that the loading amount of cesium carbonate in the modified cesium carbonate is about 31.1%.

[0051] Preparation Example 2

[0052] The preparation method of the modified cesium carbonate in this preparation example includes the following steps:

[0053] (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, then let it stand for 12 h. After filtration, wash 3 times with deionized water at 0 °C, then wash 2 times with absolute ethanol to obtain a solid;

[0054] (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 up to 45 °C, stir and mix for 4.5 h. After filtration, wash 4 times with deionized water first, then wash 2 times with absolute ethanol, dry at 60 °C, and calcine at 320 °C for 2.5 h to obtain modified cesium carbonate.

[0055] Among them, the heating rate is 1 °C / min;

[0056] Detection shows that the loading amount of cesium carbonate in the modified cesium carbonate is 31.4%.

[0057] Preparation Example 3

[0058] The preparation method of the modified cesium carbonate in this preparation example includes the following steps:

[0059] (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, then let it stand for 12 h. After filtration, wash 3 times with deionized water at 0 °C, then wash 2 times with absolute ethanol to obtain a solid;

[0060] (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 solid substances, heat up to 40 °C, stir and mix for 4 h. After filtration, wash 4 times with deionized water first, then wash 2 times with absolute ethanol, dry at 60 °C, and calcine at 300 °C for 3 h to obtain modified cesium carbonate.

[0061] Among them, the heating rate is 2 °C / min;

[0062] It can be detected that the loading amount of cesium carbonate in the modified cesium carbonate is 31.2%.

[0063] Preparation Examples 4 - 6 Modified Palladium Chloride

[0064] Preparation Example 4

[0065] The preparation method of the modified palladium chloride in this preparation example includes the following steps:

[0066] (a) Under a nitrogen atmosphere, add 9 g of Fe3O4 - SBA - 15 to 200 mL of toluene, treat it with an ultrasonic frequency of 30 kHz for 30 min, then add 4 mL of 3 - chloropropyltrimethoxysilane, stir and mix evenly, after reflux reaction for 22 h, separate the product with a magnet, wash it 3 times alternately with toluene and absolute ethanol respectively, and dry it to constant weight in a vacuum drying oven at 60 °C to obtain a pretreated product;

[0067] (b) Add the pretreated product to 200 mL of ethanol solution, treat it with an ultrasonic frequency of 30 kHz for 30 min, then add 4 g of cysteamine and 4 g of sodium carbonate, react at 20 °C for 26 h, separate the product with a magnet, wash it 3 times with absolute ethanol, and dry it to constant weight in a vacuum drying oven at 60 °C to obtain a pre - modified product;

[0068] (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 impregnate for 22 h, separate the product with a magnet, wash it 3 times with absolute ethanol, and dry it to constant weight in a vacuum drying oven at 60 °C to obtain a pre - loaded catalyst;

[0069] (d) Place the Fe3O4 - SBA - 15 catalyst loaded with palladium chloride in a tubular furnace, first displace it 3 times with high - purity nitrogen, then heat up to 60 °C, and pass in a mixed gas at a flow rate of 150 mL / min for 60 min. After completion, continue to pass in nitrogen to cool to room temperature to obtain the modified palladium chloride.

[0070] In steps (b) and (c), the ethanol solution is composed of ethanol and deionized water mixed in a volume ratio of 7:3;

[0071] The mixed gas is composed of hydrogen and nitrogen mixed in a volume ratio of 0.5:0.95.

[0072] It is detected that in the modified palladium chloride, the loading amount of palladium chloride is 18.2%.

[0073] Preparation Example 5

[0074] The preparation method of the modified palladium chloride in this preparation example includes the following steps:

[0075] (a) Under a nitrogen atmosphere, add 11 g of Fe3O4-SBA-15 to 200 mL of toluene, treat it with an ultrasonic frequency of 30 kHz for 30 min, then add 6 mL of 3-chloropropyltrimethoxysilane, stir and mix evenly, after reflux reaction for 26 h, separate the product by using a magnet, wash it alternately with toluene and absolute ethanol 3 times each, and dry it to constant weight in a vacuum drying oven at 60 °C to obtain a pretreatment product;

[0076] (b) Add the pretreatment product to 200 mL of an ethanol solution, treat it with an ultrasonic frequency of 30 kHz for 30 min, then add 6 g of cysteamine and 6 g of sodium carbonate, react at 30 °C for 22 h, separate the product by using a magnet, wash it with absolute ethanol 3 times, and dry it to constant weight in a vacuum drying oven at 60 °C to obtain a pre-modified product;

