Synthesis method of topiromilast

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of topiromilast. The preparation method comprises the following steps: reacting 2-cyanopyridine-4-formaldehyde serving as a raw material with hydrazine hydrate to obtain an intermediate product, and further reacting with 4-(aminomethyl) pyridine under the action of iodine and tert-butyl hydroperoxide; and performing post-treatment to obtain a target compound. The used raw materials and reagents are low in price and easy to obtain, and the cost advantage is achieved; the post-treatment and purification steps are simple, and the product yield and purity are high.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing topiramate. Background Art

[0002] Topiroxostat is a new type of XOR inhibitor, jointly developed by Fuji Yakuhin and Sanwa Kagaku. It was approved for marketing in Japan in June 2013 for the treatment of hyperuricemia in patients with gout or non-gout. It has good tolerance and few adverse reactions, and is currently one of the most effective drugs for the treatment of gout.

[0003] Topirastat, also known as topirastat, chemical name is 5-(2-cyano-4-pyridinyl)-3-(4-pyridinyl)-1,2,4-triazole, molecular weight: 248.24, CAS number: 577778-58-6, molecular formula: C 13 H8N6. The structural formula is as follows:

[0004]

[0005] Topiramate is composed of a triazole ring fragment and two pyridine ring fragments. Its synthesis patents can be simply summarized into three categories: one is to first introduce a cyano group at the 2-position of pyridine (or directly use a 2-cyanopyridine derivative as a starting material), and then construct a triazole ring (the splicing of the pyridine ring and the construction of the triazole ring can be completed in one pot); one is to first construct a triazole ring (the splicing of the pyridine ring and the construction of the triazole ring can be completed in one pot), and then introduce a cyano group at the 2-position of pyridine; the other is to first splice two pyridine rings, then introduce a cyano group at the 2-position of pyridine, and finally close the ring to construct the triazole ring to obtain the final product.

[0006] Patent CN1561340A reports the first synthetic route of topirostat: using isonicotinic acid-N-oxide as the starting material, firstly reacting with methanol for esterification, then reacting with trimethylsilyl cyanide (TMSCN) to obtain 2-cyanoisonicotinic acid methyl ester, then reacting with hydrazine hydrate for hydrazinolysis to obtain 2-cyanoisonicotinic acid hydrazide, and finally reacting with 4-cyanopyridine for ring closure reaction (ring closure yield of about 57.8%) to obtain the product. In this synthetic method, the starting material and TMSCN are expensive (the latter is highly toxic), the reaction time of the first two steps is too long, and column chromatography is required. In addition, the total yield of this route is only 14.8%, which is suitable for preparing the target compound in small batches. Therefore, it is difficult to apply to industrial production. The synthetic route is shown in the following formula.

[0007]

[0008] Patent CN103724329A uses methyl isonicotinate as the starting material. First, amidation reaction occurs under the action of formamide, concentrated sulfuric acid, ferrous sulfate heptahydrate and 30% hydrogen peroxide, and the compound 2-cyano methyl isonicotinate is obtained by dehydration with cyanuric chloride; then, hydrazine hydrolysis reaction occurs with hydrazine hydrate to obtain 2-cyano isonicotinate; finally, ring closure reaction occurs with 4-cyanopyridine (ring closure yield 61.8%-69.1%) to obtain the product. The total yield of the four-step reaction of this route is only 11.7%, and the process is cumbersome (ferrous sulfate heptahydrate and 30% hydrogen peroxide must be added alternately in multiple times in the first step reaction, which has high requirements for equipment, and the post-processing process is relatively cumbersome), which is not suitable for industrial production. The synthetic route is shown in the following formula.

