A method for preparing a Vericiguat intermediate

Abstract

The present invention provides a method for preparing a Vericiguat intermediate, and relates to the field of medical technology. The present invention uses 2-chloro-5-fluoronicotinonitrile and 2-fluorobenzylhydrazine as initial raw materials, undergoes a condensation cyclization reaction, and then undergoes a diazotization reaction with a diazotizing agent, and then undergoes a Sandmeyer reaction with a cyanide salt to prepare a Vericiguat intermediate-5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone-[3,4-B]pyridine-3-carbonitrile. The preparation method provided by the present invention has a short synthetic route, a high total yield of the target product, simple operation, low production cost, green environmental protection, and is suitable for industrial production. As shown in the test results of the embodiment, the total yield of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone-[3,4-B]pyridine-3-carbonitrile of the preparation method provided by the present invention is above 71.5%, and the purity is above 98.5%.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a method for preparing a vericipiracil intermediate. Background Art

[0002] Heart failure is a complex clinical syndrome with high global morbidity and mortality. Studies have shown that the 5-year survival rate of heart failure is worse than that of some cancers, but it has not received the same attention as cancer, which has delayed the treatment of the disease. Chronic diseases such as hypertension, diabetes, and coronary heart disease are prone to cause heart failure. Vericigum is a soluble guanylate cyclase (sGC) stimulator. Its mechanism of action is to directly stimulate sGC, increase the level of intracellular cGMP, thereby relaxing smooth muscles and dilating blood vessels, further reducing cardiovascular mortality and the risk of heart failure.

[0003] 5-Fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile is a key intermediate in the synthesis of vericiguat. Markus Follmann et al. (Follmann M, Ackerstaff J, Redlich G, et al. Discovery of the soluble guanylate cyclase stimulator vericiguat (BAY 1021189) for the treatment of chronic heart failure [J]. Journal of medicinal chemistry, 2017, 60(12): 5146-5161.) reported a method for preparing 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile. The target intermediate was obtained by 7 steps of reaction using tetrafluoropropanol as the starting material. The reaction route is shown in Formula 1:

[0004]

[0005] Patent WO2011147810A1 discloses that 2-chloro-5-fluoronicotinonitrile is used as a starting material, reacted with hydrazine hydrate to generate 3-amino-5-fluoro-1H-pyrazolo[3,4-B]pyridine, and then subjected to a diazotization reaction to obtain an intermediate 5-fluoro-3-iodo-7-azaindazole, which is then reacted with 2-fluorobenzyl bromide to obtain 5-fluoro-1-(2-fluorophenyl)-3-iodo-1H-pyrazolone[3,4-b]pyridine, and finally reacted with cuprous cyanide to generate a key intermediate 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile. The reaction route is shown in Formula 2:

[0006]

[0007] U.S. Patent US20130338137A1 discloses a method for preparing 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile, and the reaction route is shown in Formula 3:

[0008]

[0009] However, the above-mentioned synthesis methods generally have the problems of long reaction route and low total product yield (29.6-36%). Summary of the invention

[0010] In view of this, the object of the present invention is to provide a method for preparing a vericipiracil intermediate. The preparation method provided by the present invention has a short reaction route and a high total yield of the product.

[0011] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0012] The present invention provides a method for preparing a Vericiguat intermediate, comprising the following steps:

[0013] Mixing 2-chloro-5-fluoronicotinonitrile, 2-fluorobenzylhydrazine, a first cuprous catalyst, an alkaline agent, a ligand and an organic solvent to carry out a condensation cyclization reaction to obtain compound II;

[0014] The compound II is mixed with a diazotizing agent, an inorganic acid and water to carry out a diazotizing reaction, and the pH value is adjusted to 6.5 to 7.5 to obtain a diazotizing reaction solution; the diazotizing reaction solution is mixed with a cyanide salt and a second cuprous catalyst to carry out a Sandmeyer reaction to obtain a Vericiguat intermediate having a structure shown in Formula I;

[0015]

[0016] Preferably, the molar ratio of 2-chloro-5-fluoronicotinonitrile to 2-fluorobenzylhydrazine is 1:1 to 2.5.

