A process for the preparation of an intermediate for a human respiratory syncytial virus inhibitor

Abstract

The application discloses a preparation method of a human respiratory syncytial virus inhibitor intermediate 1-cyclopropyl-1,3-dihydroimidazo[4,5-C]pyridin-2-one, and belongs to the technical field of pharmaceutical chemistry. The synthetic method simplifies the synthesis steps, and the intermediate does not need to be purified, and the subsequent reaction is directly carried out through a one-pot method, so that the operation is simpler, the reaction time is shortened, the product has less impurities, is high in purity, and the process is relatively safe and environmentally friendly.

Description

Technical Field

[0001] This invention provides a method for preparing an intermediate of a human respiratory syncytial virus inhibitor, belonging to the field of pharmaceutical chemical synthesis technology. Background Technology

[0002] Human respiratory syncytial virus (RSV) has been proven to be a leading cause of respiratory infections in the elderly, infants, and those with weakened immune systems. The incidence of RSV infection is high in children under two years of age. Current treatments for RSV infection primarily utilize protein-based biologics containing synthetic amino acids, glycine, and a small molecule nucleoside (ribavirin). Azadiazolone derivatives are potent RSV inhibitors with good bioavailability in animal models. These compounds work by preventing viral fusion with the host membrane.

[0003] 1-Cyclopropyl-1,3-dihydroimidozopo[4,5-C]pyridin-2-one is an important pharmaceutical intermediate for the human respiratory syncytial virus (RSV) inhibitor azadiazolone derivative. RSV inhibitors exhibit inhibitory activity against RSV replication. Given the lack of effective treatments for RSV infection, the significant incidence of RSV, and the ethical implications for at-risk populations, the introduction of effective RSV agents is considered a major breakthrough in the care of these patients.

[0004] According to WO2015065338A1, 1-cyclopropyl-1,3-dihydroimidazo[4,5-C]pyridin-2-one (compound) is an important pharmaceutical intermediate of the human respiratory syncytial virus (RSV) inhibitor azabiazolone derivative. Its synthetic route, using 4-methoxy-3-nitropyridine as a starting material, is as follows:

[0005]

[0006] Furthermore, according to CN 201410066584.2, compound 5 also has important applications in the preparation of drugs against hepatitis B virus. This patent synthesizes compound 5 using 3-nitro-4-methoxypyridine as the starting material. The synthetic route is as follows:

[0007]

[0008] WO2020247298A2 discloses a pharmaceutical composition of a 1-pyrazole-5,6-disubstituted indazole derivative of an LRRK2 inhibitor for treating Parkinson's disease, and its use therein. Compound 5 is also an important intermediate for this inhibitor. In the literature, this intermediate was synthesized using 4-methoxy-3-nitropyridine as the starting material, and the specific synthetic route is as follows:

[0009]

[0010] The synthesis of 4-methoxy-3-nitropyridine from 4-hydroxy-3-nitropyridine involves numerous side reactions, resulting in high levels of impurities. Purification of 4-methoxy-3-nitropyridine is necessary, but this process is cumbersome and consumes large amounts of organic solvents, increasing synthesis costs. Furthermore, the volatile fuming nitric acid used in the synthesis of nitro compounds generates significant environmental pollution and poses considerable process risks due to the large quantities of concentrated sulfuric acid and fuming nitric acid. Additionally, the reaction between 4-methoxy-3-nitropyridine and cyclopropylamine involves rapid temperature increases, a vigorous reaction, and is prone to spillage, making the reaction difficult to control and posing significant safety risks. If CDI is used for the final cyclization step, not only is the cost high, but a large, unknown impurity is also introduced (see appendix). Figure 11 (RT 6.263 min, impurities 3-7%). However, directly synthesizing the target intermediate from 4-methoxy-3-nitropyridine increases the synthesis cost. Summary of the Invention

[0011] To address the aforementioned technical problems, this invention provides a method for preparing an intermediate of a human respiratory syncytial virus (RSV) inhibitor. We have improved the process by redesigning the synthetic route, using inexpensive and readily available raw materials, and employing microchannel reaction and a one-pot reaction method to reduce process costs, increase product yield, and improve process safety. Replacing fuming nitric acid / concentrated sulfuric acid with a recyclable solid superacid / potassium nitrate system significantly improves reactivity and is also more environmentally friendly. The product has high purity and low impurity content (impurities not exceeding 0.7% at RT 6.263 minutes).