[0009]

[0010] Patent CN108101840A discloses a method for preparing topirostat: 4-cyanopyridine is first reacted with ethanol and sodium methoxide, and then reacted with hydrazine hydrate to obtain 4-pyridinecarboximidic acid hydrazine; 4-pyridinecarboximidic acid hydrazine is further acylated with 2-cyanoisonicotinic acid to obtain 4-pyridinecarboxylic acid hydrazine-N'-(2-cyanopyridine-4-carbonyl imide) intermediate. Then, it is cyclized under the action of acid to obtain the target product. Although the overall yield of the route is high, 4-pyridinecarboximidic acid hydrazine requires a large amount of methyl tert-butyl ether for crystallization, and the purity is not very high and the stability is poor. A large amount of methyl tert-butyl ether needs to be recovered. The industrial cost will be relatively high. The synthetic route is as follows:

[0011]

[0012] Patent CN107531677A uses 2-carbamoyl-4-cyano-pyridine as a substrate, and reacts with isoniazid in a sodium methoxide / methanol system through an intermediate to obtain an intermediate product; then reacts with TFAA / TEA in a THF solvent to generate topiramate TFA salt, and finally desalts with potassium carbonate to obtain the target product. The ring-closing reaction of this route uses methanol as a solvent, and requires a long reaction at high pressure and high temperature, which is relatively risky; the preparation process involves the distillation of trifluoroacetic acid / trifluoroacetic anhydride, which has high requirements for equipment, and the post-processing process is relatively cumbersome, which is not conducive to industrial production. The synthetic route is shown in the following formula.

[0013]

[0014] Patent CN1826335A uses isoniazid as the starting material, first reacts with 4-cyanopyridine-N-oxide to undergo a ring-closing reaction to obtain an intermediate product with a yield of about 90%; then, benzyl chloromethyl ether is introduced on the triazole ring NH for protection; then, cyanidation reaction occurs under the action of TMSCN and N,N-dimethylcarbamoyl chloride (DMCl) to obtain an intermediate product; then, it reacts with p-toluenesulfonic acid monohydrate in 2-propanol to obtain a deprotected intermediate product; finally, it reacts with sodium bicarbonate to desalt and obtain the target product. This route has cumbersome steps, the intermediate has poor solubility, and a large amount of solvent extraction and washing is required, which increases the cost; and the reaction time is long, and the use of p-toluenesulfonic acid monohydrate for refining will produce impurity p-toluenesulfonate; at the same time, the use of highly toxic cyanide TMSCN to introduce cyano groups has great environmental pressure and is not conducive to industrial production. The synthetic route is shown in the following formula.

[0015]

[0016] Patent CN105367490A uses methyl isonicotinate as a raw material, and in the presence of an oxidant, oxidizes to generate methyl isonicotinate N-oxide; 2) condenses with hydrazine hydrate to obtain isonicotinate N-oxide; 3) reacts with 4-cyanopyridine under alcohol-base conditions to generate 4-(2-(imino(pyridin-4-yl)methyl)hydrazinecarbonyl)pyridine N-oxide; 4) reacts with cyanide in the presence of dimethylaminoformyl chloride to generate 2-cyano-N'-(imino(pyridin-4-yl)methyl)isonicotinamide; 5) cyclizes in the presence of an acid to obtain topiroxicam; the reaction route is as follows:

[0017]

[0018] Patent CN104411686A uses 4-cyanopyridine-N-oxide as the starting material, and reacts with isoniazid in a sodium methoxide / methanol system to obtain an intermediate compound; in DMF, a cyanation reaction occurs under the action of sodium cyanide and DMCl to obtain an intermediate product; in a 2-butanol / water system, a ring-closing reaction occurs with phosphoric acid to obtain the target product, with a total yield of about 80%. A similar patent CN116396275A discloses the use of a "cyanation-cyclization" one-pot method to directly synthesize topiramate, and its cyanation reaction reagent uses acetone cyanohydrin, which can achieve quantitative conversion. The second step reaction of the CN104411686A route uses highly toxic sodium cyanide as a cyanide source, and the two intermediates have large polarity, poor lipid solubility, and are difficult to separate and purify; the ring-closing reaction uses phosphoric acid as a condensation agent, which requires a long reaction at high temperature and a low yield; the cyano group reacts with phosphoric acid and trace water in the reagent to produce impurities C and D that are difficult to remove, making it difficult to meet the quality requirements of the drug. Therefore, this process lacks competitiveness in industrial production. The synthesis route and impurity structure are shown in the following formula.

