A method for preparing Molnupiravir

Abstract

The present invention discloses a preparation method of Molnupiravir, comprising the following steps: (1) reacting a solution of a compound of formula 2 with an acid solution in a microchannel reactor; (2) neutralizing the reaction product of step (1) with a base to obtain Molnupiravir; (3) post-treatment; wherein the solvent used in the reaction is selected from at least one of 2-methyltetrahydrofuran, dichloromethane, ethyl acetate, isopropyl acetate, acetone, and n-butanol, and the ratio of the flow rate of the solution of the compound of formula 2 to the inner diameter of the microchannel reactor is 5 to 150,000. This preparation method can simplify the operation, has high reaction efficiency, high throughput, low by-product content, controllable product quality, and simple subsequent purification treatment; the conversion rate of the starting material is as high as over 95%, the product yield is as high as over 80%, and the product purity is as high as over 99%, meeting the standards of bulk drugs; it has wide applicability and covers small-scale, pilot-scale, and industrial-scale preparations.

Description

Technical Field

[0001] The present invention relates to a preparation method of Molnupiravir, and particularly to a preparation method of Molnupiravir suitable for industrialization. Background Art

[0002] Molnupiravir (MK-4482 / EIDD-2801) is a drug jointly developed by Merck and Ridgeback Biotherapeutics.

[0003]

[0004] Patent CN112608357A discloses a method for continuously synthesizing Molnupiravir. After the deprotection reaction of the intermediate formula 2 compound solution and the acid solution in the microchannel reactor by microchannel reaction technology, the Molnupiravir is obtained by neutralization reaction with the alkaline solution in the microchannel reactor. In this method, the formula 2 compound solution and the acid solution are respectively pumped into the mixer 1 by pump 1 and pump 2, mixed and then undergo an acidolysis reaction in the microchannel reactor 1, and then mixed with the alkaline solution pumped into the mixer 2 by pump 3 and undergo a neutralization reaction in the microchannel reactor 2. The crude product solution is transferred to a collection container, and the collected crude product solutions are combined, first concentrated, directly recrystallized, filtered, or extracted, washed, concentrated, recrystallized, filtered, and dried to obtain the Molnupiravir product. Among them, the lengths of the microchannel reactors 1 and 2 are 6 meters, the total volume is 100 mL, the reaction temperature is -15 to 55 °C, the flow rate ranges of pump 1, pump 2, and pump 3 are 1 to 10 mL / min, the residence time of the reaction solution in the microchannel reactor 1 is 5 to 30 minutes, and the residence time of the reaction solution in the microchannel reactor 2 is 4 to 25 minutes.

[0005] This method selects a large variety of reaction solvents and post-treatment solvents, and has a long reaction time. For a reactor with a unit volume, the throughput is small and the production cost is high. At the same time, the content of ester hydrolysis impurities in the reaction product is relatively high, increasing the difficulty of product purification and making it difficult to obtain the raw drug meeting the quality requirements. Summary of the Invention

[0006] Object of the Invention: Aiming at the deficiencies of the existing methods, such as complex operation, low reaction efficiency, difficult product quality to meet the standard, and limited scope of application, the present invention aims to provide a preparation method of Molnupiravir that is efficient, convenient, has excellent product quality, and is suitable for industrialization.

[0007] Technical Solution: The preparation method of Molnupiravir of the present invention comprises the following steps:

[0008]

[0009] (1) The compound solution of formula (2) reacts with the acid solution in a microchannel reactor;

[0010] (2) The reaction product of step (1) is neutralized with a base to obtain Molnupiravir;

[0011] (3) Post-treatment;

[0012] Among them, the solvent used in the reaction is selected from at least one of 2-methyltetrahydrofuran, ethyl acetate, and isopropyl acetate, preferably 2-methyltetrahydrofuran; the ratio of the flow rate (mL / min) of the compound solution of formula (2) to the inner diameter (mm) of the microchannel reactor is 5 - 150000, preferably 1500 - 8000. The present invention discovers that there is a certain correlation between the ratio of the flow rate (mL / min) of the compound solution of formula (2) to the inner diameter (mm) of the microchannel reactor and the experimental effect. By using a dimensionless treatment method, the ratio range is controlled within 5 - 150000. If the ratio is too small, the mixing effect is poor; if the ratio is too large, the pressure drop of the overall system is relatively large.

