Green preparation method of anti-influenza virus derivative key intermediate dibenzoselenoheptanone compound

Abstract

The invention belongs to the field of pharmaceutical and chemical engineering, relates to a green preparation method of an anti-influenza virus derivative key intermediate dibenzoselenoheptanone compound, and belongs to the field of pharmaceutical and chemical engineering. According to the preparation method, N, N-dimethylformamide and oxalyl chloride are utilized to perform in-situ activation on carboxylic acid to obtain an acyl chloride intermediate, then an intramolecular Friedel-Crafts acylation reaction is performed under promotion of cheap lewis acid anhydrous AlCl3 or FeCl3 and superacid TMSOTf, the dibenzoselenoheptanone compound is efficiently prepared, and particularly, the invention relates to preparation of 7, 8-difluorodibenzo [b, e] selenoheptyl-11 (6H)-ketone. According to the synthesis method disclosed by the invention, the use of polyphosphoric acid in an existing synthesis route is avoided, and the reaction is completed in a mild temperature range of 0-25 DEG C by introducing superacid, so that the problem that the dibenzoselenoheptanone compound is unstable at a high temperature and is difficult to prepare is effectively solved; and meanwhile, the harsh requirement of repeated heating and cooling in the original process is avoided, the reaction time is remarkably shortened, the energy consumption is reduced, the comprehensive production cost is effectively reduced while the process safety is improved, and the method is more in line with the production concept of green chemical industry.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of medicine and chemical industry, and relates to a green preparation method of a key intermediate dibenzo selenium heptanone compound of an anti-influenza virus derivative. BACKGROUND

[0002] Influenza is caused by influenza virus, and breaks out seasonally, with about 1 billion people infected and 650,000 people died worldwide every year. The RNA polymerase of influenza virus contains cap-dependent endonuclease, and inhibiting the activity of cap-dependent endonuclease can inhibit the proliferation of the virus. Different heterocyclic compounds have been used as cap-dependent endonuclease inhibitors, among which baloxavir is a marketed cap-dependent endonuclease inhibitor, but its bioavailability is low, and there are also reports of drug resistance, so it is necessary to develop a new generation of cap-dependent endonuclease inhibitors.

[0003] Patent CN117003766A discloses a highly efficient anti-viral derivative and its use. The derivative is a compound represented by the following formula (I) or a hydrate, solvate, optical isomer, polymorph, isotopic derivative, pharmaceutically acceptable salt thereof. The compound of the application can be used for preparing a medicine for preventing / treating influenza virus.

[0004]

[0005] (I) Meanwhile, the patent describes the synthesis route of the compound, which uses 7,8-difluorodibenzo[b,e]selenoheptan-11(6H)-one as the starting material, condenses with the amide fragment after reduction, and connects the side chain after debenzyl to obtain the compound (I) with anti-viral activity. The specific reaction route is shown in the following figure:

[0006]

[0007] Patent CN115677698A describes a preparation method of the starting material 7,8-difluorodibenzo[b,e]selenoheptan-11(6H)-one: 3,4-difluoro-2-[(phenylselenyl)methyl]benzoic acid is used as the raw material, and 7,8-difluorodibenzo[b,e]selenoheptan-11(6H)-one is obtained by the action of polyphosphoric acid (PPA) at 120°C. As a protic acid catalyst, polyphosphoric acid promotes the Friedel-Crafts acylation reaction of the hydrogen carboxyl group of the aromatic ring, and polyphosphoric acid provides protons to make the carboxyl group generate acyl cation, and then the electrophilic attack on the aromatic ring generates an aromatic ketone through the deprotonation of the intermediate. The specific reaction route is shown in the following figure:

[0008] Polyphosphoric acid is a colorless transparent and very viscous liquid, which is corrosive and also a common reagent in organic synthesis. It can be used as a dehydrating agent, a cyclization reagent, an acylating reagent, and is a common catalyst or solvent for condensation, cyclization, rearrangement, substitution and other reactions. However, its high viscosity brings many inconveniences to the use, and the post-processing operation is particularly difficult when scaling up the synthesis.

