Synthesis method of macavir side chain intermediate

Abstract

The invention relates to synthesis of a side chain intermediate (2-methyl-3, 4-difluorobenzoic acid) of macavir. According to the method, 2, 3-difluorotoluene is taken as an initial raw material, and a target intermediate (2-methyl-3, 4-difluorobenzoic acid) is obtained through bromination, Grignard reagent preparation, nucleophilic addition and hydrolysis.

Description

Technical Field

[0001] This invention relates to the pharmaceutical manufacturing field, specifically to a method for synthesizing an important intermediate of the side chain of mabaloxavir. Specifically, it relates to the synthesis of 2-methyl-3,4-difluorobenzoic acid, an intermediate in the synthetic route of 7,8-difluoro-6,11-dibenzo[b,e]thieno-11-ol.

[0002] . Background Technology

[0003] Baloxavir Marboxil is a novel antiviral drug for influenza, jointly developed by Shionogi & Co., Ltd. and Roche Pharmaceuticals. It is an inhibitor of the acidic protein PA of the influenza virus RdRp complex and was approved by the US FDA in October 2018. Its chemical structure is as follows: .

[0004] Marbaloxavir is an anti-influenza drug with a novel mechanism of action. It selectively inhibits the cap-dependent endonuclease activity of influenza virus RNA polymerase, precisely targeting key stages in the viral replication cycle, thereby effectively blocking viral replication and transmission. Compared to traditional neuraminidase inhibitors, this drug exhibits significant advantages in clinical practice: it requires only a single oral dose, greatly improving patient compliance and treatment convenience; and due to its unique target, the resistance rate monitored globally remains low, demonstrating a significant resistance barrier advantage. From a market and clinical perspective, marbaloxavir not only provides an innovative option for influenza treatment, especially suitable for patients resistant to conventional drugs or requiring simplified treatment procedures, but also demonstrates enormous development potential in the highly competitive anti-influenza drug market due to its proven efficacy and convenient administration, warranting close attention in clinical practice and market strategy.

[0005] However, the reported synthetic routes for mabaloxavir, especially the process represented by "Scheme 1" in the original patent CN 109311911A, still face several bottlenecks and risks that urgently need to be addressed in practical applications. While this route starts with inexpensive and readily available 3,4-difluorobenzoic acid, offering a cost advantage, it relies on the highly hazardous reagent n-butyllithium for the targeted introduction of the aldehyde group in a key step. n-Butyllithium is extremely sensitive to air and moisture, requiring harsh reaction conditions and posing significant operational risks. It not only imposes stringent requirements for anhydrous and oxygen-free production equipment and operating environments but also harbors major safety risks such as fire and explosion, severely restricting the feasibility and economic viability of its large-scale production. Furthermore, the synthetic route is lengthy, involving multiple functional group transformations and protection / deprotection operations, including subsequent substitution, cyclization, and reduction steps. The long reaction sequence inevitably leads to a gradual decrease in overall yield and production efficiency, while the accumulated separation and purification steps significantly increase solvent consumption and the burden of waste treatment. Therefore, although this route can achieve the construction of the target molecule at the laboratory level, its inherent core defects, such as poor process safety, high operational complexity, limited overall yield, and heavy environmental burden, make it difficult to directly transform into a stable, efficient, and green production-compliant industrial solution. Developing a simpler, safer, and more atom-economical new synthetic route has become an important issue for promoting cost reduction, efficiency improvement, and large-scale supply of this drug.

[0006] .

[0007] A novel synthetic route using 2-methyl-3,4-difluorobenzoic acid as a starting material directly targets the skeletal structure through its inherent methyl functional group, significantly shortening the reaction steps and improving the overall simplicity of the process. This route completely avoids the use of the high-risk reagent n-butyllithium, greatly reducing operational risks and safety barriers in production. Simultaneously, the optimized route leads to increased yields in key steps, thereby improving overall synthetic efficiency and economics, making it more suitable for industrial production. However, the high market price of 2-methyl-3,4-difluorobenzoic acid significantly increases the overall process cost when used as a starting material.

[0008] . Summary of the Invention

[0009] To address the above problems, this invention provides a method for preparing 2-methyl-3,4-difluorobenzoic acid, a key intermediate in the side chain of mabaloxavir: .

