A method for the synthesis of toptipitab

Abstract

The application belongs to the technical field of medicine, and particularly relates to a preparation method of toptipitast, which comprises the following steps: 1) preparing compound 2 by reacting compound 1 with ammonium sulfide in an imidazole aqueous solution; 2) preparing compound 3 by reacting compound 2 with iodomethane under inert gas protection; 3) preparing compound 5 by reacting compound 3, compound 4 and silica gel under microwave irradiation; and 4) preparing toptipitast by reacting compound 5 with trifluoroacetic anhydride. The application has the following beneficial effects relative to the prior art: (1) the reagent used is low in price and has a cost advantage; (2) the use of a highly toxic cyanide reagent is avoided; (3) the operation of post-treatment is simple, the reaction condition is mild, the safety is high, and the method is suitable for commercial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for synthesizing topipustine. Background Technology

[0002] Hyperuricemia is a disease caused by various genetic and environmental factors that disrupt uric acid (UA) metabolism. Specifically, it manifests as an abnormally high level of urate in the serum, exceeding the solubility limit at physiological temperature and pH (approximately 6.8 mg / dL). This urate can form microcrystals in the capillaries of joints, leading to gout. Currently, in clinical practice, medications primarily treat gout by inhibiting UA production, reducing the activity of xanthine oxidase (XOR), inhibiting the conversion of hypoxanthine to xanthine, thereby reducing UA production and lowering the concentration of UA in the blood.

[0003] Topiroxostat is a novel 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 is well-tolerated, has few adverse reactions, and is one of the most effective drugs for treating gout.

[0004] Topipusta, chemical name 5-(2-cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole, molecular weight: 248.24, CAS number: 577778-58-6, molecular formula: C 13 H8N6. The structural formula is as follows:

[0005]

[0006] Topiprostine is composed of a triazole ring fragment and two pyridine ring fragments. Its synthetic patents can be simply summarized into three categories: one category first introduces a cyano group at the 2-position of pyridine (or directly uses a 2-cyanopyridine derivative as the starting material), and then constructs the triazole ring (the splicing of the pyridine ring and the construction of the triazole ring can be completed in one pot); another category first constructs the triazole ring (the splicing of the pyridine ring and the construction of the triazole ring can be completed in one pot), and then introduces a cyano group at the 2-position of pyridine; the third category first splices two pyridine rings, then introduces a cyano group at the 2-position of pyridine, and finally closes the ring to construct the triazole ring to obtain the final product.

[0007] Patent CN1561340A reports the first synthetic route for topipsestat: starting with isonicotinic acid-N-oxide (2), it is first esterified with methanol, then reacted with trimethylcyanosilane (TMSCN) to obtain methyl 2-cyanoisonicotinate (4), subsequently hydrazinolyzed with hydrazine hydrate to obtain 2-cyanoisonicotinamide (5), and finally cyclized with 4-cyanopyridine (6) to obtain product 1. The synthetic route is shown in the following formula. In this synthetic method, starting material 2 and TMSCN are expensive (the latter is highly toxic), the first two steps are too time-consuming, and column chromatography is required. In addition, the overall yield of this route is only 14.8%, which is suitable for small-batch preparation of the target compound. Therefore, it is difficult to apply to industrial production.

[0008]

[0009] Patent CN10372432329A uses methyl isonicotinate (12) as the starting material. First, an amidation reaction occurs under the action of formamide, concentrated sulfuric acid, ferrous sulfate heptahydrate, and 30% hydrogen peroxide. Compound 4 is then dehydrated by cyanuric chloride to obtain compound 4. Next, 4 undergoes a hydrazolysis reaction with hydrazine hydrate to obtain 5. Finally, 5 and 6 undergo a cyclization reaction to obtain product 1. The synthetic route is shown below. The overall yield of this four-step reaction is only 11.7%, and the process is cumbersome (ferrous sulfate heptahydrate and 30% hydrogen peroxide must be added alternately in multiple steps in the first step, requiring high-quality equipment and involving complex post-processing), making it unsuitable for industrial production.

