Synthesis method of macloxvir intermediate impurity

Abstract

The invention relates to synthesis of a macarovir intermediate impurity (compound 1). The chemical structure of the macarovir intermediate impurity is shown in the specification. 2, 3-difluorotoluene is used as a raw material, and the target impurity (compound 1) is obtained through benzyl bromination, substitution reaction, Friedel-Crafts acylation ring closing and sodium borohydride reduction. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a method for synthesizing impurities of an important intermediate of mabaloxavir. Specifically, the present invention relates to the synthesis of impurities in the synthesis route of 7,8-difluoro-6,11-dibenzo[b,e]thieno-11-ol. Background Art

[0002] Baloxavir Marboxil is a new anti-influenza virus drug jointly developed by Shionogi and Roche Pharmaceuticals. It is an inhibitor of the acidic protein PA of the influenza virus RdRp complex. It was approved for marketing by the US FDA in October 2018. Its chemical structure is as follows: .

[0003] Mabaloxavir can inhibit the replication of influenza virus, thus achieving the purpose of treating influenza, and the current drug resistance level is low, and only one tablet can treat influenza. It has huge market potential and deserves clinical and market attention.

[0004] In the industrial production process of the new anti-influenza virus drug Mabaloxavir, the synthesis of its important intermediate 7,8-difluoro-6,11-dibenzo[b,e]thieno-11-ol has always been the core step in the synthesis route, and its existing synthesis routes are diverse.

[0005] The existing synthetic routes are as follows, however, there are certain problems. For example, the chemical scheme reported in the original research CN 109311911A starts from the low-cost 3,4-difluorobenzoic acid, introduces the aldehyde group through the high-risk chemical n-butyl lithium, and further performs substitution, cyclization, and reduction. Not only is the route long, but it also has huge hidden dangers in industrial production.

[0006] .

[0007] The synthetic route starting from 2,3-difluorotoluene is as follows. This route avoids the use of n-butyl lithium and thiophenol, shortening the process route. However, in the cyclization step, the reaction produces a large number of side reaction impurities. The structure of the impurity is now characterized and synthesized.

[0008] . Summary of the invention

[0009] In order to solve the above problems, the present invention provides a method for preparing a mabaloxavir intermediate impurity.

[0010] .

[0011] A method for synthesizing a mabaloxavir intermediate impurity (compound 1), characterized by comprising the following steps: (1) 2,3-difluorotoluene is subjected to benzylic bromination with N-bromosuccinimide in solvent A, and then reduced with diethyl phosphite and diisopropylethylamine in solvent B to obtain 2,3-difluorobenzyl bromide (compound 2); (2) reacting the compound 2 obtained in step (1) with thiosalicylic acid in solvent C, and replacing under alkaline conditions to obtain a crude product of 2-[(2,3-difluorophenyl)thiomethyl]benzoic acid (compound 3); the crude product is purified by recrystallization using solvent D to obtain a refined product of compound 3; (3) Compound 3 obtained in step (2) is reacted with a cyclizing agent in solvent E to obtain a crude product of 7,8-difluoro-6,11-dibenzo[b,e]thieno-11-one (compound 4); the crude product is purified by post-treatment method A to obtain a refined product of compound 4.

[0012] The solvent A used in step (1) is any one of acetonitrile, carbon tetrachloride, dichloroethane, and cyclohexane, preferably acetonitrile; the molar ratio of N-bromosuccinimide to 2,3-difluorotoluene is 2.0-1.05:1, preferably 1.10; the molar ratio of the initiator to 2,3-difluorotoluene is 0.05-0.1, preferably 0.1; the reaction temperature is any one of 60 degrees Celsius, 70 degrees Celsius, and reflux, preferably 60 degrees Celsius.

[0013] The solvent B used for the reduction of the dibromo compound in step (1) is any one of tetrahydrofuran, dichloromethane and dichloroethane. The molar ratio of the reducing agent diethyl phosphite to 2,3-difluorotoluene is 4.0-0.4:1, preferably 0.4; the molar ratio of the base diisopropylethylamine to 2,3-difluorotoluene is 4.0-0.4:1, preferably 0.4.