[0017] Preferably, the first cuprous catalyst comprises cuprous iodide;

[0018] The molar ratio of the 2-chloro-5-fluoronicotinonitrile to the first cuprous catalyst is 1:0.01-0.1.

[0019] Preferably, the complexing agent comprises 1,10-phenanthroline;

[0020] The molar ratio of the 2-chloro-5-fluoronicotinonitrile to the complexing agent is 1:0.1-0.5.

[0021] Preferably, the organic solvent includes at least one of an amide solvent, a benzene solvent and a sulfone solvent.

[0022] Preferably, the temperature of the condensation cyclization reaction is 60-100° C., and the time is 4-6.5 h.

[0023] Preferably, the molar ratio of the compound II to the diazotizing agent is 1:1 to 2.5.

[0024] Preferably, the second cuprous catalyst comprises cuprous cyanide;

[0025] The molar ratio of the compound II to the second cuprous catalyst is 1:1 to 1.5.

[0026] Preferably, the cyanide salt comprises potassium cyanide and / or sodium cyanide;

[0027] The molar ratio of the compound II to the cyanide salt is 1:1.2-3.

[0028] Preferably, the temperature of the diazotization reaction is -5 to 5°C, the temperature of the Sandmeyer reaction is 60 to 80°C, and the time of the diazotization reaction and the Sandmeyer reaction is independently 10 to 40 minutes.

[0029] The present invention provides a method for preparing a Vericipirat intermediate, comprising the following steps: mixing 2-chloro-5-fluoronicotinonitrile, 2-fluorobenzylhydrazine, a first cuprous catalyst, an alkaline reagent, a ligand and an organic solvent, and performing a condensation cyclization reaction to obtain a compound II; mixing the compound II with a diazotizing agent, an inorganic acid and water, performing a diazotization reaction, and adjusting the pH value to 6.5 to 7.5 to obtain a diazotization reaction liquid; mixing the diazotization reaction liquid with a cyanide salt and a second cuprous catalyst, and performing a Sandmeyer reaction to obtain a Vericipirat intermediate having a structure shown in Formula I. The present invention uses 2-chloro-5-fluoronicotinonitrile and 2-fluorobenzylhydrazine as initial raw materials, performs a condensation cyclization reaction, and then performs a diazotization reaction with a diazotizing agent, and then performs a Sandmeyer reaction with a cyanide salt to prepare a Vericipirat intermediate—5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile. The preparation method provided by the present invention has a short synthetic route, a high total yield of the target product, simple operation, low production cost, green environmental protection, and is suitable for industrial production. As shown in the test results of the embodiment, the total yield of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone-[3,4-B]pyridine-3-carbonitrile in the preparation method provided by the present invention is above 71.5%, and the purity is above 98.5%. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The hydrogen spectrum of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile prepared in Example 1;

[0031] Figure 2 The mass spectrum of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile prepared in Example 1;

[0032] Figure 3 This is the infrared spectrum of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile prepared in Example 1. DETAILED DESCRIPTION

[0033] The present invention provides a method for preparing a Vericiguat intermediate, comprising the following steps:

[0034] Mixing 2-chloro-5-fluoronicotinonitrile, 2-fluorobenzylhydrazine, a first cuprous catalyst, an alkaline agent, a ligand and an organic solvent to carry out a condensation cyclization reaction to obtain compound II;

[0035] The compound II is mixed with a diazotizing agent, an inorganic acid and water to carry out a diazotizing reaction, and the pH value is adjusted to 6.5 to 7.5 to obtain a diazotizing reaction solution; the diazotizing reaction solution is mixed with a cyanide salt and a second cuprous catalyst to carry out a Sandmeyer reaction to obtain a Vericiguat intermediate having a structure shown in Formula I;

[0036]

[0037] In the present invention, unless otherwise specified, all raw material components are commercially available products well known to those skilled in the art.