[0010]

[0011] Patent CN1826335A uses isoniazid (17) as a starting material. First, it undergoes a cyclization reaction with 4-cyanopyridine-N-oxide (18) to obtain product 19. Then, a protecting group is introduced onto the triazole ring NH of 19 to obtain compound 20. 20 undergoes a cyanidation reaction under the action of TMSCN and DMCI to obtain product 21. 21 reacts with p-toluenesulfonic acid monohydrate in IPA to obtain the deprotected product 14. Finally, 14 reacts with sodium bicarbonate to desalt and obtain product 1. The synthetic route is shown below. This route is cumbersome, the intermediates have poor solubility, requiring large amounts of solvent extraction and washing, increasing costs. Furthermore, the reaction time is long, and the use of p-toluenesulfonic acid monohydrate for purification produces impurities such as p-toluenesulfonate esters. Simultaneously, the use of the highly toxic cyanide TMSCN to introduce the cyano group creates significant environmental pressure and is not conducive to industrial production.

[0012]

[0013] Patent CN104411686A uses 4-cyanopyridine-N-oxide (18) as the starting material. 18 undergoes a condensation reaction with isoniazid (17) in a sodium methoxide / methanol system to obtain compound 27. In DMF, 27 undergoes a cyanidation reaction with sodium cyanide and DMCl to obtain 11. 11 undergoes a cyclization reaction with phosphoric acid in a 2-butanol / water system to obtain product 1. The synthetic route is shown below. The second step of this route uses highly toxic sodium cyanide as the cyanide source. The two intermediates, 27 and 11, are highly polar and poorly lipophilic, making separation and purification difficult. The cyclization reaction uses phosphoric acid as the condensing agent, requiring a long reaction time at high temperature, resulting in a low yield. The cyano group undergoes a side reaction with the combined action of phosphoric acid and trace amounts of water in the reagents, producing impurities C and D that are difficult to remove, making it difficult to meet pharmaceutical quality requirements. Therefore, this process lacks competitiveness in industrial production.

[0014]

[0015] Patent CN107531677A describes a cyclization reaction of 2-carbamoyl-4-cyanopyridine (3) with isoniazid (5) in a sodium methoxide / methanol system via intermediate 6 to yield product 7. Compound 7 then reacts with TFAA / TEA in THF solvent to generate topipsestat TFA salt, which is finally dissolved in potassium carbonate to obtain product 1. The synthetic route is shown below. This route uses methanol as a solvent for the cyclization reaction, requiring a long reaction time under high pressure and temperature, posing a high risk. The preparation of product 1 involves the distillation of trifluoroacetic acid / trifluoroacetic anhydride, demanding sophisticated equipment and involving complex post-processing, which is unsuitable for industrial production.

[0016]

[0017] The methods mentioned above have significant drawbacks. Patents CN1826335A and CN104411686A use cyanide-based reagents to introduce a cyano group onto the pyridyl moiety. These reagents must be handled with extreme care because they hydrolyze to produce hydrogen cyanide, an extremely toxic chemical compound. On the other hand, patent CN1561340A uses expensive starting materials and has low yields. Furthermore, patent CN107531677A requires sophisticated equipment, has long reaction times, and involves cumbersome post-processing. To address these shortcomings, this invention aims to provide a synthetic route suitable for the industrial production of topipsestat. This route utilizes widely available raw materials and inexpensive reagents, offering a cost advantage; it successfully avoids the use of highly toxic cyanide reagents, simplifies post-processing, and provides mild and safe reaction conditions. Summary of the Invention

[0018] To address the problems of using highly toxic cyanide reagents, demanding reaction conditions, lengthy process routes, high raw material costs, and low yields in current topiprostat preparation methods, this invention provides a method suitable for industrial-scale production of topiprostat.

[0019] A method for synthesizing topipusta specifically includes the following steps:

[0020] 1) Compound 1 was reacted with ammonium sulfide in an aqueous solution of imidazole salt to prepare compound 2;

[0021] 2) Under inert gas protection, compound 2 reacts with iodomethane to prepare compound 3;

[0022] 3) Compound 5 was prepared by reacting compounds 3 and 4 with silica gel under microwave irradiation;

[0023] 4) Topiprestat was prepared by reacting compound 5 with trifluoroacetic anhydride;

[0024]

[0025] Preferably, the molar ratio of compound 1 to ammonium sulfide in step 1) is 1:1.1 to 1.4, and more preferably 1:1.2.

