Preparation method of topiromilast intermediate

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a topiromilast intermediate. The preparation method comprises the following steps: by taking 2-carbamoyl-4-cyano-pyridine and 4-pyridylaldehyde hydrazone as raw materials, carrying out reaction; and carrying out post-treatment to obtain the target compound topiromilast intermediate 5-(2-formamido-4-pyridyl)-3-(4-pyridyl)-1, 2, 4-triazole. The initial raw materials are simple, cheap and easily available, the production cost can be effectively reduced, the yield and purity of the product are improved, the post-treatment operation is simple, and the method is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a method for preparing a topiroxostat intermediate. Background Art

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

[0003] Topiroxostat, also known as toperisone, has the chemical name of 5-(2-cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole, molecular weight: 248.24, CAS No.: 577778-58-6, and molecular formula: C 13 H8N6. The structural formula is as follows:

[0004]

[0005] Topiroxostat is composed of a triazole ring fragment and two pyridine ring fragments. Its synthesis patents can be simply classified into three categories: one is to first introduce a cyano group at the 2-position of pyridine (or directly use a 2-cyano-pyridine derivative as the starting material), and then construct the triazole ring; another is to first construct the triazole ring and then introduce a cyano group at the 2-position of pyridine; the third is to first splice the 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] The following prior arts are disclosed for the above classification:

[0007] Patent CN1561340A reported the first synthesis route of toperisone: using isonicotinic acid-N-oxide as the starting material, first carrying out an esterification reaction with methanol, then reacting with trimethylsilyl cyanide (TMSCN) to obtain methyl 2-cyanoisonicotinate, subsequently carrying out a hydrazinolysis reaction with hydrazine hydrate to obtain 2-cyanoisonicotinohydrazide, and finally carrying out a ring closure reaction (ring closure yield is about 57.8%) with 4-cyanopyridine to obtain the product. In this synthesis 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 small-scale preparation of the target compound. Therefore, it is difficult to be applied to industrial production. The synthesis route is shown as follows.

[0008]

[0009] Patent CN103724329A uses methyl isonicotinate as the starting material. First, an amidation reaction occurs under the action of formamide, concentrated sulfuric acid, ferrous sulfate heptahydrate, and 30% hydrogen peroxide, and compound methyl 2-cyanoisonicotinate is obtained through dehydration with cyanuric chloride. Then, a hydrazinolysis reaction occurs with hydrazine hydrate to obtain 2-cyanoisonicotinohydrazide. Finally, a ring-closing reaction (ring-closing yield: 61.8% - 69.1%) occurs with 4-cyanopyridine to obtain the product. The total yield of the four-step reaction of this route is only 11.7%, and the process is cumbersome (in the first reaction, ferrous sulfate heptahydrate and 30% hydrogen peroxide must be added alternately in multiple batches, which requires high equipment requirements and the post-treatment process is relatively cumbersome), and it is not suitable for industrial production. The synthetic route is shown as follows.

[0010]

[0011] Patent CN1826335A uses isonicotinohydrazide as the starting material. First, a ring-closing reaction occurs with 4-cyanopyridine-N-oxide to obtain an intermediate with a yield of about 90%. Then, benzyl chloromethyl ether is introduced to protect the NH on the triazole ring. Then, a cyanation reaction occurs under the action of TMSCN and N,N-dimethylcarbamoyl chloride (DMCl) to obtain an intermediate. Then, it reacts with p-toluenesulfonic acid monohydrate in 2-propanol to obtain a deprotected intermediate. Finally, it reacts with sodium bicarbonate to remove the salt to obtain the target product. This route has a cumbersome process, poor solubility of the intermediate, requires a large amount of solvent extraction and washing, increasing costs; and has a long reaction time. Using p-toluenesulfonic acid monohydrate for purification will produce impurities p-toluenesulfonate; at the same time, using highly toxic cyanide TMSCN to introduce a cyano group causes great environmental protection pressure and is not conducive to industrial production. The synthetic route is shown as follows.