[0014] The solvent C used in step (2) is any one of N,N-dimethylformamide, a mixture of ethanol and water, and acetone, preferably N,N-dimethylformamide; the base used is any one of potassium carbonate, sodium carbonate, and sodium hydroxide, preferably potassium carbonate; the reaction temperature is 25 to 70 degrees Celsius, preferably 70 degrees Celsius. The crystallization solvent D is any one of methanol, ethanol, and isopropanol, preferably isopropanol; the crystallization temperature is -10 to 0 degrees Celsius, preferably -10 degrees Celsius.

[0015] In step (3), the cyclizing agent is any one of polyphosphoric acid, Eaton's reagent, phosphorus pentoxide, and aluminum chloride, preferably phosphorus pentoxide; the solvent E is any one of xylene, toluene, sulfolane, N-methylpyrrolidone, dichloromethane, and polyphosphoric acid, preferably sulfolane; the reaction temperature is 40 to 140 degrees Celsius, preferably 50 degrees Celsius. The purification method A is any one or a combination of extraction, silica gel column chromatography purification, and water separation filtration, preferably extraction and silica gel column chromatography purification.

[0016] Beneficial effects: 1. A reaction impurity of an important intermediate of Mabaloxavir was discovered, which is conducive to further improving the production route of the important intermediate of Mabaloxavir. 2. The relatively cheap 2,3-difluorotoluene was selected as the raw material of the route, which reduced the production cost. 3. The use of high-risk chemicals such as n-butyl lithium was avoided, reducing the safety hazards of production. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 Mass spectrometry characterization of impurities in the intermediate of Mabaloxavir DETAILED DESCRIPTION

[0018] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples.

[0019] Example 1 Add 2,3-difluorotoluene (20.0 g), N-bromosuccinimide (29.2 g), azobisisobutyronitrile (2.56 g) and acetonitrile (240 mL) into a 500 mL three-necked flask and heat to 60-65°C for reaction. After the reaction is completed by HPLC monitoring, add water (100 mL) and concentrate by rotary evaporation to remove most of the acetonitrile. Add dichloromethane (250 mL×2) and water (250 mL) to extract. Separate the organic phase, wash with saturated brine (250 mL), dry with anhydrous sodium sulfate, transfer to another 500 mL three-necked flask, filter and dry by rotary evaporation. The content of dibrominated product was about 10% as determined by HPLC monitoring. Dichloromethane (240 mL), diethyl phosphite (8.62 g) and diisopropylethylamine (8.06 g) were added to the three-necked flask at 0°C for reduction overnight. After the reaction was completed as monitored by TLC, 1 mol / L hydrochloric acid (240 mL), water (240 mL) and saturated brine (240 mL) were added for washing, dried over anhydrous sodium sulfate, filtered and dried to obtain 28.9 g of the target light yellow oily liquid with a yield of 90%.

[0020] Example 2 Potassium carbonate (42.6 g), thiosalicylic acid (32.0 g) and N,N-dimethylformamide (320 mL) were added to a 500 mL three-necked flask, stirred at room temperature for 0.5 hours, 2,3-difluorobenzyl bromide (50 g) was added, the temperature was raised to 70°C and stirred for 24 hours. After the reaction was completed by HPLC monitoring, the reaction solution was poured into water (425 mL), and the pH was adjusted to 1 with 4 mol / L hydrochloric acid. Solids precipitated, filtered, washed with hydrochloric acid and water, and dried to obtain a crude product. The crude product was dissolved in 70°C isopropanol, cooled at -10~0°C for crystallization, and filtered to obtain the target product. The mother liquor was repeatedly crystallized to obtain 44 g in total, with a yield of 76%.

