Synthesis of sGC agonists

Abstract

The present invention belongs to the technical field of heterocyclic compounds, and in particular to a kind of synthetic method of sGC agonist. Acid and iron powder are added to the solvent to stir and activate, and then compound I is added to react to obtain a reaction solution; the reaction solution is filtered, concentrated under reduced pressure to obtain a concentrate; the concentrate and malononitrile are refluxed in a solvent, and are cooled to room temperature to obtain a reaction solution; the reaction solution is added to water and stirred at room temperature to separate out solids, filtered, the obtained filter cake is added to 1,4-dioxane and refluxed for the first time, and crystallization is cooled to room temperature, filtered, the obtained filter cake is added to methanol and ethanol mixed solution and refluxed for the second time, filtered to room temperature, the obtained filter cake is decolorized, filtered, the filtrate is added to water and stirred at room temperature for crystallization, filtered, the obtained filter cake is vacuum dried to obtain sGC agonist. Raw materials of the present invention are easy to obtain, and the use of microwave reactors and operations such as column chromatography are avoided, which is conducive to realizing industrial amplification, and effectively reduces environmental protection costs.

Description

Technical Field

[0001] The invention belongs to the technical field of heterocyclic compounds, and particularly relates to a method for synthesizing a sGC agonist. Background Art

[0002] Pulmonary arterial hypertension (PAH) is a serious, highly fatal pulmonary vascular occlusive disease caused by a variety of causes. It is characterized by rapid disease progression and poor prognosis. It has no obvious specific clinical symptoms, and the main manifestations are fatigue, chest pain, and dyspnea.

[0003] LXH-1211 (2-(3-methyl-1-phenyl-6-((2-methyl)benzyloxy)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidine-4,6-diamine) is a sGC agonist drug. The drug has stronger anti-pulmonary artery smooth muscle cell proliferation activity than the positive drug rioxiguanidine, and its vasodilatory effect is slightly weaker than rioxiguanidine, indicating that the drug can overcome the systemic hypotension caused by existing drugs in the treatment of PAH. At the same time, because the drug also exhibits anti-pulmonary fibrosis activity, it is expected to achieve the effect of "treating both the symptoms and the root cause".

[0004] Chinese patent CN110305125A discloses a 5-pyrimidine-6-oxy-pyrazolopyridine derivative and its preparation method and application. 0.6 g of compound 6-(2-fluorobenzyloxy)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamidine (1.6 mmol) was weighed and added into a 25 mL microwave tube, and then the mixture was heated to 40 ℃ and 10 ℃ ... MeOH :V 1,4-Dioxane =1:2 ratio, 5 mL of methanol and 10 mL of 1,4-dioxane were respectively added into the microwave tube, a stirring bar was added and ultrasonicated for 5 min to fully dissolve the raw materials, 0.11 g of malononitrile (1.6 mmol) was weighed with a rubber dropper by the reduction method and slowly added dropwise into the microwave tube. After the reaction device was transferred to 130°C for microwave reaction for 2h, the reaction of the raw material 2-(6-((2-fluorobenzyloxy)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-pyridyl)formamidine was completely monitored by TLC, and the reaction was stopped. The reaction solution was transferred to 100mL and concentrated under reduced pressure to dryness to obtain 0.8g of crude product. The crude solid was dissolved in 50mL of methanol, mixed with 80-100 mesh silica gel, loaded with 200-300 mesh silica gel, and purified by column chromatography. The elution system used dichloromethane: methanol = 30:1, and 0.36g of white solid was obtained after separation and purification. The synthesis process in this patent requires a microwave catalytic device and column chromatography separation, which is not conducive to industrial scale-up production, and has a high environmental protection cost. Summary of the invention

[0005] The purpose of the present invention is to provide a method for synthesizing an sGC agonist, wherein the raw materials are readily available, the use of a microwave reactor and operations such as column chromatography are avoided, and the method is conducive to realizing industrial scale-up and effectively reducing environmental protection costs.

