Preparation method of triazine diketone compound with high chiral purity

Abstract

The invention relates to the technical field of drug synthesis, in particular to a preparation method of a high-chiral-purity triazine diketone compound, which comprises the following steps of: performing chiral reduction on a compound I by using a borane reducing agent or performing chiral resolution on the compound I by using an oxazole boron catalyst to obtain an intermediate I; carrying out coupling reaction on the intermediate I and a compound II under the action of a phosphoric anhydride condensing agent to obtain an intermediate II; performing deprotection reaction on the intermediate II to obtain a triazine diketone compound crude product; the method comprises the following steps: extracting and concentrating a triazine diketone compound crude product, adding ethyl acetate and methyl tert-butyl ether, stirring and crystallizing to obtain the high-chiral-purity triazine diketone compound with the e.e.% value of 97.50%-98.64%, the preparation method is mild in reaction condition and simple in operation process, diastereoisomer impurities are not detected, the quality of the raw material medicine is favorably controlled, and the preparation method is expected to be applied to a large-scale production process and has a wide application prospect.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a method for preparing triazinedione compounds with high chiral purity. Background Art

[0002] Influenza virus (IFV) is a segmented single-stranded negative sense RNA virus that can cause influenza in humans and animals. For influenza viruses, the commonly used drugs are neuraminidase (NA) inhibitors, such as oseltamivir, zanamivir and peramivir, but clinical studies have found that resistant virus strains have appeared for such neuraminidase inhibitors. Therefore, there is an urgent need for anti-influenza virus drugs with a new mechanism of action. Patent WO2021233302A1 discloses an anti-influenza virus prodrug compound A, the structure of which is shown below: ; And the following preparation process is disclosed in the patent document disclosed in this article: ; In the preparation process, the chiral triazinedione compound is a key intermediate in the synthesis route of compound A, and its stereo configuration directly determines the configuration of compound A. However, in the disclosed synthesis route, the compound The coupling reaction is carried out to prepare compound A containing three chiral triazine dione compound isomer impurities, and the structural formulas of the three isomer impurities are as follows: , and ; The detection ratio of chiral triazinedione compounds to their chiral isomer impurities is about 1:1:1:1. Such chiral isomer impurities are similar to the materials and chemical properties of the finished product and are difficult to remove by conventional refining methods. In order to ensure the safety and effectiveness of the API, chiral preparative chromatography is required for separation, which not only increases production costs and results in low production efficiency, but also makes it difficult to adapt to large-scale production.

[0003] Therefore, there is an urgent need for a method for preparing triazinedione compounds with high chiral purity. Summary of the invention

[0004] The present invention aims to solve at least one of the technical problems existing in the related art. To this end, the object of the present invention is to provide a method for preparing triazinedione compounds with high chiral purity.

[0005] In order to achieve the above object, the technical solution adopted by the present invention is: A method for preparing a triazine dione compound with high chiral purity, wherein the structural formula of the triazine dione compound is as follows: ; The steps include: S100, using compound Ⅰ After chiral reduction with a borane reducing agent or chiral resolution with an oxadiazole boron catalyst, intermediate Ⅰ is obtained. ; S200, the intermediate Ⅰ and compound Ⅱ Under the action of phosphoric anhydride condensation agent, a coupling reaction is performed to obtain intermediate II ; S300, intermediate II undergoes a deprotection reaction to remove the trimethylsilyl group, thereby obtaining a crude triazinedione compound; S400, the crude triazinedione compound is extracted and concentrated, and then ethyl acetate and methyl tert-butyl ether are added, stirred and crystallized to obtain a solid triazinedione compound.

[0006] Furthermore, the process of step S100 is as follows: Add compound I into organic solvent I to dissolve, then add borane reducing agent or oxazole boron catalyst, and react at -10 to 30°C with stirring for 2.5 to 16 hours to obtain organic solution I containing intermediate I; The process of step S200 is as follows: add compound II and a phosphoric anhydride condensing agent to the organic solution I, react at 20-30° C. with stirring for 15±1h, quench, extract, and concentrate the reaction solution to obtain intermediate II; The process of step S300 is as follows: anhydrous alcohol and an acid solution are added to the intermediate II, and the mixture is stirred at 20 to 30° C. for 12±1 h to remove the trimethylsilyl group, thereby obtaining an organic solution II containing a crude triazine dione compound; The process of step S400 is as follows: adjust the pH value of the organic solution II to 11-12 with an alkaline solution, stand and separate, remove the organic phase, adjust the pH value of the aqueous phase to 3-5 with an aqueous phosphoric acid solution, add an organic solvent II for extraction, separate the layers, collect the organic phase and concentrate it to dryness, add ethyl acetate and methyl tert-butyl ether, stir and crystallize at 20-30°C for 1-1.5h, filter, collect the filter cake and dry it to obtain a solid triazine dione compound.

[0007] Furthermore, the borane reducing agent in step S100 is selected from at least one of borane-tetrahydrofuran complex, borane-dimethyl sulfide complex and (-)-B-diisopinocampheyl chloroborane.

[0008] Furthermore, the molar ratio of the borane reducing agent to the compound I added in step S100 is 1:1 to 5:1.

[0009] Furthermore, the oxadiazole boron catalyst in step S100 is selected from (R)-1-methyl, 3,3-diphenyl-tetrahydro-pyrrolo(1,2-c)(1,3,2)oxadiazole borine .