[0012]

[0013] Patent CN104411686A uses 4-cyanopyridine-N-oxide as the starting material, which undergoes a condensation reaction with isoniazid in the sodium methoxide / methanol system to obtain an intermediate compound; in DMF, it then undergoes a cyanation reaction under the action of sodium cyanide and DMCl to obtain an intermediate product; and in the 2-butanol / water system, it undergoes a ring-closing reaction with phosphoric acid to obtain the target product, with an overall yield of about 80%. Similar patent CN116396275A discloses the direct synthesis of tozasertib using a "cyanation-cyclization" one-pot method. Its cyanation reaction reagent uses acetone cyanohydrin, which can achieve quantitative conversion. The second step reaction of the route of CN104411686A uses highly toxic sodium cyanide as the cyanide source. The two intermediates have large polarities and poor liposolubility, making separation and purification difficult; the ring-closing reaction uses phosphoric acid as a condensing agent, requiring a long reaction time at high temperature and resulting in a low yield; the cyanide undergoes side reactions under the combined action of phosphoric acid and trace moisture in the reagent, producing impurities C and D that are difficult to remove, making it difficult to meet the requirements of drug quality. Therefore, this process lacks competitiveness in industrial production. The synthetic route and impurity structures are shown in the following formula.

[0014]

[0015] Patent CN107531677A uses 2-carbamoyl-4-cyanopyridine as the substrate, which undergoes a ring-closing reaction with isoniazid in the sodium methoxide / methanol system through an intermediate to obtain an intermediate product; then in a THF solvent, it reacts with TFAA / TEA to generate the tozasertib TFA salt, and finally the target product is obtained by de-salting with potassium carbonate. The ring-closing reaction of this route uses methanol as the solvent, requiring a long reaction time at high pressure and high temperature, with relatively high risks; the preparation process involves the distillation of trifluoroacetic acid / trifluoroacetic anhydride, requiring high equipment requirements, and the post-treatment process is relatively cumbersome, which is not conducive to industrial production. The synthetic route is shown in the following formula.

[0016]

[0017] In CN 115477638A, using 4-cyanopyridine as the raw material, under the action of formamide, concentrated sulfuric acid, an oxidizing agent, etc., an amidation reaction is carried out to obtain the intermediate 2-carbamoyl-4-cyanopyridine; then under the action of an alcoholate and an alcohol solvent, an alcoholysis reaction is carried out, and the alcoholysis product is mixed with hydrazine hydrate to carry out a hydrazinolysis reaction. The obtained hydrazinolysis product undergoes a condensation reaction with isonicotinic acid, and the condensate undergoes a ring-closing reaction under the action of phosphoric acid and a solvent to obtain 5-(2-formamido-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole. Then, it is mixed with trifluoroacetic anhydride, a second base reagent, and a fifth solvent to carry out an amide dehydration reaction to obtain tozasertib. The synthetic route is shown as follows.

[0018]

[0019] Through the analysis of the above route, it is found that there are deficiencies in both the triazole ring cyclization reaction and the introduction of cyano groups. Among them, the intermediate compound has the following structure and plays an important role in the synthetic route. The preparation method conditions affect the yield of the entire route. Moreover, this intermediate compound is also an impurity of this tolterodine.

[0020]

[0021] In view of the above deficiencies, the applicant has studied various methods for improvement. Among them, a new synthetic route is disclosed in CN115925682A. However, the yield of the triazole ring cyclization reaction is about 80.7%, and imidazole salt needs to be prepared in the route. Microwave and other auxiliary reactions are required in the last step of the reaction. Industrial production is limited. The synthetic route is shown as follows.

[0022]

[0023] To solve the deficiencies of the above route, a new route for synthesizing the tolterodine intermediate 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 new preparation method for the tolterodine intermediate. To solve the problems of harsh reaction conditions, long process route, high raw material cost, and low yield in the prior art, the route of the present invention is novel, the raw materials are easily available, and it has a higher yield compared with the prior art and is suitable for industrial production.

[0025] To achieve the above purpose, the present invention is realized through the following scheme:

[0026] Dissolve compound 1 in an alcohol solvent in a reaction vessel, control the temperature of the system at T1, add solid sodium alkoxide, and keep stirring at a constant temperature until the reaction of compound 1 is completed; then add compound 2 and stir under reflux. After detection, when the reaction is completed, concentrate under reduced pressure to dryness; add a reaction solvent, control the temperature of the system at T2, and continue to stir at a constant temperature while passing air until the reaction ends. After post-treatment, the target product is obtained.

[0027]

[0028] In a preferred scheme, the molar ratio of the charged compound 1, sodium alkoxide, and compound 2 is 1.0:(1.0 - 1.2):(1.0 - 1.2), preferably 1.0:1.1:1.1.