[0006] The method for synthesizing the sGC agonist of the present invention comprises the following steps:

[0007] (1) adding acid and iron powder to a solvent and stirring to activate the mixture, then adding compound I to react to obtain a reaction solution; filtering the reaction solution and concentrating it under reduced pressure to obtain a concentrate;

[0008] Wherein, the structural formula of compound I is as follows:

[0009] ;

[0010] (2) the concentrate obtained in step (1) is reacted with malononitrile under reflux in a solvent and the temperature is cooled to room temperature to obtain a reaction solution;

[0011] (3) adding the reaction solution to water, stirring at room temperature to precipitate solids, filtering, adding the obtained filter cake to 1,4-dioxane for the first reflux beating, cooling to room temperature for crystallization, filtering, adding the obtained filter cake to a mixed solution of methanol and ethanol for the second reflux beating, cooling to room temperature for filtration, adding the obtained filter cake to a decolorizing solvent for reflux dissolution, adding activated carbon to the obtained solution for decolorization, filtering, and obtaining a filtrate;

[0012] (4) The filtrate obtained in step (3) is added to water and stirred at room temperature for crystallization, filtered, and the obtained filter cake is vacuum dried to obtain a sGC agonist.

[0013] The solvent in step (1) is one or both of 1,4-dioxane and methanol.

[0014] The acid in step (1) is glacial acetic acid.

[0015] In step (1), the ratio of compound I, acid, iron powder and solvent is 1:4-4.2:0.5-2.0:400, wherein compound I is measured in g, acid is measured in g, iron powder is measured in g, and solvent is measured in ml.

[0016] The activation time in step (1) is 1-1.5 hours.

[0017] In step (1), the reaction temperature is 20-50° C. and the reaction time is 23-25 ​​hours.

[0018] The mass ratio of malononitrile in step (2) to compound I in step (1) is 1-4:10.

[0019] The solvent in step (2) is one or two of 1,4-dioxane, methanol or 2-methylpyridine.

[0020] The ratio of the solvent in step (2) to the compound I in step (1) is 6-7.5:1, wherein the solvent is measured in ml and the compound I is measured in g.

[0021] In step (2), the reaction temperature is 100-130° C. and the reaction time is 2.5-5 hours.

[0022] The volume ratio of water in step (3) to the solvent in step (2) is 1-10:1.

[0023] In step (3), the first reflux beating temperature is 120-125° C., and the first reflux beating time is 1-2 hours.

[0024] In step (3), the volume ratio of methanol to ethanol in the mixed solution of methanol and ethanol is 1:1.

[0025] In step (3), the second reflux beating temperature is 80-85° C., and the second reflux beating time is 1-2 hours.

[0026] The decolorizing solvent in step (3) is N,N-dimethylformamide.

[0027] The mass ratio of the decolorizing solvent in step (3) to the compound I in step (1) is 18-20:1.

[0028] The decolorization time in step (3) is 1-2 hours.

[0029] The mass ratio of water in step (4) to the decolorizing solvent in step (3) is 8-10:1.

[0030] The reaction scheme of the present invention is as follows:

[0031]

[0032] In the present invention, the compound I is reduced by iron and acid to reduce the hydroxyamidine in the structure of the compound I, and then undergoes a cyclization reaction with malononitrile to obtain the sGC agonist LXH-1211.

[0033] The LXH-1211 of the present invention is used as an active ingredient for preparing medicines for treating pulmonary hypertension, pulmonary fibrosis and the like.

[0034] The beneficial effects of the present invention are as follows:

[0035] (1) The raw materials and reagents in the present invention are commercially available, and the target product can be obtained through a two-step reaction of reduction with iron and acid and cyclization.

[0036] (2) The present invention avoids the use of zinc powder, which is relatively expensive, and also avoids the problem of zinc powder solidifying at the bottom of the reaction tank, which makes it inconvenient to discharge.

[0037] (3) Although the microwave reactor used in the prior art can increase the probability of atomic collision, improve the reaction yield, and shorten the reaction time, the microwave reaction needs to be sealed and the reaction tube needs to be pressure-resistant. There are hidden dangers such as high energy and pressure in the reaction process and unstable energy. Industrial application is very difficult and has safety risks. The present invention can be carried out using a conventional reactor, avoiding the use of a microwave reactor, and is easy to achieve industrial scale-up.