[0012] To solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0013] A method for preparing an intermediate of a human respiratory syncytial virus inhibitor includes the following steps:

[0014] (1) 4-hydroxypyridine reacts with nitrate in the presence of a solid superacid to synthesize 4-hydroxy-3-nitropyridine (compound 2);

[0015] (2) Compound 2 was chlorinated with phosphorus oxychloride to obtain 4-chloro-3-nitropyridine solution, which was then fed into a microreactor with a solution containing cyclopropylamine and alkali to carry out a substitution reaction to synthesize compound 3.

[0016] (3) Compound 3 is converted into N-cyclopropyl-4-amino-3-aminopyridine (compound 4) under the action of Pd / C and hydrogen.

[0017] (4) Compound 4 was reacted with triphosgene to synthesize compound 1-cyclopropyl-1,3-dihydroimidazo[4,5-C]pyridin-2-one (compound 5), which is the intermediate of the human respiratory syncytial virus inhibitor mentioned above.

[0018] The chemical formula is as follows:

[0019]

[0020] The specific process is as follows:

[0021] Using 4-hydroxypyridine as the starting material, 4-hydroxy-3-nitropyridine (compound 2) was synthesized by nitration with potassium nitrate under the action of solid superacid SO42- / ZrO2 / SBA-15. N-cyclopropyl-4-amino-3-nitropyridine (compound 3) was synthesized in a one-pot process. Compound 2 was added in batches to a solution of dichloroethane containing phosphorus oxychloride, and the reaction was monitored by TLC. After the reaction was completed, a 4-chloro-3-nitropyridine solution was obtained. The 4-chloro-3-nitropyridine solution and a solution containing cyclopropylamine, ethanol, and 30% sodium hydroxide were separately pumped into a microreactor to react and synthesize compound 3. Compound 3 was reacted with Pd / C and hydrogen to generate N-cyclopropyl-4-amino-3-aminopyridine (compound 4). Compound 4 was reacted with triphosgene to synthesize compound 1-cyclopropyl-1,3-dihydroimidazo[4,5-C]pyridin-2-one (compound 5).

[0022] The following is a further explanation of the above technical solution:

[0023] In step (1), 4-hydroxypyridine is used as the raw material and reacts with potassium nitrate under the action of concentrated sulfuric acid to synthesize 4-hydroxy-3-nitropyridine (compound 2).

[0024] In step (1), 4-hydroxypyridine and solid superacid SO4 are added to dichloromethane. 2- / ZrO2 / SBA-15 was added in portions with potassium nitrate at room temperature, over 1–2 hours. The reaction was maintained at this temperature for 2–6 hours, and then monitored by TLC. The mixture was filtered, and the filtrate was washed with water and concentrated to obtain product compound 2. The filter cake was washed with water to obtain a recycled superacid. The mass ratio of 4-hydroxypyridine to the solid superacid and potassium nitrate was 1:(0.05–0.15):(0.8–3.2).

[0025] In step (2), compound 2 was added in batches to a 1,2-dichloroethane solution containing phosphorus oxychloride. After the reaction was completed by TLC monitoring, a 4-chloro-3-nitropyridine solution was obtained. Cyclopropylamine, ethanol, and 30% sodium hydroxide were mixed evenly, and the 4-chloro-3-nitropyridine solution and the cyclopropylamine mixture were separately pumped into a microreactor using a metering pump to react and form compound 3.

[0026] In step (2), the temperature of compound 2 is controlled at around 50-85°C. After the addition is complete, the mixture is heated to reflux and reacted for 2-8 hours. After the reaction is completed by TLC monitoring, a 4-chloro-3-nitropyridine solution is obtained and cooled to -10-30°C.

