Preparation method of topiromilast and intermediate I and intermediate II of topiromilast

Abstract

The invention relates to a preparation method of topiromilast and an intermediate I and an intermediate II thereof, isonicotinic acid and N-oxidized 4-cyanopyridine are used as starting materials, and the topiromilast is prepared through hydrazinolysis, condensation cyclization and cyanidation. The isonicotinic acid and the N-oxidized 4-cyanopyridine which are selected as starting raw materials are low in price and commercially available; by buckling and then cyaniding, reaction sites of a substrate are few, so that byproducts after cyaniding are few. The preparation method provided by the invention has the advantages of low production cost, high yield, high purity and less three wastes, and is suitable for industrial production of topiromilast.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis, specifically to topiramate and its intermediates as a treatment for gout. and intermediates Preparation method of . Background Technology

[0002] Topiroxostat (chemical name: 4-[5-(4-pyridyl)-1H-1,2,4-triazol-3-yl]pyridine-2-cyano), developed by Fuji Pharmaceutical Co., Ltd. of Japan, was approved by the Japanese Ministry of Health, Labour and Welfare in August 2013 and launched in Japan for the first time. Topiroxostat is a novel non-purine selective xanthine oxidoreductase (XOR) inhibitor, primarily used to treat gout and hyperuricemia. It effectively lowers blood uric acid levels by inhibiting xanthine oxidase activity, thereby reducing uric acid production. Compared to traditional purine inhibitors such as allopurinol, topiroxostat has higher selectivity and better safety because it does not inhibit other purine / pyrimidine metabolic enzymes and has no adverse effects on the cardiovascular system.

[0003] In 2013, Fuji Pharmaceutical Co., Ltd. of Japan disclosed a method for preparing topiramate in a Chinese patent application with publication number CN104411686B. The reaction formula is as follows:

[0004]

[0005] In this patent, 4-cyanopyridine N-oxide (2) is reacted with isoniazid in the presence of an alkali metal alkoxide to obtain compound (3), which is then cyanided in the presence of a cyaniding agent to obtain compound (4), and finally cyclically closed under the action of an acid catalyst to obtain the target molecule. Compound (3) generates many impurities during the cyanidation process, which is detrimental to the subsequent purification of the product, leading to a decrease in product yield during purification.

[0006] In 2014, the Shanghai Institute of Pharmaceutical Industry filed an invention patent in China with publication number CN105348264B, disclosing a method for preparing topiramate, the reaction formula of which is as follows:

[0007]

[0008] This patent describes a process involving the oxidation of isonicotinic acid methyl ester to obtain compound III, followed by hydrazolysis of compound III to obtain compound IV. Compound IV then reacts with 4-cyanopyridine under alkaline conditions to obtain compound VI, which is then cyano-treated to obtain compound VII. Finally, cyclization under acidic conditions yields topiramate. However, the synthesis of compound IV requires the hydrazolysis of compound III at 60°C under nitrogen protection; secondly, the cyanation reaction of compound VI generates numerous impurities, hindering the purification of subsequent products; and finally, the synthetic route is lengthy, resulting in a long production cycle and an overall yield of only 55%, leading to high final product costs.

[0009] In 2021, Zhai Hong filed a Chinese patent application with publication number CN113173916A, which disclosed a method for preparing topiramate, the reaction formula of which is as follows:

[0010]

[0011] This patent describes a process where 4-cyanopyridine is catalytically reacted with hydrazine hydrate in an alcohol to obtain intermediate 1. Isonicotinic acid is then oxidized in hydrogen peroxide to obtain intermediate 2. Intermediates 1 and 2 undergo a condensation reaction to obtain intermediate 3. A cyano group is added to intermediate 3 to obtain intermediate 4. Intermediate 4 is then ring-closed to obtain topiramate. The cyanation reaction of intermediate 3 generates numerous impurities, which is detrimental to the purification of the subsequent product.

[0012] The aforementioned patents basically employ similar reaction mechanisms, first cyano-forming, then ring-closing to obtain topiramate. During the cyanation process of the intermediate before ring closing, a large number of impurities are generated, and the later products need to undergo multiple purification processes to obtain qualified topiramate with a loss of yield. Summary of the Invention

[0013] Therefore, this invention proposes a method for the industrial production of topiramate and its intermediates that is simple in process, low in cost, high in yield, high in purity, and produces less waste. and intermediates Synthesis method.

