Novel synthesis method of key intermediate of contezolamide
Through the new synthesis method, the synthesis route of key contezolamide intermediates has been simplified, the problems of high cost, low yield and process complexity in the existing methods have been solved, and efficient and safe intermediate preparation is achieved, which is suitable for industrial production.
Patent Information
- Application Number
- CN202510182144.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-19
- Publication Date
- 2025-05-30
AI Technical Summary
The existing synthesis methods of key contezolamide intermediates have problems such as high cost, low yield, long routes and complex process flow, and the chemical reagents used are highly dangerous and difficult to store and transport.
Using a new synthesis method, the intermediate-1 was obtained by coupling 2,3,4,5-tetrafluoronitrobenzene with 4-oxopiperidone hydrochloride, and then dehydrogenated the pyridinone ring to dihydropyridone ring with an oxidant, and finally the nitro group was reduced to amino under the iron powder glacial acetic acid system to obtain the key intermediate of contezolamide.
The synthesis route is simplified, the total yield and purity is improved, the raw material consumption and process complexity are reduced, and the use of high-risk chemical reagents and difficult-to-storage intermediates are avoided, making it suitable for industrial production.
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Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of pharmaceutical preparation, and particularly relates to a new synthesis method of a key intermediate of contezolid. Background Art
[0002] Contezolid is a novel oxazolidinone antibiotic developed by Shanghai MicroPort Pharmaceuticals Co., Ltd. The commercial name of contezolid tablets is "Youxitai", which belongs to the first-class new drug in China and was approved for marketing by the National Medical Products Administration (NMPA) in June 2021. As a new generation of oxazolidinone antibacterial drug independently developed in China, contezolid is applicable to the treatment of complicated skin and soft tissue infections caused by Staphylococcus aureus (methicillin-sensitive and resistant strains), Streptococcus pyogenes or Streptococcus agalactiae sensitive to this product. Compared with traditional oxazolidinone antibacterial drugs such as tedizolid and linezolid, contezolid has the advantages of significantly reducing renal toxicity and neurotoxicity and shows good safety in clinical trials.
[0003] The chemical name of contezolid is: (S)-5-[(isoxazol-3-ylamino)methyl]-3-[2,3,5-trifluoro-4-[4-oxo-3,4-dihydropyridin-1(2H)-yl]phenyl]oxazolidin-2-one, and the chemical structural formula is as follows:
[0004]
[0005] 1-(4-Amino-2,3,6-trifluorophenyl)-2,3-dihydropyridin-4(1H)-one is a key intermediate for the synthesis of contezolid, and the chemical structural formula is as follows:
[0006]
[0007] Based on a comprehensive review of the literature reports, there are the following two synthetic routes for this intermediate:
[0008] Route 1: Refer to US20090048305:
[0009]
[0010] Route 2: Refer to US20100204477:
[0011]
[0012] The key intermediate of conticoxib, 1-(4-amino-2,3,6-trifluorophenyl)-2,3-dihydropyridin-4(1H)-one, has been reported in patents US20100204477, US20090048305, CN101798302 and CN101720325. The synthesis methods are not very different, all involving 4-step reactions. Using 2,3,4,5-tetrafluoronitrobenzene and 4-oxopiperidine hydrochloride as raw materials, they are coupled under alkaline conditions, and then reacted with TIPSOTf or TMSOTf under alkaline conditions to convert the ketone into enol silyl ether. Then it is oxidized by ammonium cerium nitrate, and finally the nitro group is reduced to an amino group in an iron powder-ammonium chloride system to obtain the key intermediate 1-(4-amino-2,3,6-trifluorophenyl)-2,3-dihydropyridin-4(1H)-one.
[0013] The above synthetic route has the following disadvantages:
[0014] First, the synthetic process route is long, the post-treatment operation is cumbersome, and the total yield is low, which is not suitable for industrial production scale-up.
[0015] Second, the enol silyl ether intermediate obtained in the second step is extremely prone to hydrolysis. The reaction needs to be strictly controlled under anhydrous and low-temperature conditions, and water is required for extraction during the post-treatment process, which will cause partial hydrolysis of it during the post-treatment process or the storage process of the enol silyl ether intermediate and return to the previous intermediate. This will not only lead to a significant reduction in the yield, but also expensive anhydrous solvents are needed. The reaction conditions are harsh and not suitable for industrial production scale-up.