[0013] In the above reaction process, the compound of formula (1) will continuously react under acidic conditions to generate the impurity of formula (3). The microchannel reaction technology can react quickly and quench quickly to reduce the generation of the impurity of formula (3).

[0014] The present invention adopts a heterogeneous reaction system, leveraging the characteristics of enhanced mixing and rapid heat exchange in the microchannel to achieve an effective reaction in the heterogeneous system and simultaneously achieve the effect of convenient post-treatment. Specifically, the present invention uses two groups of pumps to pump the organic solution of the material and the prepared acidic solution into the micromixer and microreactor simultaneously, enabling the two-phase reaction materials that are separated under normal conditions to be fully mixed and reacted in the equipment. After the reaction is complete, the two-phase reaction materials are in a mixed state of ultra-small droplets, and almost no phase separation occurs instantaneously when discharging the liquid. Then, a group of pumps is used to pump in the alkaline solution to quench and neutralize the entire reaction solution, achieving the purpose of quickly terminating the reaction. Subsequently, only a post-treatment kettle is needed for liquid separation and extraction to obtain the target product.

[0015] The present invention simplifies the existing process of first concentrating and then extracting by using the same solvent for the reaction process and post-treatment extraction. The solvent can be directly concentrated and recycled, and can be directly used for extraction, thereby reducing costs and realizing industrial production. It effectively shortens the reaction time, has a high raw material conversion rate, a small by-product content, simple subsequent purification treatment, saves costs, can continuously and uninterruptedly prepare a target product with stable quality, reduces the "three wastes" emissions, avoids cumbersome feeding steps, and conforms to the development concept of green and sustainable chemistry. At the same time, the microchannel reactor used has a real-time reaction system of only a few milliliters to several hundred milliliters, reducing the safety hazards of the reaction; the equipment has a high degree of automation, reducing the operation process of manually adding acid solution and ensuring the safety of operators; the material mixing effect is good and the backmixing is extremely low, which can effectively improve the reaction selectivity, precisely control the reaction time and improve the product quality; it improves the mass transfer and heat transfer efficiency and increases the safety factor of the reaction; the equipment occupies a small area, is easy to operate, can reduce the labor for operation, lower the production cost, and ensure the production economy; it is cheap, easy to transport, easy to clean, has a high mass transfer and heat transfer efficiency, and is more suitable for industrial scale-up.

[0016] The microchannel reactor consists of a mixer and a reaction module. Among them, the mixer and the reaction module are connected in series through a connecting pipeline or other connecting devices. Compound of Formula 2

((3aR,4R,6R,6aR)-6-(Z)-4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate

[0017] At the same time, Material 1 and Material 2 are pumped into the mixer for mixing, and after mixing, they are transported to Reaction Module 1 for reaction. The effluent is collected and sent to a post-treatment kettle pre-prepared with an alkali solution, and Molnupiravir

Compound of Formula 1, (2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-2-oxopyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl isobutyrate

[0018] Or, at the same time, Material 1 and Material 2 are pumped into the mixer for mixing, and after mixing, they are transported to Reaction Module 1 for reaction. The flowing reaction liquid and Material 3 are simultaneously pumped into Reaction Module 2 for quenching, and then the effluent is collected and sent to a post-treatment kettle, and Molnupiravir

Compound of Formula 1, (2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-2-oxopyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl isobutyrate

[0019] Preferably, the reaction temperature in step (1) is 10 - 95°C, more preferably 10 - 60°C, and even more preferably 10 - 30°C; the reaction time is 5 - 60 seconds.

[0020] Preferably, the post-treatment in step (3) includes extraction, concentration, and recrystallization steps.