[0038] The present invention mixes 2-chloro-5-fluoronicotinonitrile, 2-fluorobenzylhydrazine, a first cuprous catalyst, an alkaline reagent, a ligand and an organic solvent (referred to as a first mixture) and performs a condensation cyclization reaction to obtain a compound II (named 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-amine).

[0039] In the present invention, the molar ratio of 2-chloro-5-fluoronicotinonitrile to 2-fluorobenzylhydrazine is preferably 1:1-2.5, more preferably 1:1.5-2.

[0040] In the present invention, the first cuprous catalyst preferably includes cuprous iodide; the molar ratio of the 2-chloro-5-fluoronicotinonitrile to the first cuprous catalyst is preferably 1:0.01-0.1, more preferably 1:0.05-0.075.

[0041] In the present invention, the alkaline agent preferably includes cesium carbonate; the molar ratio of the 2-chloro-5-fluoronicotinonitrile to the alkaline agent is preferably 1:1-3, more preferably 1:1.4-2.

[0042] In the present invention, the complexing agent preferably includes 1,10-phenanthroline; the molar ratio of the 2-chloro-5-fluoronicotinonitrile to the complexing agent is preferably 1:0.1-0.5, more preferably 1:0.1-0.2.

[0043] In the present invention, the organic solvent preferably includes at least one of an amide solvent, a benzene solvent and a sulfone solvent, more preferably includes at least one of N,N-dimethylformamide (DMF), toluene and dimethyl sulfoxide (DMSO), and further preferably N,N-dimethylformamide. In the present invention, the ratio of the amount of the substance of 2-chloro-5-fluoronicotinonitrile to the volume of the organic solvent is preferably 1 mol: 2.5 to 5 L, more preferably 1 mol: 3 to 4.5 L.

[0044] The present invention has no special limitation on the first mixing, as long as the raw materials can be mixed evenly, such as stirring and mixing.

[0045] In the present invention, the temperature of the condensation cyclization reaction is preferably 60 to 100° C., more preferably 80 to 90° C.; the time of the condensation cyclization reaction is preferably 4 to 6.5 h, more preferably 4.5 to 5 h.

[0046] After the condensation cyclization reaction, the present invention preferably further comprises post-treatment, and the post-treatment preferably comprises: cooling the obtained condensation cyclization reaction liquid to room temperature and mixing it with water, extracting, drying the obtained organic phase with a desiccant, separating the solid and the liquid, concentrating the obtained liquid component and drying it to obtain compound II. The present invention has no special limitation on the cooling, and a cooling method well known to those skilled in the art can be adopted, such as natural cooling. In the present invention, the ratio of the amount of the substance of 2-chloro-5-fluoronicotinonitrile to the volume of water is preferably 1 mol: 2 to 8 L, more preferably 1 mol: 2.5 to 7 L. In the present invention, the organic solvent for extraction preferably comprises at least one of dichloromethane, ethyl acetate and toluene, more preferably dichloromethane, ethyl acetate or toluene; the number of extractions is preferably 1 to 5 times, more preferably 3 times; the ratio of the amount of the substance of 2-chloro-5-fluoronicotinonitrile to the volume of the organic solvent for a single extraction is preferably 1 mol: 0.5 to 3 L, more preferably 1 mol: 0.5 to 2 L. In the present invention, the desiccant preferably includes anhydrous sodium sulfate and / or anhydrous magnesium sulfate, more preferably anhydrous magnesium sulfate or anhydrous sodium sulfate. The present invention has no special limitation on the solid-liquid separation, and a solid-liquid separation method well known to those skilled in the art may be adopted, such as filtration or suction filtration. The present invention has no special limitation on the concentration, and a concentration method well known to those skilled in the art may be adopted, such as reduced pressure distillation. In the present invention, the drying temperature is preferably 35 to 65°C, more preferably 40 to 60°C; the present invention has no special limitation on the drying time, and drying to constant weight may be adopted.

[0047] After obtaining compound II, the present invention mixes the compound II with a diazotization reagent, an inorganic acid and water (referred to as the second mixing), performs a diazotization reaction, and adjusts the pH value to 6.5 to 7.5 to obtain a diazotization reaction liquid; the diazotization reaction liquid is mixed with a cyanide salt and a second cuprous catalyst (referred to as the third mixing), and performs a Sandmeyer reaction to obtain a Vericiguat intermediate (5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile) having a structure shown in formula I.