[0077] (c) Add 6 g of the pre-modified product to 500 mL of an ethanol solution, then add 2 g of palladium chloride, stir and mix evenly, adjust the temperature to 30 °C, stir and impregnate for 26 h, separate the product by using a magnet, wash it with absolute ethanol 3 times, and dry it to constant weight in a vacuum drying oven at 60 °C to obtain a pre-loaded catalyst;

[0078] (d) Place the Fe3O4-SBA-15 catalyst loaded with palladium chloride in a tubular furnace, first displace it 3 times with high-purity nitrogen, then heat it to 80 °C, and pass the mixed gas at a flow rate of 100 mL / min for 40 min. After that, continue to pass nitrogen to cool it to room temperature to obtain the modified palladium chloride.

[0079] In steps (b) and (c), the ethanol solution is composed of ethanol and deionized water mixed in a volume ratio of 1:1;

[0080] The mixed gas is composed of hydrogen and nitrogen mixed in a volume ratio of 0.15:0.85.

[0081] It is detected that in the modified palladium chloride, the loading amount of palladium chloride is 22.5%.

[0082] Preparation Example 6

[0083] The preparation method of the modified palladium chloride in this preparation example includes the following steps:

[0084] (a)Under a nitrogen atmosphere, 10 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, 5 mL of 3-chloropropyltrimethoxysilane was added, and the mixture was stirred evenly. After refluxing for 24 h, the product was separated by a magnet, washed alternately with toluene and absolute ethanol three times each, and dried to a constant weight in a vacuum drying oven at 60 °C to obtain a pretreatment product;

[0085] (b)The pretreatment product was added to 200 mL of an ethanol solution, and treated with an ultrasonic frequency of 30 kHz for 30 min. Then, 5 g of cysteamine and 5 g of sodium carbonate were added, and the reaction was carried out at 25 °C for 24 h. The product was separated by a magnet, washed three times with absolute ethanol, and dried to a constant weight in a vacuum drying oven at 60 °C to obtain a pre-modified product;

[0086] (c)5 g of the pre-modified product was added to 500 mL of an ethanol solution, then 1.5 g of palladium chloride was added, and the mixture was stirred evenly. The temperature was adjusted to 25 °C, and the mixture was stirred and impregnated for 24 h. The product was separated by a magnet, washed three times with absolute ethanol, and dried to a constant weight in a vacuum drying oven at 60 °C to obtain a pre-loaded catalyst;

[0087] (d)The Fe3O4-SBA-15 catalyst loaded with palladium chloride was placed in a tubular furnace. After purging three times with high-purity nitrogen, the temperature was raised to 70 °C, and a mixed gas was introduced at a flow rate of 120 mL / min for 50 min. After that, nitrogen was continuously introduced to cool to room temperature to obtain modified palladium chloride.

[0088] In steps (b) and (c), the ethanol solution was composed of ethanol and deionized water mixed in a volume ratio of 3:2;

[0089] The mixed gas was composed of hydrogen and nitrogen mixed in a volume ratio of 0.1:0.9.

[0090] It was detected that the loading amount of palladium chloride in the modified palladium chloride was 20.8%.

[0091] Example 1

[0092] This example provides a method for preparing nabumetone-D3, which includes the following steps:

[0093] S1: Add 10.0 g of 6-bromo-2-naphthol and 6.8 g of catalyst A into a three-necked flask, then add 150 mL of anhydrous N,N-dimethylformamide, stir and mix evenly. Then add 6.76 g of deuterated iodomethane and mix evenly. Heat up to 25 °C. After reacting for 24 h, add 1000 mL of deionized water for quenching. The amount of deionized water can be appropriately increased according to the situation, and the total amount generally does not exceed 2000 mL. Then extract with ethyl acetate 3 times. The amount of ethyl acetate used each time is in a volume ratio of 1:1 with the volume of the aqueous phase. Combine the organic phases, then wash with saturated brine with the same volume as the organic phase, and then dry with anhydrous sodium sulfate, filter by suction. Rotate and evaporate the organic phase to remove ethyl acetate to obtain the first intermediate product;

