Preparation method of anti-influenza virus derivative intermediate

Abstract

The invention belongs to the field of pharmaceutical chemicals, and relates to a preparation method of an anti-influenza virus derivative intermediate. According to the invention, a compound (a) and a compound (b) are taken as initial raw materials, and an alcoholic hydroxyl group is directly converted into an active intermediate by utilizing trimethylsilyl trifluoromethanesulfonate (TMSOTf), so that the tedious operation of firstly protecting the hydroxyl group and then carrying out substitution reaction in the traditional method is avoided, and a key intermediate (d) required for preparing the anti-influenza virus derivative can be obtained in one step. The method has the advantages of simplicity and convenience in operation, high yield, easiness in industrial amplification and the like, and is suitable for large-scale preparation of the anti-influenza virus medicine and pharmaceutically acceptable salts, esters or solvates thereof.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemical industry, and relates to a preparation method of an anti-influenza virus derivative intermediate. BACKGROUND

[0002] Influenza is a seasonal epidemic caused by influenza virus, which causes about 1 billion people to be infected and 650,000 people to die globally every year, and seriously threatens public health safety. The replication of the virus depends on the cap-dependent endonuclease activity of its RNA polymerase, which becomes an important target for the development of antiviral drugs. By inhibiting the endonuclease activity, the virus proliferation can be effectively blocked, thereby controlling the infection. At present, a variety of compounds containing heterocyclic structures have been used for the development of cap-dependent endonuclease inhibitors. Among them, baloxavir ester is used as a kind of inhibitor on the market, but its application still faces the limitations of low bioavailability and drug resistance. Therefore, it is of clear clinical demand and practical significance to develop a new generation of cap-dependent endonuclease inhibitors with higher efficiency, bioavailability and drug resistance barrier.

[0003] Patent CN117003766A discloses an efficient anti-influenza virus 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 present application can be used for preparing a drug for preventing / treating influenza virus.

[0004]

[0005] In the above-mentioned patent, the synthesis route of such compounds is also described, taking the synthesis of the following compound as an example. The condensation is carried out using compounds (e) and (f) as raw materials, and then the side chain is connected after debenzyl to obtain compound (I) with antiviral activity. The reaction route is as shown below:

[0006] The industrialization process of such drugs is significantly restricted, mainly due to the incomplete supply chain of key starting materials. The core precursor compounds have not yet been commercially supplied in kilogram quantities, and the existing methods highly rely on multi-step custom synthesis, resulting in high raw material costs and thus high overall production costs. Patents CN110637016A and CN115385932A describe the preparation method of such upstream raw materials: with 1-amino-1,4-dihydro-4-oxo-3-(benzyloxy)-2-pyridinecarboxylic acid methyl ester (b) and 2-propen-1-yl-6-methoxy-4-oxa-7-azaspiro[2.5]octane-7-carboxylate (c) as raw materials, under the action of condensing agent, to generate 6-{[3-(benzyloxy)-2-(methoxycarbonyl)-4-oxopyridin-1(4H)-yl]amino}-4-oxa-7-azaspiro[2.5]octane-7-carboxylate (d), compound (d) is cyclized to generate compound (e), compound (e) is the key raw material of the above-mentioned antiviral active drug (I), and the specific reaction route is as shown below:

[0007] And compound (c) needs to be obtained by esterification of 2-propen-1-yl-6-hydroxy-4-oxa-7-azaspiro[2.5]octane-7-carboxylate (a), and the reaction route is as shown below. Compound (a) is obtained from compound (d) by two-step reaction with a yield of 49% according to patent CN110637016A.

[0008]

[0009] In summary, the synthesis process of the antiviral derivative cap-dependent endonuclease inhibitor is complex, and reducing one synthesis step can lead to optimization and improvement of the entire process chain. In order to enhance the economic feasibility and market application potential of such anti-influenza virus drugs, it is urgent to optimize the existing synthesis path, and to focus on developing easily available and low-cost alternative starting materials to control costs from the source and ensure stable supply. SUMMARY

[0010] Therefore, the purpose of the present application is to provide a preparation method of an anti-influenza virus derivative intermediate of a cap-dependent endonuclease inhibitor.