[0029] Among them, a sufficient amount of alcohol solvent is added to enable the reaction to proceed.

[0030] In a preferred scheme, the dosage ratio of compound 1 to the alcohol solvent is 1 g:(10 - 25) mL.

[0031] Preferred embodiment: The alcohol solvent is one of methanol and ethanol, preferably methanol.

[0032] Preferred embodiment: The sodium alkoxide is one of sodium methoxide and sodium ethoxide, preferably sodium methoxide.

[0033] Preferred embodiment: The temperature control temperature T1 is 10 - 40°C, preferably 20 - 30°C.

[0034] Preferred embodiment: The temperature control temperature T2 is 110 - 120°C.

[0035] Preferred embodiment: The reaction solvent is one of N,N-dimethylformamide (DMF) and N,N-dimethylacetamide (DMA), preferably DMF.

[0036] Preferred embodiment: The post-treatment: After the reaction is completed, it is cooled to room temperature and poured into 1N hydrochloric acid aqueous solution to quench the reaction. After stirring, it is filtered by suction and the filter cake is washed successively with water and methanol. The obtained filter cake is refluxed and slurried with a water / methanol mixed solution. After the slurrying is completed, the temperature is controlled at 40 - 50°C and hot filtered. After washing the filter cake with methanol, it is dried under vacuum to obtain Compound 3.

[0037] Preferred embodiment: In the water / methanol mixed solution, the volume ratio of water to methanol is 1:1.

[0038] Compared with the prior art, the technical effects achieved by the present invention are:

[0039] (1) The starting materials of the present invention, 2-carbamoyl-4-cyano-pyridine and 4-pyridinecarboxaldehyde hydrazone, are inexpensive and readily available. The synthetic route of the prior art is simple, effectively reducing the production cost. Using the above raw materials to synthesize Compound 3, namely 5-(2-formamido-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole, the reaction conditions are mild, avoiding operations such as high pressure in the prior art.

[0040] (2) The post-treatment operation is simple, the product yield and purity are relatively high, and it is suitable for industrial production. Specific Embodiments

[0041] The present invention will be further illustrated below through examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than limiting the present invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention fall within the scope of protection required by the present invention.

[0042] Example 1

[0043] Compound 1 (14.71 g, 100 mmol) was added to methanol (147 ml). After stirring and controlling the temperature to 20 - 30 °C, solid sodium methoxide (5.67 g, 105 mmol) was added, and the mixture was stirred while maintaining the temperature until the reaction of compound 1 was complete as detected by TLC, which took 2 - 3 hours. Compound 2 (12.11 g, 100 mmol) was added and the mixture was heated to reflux with stirring until the reaction was complete, which took 2 - 4 hours. It was concentrated to dryness under reduced pressure. DMF (75 mL) was added to the reaction system, the temperature was raised to 110 °C and air was passed through, and the mixture was stirred while maintaining the temperature until the reaction was complete, which took 12 - 14 hours. The temperature was lowered to room temperature, 1N hydrochloric acid aqueous solution (120 ml) was added dropwise and stirring was continued for 1 - 2 hours. Filtration was carried out, and the filter cake was washed successively with water (30 ml) and methanol (30 ml). The wet filter cake was added to a mixture of water (50 ml) and methanol (50 ml), heated to reflux, and stirred for 1 - 2 hours. The temperature was controlled to 40 - 50 °C and hot filtration was carried out. The filter cake was washed with methanol (20 ml) and then dried in a blast dryer at 55 - 65 °C for 4 - 6 hours to obtain a pale white solid product 3, with a yield of 95.7% and an HPLC purity of 99.61%.

