Process for the preparation of vericiguat and intermediates thereof
By reacting aminomalononitrile with methyl chloroformate and then performing basic cyclization, bromination, and coupling with pinacol diboronic acid ester, the high cost and safety risks in the synthesis of veliciguat are solved, providing a safe and low-cost preparation method.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SHANDONG QIDU PHARMA
- Filing Date
- 2026-02-26
- Publication Date
- 2026-07-10
Smart Images
Figure QLYQS_1 
Figure QLYQS_2 
Figure QLYQS_3
Abstract
Description
Technical Field
[0001] This invention belongs to the field of velixicam synthesis, specifically relating to the preparation method of velixicam and its intermediate products. Background Technology
[0002] Vericiguat, chemically known as N-[4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-B]pyridin-3-yl]pyrimidin-5-yl]carbamate, is a soluble guanylate cyclase (sGC) stimulant that improves cardiovascular function by enhancing sGC activity, promoting the production of cyclic guanosine monophosphate (cGMP).
[0003] This treatment is indicated for adult patients with symptomatic chronic heart failure whose condition has stabilized after recent decompensation of heart failure with intravenous therapy and who have reduced ejection fraction (<45%), in order to reduce the risk of hospitalization for heart failure or the need for emergency intravenous diuretic therapy.
[0004] Its structural formula is as follows:
[0005] .
[0006] Currently, there are three synthetic routes for veliximab:
[0007] (1) Patent CN102939289A reported the first synthetic route, as shown below: Compound 1 and Compound 2 react under a palladium catalyst to obtain Compound 3. Compound 3 is then reduced by hydrogen to obtain Compound 4. Finally, it reacts with methyl chloroformate to obtain velixigua.
[0008] .
[0009] This route involves two steps using palladium catalysts, which are expensive; and the first step, condensation, has a low yield of only 24%. Compound 2 is currently not a mature technology in the market and is also expensive; the use of hydrogen to catalyze the reduction of nitro groups is cumbersome, and hydrogen is flammable and explosive, posing safety risks in production.
[0010] (2) The above-mentioned patent CN102939289A also reported a second synthetic route, as shown below. Starting with compound 5, compound 6 is obtained by cyano hydrolysis. Compound 6 is then cyclized with compound 7 under alkaline conditions to prepare compound 8. Compound 8 is then hydrogenated to obtain compound 4. Finally, compound 4 is reacted with methyl chloroformate to obtain velixigua.
[0011] .
[0012] This route uses palladium on carbon as a catalyst for the hydrogen reaction, which is expensive. Hydrogen is flammable and explosive, making production difficult and posing safety risks. Furthermore, the generation of the byproduct aniline puts pressure on subsequent impurity removal, increasing product costs.
[0013] (3) Patent CN115160312A reported a third synthetic route, as shown below, starting with compound 9 as the starting material and N,N-dimethylformamide as the solvent, reacting with malononitrile and sodium nitrite to generate compound 10. Compound 10 is reduced by sodium hydrosulfite to obtain compound 4, and then reacted with ethyl chloroformate to obtain velixigua.
[0014] .
[0015] This route avoids the use of heavy metals to catalyze the reduction of nitrosamines with hydrogen, which introduces aniline as a byproduct. However, the first step of the reaction uses N,N-dimethylformamide and sodium nitrite, which produces N-nitrosodimethylamine. N-nitrosodimethylamine is a potent carcinogen that can induce lung and liver cancer. The introduction of this impurity poses a significant challenge to the subsequent purification of velixiguat, making the purification process complex and ultimately impacting product costs.
[0016] Therefore, finding a simple, low-cost, and safe method for producing velixigua is an urgent technical problem to be solved in this field. Summary of the Invention
[0017] To address the aforementioned technical problems, this invention provides a method for preparing velixika, which is simple to operate, low in cost, and safe in production. This invention also provides the intermediate product obtained by the above preparation method.
[0018] Perform inverse synthesis analysis using the following formula:
[0019] ;
[0020] ;
[0021] .