[0010] A method for synthesizing a key intermediate of the mabaloxavir side chain, characterized by comprising the following steps: (1) 2,3-Difluorotoluene reacts with a bromine source in solvent A via a catalyst to obtain 2,3-difluoro-6-bromotoluene; (2) The 2,3-difluoro-6-bromotoluene obtained in step (1) is reacted with a metal or a metal halide in solvent B under the catalysis of an initiator to obtain a solution of 2-methyl-3,4-difluorophenyl magnesium bromide in solvent B. (3) The carbonyl compound is reacted with a solution of the 2-methyl-3,4-difluorophenyl magnesium bromide in solvent B in solvent C to obtain 2-methyl-3,4-difluorobenzoate. (4) The 2-methyl-3,4-difluorobenzoate obtained in step (2) is reacted with an aqueous solution of alkali in solvent D to catalyze hydrolysis to obtain 2-methyl-3,4-difluorobenzoate; 2-methyl-3,4-difluorobenzoate is acidified with hydrochloric acid to obtain crude 2-methyl-3,4-difluorobenzoic acid; and purified 2-methyl-3,4-difluorobenzoic acid is obtained by purification method A.

[0011] The solvent A used in step (1) is any one of chloroform, dichloromethane, carbon tetrachloride, dichloroethane, tetrahydrofuran, diethyl ether, and methyl tert-butyl ether, preferably chloroform; the bromine source is any one of bromine, N-bromosuccinimide, dibromohydantoin, and pyridinium tribromide, preferably bromine; the catalyst is any one of iron powder, ferric chloride, aluminum trichloride, zinc chloride, and titanium tetrachloride, preferably iron powder; the reaction temperature is 10~35 degrees Celsius, preferably 20~30 degrees Celsius.

[0012] The solvent B used in step (2) is any one of anhydrous diethyl ether, anhydrous tetrahydrofuran, and anhydrous 2-methyltetrahydrofuran, preferably anhydrous 2-methyltetrahydrofuran; the metal or metallic halocarbon is any one of magnesium shavings, isopropyl magnesium chloride, and cyclohexyl magnesium chloride, preferably magnesium shavings; the initiator used is elemental iodine, dibromoethane, or both, preferably both; the reaction temperature is 35~50 degrees Celsius, preferably 40~45 degrees Celsius; The solvent C used in step (3) is any one of anhydrous diethyl ether, anhydrous tetrahydrofuran, and anhydrous 2-methyltetrahydrofuran, preferably anhydrous 2-methyltetrahydrofuran; the carbonyl compound selected is any one of methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, dimethyl carbonate, and diethyl carbonate, preferably ethyl chloroformate; the reaction temperature is -15 to 5 degrees Celsius, preferably -5 to 0 degrees Celsius.

[0013] The solvent C used in step (4) is any one of methanol, ethanol, acetone, tetrahydrofuran, and 1,4-dioxane, preferably methanol; the base used is any one of lithium hydroxide, sodium hydroxide, and potassium hydroxide, preferably potassium hydroxide; the reaction temperature is 25~70 degrees Celsius, preferably 60~65 degrees Celsius.

[0014] Purification method A can be any one or a combination of extraction, recrystallization filtration, and silica gel column chromatography, with recrystallization being preferred.

[0015] Beneficial Effects: Significantly Reduced Raw Material Costs: 1. Using readily available and inexpensive 2,3-difluorotoluene as the starting material, replacing the more expensive 2-methyl-3,4-difluorobenzoic acid, fundamentally reduces the raw material costs of the synthetic route, enhancing the process's economics and market competitiveness. 2. Avoidance of High-Risk Reagents, Enhancing Process Safety: The entire process avoids the use of high-risk reagents sensitive to air and moisture, such as n-butyllithium. The reaction conditions are mild, and the operation is highly safe, significantly reducing safety risks during production and better complying with industrial production safety standards. 3. Simple and Efficient Route, Controllable Reaction Conditions: The target intermediate can be efficiently constructed through four reaction steps. The reaction steps are clear, the conditions are mild and controllable, and the transitions between steps are smooth, which helps improve overall reaction efficiency and operational stability. 4. Good Yields and High Product Purity: Key steps such as bromination, Grignard reaction, and esterification all use optimized reagents and conditions, resulting in high reaction conversion and selectivity. High-purity 2-methyl-3,4-difluorobenzoic acid can ultimately be obtained through recrystallization, meeting the requirements of subsequent synthesis. 5. Solvent and reagent selection considers both feasibility and green chemistry: The selected solvents and reagents are common and readily available, some of which are recyclable. Extreme high temperature and high pressure reaction conditions are avoided, ensuring reaction efficiency while reducing waste generation and possessing good potential for industrial scale-up. In summary, this invention not only provides a cost-effective, safe, reliable, and simple synthetic route for the key side-chain intermediate of mabaloxavir, but also lays a solid technological foundation for the large-scale and green production of this drug. Detailed Implementation