[0044] Example 2

[0045] Compound 1 (14.71 g, 100 mmol) was added to methanol (147 ml). After stirring and controlling the temperature to 20 - 30 °C, solid sodium methoxide (5.67 g, 105 mmol) was added, and the mixture was stirred while maintaining the temperature until the reaction of compound 1 was complete as detected by TLC, which took 2 - 3 hours. Compound 2 (13.33 g, 110 mmol) was added and the mixture was heated to reflux with stirring until the reaction was complete, which took 2 - 4 hours. It was concentrated to dryness under reduced pressure. DMF (75 mL) was added to the reaction system, the temperature was raised to 115 °C and air was passed through, and the mixture was stirred while maintaining the temperature until the reaction was complete, which took 12 - 14 hours. The temperature was lowered to room temperature, 1N hydrochloric acid aqueous solution (120 ml) was added dropwise and stirring was continued for 1 - 2 hours. Filtration was carried out, and the filter cake was washed successively with water (30 ml) and methanol (30 ml). The wet filter cake was added to a mixture of water (50 ml) and methanol (50 ml), heated to reflux, and stirred for 1 - 2 hours. The temperature was controlled to 40 - 50 °C and hot filtration was carried out. The filter cake was washed with methanol (20 ml) and then dried in a blast dryer at 55 - 65 °C for 4 - 6 hours to obtain a pale white solid product 3, with a yield of 96.4% and an HPLC purity of 99.71%.

[0046] Example 3

[0047] Compound 1 (14.71 g, 100 mmol) was added to methanol (147 ml). After stirring and controlling the temperature at 20 - 30 °C, solid sodium methoxide (5.67 g, 105 mmol) was added, and the mixture was stirred while maintaining the temperature until the reaction of compound 1 was complete as detected by TLC, which took 2 - 3 hours. Compound 2 (14.54 g, 120 mmol) was added and the mixture was heated to reflux with stirring until the reaction was complete, which took 2 - 4 hours. It was concentrated to dryness under reduced pressure. DMF (75 mL) was added to the reaction system, the temperature was raised to 120 °C and air was passed through. The mixture was stirred while maintaining the temperature until the reaction was complete, which took 12 - 14 hours. The temperature was lowered to room temperature, 1N hydrochloric acid aqueous solution (120 ml) was added dropwise and stirring was continued for 1 - 2 hours. Filtration was carried out, and the filter cake was washed successively with water (30 ml) and methanol (30 ml). The wet filter cake was added to a mixture of water (50 ml) and methanol (50 ml), heated to reflux, and stirred for 1 - 2 hours while pulping. The temperature was controlled at 40 - 50 °C and hot filtration was carried out. The filter cake was washed with methanol (20 ml) and then dried in a blast dryer at 55 - 65 °C for 4 - 6 hours to obtain a off-white solid product 3 with a yield of 95.1% and an HPLC purity of 99.60%.

[0048] Example 4

[0049] Compound 1 (14.71 g, 100 mmol) was added to ethanol (147 ml). After stirring and controlling the temperature at 20 - 30 °C, solid sodium ethoxide (7.14 g, 105 mmol) was added, and the mixture was stirred while maintaining the temperature until the reaction of compound 1 was complete as detected by TLC, which took 2 - 3 hours. Compound 2 (13.33 g, 110 mmol) was added and the mixture was heated to reflux with stirring until the reaction was complete, which took 2 - 4 hours. It was concentrated to dryness under reduced pressure. DMF (75 mL) was added to the reaction system, the temperature was raised to 115 °C and air was passed through. The mixture was stirred while maintaining the temperature until the reaction was complete, which took 12 - 14 hours. The temperature was lowered to room temperature, 1N hydrochloric acid aqueous solution (120 ml) was added dropwise and stirring was continued for 1 - 2 hours. Filtration was carried out, and the filter cake was washed successively with water (30 ml) and methanol (30 ml). The wet filter cake was added to a mixture of water (50 ml) and methanol (50 ml), heated to reflux, and stirred for 1 - 2 hours while pulping. The temperature was controlled at 40 - 50 °C and hot filtration was carried out. The filter cake was washed with methanol (20 ml) and then dried in a blast dryer at 55 - 65 °C for 4 - 6 hours to obtain a off-white solid product 3 with a yield of 96.0% and an HPLC purity of 99.65%.