[0022] Structural analysis of veliciguat reveals that the molecule can be divided into two segments, corresponding to synthon 1 and synthon 2, respectively. These correspond to two compounds: 5-fluoro-1-(2-fluorobenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridine and methyl [(4,6-diamino-2-boronatepyrimidin-5-yl)amino]carbamate. These two compounds can be used to construct veliciguat via the classic Suzuki coupling reaction. 5-fluoro-1-(2-fluorobenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridine is commercially available, while methyl [(4,6-diamino-2-boronatepyrimidin-5-yl)amino]carbamate is a compound not found in existing literature. Methyl [(4,6-diamino-2-bromopyrimidine-5-yl)amino]formate can be obtained by reacting methyl [(4,6-diamino-2-bromopyrimidine-5-yl)amino]formate with a boron reagent; methyl [(4,6-diamino-2-bromopyrimidine-5-yl)amino]formate can be obtained by brominating methyl [(4,6-diaminopyrimidine-5-yl)amino]formate with NBS; methyl [(4,6-diaminopyrimidine-5-yl)amino]formate can be divided into two parts at positions a and b based on its molecular structure, and can be reacted with formamidinium and methyl [(dicyanomethyl)amino]formate as reagents, while methyl [(dicyanomethyl)amino]formate can be obtained by reacting aminomalononitrile with methyl chloroformate. Based on the above analysis, the following synthetic route is proposed:
[0023] .
[0024] Unless otherwise specified, for compounds listed in this invention, if there is a conflict between the name and the structural formula, the structural formula shall prevail, except for those with obvious errors in the structural formula.
[0025] The method for preparing velixivaline according to the present invention includes the following steps:
[0026] (1) Aminomalononitrile reacts with methyl chloroformate to produce intermediate product one.
[0027] ;
[0028] (2) Intermediate product one undergoes cyclization with formamidin under alkaline conditions to give intermediate product two.
[0029] ;
[0030] (3) Intermediate product two undergoes a bromination reaction with N-bromosuccinimide (NBS) to yield intermediate product three.
[0031] ;
[0032] (4) Intermediate product three reacts with pinacol diboronic acid ester under the action of a catalyst to give intermediate product four.
[0033] ;
[0034] (5) The intermediate tetra was reacted with 5-fluoro-1-(2-fluorobenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridine (SM3) to prepare veliciguanidine.
[0035] .
[0036] Preferably, in step (1), the molar ratio of aminomalononitrile to methyl chloroformate is 1:(1-2); the reaction temperature is -10℃ to 40℃, more preferably 0-10℃.
[0037] Preferably, in step (2), the alkaline conditions are achieved by adding an alkaline reagent, which is sodium methoxide, sodium ethoxide, or sodium tert-butoxide, more preferably sodium tert-butoxide; the reaction temperature is 90℃-130℃, preferably 100℃-110℃; and the reaction time is 2-10h, more preferably 5h.
[0038] Preferably, the molar ratio of intermediate product 2 to N-bromosuccinimide is 1:(1-2); the reaction temperature is 20℃-70℃, more preferably 30℃-40℃.
[0039] Preferably, the reaction solvent in steps (4) and (5) is one of toluene, n-heptane, and N,N-dimethylformamide, more preferably n-heptane.
[0040] Preferably, an alkaline reagent needs to be added in both steps (4) and (5). The alkaline reagent is one of potassium acetate, sodium acetate, potassium carbonate, and cesium carbonate, with potassium acetate being more preferred.
[0041] The present invention also provides intermediate products involved in the above preparation method, which can be used in the preparation method provided by the present invention.
[0042] The present invention also provides a compound with the following formula (i.e., intermediate product two in the above-mentioned method for preparing veliciguan):
[0043] .
[0044] The present invention also provides a compound with the following formula (i.e., intermediate product three in the above-mentioned method for preparing veliciguan):
[0045] .
[0046] The present invention also provides a compound represented by the following formula (i.e., intermediate product four in the above-described method for preparing veliciguan):
[0047] .