[0014] Unlike existing technologies, the above technical solution provides a topiramate intermediate. A preparation method comprising the following steps:

[0015] 1) Weigh the raw materials according to the following molar proportions:

[0016] Raw material IIa 1.0 part;

[0017] 0.9-1.1 parts of hydrazine hydrate;

[0018] 2) At room temperature, the molecular formula is as shown in the formula. Add the raw material IIa shown to the reaction flask, add the alcoholic organic solvent A and the catalytic amount of organic base catalyst, and stir the reaction at 20-30℃ until the TLC shows that the reaction is complete.

[0019] Mode ;

[0020] 1) Pour the reaction solution from step 1) into another reaction flask, and continue to add alcoholic organic solvent A and hydrazine hydrate with a concentration of 80%. Keep the mixture warm and stir at 20-30℃ until the transition state reaction is complete as detected by TLC, at which point the reaction is stopped.

[0021] 4) Subsequently, the reaction solution was cooled to 0-10℃, and methyl tert-butyl ether was added dropwise to the reaction flask while maintaining the temperature to induce crystallization. The crystals were stirred and filtered, and the filter cake was dried to obtain the product as shown in the formula. The topiramate intermediate shown ;

[0022] Mode .

[0023] Furthermore, the organic base catalyst includes one of the following: sodium methoxide, sodium ethoxide, potassium tert-butoxide, or other sodium or potassium salts of ethoxide.

[0024] Furthermore, the alcohol organic solvent A includes one of the following: methanol, ethanol, tert-butanol, etc.

[0025] This invention also discloses a topiramate intermediate. A preparation method comprising the following steps:

[0026] 1) Weigh the raw materials according to the following molar proportions:

[0027] Molecular formula as shown in the formula The raw material IIb shown is 1.0 part;

[0028] 1-Hydroxybenzotriazole (HOBT) 1.0-1.5 parts;

[0029] Topiramate intermediate 0.9-1.0 portions;

[0030] Triethylamine 1.0-1.5 parts;

[0031] 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride EDC•HCl 1.0-1.5 parts;

[0032] 2) Add the solvent DMF and the molecular formula as shown in the formula to the reaction flask in sequence. The raw materials shown, IIb, 1-hydroxybenzotriazole HOBT and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride EDC•HCl, were stirred and mixed evenly.

[0033] Mode ;

[0034] 3) Continue adding triethylamine to the reaction flask to produce the topiramate intermediate. Add in batches, stir and react at 10-20℃ for 2-4 hours, then raise the temperature to 100℃ and continue reacting until the transition state reaction is complete as detected by TLC;

[0035] 4) Cool the reaction solution to below 30°C, add water to the reaction flask for dilution, and then adjust the pH of the reaction solution to 6.6-7.0 with a saturated sodium bicarbonate aqueous solution;

[0036] 5) Filter the reaction solution, rinse the filter cake with water, then add the filter cake to a mixed solvent of N,N-dimethylformamide and ethyl acetate in a volume ratio of 1:5 and stir for 5-7 hours; filter, dry the filter cake, and obtain the product as shown in the formula. The topiramate intermediate shown 99% purity;

[0037] Mode .

[0038] The present invention uses the above-described one-pot method to prepare the topiramate intermediate. It has fewer processes, is simple to operate, and produces high-purity products.

[0039] This invention also discloses a method for preparing topiramate, the method comprising the following steps:

[0040] 1) Weigh the raw materials according to the following molar proportions:

[0041] Topiramate intermediate 1.0 copy;

[0042] 2.0-2.5 parts of dimethylcarbamoyl chloride;

[0043] 1.0-1.5 parts of trimethylcyanosilane;

[0044] 2) The topiramate intermediate Add acetonitrile to the reaction flask, and then add dimethylcarbamoyl chloride under a nitrogen atmosphere; raise the temperature to an internal temperature of 60±2℃, dilute trimethylcyanosyl silane with acetonitrile and slowly add it dropwise, and after the addition is complete, control the temperature at 70-80℃ to carry out the reaction until TLC shows that the starting material has basically reacted, which is the reaction endpoint.

[0045] 3) After the reaction is complete, cool the reaction solution to 10-20℃; add water to dilute the reaction solution, and then adjust the pH of the reaction solution to 6.5-7.0 with 5% sodium hydroxide aqueous solution. Stir to precipitate crystals, filter, and dry the filter cake to obtain pale yellow to off-white topiramate.

