Preparation method of olpinapone

Abstract

The invention provides a preparation method of olpinapone, which comprises the following steps: 1, dissolving a compound SM1 and a hydroxylamine compound in a solvent, heating, and carrying out addition reaction to obtain M1; 2, dissolving M1 and a compound SM2 in a solvent, heating, carrying out a cyclization reaction to generate a dihydrodioxazole intermediate, adding alkali into a reaction system, carrying out an oxidation reaction to generate a 1, 2, 4-oxadiazole intermediate, when R is equal to H, pulping and purifying to obtain M2-1, and carrying out a nitration reaction to obtain a compound M2; 3, dissolving the M2 in a reaction solvent, adding aluminum trichloride, adding pyridine, heating, and carrying out a demethylation reaction to obtain M3; and step 4, adding the M3 into a reaction solvent, adding an oxidizing agent and acid anhydride, carrying out oxidation reaction, after the reaction is finished, evaporating to remove the solvent, adding residues into a benign solvent 1, heating, stirring and dissolving, dropwise adding an anti-solvent 2, and recrystallizing to obtain the oxicapone. The preparation method provided by the invention has the advantages of short reaction steps, reduced cost, mild reaction conditions and highest product purity.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and particularly to a preparation method of opicapone. Background Art

[0002] Opicapone, with the chemical name 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine N-oxide, is a long-acting, third-generation COMT enzyme inhibitor. The opicapone capsule was developed by Portuguese company Bial-Portela, and was approved for listing in the European Union in June 2016, in the United States in April 2020, and in Japan in tablet form in June 2020. The marketed specifications of the opicapone capsule are 25 mg and 50 mg. The original research manufacturer Bial-Portela disclosed a synthesis method of opicapone in patent WO 2013089573 A1, as shown in Route 1 below:

[0003] This route requires the use of thionyl chloride, and the moisture content of the system needs to be additionally controlled. Moreover, the acyl chlorination reagent corrodes the equipment severely, and the waste gas generated needs to be additionally treated; in addition, the acyl chloride has high activity, and dimeric impurities are likely to be generated during the cyclization to prepare the key intermediate 1,2,4-oxadiazole, resulting in a reduced yield. The total yield of this route is about 32%; the molecular formula of the dimeric impurity is as follows:

[0004] US 8168793 B2 disclosed a synthesis method of opicapone, as shown in Route 2 below:

[0005] This route uses a condensing agent for dehydration in the cyclization reaction, and its by-products are difficult to remove, and the reaction time is long. The materials are protected with benzyl, and finally boron tribromide is used for deprotection, which causes serious pollution, and the reaction requires -78°C, so it is not suitable as a commercial production process.

[0006] US 20180370958 A1 disclosed a synthesis method of opicapone, as shown in Route 3 below:

[0007] This route uses chlorooxime and cyanide to react to prepare the cyclization intermediate. Before cyclization, the cyanide group of the material 2,5-dichloro-4,6-dimethylnicotinonitrile is first reduced to an aldehyde, then added with hydroxylamine, and chlorinated in a total of three steps to obtain chlorooxime. The material 5-nitrovanillin is dehydrated after oximation to prepare cyanide, and then cyclized to prepare the key intermediate. The process route is long, and the reducing agent DIBAL and the chlorinating reagent NCS need to be used. Although the acyl chloride chlorination process is avoided, the production route is long and the cost is significantly higher than that of Route 1.

[0008] In summary, the key step in the synthetic process of opicapone lies in constructing the 1,2,4-oxadiazole ring intermediate M2. In Route 1, the acyl chloride is prepared from the material 5-nitrovanillic acid through thionyl chloride. 2,5-Dichloro-4,6-dimethylnicotinonitrile reacts with hydroxylamine to form an amidoxime, and then reacts with the acyl chloride through esterification and cyclization in a total of four steps to construct the 1,2,4-oxadiazole ring. The acyl chloride intermediate in the process decomposes when encountering water, so the water content in the system needs to be controlled. Moreover, the acyl chlorination reagent corrodes the equipment severely, and the generated waste gas needs to be treated additionally. In addition, due to the high activity of the acyl chloride, dimeric impurities are easily generated during the cyclization to prepare the key intermediate of 1,2,4-oxadiazole, resulting in a reduced yield. The total yield of this route is about 32%. In Route 3, the cyano group of 2,5-dichloro-4,6-dimethylnicotinonitrile is first reduced to an aldehyde, then added with hydroxylamine, and chlorinated in a total of three steps to obtain chlorooxime. The material 5-nitrovanillin is dehydrated after amidoximation to prepare a cyano group, and then cyclized with chlorooxime in a total of five steps to construct the 1,2,4-oxadiazole ring. The process route is long, and reducing agent DIBAL and chlorinating reagent NCS need to be used in the process route, and the cost is significantly higher. Therefore, there is an urgent need for a new method for preparing opicapone. Summary of the Invention