[0011] To achieve the above purpose, the present application provides the following technical solutions: A preparation method of an anti-influenza virus derivative intermediate, prepared by the following route:

[0012] Compounds (a) and (b) react in one step under the catalysis of trimethylsilyl trifluoromethanesulfonate to generate compound (d); In compound (a), R1 and R2 are each independently selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, or R1, R2 and the carbon atom attached thereto together form cyclopropyl, cyclobutyl, or deuterated cyclopropyl, deuterated cyclobutyl; R3 and R4 are each independently selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, or R3, R4 and the carbon atom attached thereto together form cyclopropyl, cyclobutyl, or deuterated cyclopropyl, deuterated cyclobutyl; X is O or N, and R5 is one of C1-C6 alkyl, C1-C6 halogen-substituted alkyl, allyl, benzyl, p-methoxybenzyl, alkyl-substituted benzyl, or halogen-substituted benzyl; In compound (b), R6 and R7 are each independently selected from one of C1-C6 alkyl, C1-C6 halogen-substituted alkyl, allyl, benzyl, p-methoxybenzyl, alkyl-substituted benzyl, and halogen-substituted benzyl.

[0013] Preferably, in compound (a), R1 and R2, together with the carbon atoms attached to them, form a cyclopropyl group, X is O, R3 and R4 are hydrogen, and R5 is allyl, so compound (a) is 2-propen-1-yl-6-hydroxy-4-oxa-7-azaspiro[2.5]octane-7-carboxylate (a-1); in compound (b), R6 is benzyl, R7 is methyl, so compound (b) is methyl 1-amino-1,4-dihydro-4-oxo-3-(benzoxy)-2-pyridinecarboxylate (b-1); and compound (d) is 6-{[3-(benzoxy)-2-(methoxycarbonyl)-4-oxopyridin-1(4H)-yl]amino}-4-oxa-7-azaspiro[2.5]octane-7-carboxylate allyl ester (d-1):

[0014] The specific preparation method is as follows: (1) Using compounds (a) and (b) as substrates, add an organic solvent and stir to react; The organic solvent is one of tetrahydrofuran, acetonitrile, N,N-dimethylformamide, pyridine, or dichloromethane; (2) Add trimethylsilyl trifluoromethanesulfonate dropwise, and raise the temperature to react after the addition is complete; (3) After the reaction is complete, the temperature is raised, the pH of the solution is adjusted, the organic solvent is removed by vacuum evaporation, ethyl acetate is added for extraction, the organic phases are combined, and the solution is concentrated to obtain compound (d).

[0015] Preferably, in step (1), the molar ratio of compound (a), compound (b) and organic solvent is 1.1~2:1:0.1~0.5; Preferably, the reaction temperature in step (1) is -30℃ to -80℃, and the reaction time is 5 to 30 min; Preferably, in step (1), anhydrous potassium carbonate is added simultaneously to absorb acidic byproducts and water; Preferably, the molar ratio of trimethylsilyl trifluoromethanesulfonate to compound (b) in step (1) in step (2) is 1.0~1.2:1; Preferably, the reaction temperature in step (2) is -30℃ to -10℃, and the reaction time is 1 to 2 h; Preferably, in step (3), the temperature is raised to 0~25℃, and the pH of the solution is adjusted to 6~7 using a saturated sodium bicarbonate solution.