[0038] (4) In the prior art, purification is required through column chromatography and other operations. The use of column chromatography not only greatly increases the cost of materials and solvents, but also generates solid waste that creates a great environmental pressure. The present invention can purify the raw materials through the pulping of reagents, which is conducive to industrial scale-up. At the same time, it also provides the possibility of further reducing production costs and environmental costs for solvent recovery in the later stage, and has a good industrial application prospect. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 This is the LC-MS spectrum of LXH-1211 prepared in Example 1.

[0040] Figure 2 It is LXH-1211 obtained in Example 1 1 H-NMR spectrum.

[0041] Figure 3 It is LXH-1211 obtained in Example 1 13 C-NMR spectrum. DETAILED DESCRIPTION

[0042] The present invention is further described below with reference to the embodiments.

[0043] Example 1

[0044] Add 200 ml of 1,4-dioxane and 200 ml of methanol to the reaction flask, weigh 120 g of glacial acetic acid and add it to the reaction flask, then add 15.0 g of iron powder, stir at room temperature for 1 hour to fully activate the iron powder, then add 30.0 g of compound I, stir at 35°C for 24 hours, monitor the reaction completion by TLC, stop the reaction, and obtain a reaction solution; filter the reaction solution, concentrate the filtrate under reduced pressure at 60°C, and use the concentrate directly in the next step without purification.

[0045] The concentrate, 100 ml of 1,4-dioxane, 100 ml of methanol and 3 g of malononitrile were stirred and refluxed at 100 ° C for 2.5 hours, and the reaction solution was cooled to room temperature. The reaction solution was added to a beaker containing 1000 ml of purified water, stirred at room temperature to precipitate solids, filtered, and the filter cake was added to 100 ml of 1,4-dioxane, refluxed and beaten for 1 hour at 120 ° C for the first time, cooled to room temperature for crystallization and filtered, and the filter cake was added to 200 ml of a mixed solution of methanol and ethanol (the volume ratio of methanol to ethanol was 1:1), refluxed and beaten for 1 hour at 80 ° C for the second time, cooled to room temperature and filtered, and the filter cake was filtered through 600 g After N,N-dimethylformamide was refluxed and dissolved, activated carbon was added to the obtained solution for decolorization for 1 hour. After the solution was hot filtered, the filtrate was added to a beaker containing 6000g of purified water, stirred at room temperature for crystallization for 12 hours, filtered, and the filter cake was vacuum dried at 80°C to obtain 5.62g of white solid, i.e., the target product LXH-1211. The LC-MS spectrum of LXH-1211 is shown in Figure 1 , LC-MS: 438.13 [M+H] + . LXH-1211 1 H-NMR spectrum is shown in Figure 2 , 1 H-NMR (DMSO-d 6 ): 8.10~8.50 (m, 3H), 7.50~7.70(m, 3H), 7.10~7.40 (m, 4H), 6.11 (br, 4H), 5.53(s, 2H), 5.41 (s, 1H), 2.54 (s, 3H), 2.40 (s, 3H). LXH-1211 13 C-NMR spectrum is shown in Figure 3 , 13 C-NMR (DMSO-d 6 ): 164.4, 163.7, 160.9, 148, 143.9, 139.6, 136.6, 135.7, 133.1, 130.3, 129.6, 128.2, 128.0, 126.1, 125.6, 121.3, 119.9, 111.6, 81.5, 66.6, 19.1, 12.7.

[0046] Example 2

[0047] Add 200 ml of 1,4-dioxane and 200 ml of methanol to the reaction bottle, weigh 120 g of glacial acetic acid and add it to the reaction bottle, then add 30.0 g of iron powder, stir at room temperature for 1 hour to fully activate the iron powder, then add 30.0 g of compound I, stir at 20°C for 25 hours, monitor the reaction completion by TLC, stop the reaction, and obtain a reaction solution; filter the reaction solution, concentrate the filtrate under reduced pressure at 60°C, and use the concentrate directly in the next step without purification.