[0021] Preferably, the feeding flow rate of the compound of formula 2 solution in step (1) is 5 - 1500 mL / min; the feeding flow rate of the acid solution is 5 - 1400 mL / min; the acid is at least one acid solution selected from hydrochloric acid, phosphoric acid, sulfuric acid, formic acid, acetic acid, methanesulfonic acid, and p-toluenesulfonic acid, preferably hydrochloric acid.

[0022] Preferably, the concentration of the compound of formula 2 in step (1) is 0.23 - 2.32 mol / L, the concentration of the acid solution is 0.1 - 18.4 mol / L, and the concentration of the acid solution is preferably 12 mol / L; the molar ratio of the two is 1:0.15 - 20.

[0023] Preferably, the concentration of the base in step (2) is 0.5 - 4.2 mol / L, the molar ratio of the compound of formula 2 to the base is 1:0.16 - 24; the base is at least one selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, triethylamine, and ammonia water, preferably potassium bicarbonate.

[0024] Preferably, the inner diameter of the microchannel reactor is 0.05 - 5 mm, and the length is 0.5 - 40 m. The microchannel reactor has a pore structure, and the number of pores can be increased or decreased as needed. The pore material is a corrosion-resistant material, such as polytetrafluoroethylene, copper oxide, carbon fiber, silicon carbide, titanium, etc.

[0025] Preferably, the neutralization in step (2) is carried out in a microchannel reactor or a reaction kettle.

[0026] Advantages: Compared with the prior art, the present invention has the following remarkable advantages:

[0027] (1) Simplify the operation, with high reaction efficiency, high throughput, low by-product content, controllable product quality, and simple subsequent purification treatment;

[0028] (2) The raw material conversion rate is up to over 95%, the product yield is up to over 80%, and the product purity is up to over 99%, meeting the API standards;

[0029] (3) Wide applicability, covering small-scale, pilot-scale, and industrial-scale preparations. Description of the Drawings

[0030] Figure 1 is a flow chart of the preparation method of the present invention;

[0031] Figure 2 The HPLC detection spectrum of the reaction monitoring of Example 1;

[0032] Figure 3 The HPLC test spectrum of the finished product prepared in Example 1;

[0033] Figure 4 The HPLC detection spectrum of the reaction monitoring of Example 2;

[0034] Figure 5 The HPLC test spectrum of the finished product prepared in Example 2;

[0035] Figure 6 The HPLC detection spectrum of the reaction monitoring of Example 3;

[0036] Figure 7 The HPLC test spectrum of the finished product prepared in Example 3;

[0037] Figure 8 This is the HPLC detection spectrum of the reaction monitoring of Comparative Example 1. DETAILED DESCRIPTION

[0038] The technical solution of the present invention is further described below in conjunction with embodiments.

[0039] Example 1

[0040] Prepare material 1 in a clean and dry 1L three-necked flask, add 180g of the compound of formula 2 and 540g of 2-methyltetrahydrofuran in sequence, heat, stir and dissolve, and maintain the temperature at 45-55°C. Prepare material 2 in a clean 1L three-necked flask, and add 816g of concentrated hydrochloric acid. Prepare material 3 in a clean 5L post-processing plastic barrel, dissolve 878g of potassium bicarbonate in 1247g of purified water, stir and keep warm at about 10°C. Pump material 1 and material 2 into the reaction system through a pump, mix them thoroughly and send them to reaction module 1 for reaction, and then the reaction liquid is directly sent to the post-processing for quenching and post-treatment. The feed flow rate of material 1 is 26.2mL / min, the feed flow rate of material 2 is 23.6mL / min, the volume of reaction module 1 is 20mL, the residence time is 24 seconds, and the reaction temperature is 30°C. After the reaction is completed, the central control conversion rate is 95.75% ( Figure 2 ), separated, extracted with 2-methyltetrahydrofuran, washed, concentrated, and recrystallized from isopropanol and methyl tert-butyl ether to obtain 144.4 g of the compound of formula 1 with a purity of 99.80% ( Figure 3 ), yield 90.3%.