[0026] Preferably, the imidazole salt in step 1) is selected from C6(mim)2Cl 2、 C4(mim)2Cl 2、 One of C8(mim)2Cl2.

[0027] More preferably, the imidazole salt in step 1) is C6(mim)2Cl2.

[0028] Preferably, the preparation method of the imidazole salt includes the following steps: adding 1-methylimidazolium to (CH2)nCl2, heating to react, cooling to room temperature, adding acetone and stirring, filtering, washing the filter cake with acetone, and drying under vacuum to obtain Cn(min)2Cl2, wherein n in (CH2)nCl2 can be 4, 6, or 8.

[0029] More preferably, the reaction temperature in the preparation method of the imidazole salt is 120-140°C.

[0030] More preferably, in the method for preparing the imidazole salt, the molar ratio of 1-methylimidazolium to (CH2)nCl2 is 2.0 to 2.5:1.

[0031] Preferably, the imidazole salt can be recycled and reused. The recycling method is as follows: the filtrate after the reaction in step 1) is washed three times with diethyl ether, the organic phases are combined, the solvent is removed by vacuum distillation, and the imidazole salt is obtained by vacuum drying.

[0032] Preferably, the imidazole salt can be reused 3 to 5 times without losing its activity.

[0033] Preferably, the molar ratio of compound 1 to the imidazole salt in step 1) is 1:1.0 to 1.2.

[0034] Preferably, the reaction temperature in step 1) is 65–75°C.

[0035] Preferably, the molar ratio of compound 2 to iodomethane in step 2) is 1:1.1 to 3.0, and more preferably 1:1.2 to 2.0.

[0036] Preferably, the solvent used in step 2) is selected from one or more of acetone, ethyl acetate, and tetrahydrofuran.

[0037] Preferably, the reaction temperature in step 2) is 40–55°C.

[0038] Preferably, the inert gas in step 2) is selected from nitrogen and argon.

[0039] Preferably, the molar ratio of compound 3 to compound 4 in step 3) is 1:1.0 to 1.3, and more preferably 1:1.2.

[0040] Preferably, the mass ratio of compound 3 to silica gel in step 3) is 1:1.8 to 2.5, and more preferably 1:1.9.

[0041] Preferably, the power of microwave irradiation in step 3) is 800-1000W, and more preferably 900W.

[0042] Preferably, the microwave irradiation time in step 3) is 10 to 20 minutes.

[0043] Preferably, step 3) further includes a post-processing step: the mixture after reaction is soaked and washed with a mixture of deionized water and triethylamine, the washing liquids are combined, the solvent is removed by distillation under vacuum, the residue is recrystallized with water / methanol, and the resulting solid is dried under vacuum to obtain compound 5.

[0044] Preferably, the mass-to-volume ratio of compound 5 to trifluoroacetic anhydride in step 4) is 1:1.5 to 3.0, where mass is in g and volume is in mL.

[0045] Preferably, the reaction in step 4) specifically includes the following steps: adding compound 5 to tetrahydrofuran, adding triethylamine dropwise, cooling, adding trifluoroacetic anhydride dropwise, and after the addition is complete, heating to room temperature to react.

[0046] Preferably, the cooling temperature is -5 to 5°C.

[0047] The present invention achieves the following beneficial effects compared to the prior art:

[0048] (1) The reagents used are inexpensive and have a cost advantage;

[0049] (2) Avoid using highly toxic cyanide reagents;

[0050] (3) The post-processing operation is simple, the reaction conditions are mild, and the safety is high. Attached Figure Description

[0051] Figure 1 PXRD powder diffraction pattern of topixate. Detailed Implementation

[0052] The beneficial effects of the present invention will be further described through the following embodiments. These embodiments are for illustrative purposes only and do not limit the scope of the present invention. At the same time, obvious changes and modifications made by those skilled in the art according to the present invention are also included within the scope of the present invention.