[0009] Aiming at the deficiencies of the existing technology, the purpose of the present invention is to provide a method for preparing opicapone, which can solve the existing problems.

[0010] In order to achieve the above purpose, the technical solution of the present invention is as follows: The present invention is realized through the following technical solutions: A method for preparing opicapone, comprising the following steps: Step 1: Dissolve the compound SM1 and the hydroxylamine compound in a solvent, heat up and carry out an addition reaction to obtain an amidoxime product M1; Step 2: Dissolve the amidoxime product M1 and the compound SM2 in a solvent, heat up and carry out a cyclization reaction to generate a dihydrodioxazole intermediate, add a base to the reaction system, and carry out an oxidation reaction to generate a 1,2,4-oxadiazole intermediate. When R = H, it is purified by pulping to obtain M2-1, and then subjected to a nitration reaction to obtain the compound M2; Step 3: Dissolve the compound M2 in a reaction solvent, add aluminum trichloride, add pyridine, heat up and carry out a demethylation reaction to obtain an intermediate M3; Step 4: Add the intermediate M3 into a reaction solvent, add an oxidizing agent and an acid anhydride, carry out an oxidation reaction. After the reaction is completed, evaporate the solvent, add a good solvent 1 to the residue, heat up and stir to dissolve, and then dropwise add an anti-solvent 2 for recrystallization to obtain opicapone; The above reaction formula is as follows: .

[0011] Preferably, in Step 1: The hydroxylamine compound includes an aqueous solution of hydroxylamine or hydroxylamine hydrochloride. When the hydroxylamine compound is hydroxylamine hydrochloride, an inorganic base is required for liberation; The solvent includes an aqueous solution of methanol or an aqueous solution of ethanol. In the aqueous solution of methanol, the mass ratio of methanol to water is 4 - 5:8, and in the aqueous solution of ethanol, the mass ratio of ethanol to water is 4 - 5:8.

[0012] Preferably, the molar ratio of the compound SM1 to the hydroxylamine compound in the feed is SM1:hydroxylamine compound = 1:3 - 5; the temperature of the addition reaction is 50 - 70 °C.

[0013] Preferably, the inorganic base includes one of sodium bicarbonate, sodium carbonate, and potassium carbonate, and the molar ratio of hydroxylamine hydrochloride to inorganic base in the feed is 2:1 - 2.

[0014] Preferably, in step two: the temperature of the cyclization reaction is 100 - 120 °C, and the solvent for the cyclization reaction includes one of dimethyl sulfoxide (DMSO), dimethylformamide (DMF), or dimethylacetamide (DMAc); The base includes one or a combination of sodium carbonate, potassium carbonate, cesium carbonate, and 1,8 - diazabicyclo[5.4.0]undec - 7 - ene (DBU); The molar ratio of the feed in step two is M1:SM2:base = 1:1.5 - 2.2:2.

[0015] Preferably, for the nitration reaction, when R = H, M2 - 1 is dissolved in a mixed acid system of nitric acid and glacial acetic acid, and the nitration reaction occurs at a temperature of 10 - 30 °C. The weight ratio of the feed is M2 - 1:nitric acid:acetic acid = 3:1:15 - 20.

[0016] Preferably, in step three, the reaction solvent includes N - methylpyrrolidone; the temperature for dropping pyridine is 0 - 10 °C, the temperature for demethylation reaction is 55 - 65 °C, and the molar ratio of the feed is M2:aluminum trichloride: pyridine = 1:1.3 - 1.5:4.

[0017] Preferably, in step four, the reaction solvent includes one of dichloromethane, chloroform, and dioxane; The oxidant includes urea peroxide (UHP), and the acid anhydride includes one of trifluoroacetic anhydride (TFAA) and phthalic anhydride (PA); When the good solvent 1 is dimethylformamide, the anti - solvent 2 is methanol; or when the good solvent 1 is formic acid, the anti - solvent 2 is isopropanol.