[0048] Compared with the prior art, the beneficial effects of the present invention are:
[0049] The advantages of this invention are: it directly uses aminomalononitrile to react with methyl chloroformate, avoiding the use of hydrogen reduction, making the operation simple, safe and hazard-free; the materials used in each step of the preparation process are all commercially available bulk materials, which are inexpensive and have low production costs.
[0050] The two-step coupling catalytic reaction in steps (4) and (5) of this invention has high selectivity, no toxic byproducts are generated, and it is easy to operate, which greatly reduces production costs and environmental pollution.
[0051] In summary, this invention provides a simple, low-cost, and safe method for preparing velixigua. Detailed Implementation
[0052] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments.
[0053] Unless otherwise specified, all raw materials used in the examples were commercially available.
[0054] The reaction route of this invention is as follows:
[0055] .
[0056] Example 1
[0057] The preparation method of the aforementioned velixivaline includes the following steps:
[0058] (1) Preparation of methyl [(dicyanomethyl)amino]formate (intermediate product 1)
[0059] Aminomalononitrile (50.00 g) was added to a reaction flask and dissolved in 400 mL of dichloromethane. Triethylamine (124.87 g) was added, and the mixture was stirred and cooled to -10 °C. A solution of methyl chloroformate (116.55 g) in dichloromethane (150 mL) was added dropwise. The reaction took about 0.5 h. The mixture was stirred at this temperature for another 4 h. The reaction was confirmed by TLC. The solution was washed three times with 20 mL of water each time. The organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain an oily substance. The oily substance was purified by column chromatography (PE / EA=4 / 1) to obtain 68.63 g of oily substance, with a yield of 80%.
[0060] Structure confirmation: 1H NMR (500 MHz, Chloroform-d) δ 5.90 (d, J = 9.0 Hz, 1H), 5.41 (d, J = 9.0 Hz, 1H), 3.80 (s, 3H).
[0061] (2) Preparation of methyl [(4,6-diaminopyrimidine-5-yl)amino]formate (intermediate product two)
[0062] Intermediate product 1 (65.00 g) and tetrahydrofuran (50 mL) were added to a reaction flask and stirred at 20 °C. Formamidin (27.17 g) was added and stirred for 10 min. Sodium methoxide (99.99 g) was added in portions over approximately 0.5 h. After the addition was complete, the temperature was raised to 90 °C and the reaction was allowed to proceed for 10 h. The reaction was monitored by TLC until it was complete. Dilute hydrochloric acid was added dropwise until the pH was approximately 9. The tetrahydrofuran was removed by vacuum distillation to obtain a pale yellow suspension. The suspension was filtered and washed with plenty of water. The filter cake was purified in an ethanol / water system to obtain 71.04 g of an off-white solid, with a yield of 83%.
[0063] Structure confirmation: 1H NMR (500 MHz, Chloroform-d) δ 8.63 (s, 1H), 8.12 (s, 1H), 5.98 (d, J = 1.3 Hz, 4H), 3.42 (s, 3H).
[0064] (3) Preparation of methyl [(4,6-diamino-2-bromopyrimidin-5-yl)amino]formate (intermediate product three)
[0065] Intermediate product 2 (70.00 g) was added to the reaction flask and dissolved in 560 mL of acetonitrile. The temperature was lowered to 0-10 °C, and NBS (102.02 g) was added in portions. After the addition was complete, the temperature was raised to 20 °C and the reaction was carried out for 6 h. The reaction was monitored by TLC until it was complete. 200 mL of 0.5% sodium bisulfite aqueous solution was added, and the mixture was stirred for 20 min. The acetonitrile was removed by concentration under reduced pressure. The mixture was extracted three times with DCM, 300 mL each time. The organic phases were combined, washed twice with water, and dried with anhydrous sodium sulfate. The solid obtained by concentration was slurried with n-heptane, filtered, and dried to obtain intermediate product 3 (82.12 g), with a yield of 82%.
[0066] Structure confirmation: 1H NMR (500 MHz, Chloroform-d) δ 8.85 (s, 1H), 6.98 (s, 2H), 6.80 (d, J = 8.6 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 3.61 (s, 3H).