[0016] The beneficial effects of this invention are as follows: This invention relates to a method for preparing an intermediate of an anti-influenza virus derivative for use with a cap-dependent endonuclease inhibitor, which has the following advantages: 1. Significantly simplified synthesis route: Compared with traditional processes, this invention utilizes trimethylsilyl trifluoromethanesulfonate (TMSOTf) to directly convert alcohol hydroxyl groups into active intermediates, avoiding the cumbersome operation of protecting hydroxyl groups before substitution reactions in traditional methods. The key intermediate (d) can be obtained in one step, thereby significantly shortening the reaction cycle, reducing the number of operation units, and improving synthesis efficiency. 2. Avoid using high-risk reagents: This method does not require the use of toxic methanol or corrosive toluenesulfonic acid, reducing safety and environmental risks and exhibiting good process friendliness; 3. Reduced purification burden: By omitting the esterification reaction, the post-processing and separation purification operations of this step are avoided, which saves time and reduces material loss, thus improving the overall reaction yield. 4. Low cost and suitable for large-scale production: The method described in this invention uses readily available raw materials, mild reaction conditions, and is easy to operate. It does not rely on custom synthesis of key precursors, making it more economical and providing a feasible path for the commercial production of key intermediate raw materials at the kilogram level and above. 5. Improved overall production efficiency: The optimization of this synthetic route significantly improves the overall production efficiency of cap-dependent endonuclease inhibitor antiviral drugs, and has good prospects for industrial application.

[0017] Other advantages, objectives, and features of the invention will be set forth in part in the description which follows, and in part will be apparent to those skilled in the art from the following examination, or may be learned from practice of the invention. The objectives and other advantages of the invention can be realized and obtained through the following description. Attached Figure Description

[0018] To make the objectives, technical solutions, and advantages of the present invention clearer, the preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings, wherein: Figure 1 The image shows the proton NMR spectrum of compound (d-1). Figure 2 The HPLC-MS chromatogram of compound (d-1) is shown. Detailed Implementation

[0019] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention. It should be noted that the illustrations provided in the following embodiments are only schematic representations of the basic concept of the present invention. Unless otherwise specified, the following embodiments and features can be combined with each other.

[0020] Example 1 The reaction mechanism for preparing compound (d) from compounds (a) and (b) is explained.

[0021] Trimethylsilyl trifluoromethanesulfonate (TMSOTf) is a highly efficient silylating agent, containing partially positively charged silicon atoms (Si... + The intermediate (a) reacts with the partially negatively charged oxygen atom on the hydroxyl group (R-OH) of the intermediate (a) to form alkoxytrimethylsilane (TMS-OR), simultaneously releasing trifluoromethanesulfonate ions (OTf). - The proton remains on the hydroxyl group. Due to the simultaneous presence of the proton and TMS, the leaving group is no longer a simple hydroxyl or siloxy anion, but rather a highly stable trimethylsilanol ((CH3)3SiOH). Under acidic conditions, it readily leaves the hydroxyl group. Simultaneously, the presence of the ortho-nitrogen atom stabilizes this electrophilic center, forming an imine ion intermediate, thus greatly promoting the leaving process. At this point, substrate (a) has been activated into an excellent electrophile. It is speculated that this reaction tends towards an SN1-like addition mechanism involving ortho-nitrogen: the leaving group first leaves with its electron pair, while the lone pair of electrons from the ortho-nitrogen atom transfers, forming an imine ion intermediate. Then, the lone pair of electrons from the nitrogen atom on the amine group (R'-NH2) of substrate (b) attacks the carbon atom. In the nucleophilic attack step, the nitrogen atom of the amine carries a positive charge; the sodium bicarbonate added during quenching will capture this proton, generating the final amine product compound (d).

[0022] Example 2 The reaction equation for the preparation of compound (d-1) is shown below, wherein compound (a-1) is 2-propen-1-yl-6-hydroxy-4-oxa-7-azaspiro[2.5]octane-7-carboxylic acid ester, compound (b-1) is methyl 1-amino-1,4-dihydro-4-oxo-3-(benzoxy)-2-pyridinecarboxylate, and the prepared compound (d-1) is 6-{[3-(benzyloxy)-2-(methoxycarbonyl)-4-oxopyridin-1(4H)-yl]amino}-4-oxa-7-azaspiro[2.5]octane-7-carboxylic acid allyl ester.