[0009] The document Green Synthesis of 7,8-Difluoro-6,11-Dihydrodibenz[B,E]Thiophene-11-One of Baloxavir Marboxil--Reducing Environmental Pollution reports a method of preparing acyl chloride first and then performing Friedel-Crafts alkylation to prepare a product with a heteroatom of sulfur instead of selenium. However, the reaction needs to be carried out at a high temperature (60-78℃), at which the acyl chloride intermediate with a heteroatom of selenium is unstable and cannot generate a dibenzoselenepinheptanone compound. Although a lower reaction temperature can avoid the decomposition of acyl chloride, the reaction activity is insufficient and it is difficult to generate the product. SUMMARY

[0010] Therefore, the purpose of the present application is to provide a green preparation method of a dibenzoselenepinheptanone compound, which is a key intermediate of an anti-influenza virus derivative.

[0011] To achieve the above-mentioned purpose, the present application provides the following technical solutions. A preparation method of a dibenzoselenepinheptanone compound, which is a key intermediate of an anti-influenza virus derivative, is as follows:

[0012] The carboxylic acid in compound (II) is activated in situ to an acyl chloride intermediate based on N,N-dimethylformamide and oxalyl chloride, and then an intramolecular Friedel-Crafts acylation reaction occurs under the promotion of anhydrous Lewis acid AlCl3 or FeCl3 or super acid TMSOTf to prepare compound (III); In compound (II), R1 and R2 are each independently selected from hydrogen, deuterium, C1-C3 alkyl, deuterated C1-C3 alkyl, or R1, R2 and the carbon atom connected thereto together form cyclopropyl or deuterated cyclopropyl; R a , R b , R c and R d are each independently selected from hydrogen, deuterium, C1-C3 alkyl, deuterated C1-C3 alkyl, C1-C3 alkoxy and deuterated C1-C3 alkoxy.

[0013] Preferably, R1and R2in the compound (II) are hydrogen, R a , R b , R c and R d are all selected from hydrogen, the compound (II) is 3,4-difluoro-2-[(phenylselenyl)methyl]benzoic acid (II-1), and the compound (III) is 7,8-difluorodibenzo[b,e]selenepentacene-11(6H)-one (III-1): .

[0014] The specific preparation method is as follows: (1) Under the protection of inert gas, a mixed solution of oxalyl chloride and N,N-dimethylformamide is added dropwise into a solution of the compound (II), and after uniform stirring, the reaction is continued under heating and stirring; (2) After the reaction of the compound (II) is completed, the reaction liquid in step (1) is cooled, anhydrous Lewis acid and trimethylsilyl superacid salt are added, and the reaction is continued after mixing; The anhydrous Lewis acid is one of anhydrous AlCl3and FeCl3, and the trimethylsilyl superacid salt is TMSOTf; (3) After the reaction is completed, the reaction liquid in step (2) is poured into an aqueous hydrochloric acid solution for quenching; (4) Dichloromethane is used for extraction three times, the organic phase is combined, washed with saturated NaHCO3solution and saturated NaCl solution, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure, evaporated to dryness, and the compound (III) is prepared.