[0067] (4) Preparation of methyl [(4,6-diamino-2-boronate pyrimidin-5-yl)amino]formate (intermediate product four)
[0068] Under nitrogen protection, 560 mL of toluene, intermediate product tris (70 g), pinacol diborate (81.36 g), palladium acetate (899 mg), tris(4-methoxyphenyl)phosphine (2.82 g), and potassium carbonate (3 eq) were added sequentially to the reaction flask. The mixture was refluxed for 2 h, and the reaction was completed by TLC. The mixture was filtered while hot, and the filtrate was stirred and cooled. Precipitation began at 40 °C. The filtrate was cooled to -5 °C and kept at this temperature for 2 h before filtration and drying to obtain 65.23 g of intermediate product tetras, with a yield of 79%.
[0069] Structure confirmation: 1H NMR (500 MHz, Chloroform-d) δ 8.56 (s, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 6.44 (d, J = 8.6 Hz, 1H), 3.86 (s, 3H), 0.98 (s, 12H).
[0070] (5) Preparation of velixivaline
[0071] Intermediate tetrakis (64 g) and n-heptane (512 mL) were added to the reaction flask. Under nitrogen protection, palladium acetate (697 mg), tris(4-methoxyphenyl)phosphine (2.19 g), potassium carbonate (85.86 g), and SM3 (77 g) were added. The mixture was heated to reflux and reacted for 3 h. The reaction was monitored by TLC until it was complete. The mixture was filtered while hot, and the filtrate was concentrated under reduced pressure until the solvent was removed. After concentration, isopropanol was added and the mixture was stirred at 70 °C for 2 h. The mixture was then cooled to 0 °C and filtered to obtain 75.92 g of virixazine, with a yield of 86%.
[0072] Structure confirmation: 1H NMR (500 MHz, DMSO-d6) δ 8.89-8.91 (dd, 1H), 8.66 (m, 1H), 8.00 (s, 1H), 7.34-7.37 (m, 1H), 7.21-7.26 (m, 1H), 7.12-7.18 (m, 2H), 6.22 (s, 4H), 5.79 (s, 2H), 3.62 (s, 3H); M+H=427.
[0073] Example 2
[0074] The preparation method of the aforementioned velixivaline includes the following steps:
[0075] (1) Preparation of methyl [(dicyanomethyl)amino]formate (intermediate product 1)
[0076] Aminomalononitrile (50.00 g) was added to a reaction flask and dissolved in 400 mL of dichloromethane. Triethylamine (124.87 g) was added, and the mixture was stirred and cooled to 0 °C. A solution of methyl chloroformate (87.41 g) in dichloromethane (150 mL) was added dropwise. The reaction took about 0.5 h. The mixture was stirred at this temperature for another 5 h. The reaction was confirmed by TLC. The solution was washed three times with 20 mL of water each time. The organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain an oily substance. The oily substance was purified by column chromatography (PE / EA=4 / 1) to obtain 70.35 g of oily substance, with a yield of 82%.
[0077] (2) Preparation of methyl [(4,6-diaminopyrimidine-5-yl)amino]formate (intermediate product two)
[0078] Intermediate product 1 (65.00 g) and tetrahydrofuran (50 mL) were added to a reaction flask and stirred at 20-25 °C. Formamidin (27.17 g) was added and stirred for 10 min. Sodium tert-butoxide (177.79 g) was added in portions over approximately 0.5 h. After the addition was complete, the temperature was raised to 130 °C and the reaction was allowed to proceed for 2 h. The reaction was monitored by TLC until complete. Dilute hydrochloric acid was added dropwise until the pH reached approximately 10. Tetrahydrofuran was removed by vacuum distillation, yielding a pale yellow suspension. The suspension was filtered and washed thoroughly with plenty of water. The filter cake was purified in an ethanol / water system to give 72.75 g of an off-white solid, with a yield of 85%. The theoretical yield was 85.59%.