[0016] The present invention will be further illustrated by way of embodiments below, but the present invention is not limited to the scope of the embodiments described herein.

[0017] Example 1 2,3-Difluorotoluene (2.0 kg), iron powder (87.4 g), and chloroform (10.5 L) were added to a 20 L reactor. Bromine (0.8 L) was slowly added at room temperature, and the mixture was stirred overnight. Water (10.5 L) was added, and the mixture was extracted with diethyl ether (21 L). The organic phase was separated and washed with 10% sodium thiosulfate aqueous solution (10.5 L) and saturated brine (10.5 L). The mixture was filtered and concentrated under vacuum. The residue was purified by vacuum distillation to obtain 3.0 kg of a colorless oily liquid, with a yield of 93%.

[0018] Example 2 Magnesium shavings (0.45 kg), elemental iodine (1.0 g), dibromoethane (1 mL), and 2-methyltetrahydrofuran (10.5 L, dehydrated with sodium) were added to a 20 L reactor. The reactor was purged three times with nitrogen. The reactor was heated to 45°C. A solution of the aforementioned colorless oily liquid (6-bromo-2,3-difluorotoluene, 3.44 kg) in 7.4 L of 2-methyltetrahydrofuran was prepared. When the internal temperature reached 35°C, 0.5–1 L of the 2-methyltetrahydrofuran solution was slowly added to the reactor until the reaction was successfully initiated. After successful initiation, the remaining 6-bromo-2,3-difluorotoluene in 2-methyltetrahydrofuran solution was added at a constant rate, maintaining an internal temperature of 75–80°C (external temperature of 45–50°C). The entire addition process took approximately 4 hours. A light brown reaction solution was obtained, and the external temperature was raised to 75-80 degrees Celsius. After reacting for an additional hour, HPLC analysis showed that the remaining amount of 6-bromo-2,3-difluorotoluene in the reaction solution was <1%. The temperature was then lowered to 25 degrees Celsius to obtain a solution of 2-methyl-3,4-difluorophenyl magnesium bromide in 2-methyltetrahydrofuran for later use.

[0019] Example 3 The reaction vessel was purged with nitrogen three times. Ethyl chloroformate (4.82 kg) and methyltetrahydrofuran (7.4 L) were added, and the mixture was cooled to -5 to 0°C (external temperature set to -15°C). The prepared Grignard reagent intermediate solution was slowly added (over approximately 5 hours), ensuring the internal temperature did not exceed 8°C (external temperature set to -15°C). After the addition was complete, the internal temperature was raised to 20°C, and the mixture was stirred for 1 hour until the residual amount of 2-methyl-3,4-difluorophenyl magnesium bromide in the reaction solution was <2% as determined by HPLC. The mixture was then cooled to -5 to 0°C, quenched with saturated ammonium chloride, and stirred for 1 hour. The methyltetrahydrofuran phase was separated, washed with saturated brine, concentrated to 0.2 L, and then 7.0 L of n-heptane was added and stirred to induce crystallization for 2–4 hours. The crystals were then filtered to obtain 3.0 kg of a white solid, with a yield of 90%.

[0020] Example 4 In a 10 L reactor, 2.0 kg of ethyl 2-methyl-3,4-difluorobenzoate and 5 L of methanol were mixed, and an aqueous solution of sodium hydroxide (0.4 kg dissolved in 3 L of water) was added slowly over half an hour. After the addition was complete, the reaction solution was heated to 60-65 degrees Celsius and reacted for 8 hours until HPLC analysis showed that the remaining amount of ethyl 2-methyl-3,4-difluorobenzoate in the reaction solution was <0.5%. After the suspension was cooled to 25 degrees Celsius, the pH was adjusted with concentrated hydrochloric acid for one hour to ensure that the internal temperature was <25 degrees Celsius and the pH of the aqueous layer was <2.