[0046] Compared with existing technologies, the beneficial effects of this invention are as follows: The synthetic route of topiramate described in this invention is as follows: using isonicotinic acid and N-oxy4-cyanopyridine as starting materials, topiramate is obtained through hydrazolysis, condensation cyclization, and cyanation. Since this invention selects isonicotinic acid and N-oxy4-cyanopyridine as starting materials, both compounds are inexpensive and commercially available; secondly, in the reaction process, cyclization occurs first, followed by cyanation, resulting in fewer substrate reaction sites and therefore fewer byproducts after cyanation. The synthesis of topiramate using this invention is low-cost, high-yield, high-purity, and produces less waste, making it suitable for industrial production. Attached Figure Description

[0047] Figure 1 The topiramate intermediate prepared in Example 1 Infrared spectrum;

[0048] Figure 2 The topiramate intermediate prepared in Example 4 Infrared spectrum;

[0049] Figure 3 The infrared spectrum of topiramate prepared in Example 7. Detailed Implementation

[0050] To explain in detail the technical content, structural features, objectives, and effects of the technical solution, the following detailed description is provided in conjunction with specific embodiments.

[0051] Example 1: Topiramate Intermediate Synthesis

[0052] 1) Weigh the raw materials according to the following molar proportions:

[0053] Raw material IIa 1.0 part;

[0054] 1.0 part of hydrazine hydrate;

[0055] 2) At room temperature, 120 g (1.0 mol) of raw material IIa was added to a 2 L three-necked flask, along with 0.5 L of ethanol and 2 g of organic base catalyst sodium methoxide. The mixture was stirred at 25 ± 5 °C for 3 h. TLC showed that the raw material was basically completely reacted.

[0056] 3) Take another 1L four-necked flask and pour in the reaction solution from step 2). Add 0.5L of anhydrous ethanol and 62.6g of 80% hydrazine hydrate (1.0mol). Keep the internal temperature at 25±5℃ and stir the reaction until the transition state reaction is complete as detected by TLC.

[0057] 4) The reaction solution was then cooled to 0-10℃, and 4L of methyl tert-butyl ether was slowly added dropwise while maintaining the temperature at 5±5℃. The mixture was stirred and crystallized for 12 hours to obtain a yellow solid. The solid was filtered, and the filter cake was washed with a small amount of methyl tert-butyl ether. The filter cake was then vacuum dried at 25-35℃ to obtain 116g of a pale yellow to red solid, with a yield of 76% and a purity of 98%. This pale yellow to red solid is the topiramate intermediate. .

[0058] The topiramate intermediate prepared in Example 1 Mass spectrometry and nuclear magnetic resonance (NMR) were performed. The proton NMR spectrum is shown below. Figure 1 The detection result was: mass spectrometry detection [MH]. - =151.1, NMR detection 1H NMR (400MHz, DMSO) δ: 8.833-8.848 (dd, 2H), 7.744-7.760 (dd, 2H), with topiramate intermediate The structure matches.

[0059] Example 2 Topiramate Intermediate Synthesis

[0060] 1) Weigh the raw materials according to the following molar proportions:

[0061] Raw material IIa 1.0 part;

[0062] 0.9 parts of hydrazine hydrate;

[0063] 2) At room temperature, 120 g (1.0 mol) of raw material IIa was added to a 2 L three-necked flask, along with 0.5 L of organic solvent methanol and 2 g of organic base catalyst sodium ethoxide. The mixture was stirred at 25 ± 5 °C for 3 h. TLC showed that the raw material was basically completely reacted.

[0064] 3) Take another 1L four-necked flask and pour in the reaction solution from step 2). Add 0.5L of organic solvent methanol and 56.3g of 80% hydrazine hydrate (0.9mol). Control the internal temperature at 25±5℃ and stir the reaction until the transition state reaction is complete as detected by TLC.

[0065] 4) The reaction solution was then cooled to 0-10℃, and 4L of methyl tert-butyl ether was slowly added dropwise while maintaining the temperature at 5±5℃. The mixture was stirred and crystallized for 12 hours to obtain a yellow solid. The solid was filtered, and the filter cake was washed with a small amount of methyl tert-butyl ether. The filter cake was vacuum dried at 25-35℃ to obtain 109.5g of a pale yellow to red solid, with a yield of 72% and a purity of 98%. This pale yellow to red solid is the topiramate intermediate. .