[0016] Third, the physical property of the enol silyl ether intermediate is a viscous oily liquid, which is difficult to store and transport, and it is difficult to accurately weigh the material weight when participating in the next reaction.
[0017] Fourth, TMSOTf or TIPSOTf used in the above route is highly dangerous, with strong corrosiveness and flammability. It will hydrolyze when encountering water and is accompanied by intense heat release, posing a high risk in industrial production.
[0018] Fifth, in the above route, enol silyl ether is formed on the pyrrolidone ring through TMSOTf or TIPSOTf, then oxidized, and at the same time the silane is removed. A large amount of impurities will be generated in this process, which are difficult to completely remove, and it does not conform to the concept of green chemistry atom economy in organic chemistry.
[0019] Sixth, reduction in an iron powder-ammonium chloride system will lead to the formation of azo compound by-products, reducing the reaction yield and greatly increasing the operation difficulty of the post-treatment.
[0020] VII. Since the intermediate 1-(4-amino-2,3,6-trifluorophenyl)-2,3-dihydropyridin-4(1H)-one has poor solubility in ethyl acetate and dichloromethane, during the post-treatment operation of the original patent, the extraction method for purification has extremely low efficiency and requires a large amount of solvent. This not only greatly increases the synthesis cost but also prolongs the subsequent vacuum concentration cycle.
[0021] After comprehensively searching the literature, there is currently no method that can avoid the many defects of the above synthesis route. To achieve the industrial production of conticoxib, it is urgent to improve the preparation method of the key intermediate 1-(4-amino-2,3,6-trifluorophenyl)-2,3-dihydropyridin-4(1H)-one to avoid the above disadvantages. Summary of the Invention
[0022] The present invention provides a new synthesis method for the key intermediate of conticoxib to solve the technical problems of high cost, low yield, long route, and complex process flow.
[0023] In view of this, a new synthesis method for the key intermediate of conticoxib provided by the present invention includes the following steps: Coupling 2,3,4,5-tetrafluoronitrobenzene with 4-oxopiperidine hydrochloride to obtain intermediate-1, then dehydrogenating and oxidizing the pyrrolidinone ring to a dihydropyridinone ring with an oxidant to obtain intermediate-2, and then reducing the nitro group to an amino group in an iron powder and glacial acetic acid system to obtain the key intermediate of conticoxib, 1-(4-amino-2,3,6-trifluorophenyl)-2,3-dihydropyridin-4(1H)-one.
[0024] Optionally, the specific preparation method of the intermediate-1 is as follows: Dissolve 2,3,4,5-tetrafluoronitrobenzene and 4-oxopiperidine hydrochloride in a reaction solvent, control the temperature, add an organic base, place the reaction solution under the reaction temperature and stir, drop the reaction solution into purified water under stirring, filter, rinse the filter cake with purified water, and dry to obtain the yellow solid intermediate-1.
[0025] Further, the specific preparation method of the intermediate-1 is as follows: Dissolve 2,3,4,5-tetrafluoronitrobenzene and 4-oxopiperidine hydrochloride in a reaction solvent, control the temperature, add an organic base, place the reaction solution under the reaction temperature and stir, drop the reaction solution into purified water under stirring, filter, rinse the filter cake with purified water, and dry to obtain the yellow solid intermediate-1;
[0026] Among them, the temperature during the addition of the organic base is 0 to 30 °C, preferably 0 to 10 °C, more preferably 0 to 5 °C; the reaction temperature is 0 to 30 °C, preferably 20 to 30 °C, more preferably 25 to 30 °C; the reaction time is 2 to 6 h, preferably 3 to 5 h; the amount of purified water used twice is 20 to 40 times (volume / weight) of 2,3,4,5-tetrafluoronitrobenzene, preferably 25 to 35 times, more preferably 30 times.
[0027] Optionally, the molar ratio of the 4-oxopiperidinone hydrochloride to 2,3,4,5-tetrafluoronitrobenzene is (1.05 - 1.3):1.
[0028] Furthermore, the molar ratio of the 4-oxopiperidinone hydrochloride to 2,3,4,5-tetrafluoronitrobenzene is (1.05 - 1.3):1, preferably (1.05 - 1.1):1.
[0029] Optionally, the reaction solvent is any one of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide or 1,4-dioxane; the organic base is any one of N,N-diisopropylethylamine, triethylamine or pyridine.