[0048] In the present invention, the diazotizing agent preferably includes at least one of sodium nitrite, tert-butyl nitrite and isoamyl nitrite, more preferably sodium nitrite, tert-butyl nitrite or isoamyl nitrite; the molar ratio of the compound II to the diazotizing agent is preferably 1:1-2.5, preferably 1:1.05-1.5.

[0049] In the present invention, the inorganic acid preferably includes concentrated hydrochloric acid or dilute sulfuric acid; the concentration of the concentrated hydrochloric acid is preferably 35-37.5wt%, more preferably 36-37wt%; the concentration of the dilute sulfuric acid is preferably 25-50wt%, more preferably 30-40wt%. In the present invention, the molar ratio of the compound II to the inorganic acid is preferably 1:3.5-7, more preferably 1:4-6.

[0050] In the present invention, the ratio of the amount of the compound II to the volume of water is preferably 1 mol: 4-8L, more preferably 1 mol: 5-7L.

[0051] The second mixing is not particularly limited in the present invention, and the raw materials can be mixed uniformly, such as stirring. In the present invention, the order of the second mixing is preferably: mixing compound II with a diazotizing agent and water, cooling to -5 to 5°C, and then dropping an inorganic acid to mix; the temperature after cooling is more preferably -5 to 0°C.

[0052] In the present invention, the temperature of the diazotization reaction is preferably -5 to 5°C, more preferably -5 to 0°C; the time of the diazotization reaction is preferably 10 to 40 min, more preferably 20 to 30 min.

[0053] In the present invention, the pH value is preferably adjusted using an alkaline reagent, the alkaline reagent preferably includes carbonate and / or bicarbonate, the carbonate preferably includes at least one of potassium carbonate, sodium carbonate and cesium carbonate; the bicarbonate preferably includes at least one of sodium bicarbonate and potassium bicarbonate. In the present invention, the pH value of the diazotization reaction solution is 6.5 to 7.5, preferably 7.

[0054] In the present invention, the cyanide salt preferably includes potassium cyanide and / or sodium cyanide, more preferably potassium cyanide or sodium cyanide; the molar ratio of the compound II to the cyanide salt is preferably 1:1.2-3, more preferably 1:2.5-2.8. In the present invention, the cyanide salt is preferably used in a cyanide salt-soluble form, and the concentration of the cyanide salt aqueous solution is preferably 0.3-0.8 mol / L, more preferably 0.45-0.65 mol / L.

[0055] In the present invention, the second cuprous catalyst preferably includes cuprous cyanide; the molar ratio of the compound II to the second cuprous catalyst is preferably 1:1 to 1.5, more preferably 1:1 to 1.2. In the present invention, the second cuprous catalyst is preferably used in the form of a second cuprous catalyst water-soluble, and the concentration of the second cuprous catalyst aqueous solution is preferably 0.1 to 0.3 mol / L, more preferably 0.15 to 0.25 mol / L.

[0056] The present invention has no special limitation on the third mixing, and the raw materials can be mixed evenly, such as stirring. In the present invention, the order of the third mixing is preferably: mixing the diazotization reaction solution with the cyanide salt and the cyanide salt-second cuprous catalyst mixed aqueous solution.

[0057] In the present invention, the temperature of the Sandmeyer reaction is preferably 60 to 80° C., more preferably 70 to 75° C.; the time of the Sandmeyer reaction is preferably 10 to 40 min, more preferably 20 to 30 min.