[0066] Example 3 Topiramate Intermediate Preparation

[0067] 1) Weigh the raw materials according to the following molar proportions:

[0068] Raw material IIa 1.0 part;

[0069] 1.1 parts of hydrazine hydrate;

[0070] 2) At room temperature, 120 g (1.0 mol) of raw material IIa was added to a 2 L three-necked flask, along with 0.5 L of organic solvent tert-butanol and 2 g of organic base catalyst potassium tert-butoxide. The mixture was stirred at 25 ± 5 °C for 3 h. TLC showed that the raw material was basically completely reacted.

[0071] 3) Take another 1L four-necked flask and pour in the reaction solution from step 2). Add 0.5L of organic solvent tert-butanol and 68.8g of 80% hydrazine hydrate (1.1mol). Control the internal temperature at 25±5℃ and stir the reaction until the transition state reaction is complete as detected by TLC.

[0072] 4) The reaction solution was then cooled to 0-10℃, and 4L of methyl tert-butyl ether was slowly added dropwise while maintaining the temperature at 5±5℃. The mixture was stirred and crystallized for 12 hours to obtain a yellow solid. The solid was filtered, and the filter cake was washed with a small amount of methyl tert-butyl ether. The filter cake was vacuum dried at 25-35℃ to obtain 111.1g of a pale yellow to red solid, with a yield of 73% and a purity of 98%. This pale yellow to red solid is the topiramate intermediate.

[0073] Example 4 Topiramate Intermediate Preparation

[0074] 1) Weigh the raw materials according to the following molar proportions:

[0075] 1.0 part of raw material IIb with the molecular formula shown in the formula;

[0076] 1-Hydroxybenzotriazole (HOBT) 1.1 parts;

[0077] Topiramate intermediate 1.0 part;

[0078] 1.1 parts of triethylamine;

[0079] 1.1 parts of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride EDC•HCl;

[0080] 2) Add 300 ml of DMF solvent to a 1 L reaction flask, then add 62.5 kg (0.5 mol) of raw material IIb, 74.3 g (0.55 mol) of 1-hydroxybenzotriazole HOBT and 105.4 g (0.55 mol) of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride EDC•HCl in sequence, and stir for 0.5 h to mix evenly.

[0081] 3) Continue to add 58g (0.57mol) of triethylamine to the reaction flask, and slowly add 76g (0.5mol) of intermediate 1 prepared in Example 1 in batches. Control the temperature at 15±5℃ and stir for 3h. Then raise the temperature to 100℃ and react until the transition state reaction is complete as detected by TLC.

[0082] 4) Cool the reaction solution to below 30°C, add 1.8L of water to the reaction flask for dilution, and then add saturated sodium bicarbonate aqueous solution dropwise (gas will be generated during the process, so control the dropping rate) to adjust the pH of the reaction solution to 6.6;

[0083] 5) Filter the reaction solution, rinse the filter cake with 1 kg of water once, then add the filter cake to a mixed solvent of 240 ml N,N-dimethylformamide and 1200 ml ethyl acetate and beat for 6 h; filter, rinse the filter cake with a small amount of mixed solvent, and dry the filter cake by blowing air to obtain 90.2 g of yellow solid, yield 75%, purity 99%, the yellow solid is topiramate intermediate.

[0084] The topiramate intermediate prepared in Example 4 Mass spectrometry and nuclear magnetic resonance (NMR) were performed. The proton NMR spectrum is shown below. Figure 2 The detection results were as follows: mass spectrometry [M+H]=240.0, nuclear magnetic resonance (NMR) 1H NMR (400MHz, DMSO) δ: 15.083-15.210 (br, 1H), 8.741-8.804 (m, 2H), 8.328-8.414 (m, 2H), 8.006-8.030 (m, 4H), which are consistent with the structure of topiramate intermediate.