[0027] In step (2), cyclopropylamine, ethanol, and 30% sodium hydroxide are mixed evenly, and then the 4-chloro-3-nitropyridine solution and the cyclopropylamine mixture are pumped into the microreactor using a metering pump to carry out the reaction. The temperature of the reaction solution in the microchannel is 30-70℃. The collected reaction solution is cooled to 0℃, filtered, and the filter cake is collected to obtain compound 3.

[0028] In step (2), the mass ratio of 4-hydroxypyridine to phosphorus oxychloride and dichloroethane is 1:(1-4):(6-12); the mass ratio of 4-hydroxypyridine to cyclopropylamine, 30% sodium hydroxide and ethanol is 1:(1-3):(2-4):(4-8); and the flow rate ratio of 4-chloro-3-nitropyridine solution and cyclopropylamine mixture is (1-2):1.

[0029] In step (3), compound 3 and 5% Pd / C (50% water) are added to the ethanol solution, and hydrogen gas is introduced. The reaction is carried out under a vacuum of 0.5 MPa at room temperature. After the reaction is completed, N-cyclopropyl-4-amino-3-aminopyridine (compound 4) is generated.

[0030] In step (3), the mass ratio of 4-hydroxypyridine to 5% Pd / C (50% water) is 1:(0.1-0.4).

[0031] In step (3), triphosgene is added to the acetonitrile solution of compound 4 at -10 to 20°C, the mixture is reacted for 1 to 4 hours, the precipitate is collected by filtration and vacuum drying to obtain the final product 1-cyclopropyl-1,3-dihydroimidazole[4,5-c]pyridin-2-one (compound 5).

[0032] In step (3), the mass ratio of 4-hydroxypyridine to triphosgene and acetonitrile is 1:(1-4):(6-12).

[0033] The preparation method described in this invention simplifies the operation steps, reduces process costs, and achieves high product yield and low impurities. The process is also relatively safe and environmentally friendly. Attached Figure Description

[0034] Figure 1 The hydrogen NMR spectrum of compound 2 prepared according to Example 1;

[0035] Figure 2 The proton NMR spectrum of compound 3 prepared according to Example 1;

[0036] Figure 3 The hydrogen NMR spectrum of compound 4 prepared according to Example 1;

[0037] Figure 4 The hydrogen NMR spectrum of compound 5 prepared according to Example 1;

[0038] Figure 5 Liquid chromatogram of compound 5 prepared according to Example 1;

[0039] Figure 6 The proton NMR spectrum of compound 2 was prepared according to patent WO2020247298A2;

[0040] Figure 7 The proton NMR spectrum of compound 4-methoxy-3-nitropyridine prepared according to patent WO2020247298A2;

[0041] Figure 8 The proton NMR spectrum of compound 3 was prepared according to patent WO2020247298A2;

[0042] Figure 9 The proton NMR spectrum of compound 4 was prepared according to patent WO2020247298A2;

[0043] Figure 10 The proton NMR spectrum of compound 5 was prepared according to patent WO2020247298A2;

[0044] Figure 11 The liquid chromatogram of compound 5 was prepared according to patent WO2020247298A2. Detailed Implementation

[0045] The preferred embodiments of the present invention are described below. It should be understood that the preferred embodiments described herein are for illustration and explanation only and are not intended to limit the present invention.

[0046] Example 1: A method for preparing an intermediate of a human respiratory syncytial virus inhibitor

[0047] Weigh 150 ml of dichloromethane into a reaction flask, add 25.0 g of 4-hydroxypyridine and 2.5 g of solid superacid SO4. 2- ZrO2 / SBA-15 (purchased from Baihua Mall) was added, followed by the addition of 32.0g of potassium nitrate in batches, with the temperature controlled at around room temperature during the addition process. After the addition was complete, the mixture was reacted at room temperature for 4 hours, and the reaction was monitored by TLC. The mixture was then filtered, and the filter cake was added to 200g of water, heated to above 90℃, stirred for 1 hour, and hot-filtered. The mixture was then cooled to -10℃ and filtered again. The resulting filter cake was dried in a vacuum drying oven to obtain 36.2g of 4-hydroxy-3-nitropyridine (compound 2) pale yellow solid with a melting point of 275.0~278.5℃ and a yield of 98.2%. The 1H NMR spectrum is shown below. Figure 1 ,1 H NMR (DMSO, 400MHz) δ: 6.49-6.51 (d, 1H), 7.78-7.80 (m, 1H), 8.81 (d, 1H), 12.30 (s, 1H).