[0048] The concentrate, 100 ml of 1,4-dioxane, 100 ml of methanol and 6 g of malononitrile were stirred and refluxed at 100 ° C for 2.5 hours, and the reaction solution was cooled to room temperature. The reaction solution was added to a beaker containing 1000 ml of purified water, stirred at room temperature to precipitate solids, filtered, and the filter cake was added to 100 ml of 1,4-dioxane, refluxed and beaten for 1 hour at 120 ° C for the first time, cooled to room temperature for crystallization and filtered, and the filter cake was added to 200 ml of a mixed solution of methanol and ethanol (the volume ratio of methanol to ethanol was 1:1), refluxed and beaten for 1 hour at 80 ° C for the second time, cooled to room temperature and filtered, and the filter cake was filtered through 600 g After N,N-dimethylformamide was refluxed and dissolved, activated carbon was added to the obtained solution for decolorization for 1 hour. After the solution was hot filtered, the filtrate was added to a beaker containing 6000 g of purified water. After stirring and crystallization at room temperature for 12 hours, it was filtered and the filter cake was vacuum dried at 80°C to obtain 6.81 g of off-white solid, i.e., the target product LXH-1211.

[0049] Example 3

[0050] Add 200 ml of 1,4-dioxane and 200 ml of methanol to the reaction flask, weigh 120 g of glacial acetic acid and add it to the reaction flask, then add 45.0 g of iron powder, stir at room temperature for 1.5 hours to fully activate the iron powder, then add 30.0 g of compound I, stir at 50°C for 23 hours, monitor the reaction completion by TLC, stop the reaction, and obtain a reaction solution; filter the reaction solution, concentrate the filtrate under reduced pressure at 60°C, and use the concentrate directly in the next step without purification.

[0051] The concentrate, 100 ml of 1,4-dioxane, 100 ml of methanol and 9 g of malononitrile were stirred and refluxed at 100 ° C for 2.5 hours, and the reaction solution was cooled to room temperature. The reaction solution was added to a beaker containing 1000 ml of purified water, stirred at room temperature to precipitate solids, filtered, and the filter cake was added to 100 ml of 1,4-dioxane, refluxed and beaten for 1 hour at 120 ° C for the first time, cooled to room temperature for crystallization and filtered, and the filter cake was added to 200 ml of a mixed solution of methanol and ethanol (the volume ratio of methanol to ethanol was 1:1), refluxed and beaten for 1 hour at 80 ° C for the second time, cooled to room temperature and filtered, and the filter cake was filtered through 600 g After N,N-dimethylformamide was refluxed and dissolved, activated carbon was added to the obtained solution for decolorization for 1 hour. After the solution was hot filtered, the filtrate was added to a beaker containing 6000 g of purified water. After stirring and crystallization at room temperature for 12 hours, it was filtered and the filter cake was vacuum dried at 80°C to obtain 5.93 g of off-white solid, i.e., the target product LXH-1211.

[0052] Example 4

[0053] Add 200 ml of 1,4-dioxane and 200 ml of methanol to the reaction bottle, weigh 120 g of glacial acetic acid and add it to the reaction bottle, then add 60.0 g of iron powder, stir at room temperature for 1 hour to fully activate the iron powder, then add 30.0 g of compound I, stir at 35°C for 24 hours, monitor the reaction completion by TLC, stop the reaction, and obtain a reaction solution; filter the reaction solution, concentrate the filtrate under reduced pressure at 60°C, and use the concentrate directly in the next step without purification.

[0054] The concentrate, 100 ml of 1,4-dioxane, 100 ml of methanol and 12 g of malononitrile were stirred and refluxed at 100 ° C for 2.5 hours, and the reaction solution was cooled to room temperature. The reaction solution was added to a beaker containing 1000 ml of purified water, stirred at room temperature to precipitate solids, filtered, and the filter cake was added to 100 ml of 1,4-dioxane, refluxed and beaten for 1 hour at 120 ° C for the first time, cooled to room temperature for crystallization and filtered, and the filter cake was added to 200 ml of a mixed solution of methanol and ethanol (the volume ratio of methanol to ethanol was 1:1), refluxed and beaten for 1 hour at 80 ° C for the second time, cooled to room temperature and filtered, and the filter cake was filtered through 600 g After N,N-dimethylformamide was refluxed and dissolved, activated carbon was added to the obtained solution for decolorization for 1 hour. After the solution was hot filtered, the filtrate was added to a beaker of 6000 g purified water. After stirring and crystallization at room temperature for 12 hours, it was filtered and the filter cake was vacuum dried at 80°C to obtain 6.71 g of off-white solid, i.e., the target product LXH-1211.