[0030] Furthermore, the reaction solvent is any one of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide or 1,4-dioxane; the organic base is any one of N,N-diisopropylethylamine, triethylamine or pyridine; the reaction solvent is preferably N-methylpyrrolidone, and the addition amount is 8 to 15 times the weight of 2,3,4,5-tetrafluoronitrobenzene, preferably 10 to 12 times; the organic base is preferably N,N-diisopropylethylamine, and the molar ratio of the addition amount to 2,3,4,5-tetrafluoronitrobenzene is (2.0 - 3.0):1; preferably 2.5:1.
[0031] Optionally, the specific preparation method of the intermediate-2 is as follows: Dissolve the intermediate-1 in N,N-dimethylformamide, control the temperature, add ammonium cerium nitrate, react at the reaction temperature to obtain a reaction mixture; add an extraction solvent to the reaction mixture, wash, separate the organic phase, dry, concentrate under reduced pressure to obtain an oil, add dichloromethane, and then dropwise add petroleum ether with stirring. During this process, a large amount of yellow solid precipitates. Filter by suction, wash the filter cake, and dry to obtain the yellow solid intermediate-2.
[0032] Further, the specific preparation method of Intermediate-2 is as follows: Dissolve Intermediate-1 in N,N-dimethylformamide, control the temperature, add ammonium cerium nitrate, and react at the reaction temperature to obtain a reaction mixture; Add an extraction solvent to the reaction mixture, wash, separate the organic phase, dry, and concentrate under reduced pressure to obtain an oil. After adding dichloromethane, petroleum ether is added dropwise with stirring. During this process, a large amount of yellow solid precipitates. Filter by suction, wash the filter cake, and dry it to obtain the yellow solid Intermediate-2;
[0033] Among them, the extraction solvent is dichloromethane or ethyl acetate, preferably dichloromethane; the solvent used for washing is purified water or saturated brine, and the addition amount is 20-40 times the weight of 2,3,4,5-tetrafluoronitrobenzene, preferably 25-35 times, more preferably 30 times; the addition amount of dichloromethane is 0.5-2 times (volume / weight) of 2,3,4,5-tetrafluoronitrobenzene, preferably 0.5-1 times, more preferably 0.5 times; the addition amount of petroleum ether used for the first time is 10-30 times (volume / weight) of 2,3,4,5-tetrafluoronitrobenzene, preferably 15-25 times, more preferably 20 times; petroleum ether is used for washing, and the addition amount is 5-15 times (volume / weight) of 2,3,4,5-tetrafluoronitrobenzene, preferably 8-12 times, more preferably 10 times.
[0034] Optionally, the molar ratio of ammonium cerium nitrate to Intermediate-1 is: (2.25-3.0):1.
[0035] Further, the molar ratio of ammonium cerium nitrate to Intermediate-1 is: (2.25-3.0):1, preferably (2.25-2.5):1; more preferably 2.3:1.
[0036] Optionally, the controlled temperature for adding ammonium cerium nitrate is 0-30°C, and the reaction temperature is 0-30°C.
[0037] Further, the controlled temperature for adding ammonium cerium nitrate is 0-30°C, preferably 0-20°C, more preferably 0-10°C; the reaction temperature is 0-30°C, preferably 0-20°C, more preferably 0-10°C; the reaction time is 0.5-3 h, preferably 1-1.5 h.
[0038] Optionally, the specific preparation method of the key intermediate of conticoxib, 1-(4-amino-2,3,6-trifluorophenyl)-2,3-dihydropyridin-4(1H)-one, is as follows: Dissolve Intermediate-2 in a reaction solvent, add glacial acetic acid, then add iron powder with stirring, and stir under heating; cool the reaction solution to room temperature, adjust the pH value with stirring, filter through diatomaceous earth, wash, and then wash with methanol until the liquid drops have no ultraviolet absorption. Concentrate the filtrate under reduced pressure and slurry with purified water to obtain the key intermediate 1-(4-amino-2,3,6-trifluorophenyl)-2,3-dihydropyridin-4(1H)-one.