[0019]

[0020] Through the analysis of the above routes, it was found that both the ring-closing reaction for constructing the triazole ring and the introduction of the cyano group had shortcomings.

[0021] In view of the above shortcomings, the applicant has also made corresponding improvements, and a new synthesis route is disclosed in CN115925682A. However, the yield of the triazole ring closure reaction is about 80.7%, and imidazole salt needs to be prepared in the route, and the reaction needs to be assisted by microwaves, etc. Industrial production is limited.

[0022]

[0023] In order to solve the shortcomings of the above routes, a new route for synthesizing topiramate needs to be sought. Summary of the invention

[0024] The purpose of the present invention is to overcome the deficiencies in the prior art and provide a method for synthesizing topirastat. The present invention solves the problems of using highly toxic cyaniding reagents, harsh reaction conditions, long process routes, high raw material costs, and low yields. The present invention provides a new method for synthesizing topirastat; the route is novel, the raw materials are easily available, and the yield is higher than that of the prior art, which is suitable for industrial production.

[0025] In order to achieve the above object, the present invention is implemented by the following scheme:

[0026] Compound 3 reacts with compound 4 under the action of iodine (I2) and tert-butyl hydroperoxide (TBHP), and compound 1, i.e., topiralast, is obtained after post-treatment. The reaction route is as follows:

[0027]

[0028] The specific operations include:

[0029] Compound 3, compound 4 and reaction solvent were added to the reaction container in sequence, and iodine (I2) and tert-butyl hydroperoxide (TBHP) were added in sequence after stirring. The system was stirred at the temperature T to react. After detection, the reaction was completed. Compound 1, i.e., topiralast, was obtained after post-treatment.

[0030] In a preferred embodiment, the molar ratio of compound 3, compound 4, iodine (I2), and tert-butyl hydroperoxide (TBHP) is 1:1.0-1.2:0.1-0.4:1.2-4, preferably 1:1.1:0.2:3.

[0031] In a preferred embodiment, the tert-butyl hydroperoxide is a tert-butyl hydroperoxide (TBHP) aqueous solution with a mass percentage of 70%.

[0032] In a preferred embodiment, the reaction solvent is one of acetonitrile, N,N-dimethylformamide and 1,4-dioxane, preferably acetonitrile.

[0033] Preferably, the reaction temperature T is 70-90°C.

[0034] The preferred embodiment, the post-treatment is as follows: after the reaction is completed, the reaction solution is cooled to room temperature and poured into a Na2S2O3 aqueous solution, stirred and filtered and washed with water, the obtained filter cake is slurried with a N,N-dimethylformamide / methanol mixed solution at 50-60°C, cooled and filtered, the filter cake is washed with methanol and then vacuum dried to obtain the compound topiramate.

[0035] In a preferred embodiment, the mass fraction of the water-soluble Na2S2O3 is 8-15%.

[0036] In a preferred embodiment, the volume ratio of the N,N-dimethylformamide / methanol mixed solution is 1:2-5.

[0037] In addition, the synthesis method of compound 3 is as follows: Compound 2 (i.e. 2-cyanopyridine-4-carboxaldehyde) is added to the reaction solvent, stirred and hydrazine hydrate is added, and stirred at room temperature overnight. The reaction solution is slowly poured into water, stirred, filtered, and dried to obtain the target product compound 3; the synthesis route is as follows

[0038]

[0039] In a preferred embodiment, the reaction solvent is one of methanol, ethanol, propanol or a mixture thereof, preferably methanol.