[0055] Example 5

[0056] Add 200 ml of 1,4-dioxane and 200 ml of methanol to the reaction flask, weigh 120 g of glacial acetic acid and add it to the reaction flask, then add 30.0 g of iron powder, stir at room temperature for 1.2 hours to fully activate the iron powder, then add 30.0 g of compound I, stir at 35°C for 24 hours, monitor the reaction until it is complete by TLC, stop the reaction, and obtain a reaction solution; filter the reaction solution, concentrate the filtrate under reduced pressure at 60°C, and use the concentrate directly in the next step without purification.

[0057] The concentrate, 225 ml of 2-methylpyridine and 9 g of malononitrile were stirred and refluxed at 130°C for 2.5 hours, and the reaction solution was cooled to room temperature. The reaction solution was added to a beaker containing 1000 ml of purified water, stirred at room temperature to precipitate a solid, and filtered. The filter cake was added to 100 ml of dioxane, refluxed and beaten for the first time at 120°C for 1 hour, cooled to room temperature for crystallization, and filtered. The filter cake was added to 200 ml of a mixed solution of methanol and ethanol (the volume ratio of methanol to ethanol was 1:1), refluxed and beaten for the second time at 80°C for 1 hour, cooled to room temperature for filtration, and the filter cake was dissolved in 600 g of N, N-dimethylformamide by reflux, and activated carbon was added to the obtained solution for decolorization for 1 hour. After the solution was hot filtered, the filtrate was added to a beaker containing 6000 g of purified water, stirred at room temperature for crystallization for 12 hours, and filtered. The filter cake was vacuum dried at 80°C to obtain 8.30 g of solid, i.e., the target product LXH-1211.

[0058] Example 6

[0059] Add 200 ml of 1,4-dioxane and 200 ml of methanol to the reaction flask, weigh 126 g of glacial acetic acid and add it to the reaction flask, then add 30.0 g of iron powder, stir at room temperature for 1 hour to fully activate the iron powder, then add 30.0 g of compound I, stir at 35°C for 24 hours, monitor the reaction completion by TLC, stop the reaction, and obtain a reaction solution; filter the reaction solution, concentrate the filtrate under reduced pressure at 60°C, and use the concentrate directly in the next step without purification.

[0060] The concentrate, 180 ml of 1,4-dioxane and 9 g of malononitrile were stirred and refluxed at 110° C. for 5 hours, and the reaction solution was cooled to room temperature. The reaction solution was added to a beaker containing 1000 ml of purified water, stirred at room temperature to precipitate solid, and filtered. The filter cake was added to 100 ml of dioxane, refluxed and slurried for the first time at 122° C. for 2 hours, cooled to room temperature for crystallization, and filtered. The filter cake was added to 200 ml of a mixed solution of methanol and ethanol (the volume ratio of methanol to ethanol was 1:1), refluxed and slurried for the second time at 85° C. for 1.5 hours, cooled to room temperature for filtration, and the filter cake was dissolved in 600 g of N, N-dimethylformamide by reflux, and activated carbon was added to the obtained solution for decolorization for 1 hour. After the solution was hot filtered, the filtrate was added to a beaker containing 6000 g of purified water, stirred at room temperature for crystallization for 12 hours, and filtered. The filter cake was vacuum dried at 80° C. to obtain 12.8 g of an off-white solid, i.e., the target product LXH-1211.

[0061] Example 7

[0062] Add 200 ml of 1,4-dioxane and 200 ml of methanol to the reaction bottle, weigh 122 g of glacial acetic acid and add it to the reaction bottle, then add 30.0 g of iron powder, stir at room temperature for 1 hour to fully activate the iron powder, then add 30.0 g of compound I, stir at 35°C for 24 hours, monitor the reaction completion by TLC, stop the reaction, and obtain a reaction solution; filter the reaction solution, concentrate the filtrate under reduced pressure at 60°C, and use the concentrate directly in the next step without purification.