[0018] Preferably, the temperature for dropping the acid anhydride is - 5 - 10 °C, the temperature for the oxidation reaction is 15 - 35 °C, and the molar ratio of the feed is M3:UHP:acid anhydride = 1:3 - 5:3.

[0019] Preferably, the temperature for heating and stirring to dissolve is 60-70 °C, and the weight ratio of the feed is M3:solvent 1:antisolvent 2 = 1:6-9:12-18.

[0020] Compared with the prior art, the beneficial effects of the present invention include: using 2,5-dichloro-4,6-dimethylnicotinonitrile to react with hydroxylamine to form an amidoxime, and then reacting with 5-nitrovanillin, a one-pot method is used to complete three consecutive reactions to directly construct a 1,2,4-oxadiazole ring. The reaction steps are short, the total yield can be up to 61.4% at most, the cost is reduced, the reaction conditions are mild, and the product purity is up to 99.9% at most. Description of the Drawings

[0021] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for use in the description of the embodiments or the prior art. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0022] Figure 1 is the HPLC chromatogram of M1 prepared in Example 1 of the present invention; Figure 2 is the HPLC chromatogram of M2 prepared in Example 9 of the present invention; Figure 3 is the HPLC chromatogram of M3 prepared in Example 13 of the present invention; Figure 4 is the HPLC chromatogram of opicapone prepared in Example 14 of the present invention; Figure 5 is the 1 1H-NMR spectrum of opicapone prepared in Example 14 of the present invention; Figure 6 is the ESI-MS spectrum of opicapone prepared in Example 14 of the present invention. Detailed Embodiments

[0023] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are clearly and completely described below. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts fall within the scope of protection of the present invention.

[0024] The present invention provides a method for preparing opicapone, which includes the following steps: Step 1: Dissolve compound SM1 and a hydroxylamine compound in a solvent, and after heating, an addition reaction occurs to obtain an amidoxime product M1; Step 2: Dissolve the amidoxime product M1 and the compound SM2 in a solvent. After heating, a cyclization reaction occurs to form a dihydrodiazole intermediate. Add a base to the reaction system to cause an oxidation reaction to form a 1,2,4-oxadiazole intermediate. When R = H, M2-1 is obtained through pulping purification, and then the compound M2 is obtained through nitration reaction. Step 3: Dissolve the compound M2 in a reaction solvent, add aluminum trichloride, add pyridine, and heat to cause a demethylation reaction to obtain the intermediate M3. Step 4: Add the intermediate M3 to a reaction solvent, add an oxidant and an acid anhydride, and carry out an oxidation reaction. After the reaction is completed, evaporate the solvent. Add a good solvent 1 to the residue, heat and stir to dissolve, and then dropwise add an anti-solvent 2 for recrystallization to obtain opicapone. The reaction formula is as follows: 。

[0025] Example One: Preparation of (Z)-2,5-dichloro-N'-hydroxy-4,6-dimethyl-3-pyridinecarboximidamide, i.e., M1. In the present invention, the compound SM1 and a hydroxylamine compound are dissolved in a solvent, and an addition reaction occurs after heating to obtain the amidoxime product M1. The reaction formula is as follows: Example 1: The amine compound is reacted using a 50% aqueous hydroxylamine solution system: Charge 20.11 g (0.1 mol) of 2,5-dichloro-4,6-dimethylnicotinonitrile (SM1), 95.54 g of methanol, 160.88 g of water, and 25.76 g (0.39 mol) of 50% aqueous hydroxylamine solution into a glass reaction flask. Heat to 70 - 80 °C and stir the reaction for 7 h. Add 160 g of water under insulation, stir for 30 min, cool to room temperature for crystallization for 2 h, filter, wash the filter cake with purified water, and dry in a blast dryer at 70 °C to obtain a white solid M1. The HPLC purity spectrum is shown in the appendix. Figure 1 。

[0026] Example 2: This example provides a preparation method of (Z)-2,5-dichloro-N'-hydroxy-4,6-dimethyl-3-pyridinecarboximidamide (M1). The difference from Example 1 is that the reaction solvent used is an ethanol aqueous solution, and the weight ratio of ethanol to water is 4:5.