[0094] S2: Under a nitrogen atmosphere, stir and mix 0.74 g of catalyst B and 60 g of tetrabutylammonium bromide evenly, heat up to 120 °C, react for 10 min, cool down to 80 °C, add 10 g of the first intermediate product, 3 g of 3-buten-2-ol and 4.2 g of sodium bicarbonate, stir and mix evenly, then heat up to 120 °C. After reacting for 24 h, cool to room temperature. Extract the reaction solution with ethyl acetate 3 times with the same volume as the reaction solution each time. Combine the organic phases, then wash 3 times with saturated brine with half of the volume of the organic phase each time, and then dry with anhydrous sodium sulfate, filter by suction. Rotate and evaporate the organic phase to obtain the crude product;

[0095] Add a mixed solvent composed of petroleum ether and ethyl acetate in a volume ratio of 20:1 to a silica gel chromatography column for filling and balance until the solvent flows out evenly. Dissolve the crude product in 23 mL of ethyl acetate and dilute with 10 mL of petroleum ether, mix evenly and load the sample. Elute with a mixed solvent composed of petroleum ether and ethyl acetate in a volume ratio of 20:1 until there are no impurities, then switch to a mixed solvent composed of petroleum ether and ethyl acetate in a volume ratio of 10:1 for elution, collect the eluate in fractions, combine the eluate containing the target product, and remove the solvent by rotary evaporation to obtain nabumetone-D3.

[0096] Among them, catalyst A is potassium carbonate and catalyst B is palladium chloride.

[0097] After detection, the yield of nabumetone-D3 is 91.5%, the isotope abundance is 98.71%, and the HPLC purity ≥ 98.0%.

[0098] Example 2

[0099] This example provides a preparation method of nabumetone-D3, including the following steps:

[0100] S1: Add 11.0 g of 6-bromo-2-naphthol and 7.0 g of catalyst A into a three-necked flask, then add 150 mL of anhydrous N,N-dimethylformamide, stir and mix evenly. Then add 7.0 g of deuterated iodomethane and mix evenly. Heat up to 30 °C. After reacting for 26 h, add 1000 mL of deionized water for quenching. The amount of deionized water can be appropriately increased according to the situation, and the total amount generally does not exceed 2000 mL. Then extract with ethyl acetate 3 times, with the volume ratio of ethyl acetate to aqueous phase being 1:1 each time. Combine the organic phases, then wash with saturated brine of the same volume as the organic phase, and then dry with anhydrous sodium sulfate, filter by suction. Rotate and evaporate the organic phase to remove ethyl acetate to obtain the first intermediate product;

[0101] S2: Under a nitrogen atmosphere, stir and mix 7.0 g of catalyst B and 65 g of tetrabutylammonium bromide evenly, heat up to 130 °C, react for 12 min, cool down to 85 °C. Add 10.5 g of the first intermediate product, 3.5 g of 3-buten-2-ol and 4.5 g of sodium bicarbonate, stir and mix evenly, then heat up to 130 °C. After reacting for 26 h, cool to room temperature. Extract the reaction solution with ethyl acetate of the same volume as the reaction solution 3 times each time, combine the organic phases, then wash with saturated brine of half the volume of the organic phase 3 times each time, and then dry with anhydrous sodium sulfate, filter by suction. Rotate and evaporate the organic phase to obtain the crude product;

[0102] Add a mixed solvent composed of petroleum ether and ethyl acetate in a volume ratio of 20:1 into a silica gel chromatography column for filling and balance until the solvent flows out evenly. Dissolve the crude product in 23 mL of ethyl acetate and dilute with 10 mL of petroleum ether, mix evenly and load the sample. Elute with a mixed solvent composed of petroleum ether and ethyl acetate in a volume ratio of 20:1 until there are no impurities, then switch to a mixed solvent composed of petroleum ether and ethyl acetate in a volume ratio of 10:1 for elution, collect the eluate in segments, combine the eluate containing the target product, and remove the solvent by rotary evaporation to obtain nabumetone-D3.

[0103] Among them, catalyst A is cesium carbonate and catalyst B is palladium chloride.

[0104] After detection, the yield of nabumetone-D3 is 91.7% and the HPLC purity ≥ 98.0%.