[0058] After the Sandmeyer reaction, the present invention preferably further includes post-treatment, and the post-treatment preferably includes: cooling the obtained Sandmeyer reaction solution to room temperature and mixing it with water, extracting, washing the obtained organic phase with water, washing with saturated salt water, drying with a desiccant and separating the solid and liquid in sequence, concentrating the obtained liquid component, and drying the obtained crude product after recrystallization to obtain a Vericiguat intermediate having a structure shown in Formula I. The present invention does not specifically limit the cooling, and a cooling method familiar to those skilled in the art can be used, such as natural cooling. In the present invention, the organic solvent for extraction preferably includes at least one of dichloromethane, ethyl acetate and toluene, more preferably dichloromethane, ethyl acetate or toluene; the number of extractions is preferably 1 to 5 times, more preferably 3 times; the ratio of the amount of the substance of the compound II to the volume of the organic solvent for a single extraction is preferably 1 mol: 2 to 4 L, more preferably 1 mol: 3 to 3.5 L. In the present invention, the number of water washings is preferably 1 to 3 times, more preferably 2 times; the ratio of the amount of the compound II to the volume of water for a single water washing is preferably 1 mol: 2 to 4 L, more preferably 1 mol: 3 to 3.5 L. In the present invention, the ratio of the amount of the compound II to the volume of saturated brine for saturated brine washing is preferably 1 mol: 2 to 4 L, more preferably 1 mol: 3 to 3.5 L. In the present invention, the desiccant preferably includes anhydrous sodium sulfate and / or anhydrous magnesium sulfate, more preferably anhydrous magnesium sulfate or anhydrous sodium sulfate. The present invention has no special limitation on the solid-liquid separation, and a solid-liquid separation method well known to those skilled in the art can be used, such as filtration or suction filtration. The present invention has no special limitation on the concentration, and a concentration method well known to those skilled in the art can be used, such as reduced pressure distillation. The present invention has no special restrictions on the solvent for recrystallization, and a solvent for crystallizing 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile known to those skilled in the art can be used, such as one or more of ethyl acetate, isopropanol and methyl tert-butyl ether. In the present invention, the drying temperature is preferably 35 to 65°C, more preferably 40 to 60°C; the present invention has no special restrictions on the drying time, and drying to constant weight is sufficient.

[0059] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0060] Example 1

[0061] The Vericipiracil intermediate was prepared according to the following reaction scheme:

[0062]

[0063] (1) Preparation of 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0064] To a 250 mL three-necked flask with mechanical stirring, 15 mmol 2-chloro-5-fluoronicotinonitrile, 0.75 mmol cuprous iodide, 21 mmol cesium carbonate, 1.5 mmol 1,10-phenanthroline (o-phen), 50 mL N,N-dimethylformamide (DMF) and 22.5 mmol 2-Fluorobenzylhydrazine was heated to 80°C for condensation and cyclization reaction for 5h (HPLC tracking showed that the reaction was complete), cooled to room temperature (25°C), the solvent was removed under reduced pressure, 100mL of water was added, and 30mL of dichloromethane was added each time for extraction, and the extraction was performed 3 times (recorded as 3×30mL). The organic phases were combined and dried over anhydrous magnesium sulfate, and the magnesium sulfate was filtered out. The organic solvent was recovered from the obtained liquid component under reduced pressure, and dried at 45°C to constant weight to obtain 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-amine (3.45g), which was directly used in the next step without purification.

[0065] (2) Preparation of Vericiguat Intermediate—5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile

[0066] 10 mmol of the 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-amine, 10.9 mmol of sodium nitrite and 50 mL of water were added to a round-bottom flask, the flask was cooled to 0°C, 6 mL of 35 wt% concentrated hydrochloric acid was added dropwise, the resulting mixture was diazotized at 0°C with stirring for 30 min, the pH value was adjusted to 7 with potassium carbonate, and the mixture was transferred to 50 mL of a mixed aqueous solution containing 25 mmol of freshly prepared potassium cyanide and 11.9 mmol of cuprous cyanide, and the reaction was carried out at 70°C with stirring for 1 h by Sandmeyer reaction, cooled to room temperature, and ethyl acetate was added. The mixture was extracted with ester for 3 times (each time with 30 mL of ethyl acetate), washed with water for 2 times (each time with 30 mL of water), washed with saturated brine once (30 mL), dried over anhydrous magnesium sulfate, filtered to remove magnesium sulfate, and the obtained liquid component was decompressed to recover the organic solvent. The obtained crude product was recrystallized using isopropanol solvent, and the obtained crystals were dried at 45°C to constant weight to obtain 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile (off-white solid, 2.2 g, the total yield of the two-step reaction of steps (1) to (2) was 72.4%, and the purity was 98.8%).