[0027] Example 3: This example provides a preparation method of (Z)-2,5-dichloro-N'-hydroxy-4,6-dimethyl-3-pyridinecarboximidamide (M1). The difference from Example 1 is that the weight ratio of methanol to water used as the reaction solvent is 4:8.

[0028] Example 4: This example provides a preparation method of (Z)-2,5-dichloro-N'-hydroxy-4,6-dimethyl-3-pyridinecarboximidamide (M1). The difference from Example 1 is that the molar ratio of SM1 to the aqueous hydroxylamine solution is 1:3.

[0029] Example 5: This example provides a preparation method of (Z)-2,5-dichloro-N'-hydroxy-4,6-dimethyl-3-pyridinecarboximidamide (M1). The difference from Example 1 is that the molar ratio of SM1 to the aqueous hydroxylamine solution is 1:5. The summary of the results of Examples 1-5 is shown in Table 1.

[0030] Table 1 Summary of the results of Examples 1-5 Example 6: The amine compound is reacted using a hydroxylamine hydrochloride system: 27.1 g (0.39 mol) of hydroxylamine hydrochloride and 160.9 g of water are added to a glass reaction flask and stirred until dissolved. Then, 32.8 g (0.39 mol) of sodium bicarbonate is added to the reaction system in five batches. After stirring the reaction until no bubbles are generated, 95.5 g of methanol and 20.11 g (0.1 mol) of SM1 are added. The temperature is raised to 75 °C and the reaction is stirred for 6 h. While maintaining the temperature, 160 g of water is added and stirred for 30 min. The temperature is then lowered to room temperature and crystallization occurs for 2 h. The mixture is filtered, and the filter cake is washed with purified water and dried in a blast dryer at 70 °C to obtain a slightly yellow solid M1.

[0031] Example 7: This example provides a preparation method of (Z)-2,5-dichloro-N'-hydroxy-4,6-dimethyl-3-pyridinecarboximidamide (M1). The difference from Example 5 is that the base for free hydroxylamine hydrochloride is sodium carbonate, and the molar ratio of hydroxylamine hydrochloride to sodium carbonate is 2:1.

[0032] Example 8: This example provides a preparation method of (Z)-2,5-dichloro-N'-hydroxy-4,6-dimethyl-3-pyridinecarboximidamide (M1). The difference from Example 5 is that the base for free hydroxylamine hydrochloride is potassium carbonate, and the molar ratio of hydroxylamine hydrochloride to potassium carbonate is 2:1. The summary of the results of Examples 6-8 is shown in Table 2.

[0033] Table 2 Summary of the results of Examples 6-8 II: Preparation of 4-[3-(2,5-dichloro-4,6-dimethyl-3-pyridyl)-1,2,4-oxadiazol-5-yl]-2-methoxy-6-nitrophenol, i.e., M2. The oximinoamine product M1 and the compound SM2 are dissolved in a solvent. After heating, a cyclization reaction occurs to form a dihydrooxadiazole intermediate. A base is added to the reaction system to cause an oxidation reaction to form a 1,2,4-oxadiazole intermediate. When R = H, M2-1 is obtained through slurrying purification, and then the compound M2 is obtained through a nitration reaction. The reaction formula when R = NO2 is as follows:

[0034] Example 9: 18.7 g (0.08 mol) of M1, 31.5 g (0.16 mol) of 5-nitrovanillin (SM2), 12.7 g (0.12 mol) of sodium carbonate, 13 g (0.04 mol) of cesium carbonate, and 130.9 g of DMSO were charged into a glass reaction flask, and the temperature was raised to 110 °C for stirring reaction. After the reaction was completed, filtration was carried out, and the filtrate was added dropwise to a 5N hydrochloric acid solution, and the internal temperature was controlled ≤20 °C during the addition process. After the addition was completed, filtration was carried out, and the filter cake was washed twice with water. 147.5 g of absolute ethanol was added, and pulping was carried out at room temperature for 3 h. Filtration was carried out, and the filter cake was washed twice with absolute ethanol, and dried by blowing air to obtain a yellow solid M2. The HPLC purity spectrum is shown in the appendix Figure 2 .