[0105] Example 3

[0106] This example provides a preparation method of nabumetone-D3, including the following steps:

[0107] S1: Add 9.0 g of 6-bromo-2-naphthol and 6.0 g of catalyst A into a three-necked flask, then add 150 mL of anhydrous N,N-dimethylformamide, stir and mix evenly. Then add 6.0 g of deuterated iodomethane and mix evenly. Heat up to 20 °C. After reacting for 22 h, add 1000 mL of deionized water for quenching. The amount of deionized water can be appropriately increased according to the situation, and the total amount generally does not exceed 2000 mL. Then extract with ethyl acetate three times. The amount of ethyl acetate used each time is in a volume ratio of 1:1 with the aqueous phase. Combine the organic phases, then wash with saturated brine in an equal volume to the organic phase, and then dry with anhydrous sodium sulfate, filter by suction. Rotate and evaporate the organic phase to remove ethyl acetate to obtain the first intermediate product;

[0108] S2: Under a nitrogen atmosphere, stir and mix 0.6 g of catalyst B and 55 g of tetrabutylammonium bromide evenly, heat up to 110 °C, react for 8 min, cool down to 75 °C. Add 9.5 g of the first intermediate product, 2.5 g of 3-buten-2-ol and 4.0 g of sodium bicarbonate, stir and mix evenly, then heat up to 110 °C. After reacting for 22 h, cool to room temperature. Extract the reaction solution with ethyl acetate three times with an equal volume to the reaction solution each time. Combine the organic phases, then wash with saturated brine in half of the volume of the organic phase three times, and then dry with anhydrous sodium sulfate, filter by suction. Rotate and evaporate the organic phase to obtain the crude product;

[0109] Add a mixed solvent composed of petroleum ether and ethyl acetate in a volume ratio of 20:1 to a silica gel chromatography column for filling and balance until the solvent flows out evenly. Dissolve the crude product in 23 mL of ethyl acetate and dilute with 10 mL of petroleum ether. After mixing evenly, load the sample. Elute with a mixed solvent composed of petroleum ether and ethyl acetate in a volume ratio of 20:1 until there are no impurities, then switch to a mixed solvent composed of petroleum ether and ethyl acetate in a volume ratio of 10:1 for elution. Collect the eluate in fractions, combine the eluate containing the target product, and remove the solvent by rotary evaporation to obtain nabumetone-D3.

[0110] Among them, catalyst A is potassium carbonate and catalyst B is palladium chloride.

[0111] After detection, the yield of nabumetone-D3 is 91.1% and the HPLC purity ≥ 98.0%.

[0112] Example 4

[0113] The difference between this example and Example 1 is:

[0114] 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, and the reaction was carried out for 10 min. Then the temperature was lowered to 75 °C. After adding 10 g of the first intermediate product, 3 g of 3-buten-2-ol, and 4.2 g of sodium bicarbonate and stirring and mixing evenly, hydrogen was slowly introduced, and the hydrogen partial pressure was controlled to be between 10 and 20 kPa. After treatment for 40 min, the introduction of hydrogen was stopped, and the pressure in the system was slowly released. After the pressure was stabilized, nitrogen was introduced to restore to 1 standard atmosphere. The temperature was raised to 120 °C, and after reacting for 24 h, it was cooled to room temperature. The reaction solution was extracted 3 times with ethyl acetate of the same volume as the reaction solution each time. The organic phases were combined, and then washed 3 times with saturated brine of half the volume of the organic phase each time. Then it was dried with anhydrous sodium sulfate, filtered by suction, and the organic phase was rotary evaporated to obtain the crude product;

[0115] A mixed solvent composed of petroleum ether and ethyl acetate mixed in a volume ratio of 10:1 was added to the silica gel chromatography column for development. Then the crude product was dissolved in 15 mL of ethyl acetate and loaded onto the silica gel chromatography column, and an eluent composed of petroleum ether and ethyl acetate mixed in a volume ratio of 20:1 was used for elution. The eluate containing the target product was collected, and the solvent was removed by rotary evaporation to obtain nabumetone-D3.

[0116] Among them, catalyst A is potassium carbonate, and catalyst B is palladium chloride.

[0117] Others are the same as in Example 1.

[0118] After detection, the yield of nabumetone-D3 was 91.7%, and the HPLC purity ≥ 98.0%.