[0063] The concentrate, 100 ml of 1,4-dioxane, 100 ml of 2-methylpyridine and 9 g of malononitrile were stirred and refluxed at 130 ° C for 3 hours, and the reaction solution was cooled to room temperature. The reaction solution was added to a beaker containing 1000 ml of purified water, stirred at room temperature to precipitate solids, and filtered. The filter cake was added to 100 ml of dioxane, refluxed and beaten for the first time at 125 ° C for 1.2 hours, cooled to room temperature for crystallization and filtered, and the filter cake was added to 200 ml of a mixed solution of methanol and ethanol (the volume ratio of methanol to ethanol is 1:1), refluxed and beaten for the second time at 82 ° C for 2 hours, cooled to room temperature and filtered, and the filter cake was filtered through 600 g After N,N-dimethylformamide was refluxed and dissolved, activated carbon was added to the obtained solution for decolorization for 1 hour. After the solution was hot filtered, the filtrate was added to a beaker containing 6000 g of purified water. After stirring and crystallization at room temperature for 12 hours, it was filtered and the filter cake was vacuum dried at 80°C to obtain 9.28 g of off-white solid, i.e., the target product LXH-1211.

[0064] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing a sGC agonist, characterized in that The steps include: (1) adding acid and iron powder to a solvent and stirring to activate the mixture, then adding compound I to react to obtain a reaction solution; filtering the reaction solution and concentrating it under reduced pressure to obtain a concentrate; Wherein, the structural formula of compound I is as follows: ； (2) the concentrate obtained in step (1) is reacted with malononitrile under reflux in a solvent and the temperature is cooled to room temperature to obtain a reaction solution; (3) adding the reaction solution to water, stirring at room temperature to precipitate solids, filtering, adding the obtained filter cake to 1,4-dioxane for the first reflux beating, cooling to room temperature for crystallization, filtering, adding the obtained filter cake to a mixed solution of methanol and ethanol for the second reflux beating, cooling to room temperature for filtration, adding the obtained filter cake to a decolorizing solvent for reflux dissolution, adding activated carbon to the obtained solution for decolorization, filtering, and obtaining a filtrate; (4) The filtrate obtained in step (3) was added to water and stirred at room temperature for crystallization, filtered, and the obtained filter cake was vacuum dried to obtain the sGC agonist LXH-1211, the structural formula of which is as follows: ； The acid in step (1) is glacial acetic acid; In step (1), the ratio of compound I, acid, iron powder and solvent is 1:4-4.2:0.5-2.0:400, wherein compound I is measured in g, acid is measured in g, iron powder is measured in g, and solvent is measured in ml; In step (1), the activation time is 1-1.5 hours; the reaction temperature is 20-50°C, and the reaction time is 23-25 ​​hours; The mass ratio of malononitrile in step (2) to compound I in step (1) is 1-4:10; In step (2), the reaction temperature is 100-130° C. and the reaction time is 2.5-5 hours.

2. The method for synthesizing the sGC agonist according to claim 1, characterized in that The solvent in step (1) is one or both of 1,4-dioxane and methanol.

3. The method for synthesizing the sGC agonist according to claim 1, characterized in that The solvent in step (2) is one or two of 1,4-dioxane, methanol or 2-methylpyridine; the ratio of the solvent to the compound I in step (1) is 6-7.5:1, wherein the solvent is measured in ml and the compound I is measured in g.

4. The method for synthesizing the sGC agonist according to claim 1, characterized in that In step (3), the first reflux beating temperature is 120-125° C., and the first reflux beating time is 1-2 hours.

5. The method for synthesizing the sGC agonist according to claim 1, characterized in that In step (3), the second reflux beating temperature is 80-85° C., and the second reflux beating time is 1-2 hours.

6. The method for synthesizing the sGC agonist according to claim 1, characterized in that The decolorizing solvent in step (3) is N,N-dimethylformamide.

Images