[0021] Discard the acidic aqueous phase, add water (2 L) to the organic phase, and adjust the pH (2 L) with 50% sodium hydroxide to ensure the pH of the aqueous layer is >10, thus obtaining the aqueous phase. Wash the aqueous phase twice with n-heptane (5 L). After cooling the aqueous phase to below 20 degrees Celsius, add concentrated hydrochloric acid (3 L) to adjust the pH to <2, thus obtaining the solid. Filter the solid to obtain the product. Wash the product with water (2*5 L) and n-heptane (5 L), and dry it under vacuum at 40 degrees Celsius to obtain the target substance, yielding 1.7 kg of white solid with a yield of 99%.

Claims

1. A method for synthesizing a mabaloxavir side-chain intermediate (2-methyl-3,4-difluorobenzoic acid), characterized in that... Includes the following steps (1) 2,3-Difluorotoluene reacts with a bromine source in solvent A via a catalyst to obtain 2,3-difluoro-6-bromotoluene; (2) The 2,3-difluoro-6-bromotoluene obtained in step (1) is reacted with a metal or a metal halide in solvent B under the catalysis of an initiator to obtain a solution of 2-methyl-3,4-difluorophenyl magnesium bromide in solvent B. (3) The carbonyl compound is reacted with a solution of the 2-methyl-3,4-difluorophenyl magnesium bromide in solvent B in solvent C to obtain 2-methyl-3,4-difluorobenzoate. (4) The 2-methyl-3,4-difluorobenzoate obtained in step (2) is reacted with an aqueous solution of alkali in solvent D to catalyze hydrolysis to obtain 2-methyl-3,4-difluorobenzoate; 2-methyl-3,4-difluorobenzoate is acidified with hydrochloric acid to obtain crude 2-methyl-3,4-difluorobenzoic acid; and purified 2-methyl-3,4-difluorobenzoic acid is obtained by purification method A.

2. The method according to claim 1, characterized in that: The solvent A used in step (1) is any one of chloroform, dichloromethane, carbon tetrachloride, dichloroethane, tetrahydrofuran, diethyl ether, and methyl tert-butyl ether, preferably chloroform; the bromine source is any one of bromine, N-bromosuccinimide, dibromohydantoin, and pyridinium tribromide, preferably bromine; the catalyst is any one of iron powder, ferric chloride, aluminum trichloride, zinc chloride, and titanium tetrachloride, preferably iron powder; the reaction temperature is 10~35 degrees Celsius, preferably 20~30 degrees Celsius.

3. The method according to claim 1, characterized in that: The solvent B used in step (2) is any one of anhydrous diethyl ether, anhydrous tetrahydrofuran, and anhydrous 2-methyltetrahydrofuran, preferably anhydrous 2-methyltetrahydrofuran; the metal or metallic halocarbon is any one of magnesium shavings, isopropyl magnesium chloride, and cyclohexyl magnesium chloride, preferably magnesium shavings; the initiator is elemental iodine, dibromoethane, or a combination of both, preferably a combination of both; the reaction temperature is 35~50 degrees Celsius, preferably 40~45 degrees Celsius.

4. The method according to claim 1, characterized in that: The solvent C used in step (3) is any one of anhydrous diethyl ether, anhydrous tetrahydrofuran, and anhydrous 2-methyltetrahydrofuran, preferably anhydrous 2-methyltetrahydrofuran; the carbonyl compound selected is any one of methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, dimethyl carbonate, and diethyl carbonate, preferably ethyl chloroformate; the reaction temperature is -15 to 5 degrees Celsius, preferably -5 to 0 degrees Celsius.

5. The method according to claim 1, characterized in that: The solvent C used in step (4) is any one of methanol, ethanol, acetone, tetrahydrofuran, and 1,4-dioxane, preferably methanol; the base used is any one of lithium hydroxide, sodium hydroxide, and potassium hydroxide, preferably potassium hydroxide; the reaction temperature is 25~70 degrees Celsius, preferably 60~65 degrees Celsius.

6. Purification method A is any one or a combination of extraction, recrystallization filtration, and silica gel column chromatography purification, with recrystallization being preferred.

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