[0053] Example 1

[0054] Preparation of C6(mim)2Cl2

[0055] 1-Methylimidazole (18.0 g, 0.22 mol) was added to 1,6-dichlorohexane (15.5 g, 0.1 mol), heated at 120 °C for 48 hours, and then cooled to room temperature. Acetone (30 mL) was added and stirred for 10 minutes. The mixture was then filtered to obtain a filter cake, which was washed with acetone (10 mL) and dried under vacuum to obtain C6(mim)2Cl2 (28.1 g, 88.3% yield based on 1,6-dichlorohexane), which was used directly in the next reaction.

[0056] Compound 1 (7.4 g, 50 mmol) and C6(mim)2Cl2 (17.5 g, 55 mmol) were added to a 20% aqueous solution of ammonium sulfide (20.4 g, 60 mmol). The mixture was heated to 65–70 °C and stirred for 1–2 hours. After the reaction was completed by TLC monitoring, deionized water (200 mL) was added to the reaction solution, and the mixture was stirred for 10 minutes. The mixture was then filtered to obtain a filter cake, which was recrystallized from ethanol and dried under vacuum to obtain compound 2 (8.0 g, yield 88.4%) with an HPLC purity of 98.76%.

[0057] Recycling and reuse of C6(mim)2Cl2

[0058] The filtrate was washed three times with ether and the solvent was removed by distillation under vacuum. After vacuum drying, C6(mim)2Cl2 was obtained, which could be reused four times without losing its activity.

[0059] Example 2

[0060] Preparation of C4(mim)2Cl2

[0061] 1-Methylimidazole (16.4 g, 0.20 mol) was added to 1,4-dichlorobutane (12.7 g, 0.1 mol), and the mixture was heated at 120 °C for 48 hours, then cooled to room temperature. Acetone (30 mL) was added and stirred for 10 minutes, then filtered to obtain a filter cake. This cake was then washed with acetone (10 mL) and dried under vacuum to obtain C4(mim)2Cl2 (25.5 g, yield 87.5%), which was directly used in the next reaction.

[0062] Compound 1 (7.4 g, 50 mmol) and C4(mim)2Cl2 (14.6 g, 50 mmol) were added to a 20% aqueous solution of ammonium sulfide (18.7 g, 55 mmol). The mixture was heated to 70–75 °C and stirred for 1–2 hours. After the reaction was completed by TLC monitoring, deionized water (200 mL) was added to the reaction solution, and the mixture was stirred for 10 minutes. The mixture was then filtered to obtain a filter cake, which was recrystallized from ethanol and dried under vacuum to obtain compound 2 (7.9 g, yield 87.2%) with an HPLC purity of 98.85%.

[0063] Recycling and reuse of C4(mim)2Cl2

[0064] The filtrate was washed four times with ether and the solvent was removed by distillation under vacuum. After vacuum drying, C4(mim)2Cl2 was obtained, which could be reused four times without losing its activity.

[0065] Example 3

[0066] Preparation of C8(mim)2Cl2

[0067] 1-Methylimidazole (16.4 g, 0.20 mol) was added to 1,8-dichlorooctane (14.6 g, 0.08 mol), heated at 130 °C for 36 hours, and then cooled to room temperature. Acetone (30 mL) was added and stirred for 10 minutes. The mixture was then filtered to obtain a filter cake, which was washed with acetone (10 mL) and dried under vacuum to obtain C8(mim)2Cl2 (24.2 g, 87.2% yield based on 1,8-dichlorooctane), which was used directly in the next reaction.

[0068] Compound 1 (7.4 g, 50 mmol) and C8(mim)2Cl2 (20.8 g, 60 mmol) were added to a 20% ammonium sulfide (23.8 g, 70 mmol) aqueous solution. The mixture was heated to 70–75 °C and stirred for 1–2 hours. After the reaction was completed by TLC monitoring, deionized water (200 mL) was added to the reaction solution, and the mixture was stirred for 10 minutes. The mixture was then filtered to obtain a filter cake, which was recrystallized from ethanol and dried under vacuum to obtain compound 2 (7.8 g, yield 86.3%) with an HPLC purity of 98.62%.

[0069] Recycling and reuse of C8(mim)2Cl2

[0070] The filtrate was washed five times with ether and the solvent was removed by distillation under vacuum. After vacuum drying, C8(mim)2Cl2 was obtained, which could be reused five times without losing its activity.