[0015] Preferably, the molar ratio of oxalyl chloride, N,N-dimethylformamide and the compound (II) in step (1) is 1-3:0.1-0.5:0.1-0.5; Preferably, the temperature of the mixed solution of oxalyl chloride and N,N-dimethylformamide and the solution of the compound (II) in step (1) is 0°C, and the stirring time is 10-60 min, and after the temperature is raised to room temperature, the reaction is continued under stirring for 1-3 h; Preferably, the solvent used for the solution of the compound (II) in step (1) is halogenated alkane or benzene solvent, the benzene solvent is benzene or benzene derivative with electron-withdrawing group, and the electron-withdrawing group is selected from one or more of nitro, cyano, halogen and trifluoromethyl; Preferably, the solvent used for the solution of the compound (II) in step (1) is one or more of dichloromethane, trichloromethane, 1,2-dichloroethane, benzene and chlorobenzene; Preferably, the molar ratio of anhydrous Lewis acid, trimethylsilyl superacid salt and oxalyl chloride in step (1) in step (2) is 1-3:0.05-1:1-3; Preferably, the reaction solution in step (2) is cooled to -20℃ to 0℃, and after mixing, the reaction temperature is -20℃ to room temperature, and the reaction time is 2 to 10 hours. Preferably, in step (3), the concentration of the hydrochloric acid aqueous solution is 0.5 to 3 M, and the temperature is 0℃.

[0016] The beneficial effects of the present application are: The present application develops a new method which is simple in operation and friendly to the environment, for synthesizing the key intermediate dibenzo selenium heptanone compound of anti-influenza virus derivatives, which is 7,8-difluoro dibenzo[b,e] selenium heptane-11(6H)-ketone. The synthesis method proposed in the present application can complete the ring closure process at room temperature, and the post-treatment is simple, and has the following advantages: 1. The present application breaks through the bottleneck in the prior art that a large amount of high-viscosity, difficult-to-handle liquid reagent polyphosphoric acid (10.0-18.5 yuan / kg) must be used, so that each link of material conveying, feeding precision, stirring mixing, sampling, reaction quenching and product purification is more simple and stable, the production safety risk is greatly reduced, and the operability of the synthesis process is significantly improved. 2. The preparation method proposed in the present application introduces an extra super acid TMSOTf for activation, so that the reaction can be carried out at a mild temperature range of 0℃ to 25℃, effectively solving the problem that dibenzo selenium heptanone compound is unstable under high temperature conditions and cannot be prepared. At the same time, the harsh requirement of repeatedly raising and lowering the temperature between 25℃ to 120℃ in the original process is avoided, thereby significantly shortening the reaction time, reducing the energy consumption, improving the process safety, effectively reducing the comprehensive production cost, and being more in line with the production concept of green chemical industry.

[0017] Other advantages, objects and features of the present application will be set forth in part in the specification which follows, and in part will become apparent to those skilled in the art upon examination of the following or can be learned from practice of the present application. The objects and other advantages of the present application can be realized and attained by the methods and combinations particularly pointed out in the written description and claims hereof. BRIEF DESCRIPTION OF DRAWINGS

[0018] In order to make the objects, technical solutions and advantages of the present application clearer, the preferred detailed description of the present application will be made below in combination with the drawings, in which: Figure 1 The nuclear magnetic resonance hydrogen spectrum of 7,8-difluoro dibenzo[b,e] selenium heptane-11(6H)-ketone. DETAILED DESCRIPTION

[0019] Following, the embodiments of the present application are described by specific examples, and other advantages and effects of the present application can be easily understood by those skilled in the art from the disclosure of the present specification. The present application can also be implemented or applied by other different embodiments, and the details in the present specification can be modified or changed in various ways based on different views and applications without departing from the spirit of the present application. It should be noted that the figures provided in the following examples only illustrate the basic concept of the present application in a schematic manner, and the following examples and features in the examples can be combined with each other without conflict.

[0020] Example 1 Reaction mechanism for preparing dibenzoselenepentacene compounds The method first uses a catalytic amount of N,N-dimethylformamide (DMF) and a chemical equivalent of oxalyl chloride ((COCl)2, 26~33 yuan / kg) to activate the carboxylic acid in situ to an acyl chloride intermediate; then, under the promotion of a chemical equivalent of cheap Lewis acid-anhydrous aluminum chloride (AlCl3, 5.2~5.5 yuan / kg) or anhydrous ferric chloride (FeCl3), a small amount of superacid TMSOTf, the intermediate undergoes intramolecular Friedel-Crafts acylation to generate dibenzoselenepentacene compound 7,8-difluorodibenzo[b,e]selenepentacene-11(6H)-one. The specific reaction mechanism is shown in the following schematic diagram:

[0021] The method newly introduces an acyl chloride intermediate in the original one-step method, which is generated during the reaction and then consumed directly with subsequent feeding, so it can still be completed directly in the same reaction kettle as the original method, without additional process steps, while avoiding the use of polyphosphoric acid.