[0067] Hydrogen spectrum data of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile: 1 HNMR (400MHz, d 6 -DMSO): δ=8.89(dd,1H),8.55(dd,1H),7.18-7.42(m,4H),5.88(s,2H).

[0068] Figure 1 The hydrogen spectrum of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile prepared in Example 1, Figure 2 The mass spectrum of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile prepared in Example 1 is shown in FIG. Figure 3 This is the infrared spectrum of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile prepared in Example 1. Figures 1 to 3 It can be seen that the present invention successfully prepared 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile.

[0069] Example 2

[0070] (1) Preparation of 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0071] To a 1000 mL three-necked flask with mechanical stirring, 60 mmol 2-chloro-5-fluoronicotinonitrile, 4.5 mmol cuprous iodide, 101 mmol cesium carbonate, 9 mmol 1,10-phenanthroline (o-phen), 250 mL N,N-dimethylformamide (DMF) and 72 mmol 2-fluorobenzylhydrazine were added in sequence, the temperature was raised to 85°C for condensation cyclization reaction for 4.5 h (HPLC tracking showed that the reaction was complete), cooled to room temperature (25°C), the solvent was removed under reduced pressure, 150 mL of water was added, and dichloromethane was extracted 3 times (30 mL of dichloromethane was used for each extraction), the organic phases were combined and dried over anhydrous magnesium sulfate, the magnesium sulfate was filtered off, the obtained liquid component was subjected to reduced pressure to recover the organic solvent, and dried at 45°C to constant weight to obtain 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-amine (13.2 g), and the product was directly used in the next reaction without purification.

[0072] (2) Preparation of Vericiguat Intermediate—5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile

[0073] 30.0 mmol of the 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-amine, 38 mmol of sodium nitrite and 200 mL of water were added to a round-bottom flask, the flask was cooled to -5°C, 22 mL of 35 wt% concentrated hydrochloric acid was added dropwise, the resulting mixture was diazotized at 0°C with stirring for 30 min, the pH value was adjusted to 7 with potassium carbonate, and the mixture was transferred to 180 mL of a mixed aqueous solution containing 82.5 mmol of freshly prepared potassium cyanide and 30.3 mmol of cuprous cyanide, and the Sandmeyer reaction was carried out at 75°C with stirring for 1 h, cooled to room temperature, and acetic acid was added. The mixture was extracted with ethyl ester three times (180 mL of ethyl acetate was used for each extraction), washed with water twice (180 mL of water was used for each wash), washed with saturated brine once (180 mL), dried over anhydrous magnesium sulfate, filtered to remove magnesium sulfate, and the obtained liquid component was decompressed to recover the organic solvent. The obtained crude product was recrystallized using isopropanol solvent, and the obtained crystals were dried at 45°C to constant weight to obtain 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile (off-white solid, 6.82 g, the total yield of the two-step reaction of steps (1) to (2) was 71.65%, and the purity was 98.5%).

[0074] Hydrogen spectrum data of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile: 1 HNMR (400MHz, d 6 -DMSO): δ=8.89(dd,1H),8.55(dd,1H),7.18-7.42(m,4H),5.88(s,2H).

[0075] Comparative Example 1

[0076] (1) Preparation of 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0077] To a 250 mL three-necked flask with mechanical stirring, 10 mmol 2-chloro-5-fluoronicotinonitrile, 15 mmol cesium carbonate, 35 mL N,N-dimethylformamide (DMF) and 15 mmol 2-fluorobenzylhydrazine were added in sequence, the temperature was raised to 80°C for condensation and cyclization reaction for 6 h (HPLC tracking showed that the reaction was complete), cooled to room temperature (25°C), the solvent was removed under reduced pressure, 60 mL of water was added, and 20 mL of dichloromethane was added each time for extraction, and the extraction was performed 3 times (recorded as 3×30 mL), the organic phases were combined and dried over anhydrous magnesium sulfate, the magnesium sulfate was filtered off, and the obtained liquid component was decompressed to recover the organic solvent, the crude product was recrystallized with isopropanol, and dried at 45°C to constant weight to obtain 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-amine (0.95 g) with a yield of 36%.