[0071] Example 4

[0072] Preparation of C2(mim)2Cl2

[0073] 1-Methylimidazole (16.4 g, 0.20 mol) was added to 1,2-dichloroethane (9.9 g, 0.1 mol), heated at 80 °C for 48 hours, and then cooled to room temperature. Acetone (30 mL) was added and stirred for 10 minutes, followed by filtration to obtain a filter cake. This cake was then washed with acetone (10 mL) and dried under vacuum to obtain C2(mim)2Cl2 (21.6 g, 82.2% yield based on 1,2-dichloroethane), which was directly used in the next reaction.

[0074] Compound 1 (7.4 g, 50 mmol) and C2(mim)2Cl2 (17.4 g, 70 mmol) were added to a 20% aqueous solution of ammonium sulfide (27.2 g, 80 mmol). The mixture was heated to 50–55 °C and stirred for 1–2 hours. After the reaction was completed by TLC monitoring, deionized water (200 mL) was added to the reaction solution, and the mixture was stirred for 10 minutes. The mixture was then filtered to obtain a filter cake, which was recrystallized from ethanol and dried under vacuum to obtain compound 2 (7.3 g, yield 81.0%) with an HPLC purity of 95.43%.

[0075] Recycling and reuse of C2(mim)2Cl2

[0076] The filtrate was washed five times with ether and the solvent was removed by distillation under vacuum. After vacuum drying, C2(mim)2Cl2 was obtained, which could be reused twice without losing its activity.

[0077] Example 5

[0078] Under nitrogen protection, compound 2 (4.5 g, 25 mmol) and iodomethane (4.2 g, 30 mmol) were added to acetone (100 mL). The mixture was stirred at 45–50 °C for 4 hours, then cooled to room temperature. The mixture was filtered and dried under vacuum to give compound 3 (7.9 g, yield 97.8%) with an HPLC purity of 98.17%.

[0079] Example 6

[0080] Under argon protection, compound 2 (4.5 g, 25 mmol) and iodomethane (5.7 g, 40 mmol) were added to ethyl acetate (100 mL). The mixture was stirred at 50–55 °C for 4 hours, then cooled to room temperature. The mixture was filtered and dried under vacuum to give compound 3 (7.8 g, yield 96.7%) with an HPLC purity of 98.03%.

[0081] Example 7

[0082] Under argon protection, compound 2 (4.5 g, 25 mmol) and iodomethane (7.1 g, 50 mmol) were added to tetrahydrofuran (100 mL). The mixture was stirred at 50–55 °C for 4 hours, then cooled to room temperature. The mixture was filtered and dried under vacuum to give compound 3 (7.9 g, yield 98.1%) with an HPLC purity of 97.80%.

[0083] Example 8

[0084] Under argon protection, compound 2 (4.5 g, 25 mmol) and iodomethane (10.6 g, 75 mmol) were added to tetrahydrofuran (100 mL). The mixture was stirred at 55–60 °C for 4 hours, then cooled to room temperature. The solvent was removed by distillation under vacuum, and the product was dried under vacuum to give compound 3 (7.6 g, yield 94.3%) with an HPLC purity of 95.63%.

[0085] Example 9

[0086] A mixture of compound 3 (6.5 g, 20 mmol), compound 4 (2.7 g, 20 mmol), and silica gel (12.5 g) was thoroughly ground with a pestle and irradiated with microwaves at 900 W for 10–20 minutes. After the reaction was completed by TLC monitoring, the mixture was washed with a mixture of deionized water and triethylamine. The washings were combined, and the solvent was removed by distillation under vacuum. The residue was recrystallized from water / methanol and dried under vacuum to give compound 5 (4.2 g, yield 78.9%) with an HPLC purity of 99.53%.

[0087] Example 10

[0088] A mixture of compound 3 (6.5 g, 20 mmol), compound 4 (3.2 g, 24 mmol), and silica gel (11.7 g) was thoroughly ground with a pestle and irradiated with microwaves at 800 W for 10–20 minutes. After the reaction was completed by TLC monitoring, the mixture was washed with a mixture of deionized water and triethylamine. The washings were combined, and the solvent was removed by distillation under vacuum. The residue was recrystallized from water / methanol and dried under vacuum to give compound 5 (4.3 g, yield 80.7%) with an HPLC purity of 99.35%.