[0035] Example 10: 18.7 g (0.08 mol) of M1, 23.6 g (0.12 mol) of 5-nitrovanillin (SM2), 22.1 g (0.16 mol) of potassium carbonate, and 130.9 g of DMF were charged into a glass reaction flask, and the temperature was raised to 100 °C for stirring reaction. After the reaction was completed, filtration was carried out, and the filtrate was added dropwise to a 5N hydrochloric acid solution, and the internal temperature was controlled ≤20 °C during the addition process. After the addition was completed, filtration was carried out, and the filter cake was washed twice with water. 150 g of acetonitrile was added, and pulping was carried out at room temperature for 3 h. Filtration was carried out, and the filter cake was washed twice with acetonitrile-free, and dried by blowing air to obtain a yellow solid M2.

[0036] Example 11: 18.7 g (0.08 mol) of M1, 34.7 g (0.18 mol) of 5-nitrovanillin (SM2), 24.3 g (0.16 mol) of DBU, and 132 g of DMAc were charged into a glass reaction flask, and the temperature was raised to 120 °C for stirring reaction. After the reaction was completed, filtration was carried out, and the filtrate was added dropwise to a 5N hydrochloric acid solution, and the internal temperature was controlled ≤20 °C during the addition process. After the addition was completed, filtration was carried out, and the filter cake was washed twice with water. 150 g of absolute ethanol was added, and pulping was carried out at room temperature for 3 h. Filtration was carried out, and the filter cake was washed twice with absolute ethanol, and dried by blowing air to obtain a yellow solid M2. The summary of the results of Examples 9-11 is shown in Table 3: Table 3 Summary of the results of Examples 9-11 Preparation of 4-[3-(2,5-dichloro-4,6-dimethyl-3-pyridyl)-1,2,4-oxadiazol-5-yl]-2-methoxy-6-nitrophenol, i.e., M2. When R = H, the reaction formula is as follows:

[0037] Example 12: Add 18.6 g (0.08 mol) of M1, 24.3 g (0.16 mol) of vanillin (SM2-1), 52.1 g (0.16 mol) of cesium carbonate, and 130.9 g of DMSO into a glass reaction flask, and heat up to 110 °C for stirring reaction. After the reaction is completed, filter, and add the filtrate dropwise to a 5N hydrochloric acid solution, controlling the internal temperature ≤ 20 °C during the dropping process. After the dropping is completed, filter, and wash the filter cake twice with water. Add 140 g of absolute ethanol and slurry at room temperature for 3 h. Filter, wash the filter cake twice with absolute ethanol, and dry under blowing to obtain M2-1.

[0038] Add 24.8 g of M2-1 into a flask, add 148.8 g of glacial acetic acid, cool down to 10 °C, add 8.3 g of nitric acid, and react while controlling the temperature at 10 - 30 °C. After the reaction is completed, add the reaction solution dropwise to 600 ml of water, precipitate a solid, filter, and wash the filter cake with water until it is neutral. Dry under blowing to obtain a yellow solid M2, and the yield based on M1 is 80.5%.

[0039] III: Preparation of 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)-3-nitrobenzene-1,2-diol, i.e., M3: Dissolve compound M2 in a reaction solvent, add aluminum trichloride, add pyridine, and heat up to undergo a demethylation reaction to obtain intermediate M3. The reaction formula is as follows:

[0040] Example 13: Add 23.2 g (0.06 mol) of M2 and 208.9 g of NMP into a flask, start stirring, cool the reaction solution to 0 - 8 °C, and add 11.2 g (0.084 mol) of aluminum trichloride in batches, controlling the temperature ≤ 10 °C. After adding, start to dropwise add 19 g (0.24 mol) of pyridine, controlling the temperature at 0 - 10 °C. After the dropping is completed, heat up to 55 - 65 °C for reaction. Add the above reaction solution dropwise to 460 g of a 5N hydrochloric acid solution, controlling the internal temperature at 15 - 25 °C during the dropping process. After the dropping is completed, filter, wash the filter cake with water until it is neutral, wash it twice with methanol, slurry and purify 232 g of the filter cake with acetonitrile, filter, and dry the filter cake at 60 - 70 °C under blowing to obtain a yellow solid M3, with a yield of 90.5% and a purity of 99.7%. For the HPLC purity spectrum, please refer to the appendix Figure 3 。