[0039] Further, the specific preparation method of the key intermediate of conticoxib, 1-(4-amino-2,3,6-trifluorophenyl)-2,3-dihydropyridin-4(1H)-one, is as follows: Dissolve Intermediate-2 in a reaction solvent, add glacial acetic acid, then add iron powder with stirring, and stir under heating; cool the reaction solution to room temperature, add saturated sodium carbonate aqueous solution with stirring to adjust the pH value to 7-8, filter through diatomaceous earth, wash with purified water, change to another clean filter flask, and then wash with methanol until the liquid drops have no ultraviolet absorption. Concentrate the filtrate under reduced pressure and slurry with purified water to obtain the key intermediate 1-(4-amino-2,3,6-trifluorophenyl)-2,3-dihydropyridin-4(1H)-one;
[0040] Among them, the molar ratio of glacial acetic acid to Intermediate-2 is (4.0-10.0):1, preferably (6.0-8.0):1, and more preferably 7.0:1; the heating temperature is 60-85°C, preferably 80-85°C; the amount of purified water used for slurrying with purified water is 10-20 times (volume / weight) of Intermediate-2, preferably 20 times.
[0041] Optionally, the molar ratio of the iron powder to Intermediate-2 is (3.5-6.0):1.
[0042] Further, the molar ratio of the iron powder to Intermediate-2 is (3.5-6.0):1, preferably (4.0-5.0):1, and more preferably 4.0:1.
[0043] Optionally, the reaction solvent is a mixed solvent of ethanol and purified water or a mixed solvent of methanol and purified water, and the volume ratio of alcohol:purified water = (2:1)-(5:1), and the addition amount is 10-15 times (volume / weight) of Intermediate-2.
[0044] Further, the reaction solvent is a mixed solvent of ethanol and purified water or a mixed solvent of methanol and purified water, preferably a mixed solvent of methanol and purified water; the volume ratio of alcohol:purified water = (2:1)-(5:1), preferably 10:3; the addition amount is 10-15 times (volume / weight) of Intermediate-2, preferably 13 times.
[0045] The present invention adopts the following process route:
[0046]
[0047] As can be seen from the above technical solutions, the embodiments of the present invention have the following advantages:
[0048] 1. The present invention optimizes the dosage of raw materials in each step of the reaction, reduces the raw material consumption cost, and has high yields and conversion rates in each step. The reaction conditions are mild and easy to control, which is suitable for industrial scale-up production.
[0049] 2. The present invention directly oxidizes the pyrrolidone ring to the dihydropyridone ring in one step without enol silylation. Under the premise of maintaining high selectivity, the reaction conversion rate can reach over 99.5% in a short time. This discovery can directly skip the unstable and viscous oily enol silyl ether intermediate, shorten the reaction route from 4 steps to 3 steps, greatly improve the overall reaction yield, and avoid using expensive anhydrous solvents and strict nitrogen protection and harsh reaction conditions.
[0050] 3. Avoid using highly dangerous chemical reagents such as TMSOTf or TIPSOTf, and at the same time solve the problems that the enol silyl ether intermediate is difficult to store and transport, and it is difficult to accurately weigh the material weight when participating in the next reaction.
[0051] 4. Skip the process of removing the silyl group after forming the enol silyl ether intermediate, which conforms to the atom economy of green chemistry and avoids the formation of a large amount of impurities and by-products.
[0052] 5. The present invention uses an iron powder - glacial acetic acid system to replace the iron powder - ammonium chloride system in the original method for the reduction reaction, completely avoiding the incomplete reduction caused by the weak acidity of ammonium chloride, and thus preventing the generation of azo compound by-products. While greatly increasing the reaction yield, it also simplifies the post-treatment operation method. BRIEF DESCRIPTION OF THE DRAWINGS
[0053] The present invention will be further described in detail below with reference to the drawings and specific embodiments.
[0054] Figure 1 is the LC-MS spectrum of Intermediate - 1.
[0055] Figure 2 is the 1H NMR spectrum of Intermediate - 1.
[0056] Figure 3 is the LC-MS spectrum of Intermediate - 2.
[0057] Figure 4 is the 1H NMR spectrum of Intermediate - 2.
[0058] Figure 5 LC-MS spectrum of the key intermediate of conticoxib
[0059] Figure 6 1H NMR spectrum of the key intermediate of conticoxib Detailed implementation manners
[0060] In order to enable those skilled in the art to better understand the solution of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts fall within the protection scope of the present invention. Unless otherwise specifically stated, various raw materials, reagents, instruments, and equipment used in the present invention can be obtained through the market or can be prepared by existing methods.