[0089] Example 11

[0090] A mixture of compound 3 (6.5 g, 20 mmol), compound 4 (3.5 g, 26 mmol), and silica gel (16.3 g) was thoroughly ground with a pestle and irradiated with microwave at 1000 W for 10–20 minutes. After the reaction was completed by TLC monitoring, the mixture was washed with a mixture of deionized water and triethylamine. The washings were combined, and the solvent was removed by distillation under vacuum. The residue was recrystallized with water / methanol and dried under vacuum to give compound 5 (4.1 g, yield 77.5%) with an HPLC purity of 99.57%.

[0091] Example 12

[0092] A mixture of compound 3 (6.5 g, 20 mmol), compound 4 (4.1 g, 30 mmol), and silica gel (9.7 g) was thoroughly ground with a pestle and irradiated with microwaves at 700 W for 10–20 minutes. After the reaction was completed by TLC monitoring, the mixture was washed with a mixture of deionized water and triethylamine. The washings were combined, and the solvent was removed by distillation under vacuum. The residue was recrystallized from water / methanol and dried under vacuum to give compound 5 (3.7 g, yield 70.1%) with an HPLC purity of 97.65%.

[0093] Example 13

[0094] Compound 5 (3.2 g, 12 mmol) was added to tetrahydrofuran (20 mL), stirred, and triethylamine (9 mL) was added dropwise. The reaction solution was cooled to 0 °C, and trifluoroacetic anhydride (5 mL) was added dropwise. After the addition was complete, the reaction solution was stirred at room temperature for 3–4 hours. After the reaction was completed by TLC monitoring, the pH was adjusted to 6–7, and the mixture was filtered. The resulting filter cake was slurried with N,N-dimethylformamide (5 mL) / methanol (15 mL) for 1–2 hours, filtered, washed with methanol (5 mL), and dried under vacuum to obtain compound 6 (i.e., Topiroxostat, 2.3 g, yield 77.2%), with an HPLC purity of 99.77%.

[0095] Topiprolat prepared according to the technical solution of this invention is a white crystalline powder. The PXRD powder diffraction pattern is attached. Figure 1Topiprostine has high purity and low solvent residue. The test results of the finished topiprostine product are shown in Table 1.

[0096] Table 1

[0097]

[0098]

Claims

1. A method for synthesizing topipusta, characterized in that, Includes the following steps: 1) Compound 1 was reacted with ammonium sulfide in an aqueous solution of imidazole salt to prepare compound 2; 2) Under inert gas protection, compound 2 reacts with iodomethane to prepare compound 3; 3) Compound 5 was prepared by reacting compounds 3 and 4 with silica gel under microwave irradiation; 4) Topiprestat was prepared by reacting compound 5 with trifluoroacetic anhydride; ； The imidazole salt mentioned in step 1) is selected from C6(mim)2Cl2 C4(mim)2Cl2 C8(mim)2Cl2 One of them.

2. The synthesis method according to claim 1, characterized in that, In step 1), the molar ratio of compound 1 to ammonium sulfide is 1:1.1 to 1.

4.

3. The synthesis method according to claim 1, characterized in that, In step 1), the molar ratio of compound 1 to the imidazole salt is 1:1.0 to 1.

2.

4. The synthesis method according to claim 1, characterized in that, The reaction temperature in step 1) is 65–75°C.

5. The synthesis method according to claim 1, characterized in that, The molar ratio of compound 2 to iodomethane in step 2) is 1:1.1 to 3.

0.

6. The synthesis method according to claim 5, characterized in that, The molar ratio of compound 2 to iodomethane in step 2) is 1:1.2 to 2.

0.

7. The synthesis method according to claim 1, characterized in that, The solvent used in step 2) is selected from one or more of acetone, ethyl acetate, and tetrahydrofuran.

8. The synthesis method according to claim 1, characterized in that, The reaction temperature in step 2) is 40–55°C.

9. The synthesis method according to claim 1, characterized in that, In step 3), the molar ratio of compound 3 to compound 4 is 1:1.0 to 1.

3.

10. The synthesis method according to claim 1, characterized in that, In step 3), the mass ratio of compound 3 to the silica gel is 1:1.8 to 2.5.

Images