[0041] IV: Preparation of opicapone. Add intermediate M3 into a reaction solvent, add an oxidant and an acid anhydride, and carry out an oxidation reaction. After the reaction is completed, evaporate the solvent, add a good solvent 1 to the residue, heat and stir to dissolve, and then dropwise add an anti-solvent 2 for recrystallization to obtain opicapone. The reaction formula is as follows:

[0042] Example 14: 20 g (0.05 mol) of M3 and 340 g of dichloromethane were added to a reaction flask. Stirring was started, and the reaction solution was cooled to 0 - 8 °C. 18.8 g of UHP (0.2 mol) was added in portions, with the temperature controlled at ≤10 °C. The addition was completed in about 40 min. The temperature was cooled to -5 - 8 °C, and 31.5 g (0.15 mol) of TFAA was added dropwise, with the temperature controlled at -5 - 10 °C. After the dropwise addition was completed, the mixture was stirred at a constant temperature for 30 min. The reaction was carried out at 15 - 35 °C for more than 20 h. The mixture was filtered, and the filter cake was washed once with DCM. The filtrates were combined and concentrated under reduced pressure to remove the solvent. 160 g of DMF was added to the distillation residue, and the temperature was raised to 65 °C and stirred until dissolved. After the solution was clear, 320 g of methanol was added dropwise. After the dropwise addition was completed, the mixture was stirred for crystallization. The mixture was filtered, and the filter cake was washed twice with methanol and then dried by blowing air to obtain opicapone. The recrystallization process can be repeated multiple times. The HPLC purity spectrum is shown in the appendix Figure 4 , and the 1H-NMR spectrum is shown in the appendix Figure 5 , and the ESI-MS spectrum is shown in the appendix Figure 6 .

[0043] Example 15: This example provides a method for preparing opicapone, which is different from Example 14 in that the reaction solvent is chloroform.

[0044] Example 16: This example provides a method for preparing opicapone, which is different from Example 14 in that the reaction solvent is dioxane.

[0045] Example 17: 20 g (0.05 mol) of M3 and 340 g of DCM were added to a reaction flask. Stirring was started, and the reaction solution was cooled to 0 - 8 °C. 23.5 g of UHP (0.25 mol) was added in portions, with the temperature controlled at ≤10 °C. The addition was completed in about 40 min. The temperature was cooled to -5 - 8 °C, and 22.2 g (0.15 mol) of PA was added dropwise, with the temperature controlled at -5 - 10 °C. After the dropwise addition was completed, the mixture was stirred at a constant temperature for 30 min. The reaction was carried out at 15 - 35 °C for more than 20 h. The mixture was filtered, and the filter cake was washed once with DCM. The filtrates were combined and concentrated under reduced pressure to remove the solvent. 180 g of formic acid was added to the distillation residue, and the temperature was raised to 70 °C and stirred until dissolved. After the solution was clear, 360 g of isopropanol was added dropwise. After the dropwise addition was completed, the mixture was stirred for crystallization. The mixture was filtered, and the filter cake was washed twice with isopropanol and then dried by blowing air to obtain opicapone. The recrystallization process can be repeated multiple times. The summary of the results of Examples 15 - 17 is shown in Table 4.

[0046] Table 4 Summary of the results of Examples 15 - 17 It can be concluded from the above examples that the highest yield of the preparation process of this scheme can reach 88.1% × 89.3% × 90.5% × 86.2% = 61.4%, and the purity can reach 99.9%.

[0047] The method of the present invention uses 2,5-dichloro-4,6-dimethylnicotinonitrile to generate an amidoxime with hydroxylamine, and then reacts with 5-nitrovanillin to directly construct a 1,2,4-oxadiazole ring through three consecutive reactions in one pot. The reaction steps are short, the total yield can reach up to 61.4% at most, the cost is reduced, the reaction conditions are mild, and the product purity is up to 99.9%.

[0048] It should be noted that in this article, relational terms such as first and second are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the term "comprising", "including" or any other variant thereof is intended to cover non-exclusive inclusion, so that a process, method, article or device comprising a series of elements not only includes those elements, but also includes other elements not expressly listed, or further includes elements inherent to such process, method, article or device. Without further limitation, an element defined by the statement "comprising an..." does not exclude the existence of additional identical elements in the process, method, article or device comprising the element.