[0021] Example 3 Phosphorus pentoxide (28.8 g) and sulfolane (90 mL) were added to a 500 mL three-necked flask, stirred to dissolve, 2-[(2,3-difluorophenyl)thiomethyl]benzoic acid (13.2 g) was added, the temperature was raised to 50°C and stirred overnight, and after the reaction was completed by HPLC monitoring, the reaction solution was quenched with water (600 mL), extracted three times with tert-methyl ether (600 mL), and the organic phases were combined and washed with water (600 mL), 1 mol / L sodium hydroxide aqueous solution (600 mL) and saturated brine (600 mL), dried over anhydrous sodium sulfate, filtered and dried to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 5.5 g of 7,8-difluoro-6,11-dibenzo[b,e]thieno-11-one, with a yield of 35%, and 11.1 g of compound 1, with a yield of 44%.

Claims

1. A method for synthesizing a mabaloxavir intermediate impurity (compound 1), characterized in that The following steps are involved: (1) 2,3-difluorotoluene is subjected to benzylic bromination with N-bromosuccinimide in solvent A, and then reduced with diethyl phosphite and diisopropylethylamine in solvent B to obtain 2,3-difluorobenzyl bromide (compound 2); (2) reacting the compound 2 obtained in step (1) with thiosalicylic acid in solvent C, and replacing under alkaline conditions to obtain a crude product of 2-[(2,3-difluorophenyl)thiomethyl]benzoic acid (compound 3); the crude product is purified by recrystallization using solvent D to obtain a refined product of compound 3; (3) Compound 3 obtained in step (2) is reacted with a cyclizing agent in solvent E to obtain crude 7,8-difluoro-6,11-dibenzo[b,e]thieno-11-one (compound 4) and impurities (compound 1); and a refined product of compound 1 is obtained by purification method A.

2. The method according to claim 1, characterized in that: The solvent A used in the step (1) is any one of acetonitrile, carbon tetrachloride, dichloroethane, and cyclohexane, preferably acetonitrile; the molar ratio of N-bromosuccinimide to 2,3-difluorotoluene is 2.0-1.05:1, preferably 1.10; the molar ratio of the initiator to 2,3-difluorotoluene is 0.05-0.1, preferably 0.1; the reaction temperature is any one of 60 degrees Celsius, 70 degrees Celsius, and reflux, preferably 60 degrees Celsius.

3. The method according to claim 1, characterized in that: The solvent B used for the reduction of the dibromo compound in step (1) is any one of tetrahydrofuran, dichloromethane and dichloroethane. The molar ratio of the reducing agent diethyl phosphite to 2,3-difluorotoluene is 4.0-0.4:1, preferably 0.4; the molar ratio of the base diisopropylethylamine to 2,3-difluorotoluene is 4.0-0.4:1, preferably 0.

4.

4. The method according to claim 1, characterized in that: The solvent C used in step (2) is any one of N,N-dimethylformamide, a mixture of ethanol and water, and acetone, preferably N,N-dimethylformamide; the base used is any one of potassium carbonate, sodium carbonate, and sodium hydroxide, preferably potassium carbonate; the reaction temperature is 25 to 70 degrees Celsius, preferably 70 degrees Celsius.

5. The method according to claim 1, characterized in that: In the step (2), the crystallization solvent D is any one of methanol, ethanol and isopropanol, preferably isopropanol; the crystallization temperature is -10 to 0 degrees Celsius, preferably -10 degrees Celsius.

6. The method according to claim 1, characterized in that: In the step (3), the cyclizing agent is any one of polyphosphoric acid, Eaton's reagent, phosphorus pentoxide, and aluminum chloride, preferably phosphorus pentoxide; the solvent E is any one of xylene, toluene, sulfolane, N-methylpyrrolidone, dichloromethane, and polyphosphoric acid, preferably sulfolane; and the reaction temperature is 40 to 140 degrees Celsius, preferably 50 degrees Celsius.

7. The method according to claim 1, characterized in that: In step (3), purification method A is any one or a combination of extraction, silica gel column chromatography purification, and water filtration, preferably silica gel column chromatography purification.

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