[0041] Example 2

[0042] Prepare material 1 in a clean and dry 1000L reactor, add 180kg of the compound of formula 2 and 540kg of 2-methyltetrahydrofuran in sequence, heat, stir and dissolve, and maintain the temperature at 45-55°C. Prepare material 2 in a clean 1000L reactor and add 816kg of concentrated hydrochloric acid. Prepare material 3 in a clean 3000L post-treatment reactor, dissolve 878kg of potassium bicarbonate in 1247kg of purified water, stir and keep warm at about 10°C. Pump material 1 and material 2 into the reaction system through a pump, mix them thoroughly and send them to reaction module 1 for reaction, and then send the reaction liquid directly to the post-treatment for quenching and post-treatment. The feed flow rate of material 1 is 787mL / min, the feed flow rate of material 2 is 689mL / min, the volume of reaction module 1 is 660mL, the residence time is 27 seconds, and the reaction temperature is 30°C. After the reaction is completed, the central control conversion rate is 98.23% ( Figure 4 ). Post-treatment: separation, extraction with 2-methyltetrahydrofuran, washing, concentration, recrystallization with isopropanol and methyl tert-butyl ether to obtain 147.6 kg of the compound of formula 1 with a purity of 99.97% ( Figure 5 ), yield 92.1%.

[0043] Example 3

[0044] Prepare material 1 in a clean and dry 1000L reactor, add 180kg of the compound of formula 2 in sequence, recover 540kg of 2-methyltetrahydrofuran, heat, stir and dissolve, and maintain the temperature at 45-55°C. Prepare material 2 in a clean 1000L reactor, and add 816kg of concentrated hydrochloric acid. Prepare material 3 in a clean 3000L post-treatment kettle, dissolve 878kg of potassium bicarbonate in 1247kg of purified water, stir and keep warm at about 10°C. Pump material 1 and material 2 into the reaction system through a pump, mix them thoroughly and send them to reaction module 1 for reaction, and then the reaction liquid is directly sent to the post-treatment for quenching and post-treatment. The feed flow rate of material 1 is 787mL / min, the feed flow rate of material 2 is 689mL / min, the volume of reaction module 1 is 660mL, the residence time is 27 seconds, and the reaction temperature is 30°C. After the reaction is completed, the central control conversion rate is 98.79% ( Figure 6 ). Post-treatment: liquid separation, recovery of 2-methyltetrahydrofuran extraction, washing, concentration, recrystallization with isopropanol and methyl tert-butyl ether to obtain 146.7 kg of compound of formula 1 with a purity of 99.97% ( Figure 7 ), yield 91.4%.

[0045] Example 4

[0046] Prepare Material 1 in a clean and dry 1000 L reactor. Sequentially add 180 kg of the compound of Formula 2 and 540 kg of acetone. After heating and stirring to dissolve, maintain the temperature at 45 - 55 °C. Prepare Material 2 in a clean 1000 L reactor and add 960 kg of industrial hydrochloric acid. Prepare Material 3 in a clean 1500 L reactor by dissolving 464 kg of sodium carbonate in 950 kg of purified water and stirring. Pump Material 1 and Material 2 into the reaction system through an injection pump. After thorough mixing, send them into the reaction module for reaction. Then send the reaction solution into Reaction Module 2. After pumping in Material 3, quench the reaction, and then send it to the post-treatment kettle for post-treatment. The feeding flow rate of Material 1 is 830 mL / min, the feeding flow rate of Material 2 is 830 mL / min, the feeding flow rate of Material 3 is 950 mL / min. The volume of Reaction Module 1 is 660 mL, the residence time is 24 seconds, and the reaction temperature is 30 °C. After the reaction is completed, extract with 2-methyltetrahydrofuran, wash, concentrate, and recrystallize with isopropanol and methyl tert-butyl ether to obtain 130.8 kg of the compound of Formula 1, with a purity of 99.73% and a yield of 81.5%.