[0048] 100g of compound 2 and 571ml of 1,2-dichloroethane were added to a reaction flask and heated to 80°C. 80ml of phosphorus oxychloride was added dropwise, controlling the addition temperature at approximately 80°C. After the addition was complete, the mixture was heated to 85°C and reacted for 8 hours to obtain a 4-chloro-3-nitropyridine solution. 192g of 30% sodium hydroxide and 100g of cyclopropylamine were added to 500ml of ethanol and mixed thoroughly. The 4-chloro-3-nitropyridine solution and the cyclopropylamine mixture were separately pumped into a microreactor using a metering pump to synthesize compound 3 at a mass flow ratio of 1.4:1. The reaction temperature was maintained at approximately 45°C, and the reaction was completed in 2.5 hours. The reaction solution was then cooled to 0°C, and the filter cake was collected. The filter cake was soaked in cold ethanol (2×30ml) to obtain 89.9g of N-cyclopropyl-4-amino-3-nitropyridine (compound 3). Yellow solid, melting point 110.2–111.3 °C, yield 70.3%. 1H NMR spectrum shown below. Figure 2 , 1 H NMR (DMSO, 400MHz) δ: 0.51-0.55 (m, 2H), 0.72-0.76 (m, 2H), 7.09-7.10 (d, 1H), 8.10 (s, 1H), 8.18-8.19 (d, 1H), 8.85 (s, 1H).

[0049] 120 g of N-cyclopropyl-4-amino-3-nitropyridine and 24 g of 5% Pd / C (50% water) were added to a flask containing 1 L of ethanol. Hydrogen gas was introduced, and the mixture was reacted at room temperature under a vacuum of 0.5 mPa for 4–6 hours. After passing the control test, the solution was filtered and concentrated to dryness. Ethanol was added to the solid for recrystallization, and the mixture was filtered. The filter cake was dried under vacuum to obtain 98.0 g of N-cyclopropyl-3,4-diaminopyridine (compound 4). It is a red solid with a melting point of 172.4–176.3 °C and a yield of 98.1%. The 1H NMR spectrum is shown in [reference needed]. Figure 3 , δ: 0.40-0.44 (m, 2H), 0.71-0.76 (m, 2H), 2.38 (s, 1H), 4.51 (s, 2H), 5.76 (s, 1H), 6.65-6.66 (d, 1H), 7.61-7.63 (m, 2H).

[0050] Add 20.0 g of compound 4 to 268 ml of acetonitrile, cool to 0 °C, then add 45.0 g of triphosgene. React the mixture for at least 1 hour, filter to collect the precipitate, and vacuum dry to obtain 16.8 g of 1-cyclopropyl-1,3-dihydroimidazole[4,5-c]pyridin-2-one (compound 5), an off-white solid with a melting point of 177.0–179.5 °C, a yield of 71.5%, and a liquid chromatography purity of 99.99%. (Liquid chromatography chromatogram is shown.) Figure 5 The proton NMR spectrum is shown below. Figure 4 , δ: 0.85-0.89 (m, 2H), 0.96-1.04 (m, 2H), 2.88-2.90 (m, 1H), 7.17-7.18 (d, 1H), 8.16-8.19 (m, 2H), 11.01 (s, 1H).

[0051] Example 2: Preparation of 4-hydroxy-3-nitropyridine (compound 2) using perfluorosulfonic acid resin (Nafion-H).