[0049] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements on some of the technical features; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A preparation method of opicapone, characterized in that, It includes the following steps: Step 1: Dissolve compound SM1 and a hydroxylamine compound in a solvent, and after heating, an addition reaction occurs to obtain an amidoxime product M1; Step 2: Dissolve the amidoxime product M1 and compound SM2 in a solvent, and after heating, a cyclization reaction occurs to generate a dihydrodioxazole intermediate. Add a base to the reaction system, and an oxidation reaction occurs to generate a 1,2,4-oxadiazole intermediate. When R = H, it is purified by slurrying to obtain M2-1, and then a nitration reaction is carried out to obtain compound M2; Step 3: Dissolve compound M2 in a reaction solvent, add aluminum trichloride, add pyridine, and heat to carry out a demethylation reaction to obtain intermediate M3; Step 4: Add intermediate M3 to a reaction solvent, add an oxidant and an acid anhydride, and carry out an oxidation reaction. After the reaction is completed, evaporate the solvent. Add a good solvent 1 to the residue, heat and stir to dissolve it, and then dropwise add an anti-solvent 2 for recrystallization to obtain opicapone; The above reaction formula is as follows:

2. The preparation method of opicapone according to claim 1, characterized in that, In Step 1: The hydroxylamine compound includes an aqueous solution of hydroxylamine or hydroxylamine hydrochloride. When the hydroxylamine compound is hydroxylamine hydrochloride, an inorganic base is needed for liberation; The solvent includes an aqueous solution of methanol or an aqueous solution of ethanol. In the aqueous solution of methanol, the mass ratio of methanol to water is 4 - 5:8, and in the aqueous solution of ethanol, the mass ratio of ethanol to water is 4 - 5:

8.

3. The preparation method of opicapone according to claim 1, characterized in that, The molar ratio of the feed of compound SM1 to the hydroxylamine compound is SM1:hydroxylamine compound = 1:3 - 5; the temperature of the addition reaction is 50 - 70°C.

4. The preparation method of opicapone according to claim 2, characterized in that, The inorganic base includes one of sodium bicarbonate, sodium carbonate, and potassium carbonate, and the molar ratio of the feed is hydroxylamine hydrochloride:inorganic base = 2:1 - 2.

5. A method for preparing opicapone according to claim 1, characterized in that, In Step 2: The temperature of the cyclization reaction is 100 - 120°C, and the solvent for the cyclization reaction includes one of dimethyl sulfoxide, dimethylformamide, or dimethylacetamide; The base includes one or a combination of sodium carbonate, potassium carbonate, cesium carbonate, and 1,8-diazabicyclo[5.4.0]undec-7-ene; The molar ratio of the feed in Step 2 is M1:SM2:base = 1:1.5 - 2.2:

2.

6. The preparation method of opicapone according to claim 5, characterized in that, The nitration reaction includes when R = H, M2-1 is dissolved in a mixed acid system of nitric acid and glacial acetic acid, and a nitration reaction occurs. The temperature of the nitration reaction is 10 - 30°C, and the weight ratio of the feed is M2-1:nitric acid:acetic acid = 3:1:15 - 20.

7. A method for preparing opicapone according to claim 1, characterized in that, In Step 3, the reaction solvent includes N-methylpyrrolidone; the temperature for dropping pyridine is 0 - 10°C, the temperature of the demethylation reaction is 55 - 65°C, and the molar ratio of the feed is M2:aluminum trichloride:pyridine = 1:1.3 - 1.5:

4.

8. The preparation method of opicapone according to claim 1, characterized in that, In Step 4, the reaction solvent includes one of dichloromethane, chloroform, and dioxane; The oxidant includes urea peroxide, and the acid anhydride includes one of trifluoroacetic anhydride and phthalic anhydride; When the good solvent 1 is dimethylformamide, the anti-solvent 2 is methanol; or when the good solvent 1 is formic acid, the anti-solvent 2 is isopropanol.

9. The preparation method of opicapone according to claim 8, characterized in that, The temperature for dropping the acid anhydride is -5 - 10°C, the temperature of the oxidation reaction is 15 - 35°C, and the molar ratio of the feed is M3:urea peroxide:acid anhydride = 1:3 - 5:

3.

10. A method for preparing opicapone according to claim 9, characterized in that, The temperature for heating and stirring to dissolve is 60-70°C, and the weight ratio of the feed is M3:solvent 1:antisolvent 2 = 1:6-9:12-18.

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