[0078] (2) Preparation of Vericiguat Intermediate—5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile

[0079] 3.65 mmol of the 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-amine, 4 mmol of sodium nitrite and 35 mL of water were added to a round-bottom flask, the flask was cooled to 0°C, 2.5 mL of 35 wt% concentrated hydrochloric acid was added dropwise, the resulting mixture was diazotized for 30 min at -5 to 0°C with stirring, the pH value was adjusted to 7 with potassium carbonate, and the mixture was transferred to 20 mL of a mixed aqueous solution containing 9 mmol of freshly prepared potassium cyanide and 4.4 mmol of cuprous cyanide, and the mixture was subjected to a Sandmeyer reaction at 75°C with stirring for 0.5 h, and then cooled to room temperature. The mixture was extracted with ethyl acetate three times (15 mL of ethyl acetate for each extraction), washed with water twice (30 mL of water for each wash), washed with saturated brine once (30 mL), and dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered out and the obtained liquid component was decompressed to recover the organic solvent. The obtained crude product was recrystallized with isopropanol solvent and the obtained crystals were dried at 45°C to constant weight to obtain 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile (off-white solid, 0.85 g, the total yield of the two-step reaction of steps (1) to (2) was 31%, and the purity was 99.2%).

[0080] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing a Vericiguat intermediate, characterized in that: The following steps are involved: 2-chloro-5-fluoronicotinonitrile, 2-fluorobenzylhydrazine, a first cuprous catalyst, an alkaline reagent, a ligand and an organic solvent are mixed to carry out a condensation cyclization reaction to obtain compound II; the first cuprous catalyst is cuprous iodide; the ligand is 1,10-phenanthroline; The compound II is mixed with a diazotization reagent, an inorganic acid and water to carry out a diazotization reaction, and the pH value is adjusted to 6.5 to 7.5 to obtain a diazotization reaction solution; The diazotization reaction solution is mixed with a cyanide salt and a second cuprous catalyst to perform a Sandmeyer reaction to obtain a Vericiguat intermediate having a structure shown in Formula I; the cyanide salt is potassium cyanide and / or sodium cyanide; and the second cuprous catalyst is cuprous cyanide; 2. The preparation method according to claim 1, characterized in that: The molar ratio of the 2-chloro-5-fluoronicotinonitrile to 2-fluorobenzylhydrazine is 1:1 to 2.

5.

3. The preparation method according to claim 1, characterized in that: The molar ratio of the 2-chloro-5-fluoronicotinonitrile to the first cuprous catalyst is 1:0.01-0.

1.

4. The preparation method according to claim 1, characterized in that: The molar ratio of the 2-chloro-5-fluoronicotinonitrile to the complexing agent is 1:0.1-0.

5.

5. The preparation method according to claim 1, characterized in that: The organic solvent is at least one of an amide solvent, a benzene solvent and a sulfone solvent.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The temperature of the condensation cyclization reaction is 60-100° C., and the time is 4-6.5 hours.

7. The preparation method according to claim 1, characterized in that: The molar ratio of the compound II to the diazotizing agent is 1:1-2.

5.

8. The preparation method according to claim 1, characterized in that: The molar ratio of the compound II to the second cuprous catalyst is 1:1 to 1.

5.

9. The preparation method according to claim 1, characterized in that: The molar ratio of the compound II to the cyanide salt is 1:1.2-3.

10. The preparation method according to claim 1, 7, 8 or 9, characterized in that: The temperature of the diazotization reaction is -5 to 5°C, the temperature of the Sandmeyer reaction is 60 to 80°C, and the time of the diazotization reaction and the Sandmeyer reaction is independently 10 to 40 minutes.

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