[0085] Example 5 Topiramate Intermediate Preparation

[0086] 1) Weigh the raw materials according to the following molar proportions:

[0087] 1.0 part of raw material IIb with the molecular formula shown in the formula;

[0088] 1.5 parts of 1-hydroxybenzotriazole (HOBT);

[0089] Topiramate intermediate 1.0 part;

[0090] 1.5 parts of triethylamine;

[0091] 1.5 parts of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride EDC•HCl;

[0092] 2) Add 300 ml of DMF solvent to a 1 L reaction flask, then add 62.5 kg (0.5 mol) of raw material IIb, 101.3 g (0.75 mol) of 1-hydroxybenzotriazole HOBT and 143.8 g (0.75 mol) of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride EDC•HCl, and stir for 0.5 h to mix evenly.

[0093] 3) Continue to add 75.9 g (0.75 mol) of triethylamine to the reaction flask, and slowly add 76 g (0.5 mol) of intermediate 1 prepared in Example 2 in batches. Control the temperature at 15±5℃ and stir for 4 h. Then raise the temperature to 100℃ and react until the transition state reaction is complete as detected by TLC.

[0094] 4) Cool the reaction solution to below 30°C, add 1.8L of water to the reaction flask for dilution, and then add saturated sodium bicarbonate aqueous solution dropwise (gas will be generated during the process, so control the dropping rate) to adjust the pH of the reaction solution to 7.0;

[0095] 5) Filter the reaction solution, rinse the filter cake with 1 kg of water once, then add the filter cake to a mixed solvent of 240 ml N,N-dimethylformamide and 1200 ml ethyl acetate and stir for 5 h; filter, rinse the filter cake with a small amount of mixed solvent, and dry the filter cake by blowing air to obtain 87.3 g of yellow solid, yield 73%, purity 99%, the yellow solid is topiramate intermediate.

[0096] Example 6 Topiramate Intermediate Preparation

[0097] 1) Weigh the raw materials according to the following molar proportions:

[0098] 1.0 part of raw material IIb with the molecular formula shown in the formula;

[0099] 1.0 part of 1-hydroxybenzotriazole (HOBT);

[0100] Topiramate intermediate 1.0 part;

[0101] 1.0 part of triethylamine;

[0102] 1.0 part of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride EDC•HCl;

[0103] 2) Add 300 ml of DMF solvent to a 1 L reaction flask, then add 62.5 kg (0.5 mol) of raw material IIb, 67.5 g (0.5 mol) of 1-hydroxybenzotriazole HOBT and 105.4 g (0.5 mol) of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride EDC•HCl in sequence, and stir for 0.5 h to mix evenly.

[0104] 3) Continue to add 50.6 g (0.5 mol) of triethylamine to the reaction flask, and slowly add 76 g (0.5 mol) of intermediate 1 prepared in Example 3 in batches. Control the temperature at 15±5℃ and stir for 2 h. Then raise the temperature to 100℃ and react until the transition state reaction is complete as detected by TLC.

[0105] 4) Cool the reaction solution to below 30°C, add 1.8L of water to the reaction flask for dilution, and then add saturated sodium bicarbonate aqueous solution dropwise (gas will be generated during the process, so control the dropping rate) to adjust the pH of the reaction solution to 6.8;

[0106] 5) Filter the reaction solution, rinse the filter cake with 1 kg of water once, then add the filter cake to a mixed solvent of 240 ml N,N-dimethylformamide and 1200 ml ethyl acetate and beat for 7 h; filter, rinse the filter cake with a small amount of mixed solvent, and dry the filter cake by blowing air to obtain 85.4 g of yellow solid, with a yield of 71% and a purity of 99%. The yellow solid is a topiramate intermediate.

[0107]

[0108] Example 7: Synthesis of Topiramate

[0109] 1) Weigh the raw materials according to the following molar proportions:

[0110] Topiramate intermediate 1.0 part;

[0111] 2.4 parts of dimethylcarbamoyl chloride;

[0112] 1.6 parts of trimethylcyanosilane;

[0113] 2) Add 95.6 g (0.37 mol) of the topiramate intermediate prepared in Example 4 and 500 ml of acetonitrile to a 2 L reaction flask, and purge with nitrogen three times; then add 94.6 g (0.88 mol) of dimethylcarbamoyl chloride; heat to an internal temperature of 60 ± 2 °C, and slowly add 59.5 g (0.6 mol) of trimethylcyanosilane diluted with 100 ml of acetonitrile. After the addition is complete, maintain the temperature at 75 ± 5 °C for the reaction. The reaction endpoint is indicated by TLC showing that the starting material has basically reacted.