[0040] In a preferred embodiment, the molar ratio of the compound 2 to hydrazine hydrate is 1:1.1-4; preferably 1:1.4-3.

[0041] Compared with the prior art, the technical effects achieved by the present invention are:

[0042] (1) The raw materials and reagents used are cheap and readily available, which has cost advantages; the post-treatment and purification steps are simple, and the yield and product purity are high.

[0043] (2) Avoid using highly toxic cyaniding reagents in the prior art, such as potassium cyanide, sodium cyanide, trimethylsilyl cyanide, etc., to reduce environmental hazards, reduce operational difficulty and post-reaction treatment burden, and reduce cumbersome steps.

[0044] (3) The reaction conditions are mild, the safety is high, the operation is simple, the controllability is strong, and it is suitable for industrial production. DETAILED DESCRIPTION

[0045] The present invention is further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention based on the method of the present invention are all within the scope of protection claimed by the present invention.

[0046] Synthesis of compound 3:

[0047]

[0048] Structural identification data of compound 3: ESI-MS (m / z) 147.07 [M+H] + ; 1 H NMR (400MHz, CDCl3): δ = 9.03 (d, 1H), 8.14 (s, 1H), 7.94 (d, 1H), 7.69 (s, 1H).

[0049] Example 1

[0050] Compound 2 (13.2 g, 100 mmol, 1.0 eq) was added to methanol (100 mL), stirred and hydrazine hydrate (85%, 17.1 mL, 300 mmol, 3.0 eq.) was added, and stirred at room temperature overnight. The reaction solution was slowly poured into water (400 mL), stirred for half an hour, filtered, and dried to obtain the target product compound 3, with a yield of 96.2% and a HPLC purity of 97.6%.

[0051] Example 2

[0052] Compound 2 (13.2 g, 100 mmol, 1.0 eq) was added to methanol (100 mL), stirred and hydrazine hydrate (85%, 11.4 mL, 200 mmol, 2.0 eq.) was added, and stirred at room temperature overnight. The reaction solution was slowly poured into water (400 mL), stirred for half an hour, filtered, and dried to obtain the target product compound 3, with a yield of 95.6% and a HPLC purity of 97.2%.

[0053] Example 3

[0054] Compound 2 (13.2 g, 100 mmol, 1.0 eq) was added to methanol (100 mL), stirred and hydrazine hydrate (85%, 8.0 mL, 140 mmol, 1.4 eq.) was added, and stirred at room temperature overnight. The reaction solution was slowly poured into water (400 mL), stirred for half an hour, filtered, and dried to obtain the target product compound 3, with a yield of 93.4% and a HPLC purity of 95.1%.

[0055] Synthesis of Topiralast

[0056]

[0057] Example 4

[0058] Compound 3 (14.6 g, 100 mmol, 1.0 eq.) and compound 4 (11.9 g, 110 mmol, 1.1 eq.) were added to acetonitrile (100 mL), stirred and I2 (5.07 g, 20 mmol, 0.2 eq.) and tert-butyl hydroperoxide (TBHP, 70% aq., 38.6 g, 300 mmol, 3.0 eq.) were added, and heated to reflux at 80°C for 4-5 hours. After detection, the reaction was completed, cooled and the reaction solution was poured into 10% Na2S2O3 (400 mL), stirred for half an hour, filtered and washed with water. The obtained filter cake was slurried with N, N-dimethylformamide (30 mL) / methanol (90 mL) at 60°C for 1-2 hours, cooled and filtered, washed with methanol (50 mL) and vacuum dried to obtain compound 1 (i.e., Topiroxostat) with a yield of 91.8% and an HPLC purity of 99.78%.