[0022] Example 2 Preparation of dibenzoselenepentacene compounds, the reaction equation is shown below, wherein compound (II-1) is 3,4-difluoro-2-[(phenylselenyl)methyl]benzoic acid, and compound (III-1) is 7,8-difluorodibenzo[b,e]selenepentacene-11(6H)-one.

[0023]

[0024] The specific preparation process is as follows: (1) 3,4-Difluoro-2-[(phenylselenyl)methyl]benzoic acid (32.8 g, 0.1 mol) was used as raw material, and a mixture solution of oxalyl chloride (25.5 g, 0.2 mol, 2.0 eq) and N,N-dimethylformamide (3.9 mL, 0.05 mol, 0.5 eq) at 0°C was added dropwise into a solution of the raw material in chloroform (0.1 M) at 0°C under inert gas protection. After stirring for 30 min, the temperature was naturally increased to room temperature, and the reaction was stirred for 1 h; (2) A small amount of the reaction solution was quenched with methanol, and thin layer chromatography showed that the raw material was consumed. After the reaction solution was cooled to -30°C, anhydrous aluminum chloride (20 g, 0.15 mol, 1.5 eq) and TMSOTf (0.8 mL, 0.00 5mol, 0.05 eq) were added, and the mixture was stirred at low temperature; (3) The formation of the product was monitored by thin layer chromatography, and the reaction was terminated when the product no longer changed. The reaction solution was poured into 2M hydrochloric acid aqueous solution at 0°C for quenching; (4) After separation, the aqueous phase was extracted with dichloromethane three times (3 x 200 mL), and the organic phase was combined and washed with 500 mL of saturated NaHCO3 solution and 500 mL of saturated NaCl aqueous solution once. Anhydrous sodium sulfate was added for drying, and the filtrate was concentrated under reduced pressure and evaporated to dryness to obtain 7,8-difluorodibenzo[b,e]selenepentacene-11(6H)-ketone.

[0025] Experimental results: The theoretical yield was 30.92 g, and the actual yield was 10.54 g, with a reaction yield of 34.1%.

[0026] The nuclear magnetic resonance hydrogen spectrum of compound 7,8-difluorodibenzo[b,e]selenepentacene-11(6H)-ketone is shown in Figure 1

[0027] Example 3 Preparation of dipyridine selenepentanone compounds, the reaction equation is referred to Example 2, and compound (III-1) (7,8-difluorodibenzo[b,e]selenepentacene-11(6H)-ketone) is prepared based on compound (II-1) (3,4-difluoro-2-[(phenylselenyl)methyl]benzoic acid).

[0028] The specific preparation process is as follows: ​(1) 3,4-Difluoro-2-[(phenylselenyl)methyl]benzoic acid (15.0 g, 0.046 mol) was used as raw material, and a mixture of oxalyl chloride (11.9 g, 0.09 mol, 2.0 eq) and N,N-dimethylformamide (0.36 mL, 0.005 mol, 0.1 eq) at 0°C was added dropwise to a dichloromethane solution (0.5 M) of the raw material at 0°C, stirred for 10 min, and then naturally raised to room temperature, and stirred for 1 h; (2) A small amount of reaction liquid was quenched with methanol, and thin layer chromatography showed that the raw material was consumed. After the reaction liquid was reduced to -20°C, anhydrous aluminum chloride (9 g, 0.07 mol, 1.5 eq) and TMSOTf (0.74 mL, 0.0046 mol, 0.1 eq) were added, and the mixture was stirred at low temperature; (3) The product formation was monitored by thin layer chromatography, and the reaction was terminated when the product no longer changed. The reaction liquid was poured into 0°C 2M hydrochloric acid aqueous solution for quenching; (4) After separation, the aqueous phase was extracted with dichloromethane three times (3x150 mL), the organic phases were combined, washed with 500 mL saturated NaHCO3 solution and 500 mL saturated NaCl aqueous solution once respectively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and evaporated to dryness to obtain 7,8-difluorodibenzo[b,e]selenepentan-11(6H)-one.