[0114] 3) After the reaction was completed, the reaction solution was cooled to 15±5℃, 3000ml of water was added to dilute the reaction solution, and then 5% sodium hydroxide aqueous solution was slowly added dropwise to adjust the pH of the reaction solution to 7.0. The mixture was stirred and crystallized for 4 hours, filtered, and the filter cake was dried by forced air at 80℃ to obtain 89.3g of off-white solid, with a yield of 97% and a purity of 99.8%. The off-white solid was topiramate.

[0115]

[0116] The topiramate prepared in Example 7 was subjected to mass spectrometry and nuclear magnetic resonance (NMR) analysis. The proton NMR spectrum is shown below. Figure 2 The detection results were as follows: mass spectrometry [M+H]=249.3, nuclear magnetic resonance (NMR) 1H NMR (400MHz, DMSO) δ: 15.049 (d, 1H), 8.897-909 (d, 1H), 8.778-8.793 (d, 2H), 8.502-8.507 (d, 1H), 8.277-8.294 (dd, 1H), 7.989-8.004 (dd, 2H), which are consistent with the structure of topiramate.

[0117] Example 8: Synthesis of Topiramate

[0118] 1) Weigh the raw materials according to the following molar proportions:

[0119] Topiramate intermediate 1.0 part;

[0120] 2.0 parts of dimethylcarbamoyl chloride;

[0121] 1.0 part of trimethylcyanosilane;

[0122] 2) Add 95.6 g (0.37 mol) of the topiramate intermediate prepared in Example 5 and 500 ml of acetonitrile to a 2 L reaction flask, and purge with nitrogen three times; then add 79.6 g (0.74 mol) of dimethylcarbamoyl chloride; heat to an internal temperature of 60 ± 2 °C, and slowly add 36.7 g (0.37 mol) of trimethylcyanosilane diluted with 100 ml of acetonitrile. After the addition is complete, maintain the temperature at 75 ± 5 °C for the reaction. The reaction endpoint is indicated by TLC showing that the starting material has basically reacted.

[0123] 3) After the reaction was completed, the reaction solution was cooled to 15±5℃, 3000ml of water was added to dilute the reaction solution, and then 5% sodium hydroxide aqueous solution was slowly added dropwise to adjust the pH of the reaction solution to 6.5. The mixture was stirred and crystallized for 4 hours, filtered, and the filter cake was dried by forced air at 80℃ to obtain 80.4g of pale yellow solid, with a yield of 87% and a purity of 99.8%. The pale yellow solid was topiramate.

[0124] Example 9: Synthesis of Topiramate

[0125] 1) Weigh the raw materials according to the following molar proportions:

[0126] Topiramate intermediate II 1.0 part;

[0127] 2.5 parts of dimethylcarbamoyl chloride;

[0128] 1.3 parts of trimethylcyanosilane;

[0129] 2) Add 95.6 g (0.37 mol) of the topiramate intermediate II prepared in Example 6 and 500 ml of acetonitrile to a 2 L reaction flask, and purge with nitrogen three times; then add 99.5 g (0.93 mol) of dimethylcarbamoyl chloride; heat to an internal temperature of 60 ± 2 °C, and slowly add 47.7 g (0.48 mol) of trimethylcyanosilane diluted with 100 ml of acetonitrile. After the addition is complete, maintain the temperature at 75 ± 5 °C for the reaction. The reaction endpoint is indicated by TLC showing that the starting material has basically reacted.

[0130] 3) After the reaction was completed, the reaction solution was cooled to 15±5℃, 3000ml of water was added to dilute the reaction solution, and then 5% sodium hydroxide aqueous solution was slowly added dropwise to adjust the pH of the reaction solution to 6.8. The mixture was stirred and crystallized for 4 hours, filtered, and the filter cake was dried by forced air at 80℃ to obtain 83.3g of off-white solid, with a yield of 91% and a purity of 99.8%. The off-white solid was topiramate.

[0131] It should be noted that, in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or terminal device that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or terminal device. Unless otherwise specified, an element defined by the phrase "comprising..." or "including..." does not exclude the presence of additional elements in the process, method, article, or terminal device that includes said element. Additionally, in this document, "greater than," "less than," "exceeding," etc., are understood to exclude the stated number; "above," "below," "within," etc., are understood to include the stated number.