[0061] Preparation examples
[0062] Preparation example 1
[0063] An intermediate-1 was prepared by the following method:
[0064] 100.00 g (512.6 mmol, 1.0 eq) of 2,3,4,5-tetrafluoronitrobenzene, 72.98 g (538.3 mmol, 1.05 eq) of 4-oxopiperidone hydrochloride and 1000 mL (10 V / m) of N-methylpyrrolidone were added to a 2 L three-necked flask. The solution was cooled to 5 °C, and 165.65 g (1281.6 mmol, 2.5 eq) of N,N-diisopropylethylamine was added dropwise with stirring while maintaining the temperature at 5 °C during the dropping process. After the addition, the reaction solution was heated to 25 °C and stirred. The consumption of 2,3,4,5-tetrafluoronitrobenzene was monitored by thin layer chromatography (ethyl acetate: petroleum ether = 1:4). When the 2,3,4,5-tetrafluoronitrobenzene was completely consumed, the reaction solution was slowly dropped into 3000 mL (30 V) of purified water and stirred vigorously for 30 min. During this period, a large amount of yellow solid was produced. The suspension was filtered, and the filter cake was rinsed with 3000 mL (30 V) of purified water. The filter cake was placed in a vacuum dryer at 53 °C for 10 h to obtain 134.04 g of yellow solid intermediate-1. The theoretical yield was 140.50 g, the yield was 95.4%, and the purity was 99.5%.
[0065] Preparation example 2
[0066] An intermediate-2 was prepared by the following method:
[0067] Dissolve 100.00 g (364.7 mmol, 1.0 eq) of Intermediate-1 prepared in Preparation Example 1 in 1000 mL (10 V / m) of N,N-dimethylformamide. While controlling the temperature at 5 °C and stirring, add ammonium cerium nitrate 459.85 g (838.8 mmol, 2.3 eq) portionwise. React at 5 °C and monitor the reaction by thin layer chromatography (ethyl acetate: petroleum ether = 1:2). After Intermediate-1 is completely consumed, add 2000 mL (20 V / m) of dichloromethane to the reaction mixture. Wash it twice with 2000 mL (2×20 V / m) of purified water and once with 2000 mL (20 V / m) of saturated brine respectively. Separate the organic phase, dry it with anhydrous sodium sulfate, and concentrate it under reduced pressure to obtain an oily substance. After adding 50 mL (0.5 V / m) of dichloromethane, slowly add 2000 mL (20 V / m) of petroleum ether dropwise with stirring and slurry for 30 min. During this period, a large amount of yellow solid precipitates. Filter by suction, wash the filter cake with 1000 mL (10 V / m) of petroleum ether, and place the filter cake in a vacuum dryer at 52 °C for 10 h to obtain 85.76 g of yellow solid Intermediate-2. The theoretical yield is 99.26 g, the yield is 86.4%, and the purity is 95.94%.
[0068] Example
[0069] Example 1
[0070] A new synthesis method for a key intermediate of conticoxib amine, comprising the following steps:
[0071] Dissolve 100.00 g (367.4 mmol, 1.0 eq) of Intermediate-2 prepared in Preparation Example 2 in a mixed solvent of 1000 mL (10 V) of methanol and 300 mL (3 V) of purified water. Add 132.38 g (2204.4 mmol, 6.0 eq) of glacial acetic acid, and then add 102.60 g (1837.0 mmol, 5.0 eq) of iron powder portionwise with stirring. Heat the mixture to 82 °C and stir vigorously. Monitor the consumption of Intermediate-2 by thin layer chromatography (ethyl acetate: petroleum ether = 1:1 + TEA). After Intermediate-2 is completely consumed, cool the reaction solution to room temperature. Adjust the pH to 7.5 by adding saturated sodium carbonate aqueous solution with stirring and stir for 30 min. Filter the mixture through a diatomaceous earth pad, wash the filter cake with 2000 mL (20 V / m) of purified water. Replace with another clean suction flask and wash with methanol until the liquid drops have no ultraviolet absorption. Concentrate the filtrate under reduced pressure and slurry with 2000 mL (20 V / m) of purified water. Obtain 73.33 g of off-white solid key intermediate of conticoxib amine. The theoretical yield is 88.99 g, the yield is 82.4%, and the purity is 98.5%.