[0052] Weigh 150 ml of dichloromethane into a reaction flask, add 25.0 g of 4-hydroxypyridine and 2.5 g of perfluorosulfonic acid resin (purchased from Baihua Mall), and then add 32.0 g of potassium nitrate in batches, controlling the temperature at room temperature during the addition process. After the addition is complete, let the mixture react at room temperature for 6.0 hours, and monitor the reaction completion by TLC. Filter, add the filter cake to 200 g of water, heat to above 90 °C, stir for 1 hour, and hot filter. Then cool to -10 °C and filter. Dry the obtained filter cake in a vacuum drying oven to obtain 32.0 g of 4-hydroxy-3-nitropyridine (compound 2) pale yellow solid, melting point 275.0~278.5 °C, yield 89.4%, liquid phase purity 93.7%.

[0053] Example 3: Solid superacid SO4 2- / TiO2 was used to prepare 4-hydroxy-3-nitropyridine (compound 2)

[0054] Weigh 150 ml of dichloromethane into a reaction flask, add 25.0 g of 4-hydroxypyridine and 2.5 g of solid superacid SO4. 2- TiO2 (purchased from Baihua Mall) was added, followed by 32.0g of potassium nitrate in batches, with the temperature controlled at around room temperature during the addition process. After the addition was complete, the mixture was allowed to react at room temperature for 7.5 hours, and the reaction was monitored by TLC. The mixture was then filtered, and the filter cake was added to 200g of water, heated to above 90℃, stirred for 1 hour, and hot-filtered. Then, it was cooled to -10℃ and filtered again. The resulting filter cake was dried in a vacuum drying oven to obtain 32.0g of 4-hydroxy-3-nitropyridine (compound 2) pale yellow solid, with a melting point of 275.0~278.5℃, a yield of 86.7%, and a liquid phase purity of 95.4%.

[0055] Example 44: Preparation of N-cyclopropyl-4-amino-3-nitropyridine by reacting 4-methoxy-3-nitropyridine with cyclopropylamine

[0056] Add 500 ml of ethanol, 192 g of 30% sodium hydroxide, and 100 g of cyclopropylamine to a reaction flask and mix thoroughly. Add 4-methoxy-3-nitropyridine in portions slowly, controlling the temperature of the solution below 20°C. The reaction was too vigorous, and the temperature rose too quickly, causing a backflow. After the addition was complete, react at below 20°C for half an hour, then heat to reflux. After refluxing the reaction solution for 3 hours, the reaction temperature was lowered to 0°C, and the filter cake was collected. The filter cake was soaked in cold ethanol (2 × 30 ml) to obtain 57.6 g of N-cyclopropyl-4-amino-3-nitropyridine (compound 3). Due to the backflow, the yield could not be calculated.

[0057] Example 5: Preparation of 1-cyclopropyl-1,3-dihydroimidazolium[4,5-c]pyridin-2-one by CDI

[0058] 20.0 g of compound 4 was added to 268 ml of acetonitrile. After cooling to 0 °C, 22.8 ml of CDI (N,N-carbonyldiimidazole) was added. The mixture was reacted for at least 1 hour. The precipitate was collected by filtration and dried under vacuum to obtain 16.8 g of 1-cyclopropyl-1,3-dihydroimidazole[4,5-c]pyridin-2-one (compound 5), an off-white solid with a melting point of 177.0–179.5 °C, a yield of 71.8%, a liquid phase purity of 94.8%, an RT of 7.137 min, and 5.2% impurities.

[0059] Example 6: Synthesis of N-cyclopropyl-4-amino-3-nitropyridine by controlling the reaction temperature

[0060] 100g of compound 2 and 571ml of 1,2-dichloroethane were added to a reaction flask and heated to 80°C. 80ml of phosphorus oxychloride was added dropwise, controlling the addition temperature at approximately 80°C. After the addition was complete, the mixture was heated to 85°C and reacted for 8 hours to obtain a 4-chloro-3-nitropyridine solution. 192g of 30% sodium hydroxide and 100g of cyclopropylamine were added to 500ml of ethanol and mixed thoroughly. The 4-chloro-3-nitropyridine solution and the cyclopropylamine mixture were separately pumped into a microreactor using a metering pump to react and form compound 3 at a mass flow ratio of 1.4:1. The reaction temperature was maintained at approximately 25°C, and the reaction was completed in 2.5 hours. The reaction solution was then cooled to 0°C, and the filter cake was collected. The filter cake was soaked in cold ethanol (2×30ml) to obtain 81.5g of N-cyclopropyl-4-amino-3-nitropyridine (compound 3). Yellow solid, melting point 110.2–111.3℃, yield 63.73%.