[0023]

[0024] The specific preparation process is as follows: (1) Weigh 2-propen-1-yl-6-hydroxy-4-oxa-7-azaspiro[2.5]octane-7-carboxylic acid ester (23.6 g, 0.11 mol, 1.1 eq) and methyl 1-amino-1,4-dihydro-4-oxo-3-(benzoxy)-2-pyridinecarboxylate (27.5 g, 0.1 mol, 1.0 eq), add 200 mL tetrahydrofuran (0.5 M), stir the reaction, and keep warm at -80℃ for 10 min; (2) Trimethylsilyl trifluoromethanesulfonate (TMSOTf, 24.5 g, 0.11 mol, 1.1 eq) was slowly added dropwise. After the addition of TMSOTf was completed, the temperature was slowly raised to -30℃ and kept at -30℃ for 1 h. (3) Take a small amount of reaction solution, add saturated sodium bicarbonate solution to quench it, and thin-layer chromatography detection shows that the raw materials are completely consumed. Take 0.1 mL of reaction solution, add saturated sodium bicarbonate solution to the above reaction solution to quench it, centrifuge, take the upper organic phase, dilute it 10 times with 70% acetonitrile, filter it with a microporous membrane, and detect it with HPLC. When the product content no longer changes, the reaction is terminated. (4) The temperature of the reaction system was slowly raised to 10°C, the pH was adjusted to 6-7 with saturated NaHCO3 solution, most of the tetrahydrofuran was removed by vacuum evaporation, ethyl acetate was added for extraction, and the mixture was concentrated to obtain compound (d-1).

[0025] Experimental results: The theoretical yield was 46.9 g, the actual yield was 28.3 g, the reaction yield was 60.4%, and the purity of compound (d-1) was 91.2%.

[0026] The proton NMR spectrum of compound (d-1) is shown below. Figure 1Shown, HNMR (CDCl3, 600MHz): δ 7.51-7.22 (m, 6H), 6.82-6.23 (m, 1H), 5.99-5.61 (m, 1H), 5.33-5.10 (m, 5H), 4.66-4.23 (m, 2H), 3.94-3.69 (m, 6H), 3.43-3.16 (m, 1H), 1.06-0.84 (m, 1H), 0.79-0.63 (m, 2H), 0.61-0.46 (m 1H).

[0027] The HPLC-MS chromatogram of compound (d-1) is shown below. Figure 2 As shown, compound (d-1) has a retention time of 4.98 min, and its mass spectrometry information is [M+H]. + = m / z 470.19.

[0028] Example 3 The preparation of compound (d-1) was carried out according to the reaction equation in Example 1, wherein compound (a-1) was 2-propen-1-yl-6-hydroxy-4-oxa-7-azaspiro[2.5]octane-7-carboxylic acid ester, compound (b-1) was methyl 1-amino-1,4-dihydro-4-oxo-3-(benzoxy)-2-pyridinecarboxylate, and the resulting compound (d-1) was 6-{[3-(benzyloxy)-2-(methoxycarbonyl)-4-oxopyridin-1(4H)-yl]amino}-4-oxa-7-azaspiro[2.5]octane-7-carboxylic acid allyl ester.