[0119] Example 5

[0120] The difference between this example and Example 4 is that:

[0121] 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, and the reaction was carried out for 10 min. Then the temperature was lowered to 85 °C. After adding 10 g of the first intermediate product, 3 g of 3-buten-2-ol, and 4.2 g of sodium bicarbonate and stirring and mixing evenly, hydrogen was slowly introduced, and the hydrogen partial pressure was controlled to be between 20 and 40 kPa. After treatment for 60 min, the introduction of hydrogen was stopped, and the pressure in the system was slowly released. After the pressure was stabilized, nitrogen was introduced to restore to 1 standard atmosphere. The temperature was raised to 120 °C, and after reacting for 24 h, it was cooled to room temperature. The reaction solution was extracted 3 times with ethyl acetate of the same volume as the reaction solution each time. The organic phases were combined, and then washed 3 times with saturated brine of half the volume of the organic phase each time. Then it was dried with anhydrous sodium sulfate, filtered by suction, and the organic phase was rotary evaporated to obtain the crude product;

[0122] A mixed solvent composed of petroleum ether and ethyl acetate in a volume ratio of 10:1 was added to a silica gel chromatography column for development. Then, the crude product was dissolved in 15 mL of ethyl acetate, loaded onto the silica gel chromatography column, and eluted with an eluent composed 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.

[0123] Others are the same as in Example 4.

[0124] After detection, the yield of nabumetone-D3 was 91.9%, and the HPLC purity was ≥98.0%.

[0125] Example 6

[0126] The difference between this example and Example 1 is that:

[0127] Catalyst A is modified cesium carbonate, from Preparation Example 1, and catalyst B is modified palladium chloride, from Preparation Example 4;

[0128] The dosage of catalyst A is 21.86 g; the dosage of catalyst B is 4.07 g;

[0129] Others are the same as in Example 1.

[0130] After detection, the yield of nabumetone-D3 was 92.6%, and the HPLC purity was ≥99.0%.

[0131] Example 7

[0132] The difference between this example and Example 1 is that:

[0133] Catalyst A is modified cesium carbonate, from Preparation Example 2, and catalyst B is modified palladium chloride, from Preparation Example 5;

[0134] The dosage of catalyst A is 17.33 g; the dosage of catalyst B is 2.63 g;

[0135] Others are the same as in Example 1.

[0136] After detection, the yield of nabumetone-D3 was 92.3%, and the HPLC purity was ≥99.0%.

[0137] Example 8

[0138] The difference between this example and Example 1 is that:

[0139] Catalyst A is modified cesium carbonate, from Preparation Example 3, and catalyst B is modified palladium chloride, from Preparation Example 6;

[0140] The dosage of catalyst A is 13.08 g; the dosage of catalyst B is 2.14 g;

[0141] The rest is the same as in Example 1.

[0142] After detection, the yield of nabumetone-D3 was 92.1%, and the HPLC purity was ≥99.0%.

[0143] Example 9

[0144] The difference between this example and Example 8 is that:

[0145] In step S1, after adding catalyst A, it further includes the step of adding 0.3 g of potassium iodide;

[0146] In step S2, while adding sodium bicarbonate, it also includes the step of adding 0.3 g of potassium iodide.

[0147] The rest is the same as in Example 8.

[0148] After detection, the yield of nabumetone-D3 was 92.7%, and the HPLC purity was ≥99.0%.

[0149] Example 10

[0150] The difference between this example and Example 9 is that:

[0151] In step S1, after adding catalyst A, it further includes the step of adding 0.4 g of potassium iodide;

[0152] In step S2, while adding sodium bicarbonate, it also includes the step of adding 0.4 g of potassium iodide.

[0153] The rest is the same as in Example 9.

[0154] After detection, the yield of nabumetone-D3 was 92.8%, and the HPLC purity was ≥99.0%.

[0155] Comparative Example 1

[0156] The difference between this comparative example and Example 1 is that:

[0157] Sodium bicarbonate was not added in step S2;

[0158] The rest is the same as in Example 1.

[0159] The yield of nabumetone-D3 was 83%, and the HPLC purity was 92.8%.

[0160] Analyze Example 1 and combine with 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 the same as the theoretical molecular weight of nabumetone-D3 (the molecular formula of nabumetone-D3 is C 15 H 13 D3O2, the theoretical molecular weight is 231.3, plus H+ It is close to the mass-to-charge ratio of about 332.3), and although there is a slight deviation, it can still prove that deuterium atoms are successfully introduced into the product, verifying the correctness of the deuterated structure. This is consistent with the high deuteration rate result of 98.71% of the isotope abundance in Example 1. Moreover, there are no significant miscellaneous peaks in the mass spectrum except for the relevant ion peaks of nabumetone-D3, indicating that the impurity content in the surface product is extremely low, which shows that the nabumetone-D3 prepared in Example 1 has a high purity.