[0050] Example 5

[0051] Compound 1 (14.71 g, 100 mmol) was added to methanol (147 ml). After stirring and controlling the temperature to 20 - 30 °C, solid sodium methoxide (5.67 g, 105 mmol) was added, and the mixture was stirred while maintaining the temperature until the reaction of Compound 1 was complete as detected by TLC, which took 2 - 3 hours; Compound 2 (13.33 g, 110 mmol) was added and the mixture was heated to reflux with stirring until the reaction was complete, which took 2 - 4 hours, and then concentrated to dryness under reduced pressure; DMA (75 mL) was added to the reaction system, the temperature was raised to 100 °C and air was passed through, and the mixture was stirred while maintaining the temperature until the reaction was complete, which took 16 hours. The temperature was lowered to room temperature, 1N hydrochloric acid aqueous solution (120 ml) was added dropwise and stirring was continued for 1 - 2 hours. The mixture was filtered, and the filter cake was washed successively with water (30 ml) and methanol (30 ml). The wet filter cake was added to a mixture of water (50 ml) and methanol (50 ml), the temperature was raised to reflux, and the mixture was stirred for 1 - 2 hours. The temperature was controlled to 40 - 50 °C and hot filtration was carried out. The filter cake was washed with methanol (20 ml) and then dried in a blast dryer at 55 - 65 °C for 4 - 6 hours to obtain a off-white solid product 3 with a yield of 94.8% and an HPLC purity of 99.70%.

[0052] Example 6

[0053] Compound 1 (14.71 g, 100 mmol) was added to methanol (147 ml). After stirring and controlling the temperature to 20 - 30 °C, solid sodium methoxide (5.67 g, 105 mmol) was added, and the mixture was stirred while maintaining the temperature until the reaction of Compound 1 was complete as detected by TLC, which took 2 - 3 hours; Compound 2 (13.33 g, 110 mmol) was added and the mixture was heated to reflux with stirring until the reaction was complete, which took 2 - 4 hours, and then concentrated to dryness under reduced pressure; DMA (75 mL) was added to the reaction system, the temperature was raised to 125 °C and air was passed through, and the mixture was stirred while maintaining the temperature until the reaction was complete, which took 13 hours. The temperature was lowered to room temperature, 1N hydrochloric acid aqueous solution (120 ml) was added dropwise and stirring was continued for 1 - 2 hours. The mixture was filtered, and the filter cake was washed successively with water (30 ml) and methanol (30 ml). The wet filter cake was added to a mixture of water (50 ml) and methanol (50 ml), the temperature was raised to reflux, and the mixture was stirred for 1 - 2 hours. The temperature was controlled to 40 - 50 °C and hot filtration was carried out. The filter cake was washed with methanol (20 ml) and then dried in a blast dryer at 55 - 65 °C for 4 - 6 hours to obtain a off-white solid product 3 with a yield of 95.8% and an HPLC purity of 99.50%.

Claims

1. A preparation method of tolterodine intermediate, characterized in that, Dissolve Compound 1 in an alcohol solvent in a reaction vessel. Control the temperature of the system at T1 and add solid sodium alkoxide. Keep the temperature and stir until the reaction of Compound 1 is complete. Then add Compound 2 and reflux and stir for reaction. After detection, when the reaction is complete, concentrate under reduced pressure to dryness. Add a reaction solvent, control the temperature of the system at T2, and continue to stir while passing air until the reaction ends. After post-treatment, the target product is obtained. The reaction route is as follows:

2. The preparation method according to claim 1, characterized in that, The molar ratio of the charged Compound 1, sodium alkoxide, and Compound 2 is 1.0:(1.0 - 1.2):(1.0 - 1.2), preferably 1.0:1.1:1.

1.

3. The preparation method according to claim 1, characterized in that, The alcohol solvent is one of methanol and ethanol, preferably methanol.

4. The preparation method according to claim 1, characterized in that, The sodium alkoxide is one of sodium methoxide and sodium ethoxide, preferably sodium methoxide.

5. The preparation method according to claim 1, characterized in that, The controlled temperature T1 is 10 - 40 °C; preferably 20 - 30 °C.

6. The preparation method according to claim 1, characterized in that, The controlled temperature T2 is 110 - 120 °C.

7. The preparation method according to claim 1, characterized in that, The reaction solvent is one of N,N-dimethylformamide and N,N-dimethylacetamide, preferably N,N-dimethylformamide.

8. The preparation method according to claim 1, characterized in that, After the reaction ends, cool to room temperature and pour into an aqueous hydrochloric acid solution to quench the reaction. Stir and then filter by suction. Wash the filter cake successively with water and methanol. Reflux and slurry the obtained filter cake with a water / methanol mixed solution. After the slurry is completed, control the temperature at 40 - 50 °C and filter while hot. Wash the filter cake with methanol and then dry it under vacuum to obtain Compound 3.

9. The preparation method according to claim 8, characterized in that, In the water / methanol mixed solution, the volume ratio of water to methanol is 1:1.

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