[0029] The specific preparation process is as follows: (1) Weigh 12.0 g, 0.06 mol, 1.1 eq of 2-propen-1-yl-6-hydroxy-4-oxa-7-azaspiro[2.5]octane-7-carboxylic acid ester (14.0 g, 0.05 mol, 1.0 eq) and methyl 1-amino-1,4-dihydro-4-oxo-3-(benzoxy)-2-pyridinecarboxylate ester (14.0 g, 0.05 mol, 1.0 eq), add 100 mL of tetrahydrofuran (0.5 M) and anhydrous potassium carbonate (21.0 g, 0.15 mol, 3.0 eq), start stirring, and keep warm at -20℃ for 10 min; (2) Trimethylsilyl trifluoromethanesulfonate (TMSOTf, 11.1 g, 0.05 mol, 1.0 eq) was slowly added dropwise. After the addition of TMSOTf was completed, the reaction was kept at -20℃ for 1 h. (3) Take a small amount of reaction solution, add saturated sodium bicarbonate solution to quench it, and thin-layer chromatography detection shows that the raw materials are completely consumed. Take 0.1 mL of reaction solution, add saturated sodium bicarbonate solution to the above reaction solution to quench it, centrifuge, take the upper organic phase, dilute it 10 times with 70% acetonitrile, filter it through a microporous membrane, and detect it by HPLC. When the product content no longer changes, the reaction is terminated. (4) The temperature of the reaction system was slowly raised to room temperature, the pH was adjusted to 6-7 with saturated NaHCO3 solution, most of the tetrahydrofuran was removed by vacuum evaporation, ethyl acetate was added for extraction, and the mixture was concentrated to obtain compound (d-1).

[0030] Experimental results: The theoretical yield was 24.9 g, the actual yield was 15.2 g, the reaction yield was 61.1%, and the purity of compound (d-1) was 83.6%. Example 4 The preparation of compound (d-1) is described in Example 1, with reaction equations provided. Compound (a-1) is 2-propen-1-yl-6-hydroxy-4-oxa-7-azaspiro[2.5]octane-7-carboxylic acid ester, and compound (b-1) is methyl 1-amino-1,4-dihydro-4-oxo-3-(benzoxy)-2-pyridinecarboxylate. The resulting compound (d-1) is 6-{[3-(benzyloxy)-2-(methoxycarbonyl)-4-oxopyridin-1(4H)-yl]amino}-4-oxa-7-azaspiro[2.5]octane-7-carboxylic acid allyl ester.

[0031] The specific preparation process is as follows: (1) Weigh 12.0 g, 0.06 mol, 1.1 eq of 2-propen-1-yl-6-hydroxy-4-oxa-7-azaspiro[2.5]octane-7-carboxylic acid ester (14.0 g, 0.05 mol, 1.0 eq) and methyl 1-amino-1,4-dihydro-4-oxo-3-(benzoxy)-2-pyridinecarboxylate ester (14.0 g, 0.05 mol, 1.0 eq), add 200 mL of tetrahydrofuran (0.25 M), start stirring, and keep warm at -30℃ for 10 min; (2) Trimethylsilyl trifluoromethanesulfonate (TMSOTf, 13.3 g, 0.06 mol, 1.2 eq) was slowly added dropwise. After the addition of TMSOTf was completed, the temperature was slowly raised to -30℃ and the reaction was carried out at -30℃ for 1 h. (3) Take a small amount of reaction solution, add saturated sodium bicarbonate solution to quench it, and thin-layer chromatography shows that the raw materials are completely consumed. Take 0.1 mL of reaction solution, add saturated sodium bicarbonate solution to quench it, centrifuge, take the upper organic phase, dilute it 10 times with 70% acetonitrile, filter it through a microporous membrane, and detect it by HPLC. When the product content no longer changes, the reaction is terminated. (4) The temperature of the reaction system was slowly raised to 10℃, the pH was adjusted to 6~7 with saturated NaHCO3 solution, most of the tetrahydrofuran was removed by vacuum evaporation, ethyl acetate was added for extraction, and the mixture was concentrated to obtain compound (d-1).

[0032] Experimental results: The theoretical yield was 24.9 g, the actual yield was 13.4 g, the reaction yield was 53.8%, and the purity of compound (d-1) was 89.3%.