[0161] Analyze Example 1 and combine it with Figures 2 to 3 It can be known that by comparing Figure 2 It can be known that in Figure 3 the hydrogen atom signal corresponding to the deuterated site marked in nabumetone-D3 disappears, indicating that in the nabumetone-D3 prepared in Example 1, deuterium atoms successfully replace the target hydrogen atoms. There are no significant miscellaneous peaks in the two figures except for the hydrogen signal of the target molecule, indicating that the impurity content in the synthesized product is extremely low.

[0162] This specific embodiment is only an interpretation of the present application, and it is not a limitation of the present application. After reading this specification, those skilled in the art can make modifications without creative contributions to this embodiment as needed, but as long as it is within the scope of the claims of the present application, it is protected by the patent law.

Claims

1. A preparation method of nabumetone-D3, characterized in that, It includes the following steps: S1: Mix 9 - 11 g of 6 - bromo - 2 - naphthol, 6.0 - 21.9 g of catalyst A and anhydrous N,N - dimethylformamide evenly, then add 6.0 - 7.0 g of deuterated iodomethane. After mixing evenly, adjust the temperature to 20 - 30 °C, react for 22 - 26 h, quench, extract, wash, dry, and concentrate to obtain the first intermediate product; S2: Under an inert atmosphere, mix 0.6 - 4.1 g of catalyst B and 55 - 65 g of tetrabutylammonium bromide evenly, heat up to 110 - 130 °C, react for 8 - 12 min, cool down to 75 - 85 °C, add 9.5 - 10.5 g of the first intermediate product, 2.5 - 3.5 g of 3 - buten - 2 - ol and 4 - 4.5 g of sodium bicarbonate, mix evenly, then heat up to 110 - 130 °C, react for 22 - 26 h, cool, extract, wash, dry, purify, and elute to obtain nabumetone - D3; The catalyst A is prepared by the following steps: (1) Dissolve 28.5 - 35.0 g of cesium nitrate in water, add 45 - 55 g of mesoporous material, mix evenly, let stand, carry out solid - liquid separation, wash to 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, heat up to 35 - 45 °C, mix for 3.5 - 4.5 h, carry out solid - liquid separation, wash, dry, and calcine to obtain it; The calcination temperature in step (2) is 280 - 320 °C, and the calcination time is 2.5 - 3.5 h; The catalyst B is prepared by the following steps: (a) Under an inert atmosphere, disperse 9 - 11 g of magnetic mesoporous material in toluene, then add 4 - 6 mL of 3 - chloropropyltrimethoxysilane, mix evenly, reflux and react for 22 - 26 h, carry out solid - liquid separation, wash, dry to obtain a pretreated product; (b) Disperse the pretreated product in an ethanol solution, then add 4 - 6 g of cysteamine and 4 - 6 g of sodium carbonate, mix evenly, adjust the temperature to 20 - 30 °C, react for 22 - 26 h, carry out solid - liquid separation, wash, dry to obtain a pre - modified product; (c) Disperse 4 - 6 g of the pre - modified product in an ethanol solution, then add 1 - 2 g of palladium chloride and mix evenly, adjust the temperature to 20 - 30 °C, impregnate for 22 - 26 h, carry out solid - liquid separation, wash, dry to obtain a pre - supported catalyst; (d) Under a mixed atmosphere, heat up to 60 - 80 °C, carry out reduction treatment on the pre - supported catalyst for 40 - 60 min, then cool to obtain it.

2. The preparation method of nabumetone-D3 according to claim 1, characterized in that, In step S2, after adding the first intermediate product, 3 - buten - 2 - ol and sodium bicarbonate and mixing evenly, keep the temperature at 75 - 85 °C, introduce hydrogen, control the hydrogen partial pressure between 10 - 40 kPa, after treatment for 40 - 60 min, release the pressure, and introduce an inert gas.

3. The preparation method of nabumetone-D3 according to claim 1, characterized in that, The mixed atmosphere is composed of hydrogen and nitrogen mixed according to a volume ratio of (0.5 - 1.5):(8.5 - 9.5).

4. The preparation method of nabumetone-D3 according to claim 1, characterized in that, In the mixed atmosphere, the flow rate of the mixed gas is 100 - 150 mL / min.

5. The preparation method of nabumetone-D3 according to claim 1, characterized in that, In step S1, after adding catalyst A, it further includes the step of adding 0.3 - 0.4 g of potassium iodide.

6. The preparation method of nabumetone-D3 according to claim 1, wherein, In step S2, when adding sodium bicarbonate, it also includes the step of adding 0.3 - 0.4 g of potassium iodide.

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