[0079] (3) Preparation of methyl [(4,6-diamino-2-bromopyrimidin-5-yl)amino]formate (intermediate product three)
[0080] Intermediate product 2 (70.00 g) was added to the reaction flask and dissolved in 560 mL of acetonitrile. The temperature was lowered to 0-10 °C, and NBS (102.02 g) was added in portions. After the addition was complete, the temperature was raised to 40 °C and the reaction was carried out for 3 h. The reaction was monitored by TLC until it was complete. 200 mL of 0.5% sodium bisulfite aqueous solution was added, and the mixture was stirred for 20 min. The acetonitrile was removed by concentration under reduced pressure. The mixture was extracted three times with DCM, 300 mL each time. The organic phases were combined, washed twice with water, and dried with anhydrous sodium sulfate. The solid obtained by concentration was slurried with n-heptane, filtered, and dried to obtain intermediate product 3 (82.12 g), with a yield of 82%.
[0081] (4) Preparation of methyl [(4,6-diamino-2-boronate pyrimidin-5-yl)amino]formate (intermediate product four)
[0082] Under nitrogen protection, 560 mL of n-heptane, intermediate product tris (70 g), pinacol diborate (81.36 g), palladium acetate (899 mg), tris(4-methoxyphenyl)phosphine (2.82 g), and potassium acetate (78.64 g) were added sequentially to the reaction flask. The mixture was refluxed for 2 h, and the reaction was completed by TLC. The mixture was filtered while hot, and the filtrate was stirred and cooled. Precipitation began at 40 °C. The filtrate was cooled to -5 °C and kept at this temperature for 2 h before filtration and drying to obtain 68.53 g of intermediate product tetras, with a yield of 83%.
[0083] (5) Preparation of velixivaline
[0084] The intermediate tetrakis (64 g) and n-heptane (512 mL) were added to the reaction flask. Under nitrogen protection and stirring, palladium acetate (697 mg), tris(4-methoxyphenyl)phosphine (2.19 g), potassium acetate (60.97 g), and SM3 (80 g) were added. The mixture was heated to reflux and reacted for 3 h. The reaction was monitored by TLC until it was complete. The mixture was filtered while hot, and the filtrate was concentrated under reduced pressure until no solvent was present. After concentration, isopropanol was added and the mixture was stirred at 65 °C for 2 h. The mixture was then cooled to 0 °C and filtered to obtain 77.69 g of virixazine, with a yield of 88%.
[0085] Example 3
[0086] The preparation method of the aforementioned velixivaline includes the following steps:
[0087] (1) Preparation of methyl [(dicyanomethyl)amino]formate (intermediate product 1)
[0088] Aminomalononitrile (50.00 g) was added to a reaction flask and dissolved in 400 mL of dichloromethane. Triethylamine (124.87 g) was added, and the mixture was stirred and cooled to 40 °C. A solution of methyl chloroformate (58.57 g) in dichloromethane (150 mL) was added dropwise. The reaction took about 0.5 h. The mixture was stirred at this temperature for another 4 h. The reaction was confirmed by TLC. The solution was washed three times with 20 mL of water each time. The organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain an oily substance. The oily substance was purified by column chromatography (PE / EA = 4 / 1) to obtain 69.49 g of oily substance, with a yield of 81%.
[0089] (2) Preparation of methyl [(4,6-diaminopyrimidine-5-yl)amino]formate (intermediate product two)
[0090] Intermediate product 1 (65.00 g) and tetrahydrofuran (50 mL) were added to a reaction flask and stirred at 20-25 °C. Formamidin (27.17 g) was added and stirred for 10 min. Sodium ethoxide (125.96 g) was added in portions over approximately 0.5 h. After the addition was complete, the temperature was raised to 110 °C and the reaction was allowed to proceed for 3 h. The reaction was monitored by TLC until it was complete. Dilute hydrochloric acid was added dropwise until the pH reached approximately 10. The tetrahydrofuran was removed by vacuum distillation to obtain a pale yellow suspension. The suspension was filtered and washed with plenty of water. The filter cake was purified in an ethanol / water system to obtain 71.04 g of an off-white solid, with a yield of 83%.