[0033] In summary, this invention relates to a method for preparing a key intermediate for synthesizing cap-dependent endonuclease inhibitors of antiviral drugs. The method significantly shortens the synthetic pathway of the key intermediate, effectively reduces reaction steps, and improves synthetic efficiency, thereby significantly simplifying the production process of a class of cap-dependent endonuclease inhibitors of anti-influenza virus drugs. This method has advantages such as simple operation, high yield, and ease of industrial scale-up, and is suitable for the large-scale preparation of the aforementioned anti-influenza virus drugs and their pharmaceutically acceptable salts, esters, or solvates.

[0034] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A method for preparing an intermediate of an anti-influenza virus derivative, characterized in that, Prepared via the following route: Compounds (a) and (b) were reacted in one step to form compound (d) under the catalysis of trimethylsilyl trifluoromethanesulfonate. in In compound (a), R1 and R2 are each independently selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, or R1, R2 and the carbon atom attached thereto together form cyclopropyl, cyclobutyl, or deuterated cyclopropyl, deuterated cyclobutyl; R3 and R4 are each independently selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, or R3, R4 and the carbon atom attached thereto together form cyclopropyl, cyclobutyl, or deuterated cyclopropyl, deuterated cyclobutyl; X is O or N, and R5 is one of C1-C6 alkyl, C1-C6 halogen-substituted alkyl, allyl, benzyl, p-methoxybenzyl, alkyl-substituted benzyl, or halogen-substituted benzyl; In compound (b), R6 and R7 are each independently selected from one of C1-C6 alkyl, C1-C6 halogen-substituted alkyl, allyl, benzyl, p-methoxybenzyl, alkyl-substituted benzyl, and halogen-substituted benzyl.

2. The preparation method according to claim 1, characterized in that, In compound (a), R1 and R2 form a cyclopropyl group with the carbon atom attached to them, X is O, R3 and R4 are hydrogen, and R5 is allyl. Compound (a) is 2-propen-1-yl-6-hydroxy-4-oxa-7-azaspiro[2.5]octane-7-carboxylate (a-1). In compound (b), R6 is benzyl, R7 is methyl, and compound (b) is methyl 1-amino-1,4-dihydro-4-oxo-3-(benzoxy)-2-pyridinecarboxylate (b-1). Compound (d) is 6-{[3-(benzoxy)-2-(methoxycarbonyl)-4-oxopyridin-1(4H)-yl]amino}-4-oxa-7-azaspiro[2.5]octane-7-carboxylate allyl ester (d-1). 。 3. The preparation method according to any one of claims 1 to 2, characterized in that, The preparation method is as follows: (1) Using compounds (a) and (b) as substrates, add an organic solvent and stir to react; The organic solvent is one of tetrahydrofuran, acetonitrile, N,N-dimethylformamide, pyridine, or dichloromethane; (2) Add trimethylsilyl trifluoromethanesulfonate dropwise, and raise the temperature to react after the addition is complete; (3) After the reaction is complete, the temperature is raised, the pH of the solution is adjusted, the organic solvent is removed by vacuum evaporation, ethyl acetate is added for extraction, the organic phases are combined, and the solution is concentrated to obtain compound (d).

4. The preparation method according to claim 3, characterized in that, In step (1), the molar ratio of compound (a), compound (b) and organic solvent is 1.1~2:1:0.1~0.

5.

5. The preparation method according to claim 3, characterized in that, The reaction temperature in step (1) is -30℃ to -80℃, and the reaction time is 5 to 30 min.

6. The preparation method according to claim 3, characterized in that, In step (1), anhydrous potassium carbonate is added simultaneously to absorb the acidic byproducts and water.

7. The preparation method according to claim 3, characterized in that, In step (2), the molar ratio of trimethylsilyl trifluoromethanesulfonate to compound (b) in step (1) is 1.0~1.2:

1.

8. The preparation method according to claim 3, characterized in that, The reaction temperature in step (2) is -30℃ to -10℃, and the reaction time is 1 to 2 hours.

9. The preparation method according to claim 3, characterized in that, In step (3), the temperature is raised to 0~25℃, and the pH of the solution is adjusted to 6~7 using a saturated sodium bicarbonate solution.

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