[0132] It should be noted that although the above embodiments have been described herein, this does not limit the scope of patent protection for this invention. Therefore, any changes and modifications made to the embodiments described herein based on the innovative concept of this invention, or any equivalent structural or procedural transformations made using the content of this specification, directly or indirectly applying the above technical solutions to other related technical fields, are all included within the scope of patent protection for this invention.

Claims

1. A topiramate intermediate The preparation method of the [method] is characterized by, The preparation method includes the following steps: 1) Weigh the raw materials according to the following molar proportions: Raw material IIa 1.0 part; 0.9-1.1 parts of hydrazine hydrate; 2) At room temperature, the molecular formula is as shown in the formula. Add the raw material IIa shown to the reaction flask, add the alcoholic organic solvent A and the catalytic amount of organic base catalyst, and stir the reaction at 20-30℃ until the TLC shows that the reaction is complete. Mode ; 3) Pour the reaction solution from step 1) into another reaction flask, and continue to add alcoholic organic solvent A and hydrazine hydrate with a concentration of 80%. Keep the mixture warm and stir at 20-30°C until the transition state reaction is complete as detected by TLC, at which point the reaction is stopped. 4) Subsequently, the reaction solution was cooled to 0-10℃, and methyl tert-butyl ether was added dropwise to the reaction flask while maintaining the temperature to induce crystallization. The crystals were stirred and filtered, and the filter cake was dried to obtain the product as shown in the formula. The topiramate intermediate shown ; Mode .

2. The topiramate intermediate according to claim 1 The preparation method is characterized by: The organic base catalyst includes one of the following: sodium methoxide, sodium ethoxide, or potassium tert-butoxide.

3. The topiramate intermediate according to claim 1 The preparation method is characterized by: The alcoholic organic solvent A includes one of the following: methanol, ethanol, or tert-butanol.

4. A topiramate intermediate The preparation method of the [method] is characterized by, The preparation method includes the following steps: 1) Weigh the raw materials according to the following molar proportions: Molecular formula as shown in the formula The raw material IIb shown is 1.0 part; 1-Hydroxybenzotriazole (HOBT) 1.0-1.5 parts; Topiramate intermediate 0.9-1.0 portions; Triethylamine 1.0-1.5 parts; 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride EDC•HCl 1.0-1.5 parts; 2) Add the solvent DMF and the molecular formula as shown in the formula to the reaction flask in sequence. The raw materials shown, IIb, 1-hydroxybenzotriazole HOBT and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride EDC•HCl, were stirred and mixed evenly. Mode ; 3) Triethylamine is added to the reaction flask to produce the topiramate intermediate prepared according to claim 1. Add in batches, stir and react at 10-20℃ for 2-4 hours, then raise the temperature to 100℃ and continue reacting until the transition state reaction is complete as detected by TLC; 4) Cool the reaction solution to below 30°C, add water to the reaction flask for dilution, and then adjust the pH of the reaction solution to 6.6-7.0 with a saturated sodium bicarbonate aqueous solution; 5) Filter the reaction solution, rinse the filter cake with water, then add the filter cake to a mixed solvent of N,N-dimethylformamide and ethyl acetate in a volume ratio of 1:5 and stir for 5-7 hours; filter, dry the filter cake, and obtain the product as shown in the formula. The topiramate intermediate shown 99% purity; Mode .

5. A method for preparing topiramate, characterized in that, The preparation method includes the following steps: 1) Weigh the raw materials according to the following molar proportions: Topiramate intermediate 1.0 copy; 2.0-2.5 parts of dimethylcarbamoyl chloride; 1.0-1.5 parts of trimethylcyanosilane; 2) The topiramate intermediate prepared according to claim 2 Add acetonitrile solvent to the reaction flask, and then add dimethylcarbamoyl chloride under a nitrogen atmosphere; raise the temperature to an internal temperature of 60±2℃, dilute trimethylcyanosyl silane with acetonitrile solvent and slowly add it dropwise, and after the addition is complete, control the temperature at 70-80℃ to carry out the reaction until TLC shows that the raw materials have basically reacted, which is the reaction endpoint; 3) After the reaction is complete, cool the reaction solution to 10-20℃; add water to dilute the reaction solution, and then adjust the pH of the reaction solution to 6.5-7.0 with 5% sodium hydroxide aqueous solution. Stir to precipitate crystals, filter, and dry the filter cake to obtain pale yellow to off-white topiramate.

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