[0047] Example 5

[0048] Prepare Material 1 in a clean and dry 20 L reactor. Sequentially add 3.6 kg of the compound of Formula 2 and 21.6 kg of dichloromethane and stir to dissolve. Prepare Material 2 in a clean 20 L reactor and add 4.74 kg of industrial hydrochloric acid. Prepare Material 3 in a clean 10 L reactor by stirring 6.76 kg of ammonia water. Pump Material 1 and Material 2 into the reaction system through an injection pump. After thorough mixing, send them into the reaction module for reaction. Then send the reaction solution into Reaction Module 2. After pumping in Material 3, quench the reaction, and then send it to the post-treatment kettle for post-treatment. The feeding flow rate of Material 1 is 19.4 mL / min, the feeding flow rate of Material 2 is 4.2 mL / min, the feeding flow rate of Material 3 is 8.4 mL / min. The volume of Reaction Module 1 is 24 mL, the residence time is 60 seconds, and the reaction temperature is 10 °C. After the reaction is completed, separate the layers. Extract the aqueous phase with 2-methyltetrahydrofuran, wash, concentrate, and recrystallize with isopropanol and methyl tert-butyl ether to obtain 2.67 kg of the compound of Formula 1, with a purity of 99.66% and a yield of 83.4%.

[0049] Comparative Example 1

[0050] With reference to the method disclosed in patent CN112608357A, compound 3 (36.94 g, 100 mmol) of formula 2 was prepared into 400 mL of isopropanol solution (0.25 mmol / mL), concentrated hydrochloric acid (36%, 20.26 g, 200 mmol) was prepared into 200 mL of aqueous solution (1.0 mmol / mL), and sodium carbonate (27.64 g, 200 mmol) was prepared into 200 mL of aqueous solution (1.0 mmol / mL); the flow rate of pump 1, the flow rate of pump 2, the flow rate of pump 3, the flow rate of pump 3, the temperature of microchannel reactor 1 was 45° C., and the retention time was 5.0 minutes; the reaction temperature of microchannel reactor 2 was 0° C., and the retention time was 3.33 minutes.

[0051] like Figure 8 It can be seen that the reaction conversion rate is 92.6%, and the impurity of formula 3 has reached 6.59%; and the impurity content of formula 3 continues to increase during the post-treatment process of reducing pressure to remove most of the solvent. Analysis shows that the alcohol protic solvent present in the reaction system will undergo an ester exchange side reaction with the isobutyl ester group during the heating and concentration process. Therefore, this method is not conducive to large-scale and long-term process operations.

Claims

1. A preparation method of Molnupiravir, characterized in that, It includes the following steps: (1) React the compound solution of formula 2 with an acid solution in a microchannel reactor; (2) Neutralize the reaction product of step (1) with a base to obtain Molnupiravir; (3) Post-treatment, including extraction, concentration, and recrystallization steps; Among them, the solvents used for the reaction and extraction are selected from 2-methyltetrahydrofuran, and the ratio of the flow rate of the compound solution of formula 2 to the inner diameter of the microchannel reactor is 1500 - 8000.

2. The preparation method according to claim 1, wherein The reaction temperature of step (1) is 10 - 30 °C.

3. The preparation method according to claim 1, wherein The reaction time of step (1) is 5 - 60 seconds.

4. The preparation method according to claim 1, characterized in that, The feed flow rate of the compound solution of formula 2 in step (1) is 5 - 1500 mL / min.

5. The preparation method according to claim 1, characterized in that, The feed flow rate of the acid solution in step (1) is 5 - 1400 mL / min.

6. The preparation method according to claim 1, characterized in that, The concentration of the compound of formula 2 in step (1) is 0.23 - 2.32 mol / L, the concentration of the acid solution is 0.1 - 18.4 mol / L, and the molar ratio of the two is 1:0.15 - 20.

7. The preparation method according to claim 1, characterized in that, The concentration of the base in step (2) is 0.5 - 4.2 mol / L, and the molar ratio of the compound of formula 2 to the base is 1:0.16 - 24.

8. The preparation method according to claim 1, characterized in that, The inner diameter of the microchannel reactor is 0.05 - 5 mm, and the length is 0.5 - 40 m.

9. The preparation method according to claim 1, characterized in that, The neutralization operation of step (2) is carried out in a microchannel reactor or a reaction kettle.

Images