[0029] Experimental results: The theoretical yield was 14.1 g, and the actual yield was 6.2 g, with a reaction yield of 44.0%.

[0030] Example 4 Preparation of dibenzo selenepentanone compounds, the reaction equation is referred to Example 2, and compound (III-1) (7,8-difluorodibenzo[b,e]selenepentan-11(6H)-one) is prepared based on compound (II-1) (3,4-difluoro-2-[(phenylselenyl)methyl]benzoic acid).

[0031] The specific preparation process is as follows: (1) 3,4-Difluoro-2-[(phenylselenyl)methyl]benzoic acid (15.0 g, 0.046 mol) was used as raw material, and a mixture of oxalyl chloride (11.9 g, 0.09 mol, 2.0 eq) and N,N-dimethylformamide (0.36 mL, 0.005 mol, 0.1 eq) at 0°C was added dropwise to a dichloromethane solution (0.5 M) of the raw material at 0°C, stirred for 10 min, and then naturally raised to room temperature, and stirred for 1 h; (2) Take a small amount of reaction solution with methanol quenching, thin layer chromatography detection shows that the raw material is exhausted, the above reaction liquid is reduced to 0℃, then add anhydrous ferric chloride (3.9 g, 0.024 mol, 1.5 eq) and TMSOTf (0.26 mL, 0.0016 mol, 0.1 eq), mix well, then the reaction is raised to room temperature; (3) The thin layer chromatography monitors the generation of the product, and the reaction is terminated after the product no longer changes, and the reaction liquid is poured into 0℃ 2M hydrochloric acid aqueous solution for quenching; (4) After separation, continue to extract the aqueous phase with dichloromethane three times (3*100 mL), combine the organic phase, wash with 500 mL saturated NaHCO3 solution and 500 mL saturated NaCl aqueous solution respectively, dry with anhydrous sodium sulfate, filter, reduce pressure concentration, and evaporate to dryness to prepare compound 7,8-difluorodibenzo[b,e] selenepentafulvene-11 (6H)-ketone.

[0032] Experimental results: the theoretical yield is 4.9 g, the actual output is 0.89 g, and the reaction yield is 18.2%.

[0033] In summary, the present application develops a new method which is simple in operation and friendly to the environment, for synthesizing the key intermediate of anti-influenza virus derivatives, dipheno selenepentafulvene ketone compound, which can be 7,8-difluorodibenzo[b,e] selenepentafulvene-11 (6H)-ketone. On the one hand, the present application breaks through the bottleneck in the prior art that a large amount of high-viscosity and difficult-to-handle liquid reagent polyphosphoric acid must be used, so that the material conveying, feeding precision, stirring mixing, sampling detection, reaction quenching and product purification and other aspects are more simple and stable, the production safety risk is greatly reduced, and the operability of the synthesis process is significantly improved. On the other hand, the preparation method proposed by the present application introduces an extra super strong acid TMSOTf for activation, so that the reaction can be carried out at a mild temperature range of 0℃ to 25℃, effectively solving the problem that dipheno selenepentafulvene ketone compound cannot be prepared due to instability at high temperature, and avoiding the harsh requirement of repeatedly raising and lowering the temperature between 25℃ and 120℃ in the original process, thereby significantly shortening the reaction time, reducing the energy consumption, improving the process safety, effectively reducing the comprehensive production cost, and being more in line with the production concept of green chemical industry.

[0034] Finally, it should be pointed out that the above examples are only used to illustrate the technical solutions of the present application and not to limit it, although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or replaced by equivalents without departing from the purpose and scope of the technical solutions, which should be covered in the scope of the claims of the present application.