[0059] Example 5

[0060] Compound 3 (14.6 g, 100 mmol, 1.0 eq.) and compound 4 (11.9 g, 110 mmol, 1.1 eq.) were added to acetonitrile (100 mL), stirred and I2 (2.54 g, 10 mmol, 0.1 eq.) and tert-butyl hydroperoxide (TBHP, 70% aq., 38.6 g, 300 mmol, 3.0 eq.) were added, and heated to reflux at 80°C for 4-5 hours. After detection, the reaction was completed, cooled and the reaction solution was poured into 10% Na2S2O3 (400 mL), stirred for half an hour, filtered and washed with water. The obtained filter cake was slurried with N, N-dimethylformamide (30 mL) / methanol (90 mL) at 60°C for 1-2 hours, cooled and filtered, washed with methanol (50 mL) and vacuum dried to obtain compound 1 (i.e., Topiroxostat) with a yield of 85.1% and an HPLC purity of 99.76%.

[0061] Example 6

[0062] Compound 3 (14.6 g, 100 mmol, 1.0 eq.) and compound 4 (11.9 g, 110 mmol, 1.1 eq.) were added to acetonitrile (100 mL), stirred and I2 (10.16 g, 40 mmol, 0.4 eq.) and tert-butyl hydroperoxide (TBHP, 70% aq., 38.6 g, 300 mmol, 3.0 eq.) were added, and heated to reflux at 80°C for 4-5 hours. After detection, the reaction was completed, cooled and the reaction solution was poured into 10% Na2S2O3 (400 mL), stirred for half an hour, filtered and washed with water. The obtained filter cake was slurried with N, N-dimethylformamide (30 mL) / methanol (90 mL) at 60°C for 1-2 hours, cooled and filtered, washed with methanol (50 mL) and vacuum dried to obtain compound 1 (i.e., Topiroxostat) with a yield of 87.0% and an HPLC purity of 99.70%.

[0063] Example 7

[0064] Compound 3 (14.6 g, 100 mmol, 1.0 eq.) and compound 4 (11.9 g, 110 mmol, 1.1 eq.) were added to acetonitrile (100 mL), stirred and I2 (2.54 g, 10 mmol, 0.1 eq.) and tert-butyl hydroperoxide (TBHP, 70% aq., 15.5 g, 120 mmol, 1.2 eq.) were added, and heated to reflux at 80°C for 4-5 hours. After detection, the reaction was completed, cooled and the reaction solution was poured into 10% Na2S2O3 (400 mL), stirred for half an hour, filtered and washed with water. The obtained filter cake was slurried with N, N-dimethylformamide (30 mL) / methanol (120 mL) at 60°C for 1-2 hours, cooled and filtered, washed with methanol (50 mL) and vacuum dried to obtain compound 1 (i.e., Topiroxostat) with a yield of 81.8% and an HPLC purity of 99.70%.

[0065] Example 8

[0066] Compound 3 (14.6 g, 100 mmol, 1.0 eq.) and compound 4 (11.9 g, 110 mmol, 1.1 eq.) were added to N,N-dimethylformamide (100 mL), stirred, and I2 (5.07 g, 20 mmol, 0.2 eq.) and tert-butyl hydroperoxide (TBHP, 70% aq., 38.6 g, 300 mmol, 3.0 eq.) were added, and heated under reflux at 90°C for 3-4 hours. After detection, the reaction was completed, cooled, and the reaction solution was poured into 10% Na2S2O3 (400 mL), stirred for half an hour, and then filtered and washed with water. The obtained filter cake was slurried with N,N-dimethylformamide (20 mL) / methanol (100 mL) at 60°C for 1-2 hours, cooled and filtered, washed with methanol (50 mL) and vacuum dried to obtain compound 1 (i.e., Topiroxostat) with a yield of 84.2% and an HPLC purity of 99.74%.