[0091] (3) Preparation of methyl [(4,6-diamino-2-bromopyrimidin-5-yl)amino]formate (intermediate product three)
[0092] Intermediate product 2 (70.00 g) was added to the reaction flask and dissolved in 560 mL of acetonitrile. The temperature was lowered to 0-10 °C, and NBS (102.02 g) was added in portions. After the addition was complete, the temperature was raised to 70 °C and the reaction was carried out for 1 h. The reaction was monitored by TLC until it was complete. 200 mL of 0.5% sodium bisulfite aqueous solution was added, and the mixture was stirred for 20 min. The acetonitrile was removed by concentration under reduced pressure. The mixture was extracted three times with DCM, 300 mL each time. The organic phases were combined, washed twice with water, and dried with anhydrous sodium sulfate. The solid obtained by concentration was slurried with n-heptane, filtered, and dried to obtain intermediate product 3 (82.12 g), with a yield of 82%.
[0093] (4) Preparation of methyl [(4,6-diamino-2-boronate pyrimidin-5-yl)amino]formate (intermediate product four)
[0094] Under nitrogen protection, 560 mL of n-heptane, intermediate product tris (70 g), pinacol diborate (81.36 g), palladium acetate (899 mg), tris(4-methoxyphenyl)phosphine (2.82 g), and cesium carbonate (261.08 g) were added sequentially to the reaction flask. The mixture was refluxed for 2 h, and the reaction was completed by TLC. The mixture was filtered while hot, and the filtrate was stirred and cooled. Precipitation began at 40 °C. The mixture was cooled to 0 °C, kept at that temperature for 2 h, filtered, and dried to obtain 66.88 g of intermediate product tetras, with a yield of 81%.
[0095] (5) Preparation of velixivaline
[0096] Intermediate tetrakis (64 g) and n-heptane (512 mL) were added to the reaction flask. Under nitrogen protection, palladium acetate (697 mg), tris(4-methoxyphenyl)phosphine (2.19 g), cesium carbonate (202.41 g), and SM3 (80 g) were added. The mixture was heated to reflux and reacted for 3 h. The reaction was monitored by TLC until it was complete. The mixture was filtered while hot, and the filtrate was concentrated under reduced pressure until solvent-free. After concentration, isopropanol was added and the mixture was stirred at 60 °C for 2 h. The mixture was then cooled to 3 °C and filtered to obtain 75.92 g of virixazine, with a yield of 86%.
Claims
1. A method for preparing velixika, characterized in that, Includes the following steps: (1) Aminomalononitrile reacts with methyl chloroformate to produce intermediate product one. ； (2) Intermediate product one undergoes cyclization with formamidin under alkaline conditions to give intermediate product two. ； (3) Intermediate product two undergoes a bromination reaction with N-bromosuccinimide to yield intermediate product three. ； (4) Intermediate product three reacts with pinacol diboronic acid ester under the action of a catalyst to give intermediate product four. ； (5) The intermediate tetra reacted with 5-fluoro-1-(2-fluorobenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridine to prepare veliciguanidine. ； In step (1), the molar ratio of aminomalononitrile to methyl chloroformate is 1:(1-2); the reaction temperature is -10℃ to 40℃. In step (2), alkaline conditions are achieved by adding alkaline reagents, such as sodium methoxide, sodium ethoxide, and sodium tert-butoxide; the reaction temperature is 90℃-130℃; and the reaction time is 2-10h.
2. The method for preparing velixivaline according to claim 1, characterized in that, In step (3), the molar ratio of intermediate product 2 to N-bromosuccinimide is 1:(1-2); the reaction temperature is 20℃-70℃.
3. The method for preparing velixivaline according to claim 1, characterized in that, The reaction solvent in steps (4) and (5) is one of toluene, n-heptane, or N,N-dimethylformamide.
4. The method for preparing velixivaline according to claim 1, characterized in that, In steps (4) and (5), an alkaline reagent needs to be added. The alkaline reagent is one of potassium acetate, sodium acetate, potassium carbonate, or cesium carbonate.