[0072] This application improves the yield and purity of the key intermediate of conticoxib. The yield can reach 82.4% and the purity can reach 98.5%. By controlling the dosage of the oxidant and the reaction temperature, the pyrrolidinone ring can be directly oxidized to the dihydropyridone ring in one step without enol silylation. Under the premise of maintaining high selectivity, the "point-to-point" reaction effect can be achieved. This discovery can directly skip the enol silyl ether intermediate with poor stability, viscous oil-like state, difficult to store and transport. The reaction route is shortened from 4 steps to 3 steps, greatly improving the total reaction yield, and avoiding the use of expensive anhydrous solvents and harsh reaction conditions with strict nitrogen protection, and avoiding the use of highly dangerous chemical reagents such as TMSOTf or TIPSOTf.
[0073] As described above, 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 make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims
1. A novel synthesis method of a key intermediate of contizolamide, characterized in that: The method comprises the following steps: coupling 2,3,4,5-tetrafluoronitrobenzene with 4-oxopiperidone hydrochloride to obtain intermediate-1, then using an oxidant to dehydrogenate the pyridinone ring into a dihydropyridone ring to obtain intermediate-2, and then reducing the nitro group to an amino group in an iron powder glacial acetic acid system to obtain the key intermediate 1-(4-amino-2,3,6-trifluorophenyl)-2,3-dihydropyridine-4(1H)-one of contizolamide.
2. The novel synthesis method of the key intermediate of contizolamide according to claim 1, characterized in that: The specific preparation method of the intermediate-1 is as follows: dissolving 2,3,4,5-tetrafluoronitrobenzene and 4-oxopiperidone hydrochloride in a reaction solvent, controlling the temperature, adding an organic base, stirring the reaction solution at the reaction temperature, dropping the reaction solution into purified water under stirring, filtering, rinsing the filter cake with purified water, and drying to obtain a yellow solid intermediate-1.
3. The novel synthesis method of the key intermediate of contizolamide according to claim 2, characterized in that: The molar ratio of the 4-oxopiperidone hydrochloride to 2,3,4,5-tetrafluoronitrobenzene is (1.05-1.3):
1.
4. The novel synthesis method of the key intermediate of contezolamide according to claim 2, characterized in that: The reaction solvent is any one of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide or 1,4-dioxane; the organic base is any one of N,N-diisopropylethylamine, triethylamine or pyridine.
5. The novel synthesis method of the key intermediate of contizolamide according to claim 1, characterized in that: The specific preparation method of the intermediate-2 is as follows: dissolving the intermediate-1 in N,N-dimethylformamide, controlling the temperature, adding ammonium cerium nitrate, reacting at the reaction temperature to obtain a reaction mixture; adding an extraction solvent to the reaction mixture, washing, separating the organic phase, drying, and concentrating under reduced pressure to obtain an oily substance, adding dichloromethane, and then dropping petroleum ether under stirring, during which a large amount of yellow solid is precipitated, suction filtering, eluting the filter cake, and drying to obtain the intermediate-2 as a yellow solid.
6. The novel synthesis method of the key intermediate of contizolamide according to claim 5, characterized in that: The molar ratio of the ammonium cerium nitrate to the intermediate-1 is: (2.25-3.0):
1.
7. The novel synthesis method of the key intermediate of contizolamide according to claim 5, characterized in that: The control temperature of adding ammonium cerium nitrate is 0-30°C, and the reaction temperature is 0-30°C.
8. The novel synthesis method of the key intermediate of contizolamide according to claim 1, characterized in that: The specific preparation method of the key intermediate of contizolamide 1-(4-amino-2,3,6-trifluorophenyl)-2,3-dihydropyridine-4(1H)-one is as follows: dissolving intermediate-2 in a reaction solvent, adding glacial acetic acid, and then adding iron powder under stirring, and stirring under heating; cooling the reaction solution to room temperature, adjusting the pH value under stirring, filtering through diatomaceous earth, eluting, and then eluting with methanol until the droplets have no ultraviolet absorption, decompressing and concentrating the filtrate, and slurrying with purified water to obtain the key intermediate 1-(4-amino-2,3,6-trifluorophenyl)-2,3-dihydropyridine-4(1H)-one.
9. The novel synthesis method of the key intermediate of contizolamide according to claim 8, characterized in that: The molar ratio of the iron powder to the intermediate-2 is (3.5-6.0):
1.
10. The novel synthesis method of the key intermediate of contizolamide according to claim 8, characterized in that: The reaction solvent is a mixed solvent of ethanol and purified water or a mixed solvent of methanol and purified water, the volume ratio of alcohol: purified water = (2:1) to (5:1), and the added amount is 10 to 15 times the weight of the intermediate-2.
Citation Information
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