[0067] Example 9

[0068] Compound 3 (14.6 g, 100 mmol, 1.0 eq.) and compound 4 (11.9 g, 110 mmol, 1.1 eq.) were added to 1,4-dioxane (100 mL), stirred, and I2 (5.07 g, 20 mmol, 0.2 eq.) and tert-butyl hydroperoxide (TBHP, 70% aq., 38.6 g, 300 mmol, 3.0 eq.) were added, and heated under reflux at 70°C for 5-8 hours. After detection, the reaction was completed, cooled, and the reaction solution was poured into 10% Na2S2O3 (400 mL), stirred for half an hour, and then filtered and washed with water. The obtained filter cake was slurried with N,N-dimethylformamide (30 mL) / methanol (90 mL) at 60°C for 1-2 hours, cooled and filtered, washed with methanol (50 mL) and vacuum dried to obtain compound 1 (i.e., Topiroxostat) with a yield of 78.8% and an HPLC purity of 99.72%.

[0069] Comparative Example 1

[0070] Compound 3 (14.6 g, 100 mmol, 1.0 eq.) and compound 4 (11.9 g, 110 mmol, 1.1 eq.) were added to acetonitrile (100 mL), stirred and added with KI (3.32 g, 20 mmol, 0.2 eq.) and tert-butyl hydroperoxide (TBHP, 70% aq., 38.6 g, 300 mmol, 3.0 eq.), and heated to reflux at 80°C for 4-5 hours. After detection, the reaction was completed, cooled and the reaction solution was poured into 10% Na2S2O3 (400 mL), stirred for half an hour, filtered and washed with water. The obtained filter cake was slurried with N, N-dimethylformamide (30 mL) / methanol (90 mL) at 60°C for 1-2 hours, cooled and filtered, washed with methanol (50 mL) and vacuum dried to obtain compound 1 (i.e., Topiroxostat) with a yield of 70.7% and an HPLC purity of 99.50%.

Claims

1. A method for synthesizing topirastat, characterized in that: Compound 3 reacts with compound 4 under the action of iodine and tert-butyl hydrogen peroxide, and compound 1, i.e., topirastat, is obtained after post-treatment. The reaction route is as follows:

2. The synthesis method according to claim 1, characterized in that It specifically includes the following operations: Compound 3, compound 4 and reaction solvent were sequentially added into the reaction container, and iodine and tert-butyl hydroperoxide were sequentially added with stirring. The system was controlled at temperature T and stirred for reaction. After detection, the reaction was completed. Compound 1, i.e., topiralast, was obtained after post-treatment.

3. The synthesis method according to claim 1 or 2, characterized in that The molar ratio of compound 3, compound 4, iodine and tert-butyl hydroperoxide is 1:1.0-1.2:0.1-0.4:1.2-4, preferably 1:1.1:0.2:

3.

4. The synthesis method according to claim 2, characterized in that The reaction solvent is one of acetonitrile, N,N-dimethylformamide and 1,4-dioxane, preferably acetonitrile.

5. The synthesis method according to claim 2, characterized in that The reaction temperature T is 70-90°C.

6. The synthesis method according to claim 2, characterized in that The post-treatment: After the reaction is completed, cool to room temperature and pour the reaction solution into a Na2S2O3 aqueous solution, stir and filter and wash with water, beat the obtained filter cake with a N,N-dimethylformamide / methanol mixed solution at 50-60°C, cool and filter, wash the filter cake with methanol and then vacuum dry to obtain compound 1, namely, topiramate.

7. The synthesis method according to claim 6, characterized in that The volume ratio of the N,N-dimethylformamide / methanol mixed solution is 1:2-5.

8. The synthesis method according to claim 1, characterized in that The synthesis method of compound 3 is as follows: Compound 2 is added to a reaction solvent, stirred and hydrazine hydrate is added, and stirred at room temperature overnight; the reaction solution is slowly poured into water, stirred, filtered, and dried to obtain the target product compound 3. The synthesis route is as follows:

9. The synthesis method according to claim 8, characterized in that The reaction solvent is one of methanol, ethanol and propanol or a mixture thereof, preferably methanol.

10. The synthesis method according to claim 8, characterized in that The molar ratio of the compound 2 to hydrazine hydrate is 1:1.1-4, preferably 1:1.4-3.

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