[0061] Example 6: Synthesis of 1-cyclopropyl-1,3-dihydroimidazolium[4,5-c]pyridin-2-one by controlling the reaction ratio

[0062] Add 20.0 g of compound 4 to 268 ml of acetonitrile, cool to 0 °C, then add 40.0 g of triphosgene. React the mixture for at least 1 hour, filter to collect the precipitate, and vacuum dry to obtain 14.2 g of 1-cyclopropyl-1,3-dihydroimidazole[4,5-c]pyridin-2-one (compound 5), an off-white solid with a melting point of 177.0–179.5 °C, a yield of 67.9%, and a liquid phase purity of 99.97%.

[0063] Unless otherwise stated, all percentages used in this invention are mass percentages.

[0064] Finally, it should be noted that the above descriptions are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing an intermediate of a human respiratory syncytial virus inhibitor, characterized in that, Includes the following steps: (1) 4-hydroxypyridine reacts with nitrate in the presence of a solid superacid to synthesize compound 2; (2) Compound 2 was chlorinated with phosphorus oxychloride to obtain 4-chloro-3-nitropyridine solution, which was then fed into a microreactor with a solution containing cyclopropylamine and alkali to carry out a substitution reaction to synthesize compound 3; (3) Compound 3 reacts with Pd / C and hydrogen to form compound 4; (4) Compound 4 reacts with triphosgene to synthesize compound 5, which is the intermediate of the human respiratory syncytial virus inhibitor described above; The chemical equation is as follows: ； Solid superacid is recyclable SO4 2- / ZrO2 / SBA-15, perfluorosulfonic acid resin Nafion-H, SO4 2- One or more of / TiO2; In step (2), the chlorination reaction is carried out in 1,2-dichloroethane; after the chlorination reaction is completed, the chlorination reaction solution is directly passed into the microreactor for further reaction without post-treatment. The reaction in step (4) is carried out in acetonitrile; The mass ratio of compound 5 to triphosgene and acetonitrile is 1:(1-4):(6-12).

2. The method for preparing the intermediate of the human respiratory syncytial virus inhibitor according to claim 1, characterized in that: In step (1), the nitrate is at least one of potassium nitrate, sodium nitrate, ammonium nitrate, and calcium nitrate.

3. The method for preparing the intermediate of the human respiratory syncytial virus inhibitor according to claim 2, characterized in that: The mass ratio of 4-hydroxypyridine to solid superacid and nitrate is 1:(0.05~0.15):(0.8~3.2).

4. The method for preparing the intermediate of the human respiratory syncytial virus inhibitor according to claim 1, characterized in that, In step (2), the alkali is at least one of sodium hydroxide, potassium hydroxide, and cesium hydroxide; the substitution reaction is carried out in an alcohol solution; the alcohol solution is methanol, ethanol, isopropanol, or tert-butanol.

5. The method for preparing the intermediate of the human respiratory syncytial virus inhibitor according to claim 4, characterized in that: The mass ratio of 4-hydroxypyridine to phosphorus oxychloride and 1,2-dichloroethane is 1:(1-4):(6-12); the mass ratio of 4-hydroxypyridine to cyclopropylamine, sodium hydroxide and alcohol solution is 1:(1-3):(2-4):(4-8); the flow rate ratio of 4-chloro-3-nitropyridine feed solution and cyclopropylamine mixture is (1-2):

1.

6. The method for preparing the intermediate of the human respiratory syncytial virus inhibitor according to claim 1, characterized in that: The mass ratio of compound 3 to Pd / C is 1:(0.1–0.4); the reaction is carried out in methanol, ethanol, isopropanol, or tert-butanol.

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