Claims

1. A method for preparing a key intermediate of anti-influenza virus derivative dibenzo-selenoheptanone compounds, characterized in that, The preparation method is as follows: The carboxylic acid in compound (II) is activated in-situ into an acyl chloride intermediate based on N,N-dimethylformamide and oxalyl chloride, then intramolecular Friedel-Crafts acylation reaction occurs under the promotion of anhydrous Lewis acid AlCl3 or FeCl3 or TMSOTf, to prepare compound (III); wherein in compound (II), R1and R2are each independently selected from hydrogen, deuterium, C1-C3alkyl, deuterated C1-C3alkyl, or R1, R2and the carbon atom to which they are attached collectively form cyclopropyl or deuterated cyclopropyl; R a , R b , R c and R d are each independently selected from hydrogen, deuterium, C1-C3alkyl, deuterated C1-C3alkyl, C1-C3alkoxy, deuterated C1-C3alkoxy.

2. The production method according to claim 1, characterized by, R1and R2in the compound (II) are hydrogen, R a , R b , R c and R d are each selected from hydrogen, the compound (II) is 3,4-difluoro-2-[(phenylselenyl)methyl]benzoic acid (II-1); and the compound (III) is 7,8-difluorodibenzo[b,e]selenepene-11(6H)-one (III-1): 。 3. The method of any one of claims 1-2, wherein, The preparation method is as follows: (1) under the protection of inert gas, drop the mixed solution of oxalyl chloride and N,N-dimethylformamide into the solution of compound (II), stir uniformly, then heat, and continue to stir reaction; (2) after the reaction of compound (II) is completed, cool the reaction liquid in step (1), add anhydrous Lewis acid and trimethylsilyl super acid salt, mix uniformly, and continue to react; The anhydrous Lewis acid is one of anhydrous AlCl3 and FeCl3, and the trimethylsilyl super acid salt is TMSOTf; (3) after the reaction is completed, pour the reaction liquid in step (2) into hydrochloric acid aqueous solution for quenching; (4) extract three times using dichloromethane, combine the organic phase, wash using saturated NaHCO3 solution and saturated NaCl solution, dry using anhydrous sodium sulfate, filter, reduce pressure to concentrate the filtrate, and evaporate to dryness, to prepare compound (III).

4. The production method according to claim 3, characterized by, The molar ratio of oxalyl chloride, N,N-dimethylformamide and compound (II) in step (1) is 1-3:0.1-0.5:0.1-0.

5.

5. The preparation method according to claim 3, characterized in that, The temperature of the mixed solution of oxalyl chloride and N,N-dimethylformamide, and the solution of compound (II) in step (1) is 0℃, and the stirring time is 10-60 min, then continue to stir reaction at room temperature for 1-3 h.

6. The preparation method according to claim 3, characterized in that, The solvent used for the solution of compound (II) in step (1) is halogenated alkane or benzene solvent, the benzene solvent is benzene or benzene derivative with electron-withdrawing group, and the electron-withdrawing group is selected from one or more of nitro, cyano, halogen and trifluoromethyl.

7. The production method according to claim 6, characterized by, The solvent used for the solution of compound (II) in step (1) is one or more of dichloromethane, chloroform, 1,2-dichloroethane, benzene and chlorobenzene.

8. The preparation method according to claim 3, characterized in that, The molar ratio of anhydrous Lewis acid, trimethylsilyl super acid salt and oxalyl chloride in step (1) is 1-3:0.05-1:1-3.

9. The preparation method according to claim 3, characterized in that, The reaction liquid is cooled to-20℃-0℃ in step (2), and the reaction temperature is-20℃-room temperature after mixing, and the reaction time is 2-10 h.

10. The method of claim 3, wherein, In step (3), the concentration of hydrochloric acid aqueous solution is 0.5-3 M, and the temperature is 0℃.

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