[0010] Furthermore, the organic solvent I in step S100 is selected from toluene and / or tetrahydrofuran.

[0011] Furthermore, the phosphoric anhydride condensing agent in step S200 is selected from n-butyl phosphoric anhydride.

[0012] Furthermore, the molar ratio of the phosphoric anhydride condensing agent to the compound II added in step S200 is 1:1 to 5:1.

[0013] Furthermore, the anhydrous alcohol in step S300 is selected from anhydrous methanol, and the acid solution is selected from 36 wt % hydrochloric acid.

[0014] Furthermore, in step S400, the alkaline solution is selected from sodium hydroxide aqueous solution and / or potassium hydroxide aqueous solution, and the organic solvent II is selected from dichloromethane.

[0015] The above one or more technical solutions in the embodiments of the present invention have at least one of the following technical effects: The invention provides a method for preparing a triazinedione compound with high chiral purity. The structure of an initial compound I includes a strong steric hindrance functional group, which can effectively improve the stability of the preparation process and avoid the generation of self-polymerized impurities. At the same time, the initial compound I is subjected to chiral reduction or chiral splitting to form an intermediate I with a single configuration. The intermediate I and compound II are subjected to coupling reaction to obtain an intermediate II with a spatial configuration. After the intermediate II is deprotected, extracted and concentrated, ethyl acetate and methyl tert-butyl ether are added. The chiral purity of the target compound triazinedione compound is improved by the synergistic effect of ethyl acetate and methyl tert-butyl ether. The ee% value of the finally obtained solid triazinedione compound is as high as 97.5% to 98.64%, and no diastereoisomer impurities are detected.

[0016] The preparation method provided by the present invention has mild reaction conditions, simple operation process, no diastereoisomer chiral isomer impurities are generated, and is more conducive to controlling the quality of the raw material drug while taking into account safety and cost-effectiveness. It is expected to be applied to large-scale production processes and has broad application prospects.

[0017] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 This is the chiral purity detection spectrum of the triazinedione compound provided in Example 1 of the present invention.

[0019] Figure 2 This is the chiral purity detection spectrum of the triazinedione compound provided in Example 2 of the present invention.

[0020] Figure 3 This is the chiral purity detection spectrum of triazinedione compounds provided in Example 3 of the present invention. DETAILED DESCRIPTION

[0021] In order to make the purpose, technical scheme and advantages of the present invention clearer, the technical scheme in the present invention will be clearly and completely described below in conjunction with specific embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present invention. The following embodiments are used to illustrate the present invention, but cannot be used to limit the scope of the present invention.

[0022] In the following examples, the experimental methods used are conventional methods unless otherwise specified, and are carried out according to the techniques or conditions described in the literature in the field or according to the product instructions. The materials, reagents, etc. used are all commercially available unless otherwise specified.

[0023] A triazine dione compound with high chiral purity , its synthetic route is as follows: ; The preparation method thereof comprises the following steps: S100, to compound Ⅰ After adding organic solvent I to dissolve, add borane reducing agent or oxazolidinone catalyst, and react at -10 to 30°C with stirring for 2.5 to 16 hours to obtain intermediate I of organic solution Ⅰ; S200, add compound II to organic solution I and a phosphoric anhydride condensing agent, react at 20-30°C with stirring for 15±1h, then quench, extract and concentrate the reaction solution to obtain intermediate II ; S300, adding anhydrous alcohol and acid solution to the intermediate II, stirring and reacting at 20-30°C for 12±1h to remove the trimethylsilyl group, and obtaining an organic solution II containing a crude triazinedione compound; S400, adjusting the pH value of the organic solution II to 11-12 with an alkaline solution, standing and separating to remove the organic phase, adjusting the pH value of the aqueous phase to 3-5 with an aqueous phosphoric acid solution, adding an organic solvent II for extraction, separating the layers, collecting the organic phase and concentrating it to dryness, adding ethyl acetate and methyl tert-butyl ether, stirring and crystallizing at 20-30° C. for 1-1.5 hours, filtering, collecting the filter cake and drying it to obtain a solid triazinedione compound.

[0024] Example 1 The starting compound Ⅰ (74.39 g, 213.49 mmol) was added to toluene (500 ml) to dissolve, and (-)-B-diisopinocampheyl chloroborane (68.48 g, 213.49 mmol) was slowly added at 0°C, and then the temperature was raised to 30°C. After stirring and reacting for 16 hours, the temperature was controlled not to exceed 30°C, and potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution with a pH of 7.4 was slowly added to quench the reaction, and the mixture of the toluene layer was collected, dried over anhydrous magnesium sulfate, and filtered to obtain a toluene solution containing the intermediate Ⅰ, i.e., the organic solution Ⅰ, which was directly used for the next step reaction; Compound Ⅱ (60.00 g, 105.68 mmol) and n-butylphosphonic anhydride (50 wt% ethyl acetate solution) (76.14 g, 105.68 mol) were added to the organic solution Ⅰ, mixed evenly, stirred and reacted at 20°C for 15 h, purified water was added to the reaction solution for quenching, extracted with toluene twice (600 ml×2), all toluene mixtures were collected, and concentrated to dryness under reduced pressure to obtain intermediate Ⅱ, anhydrous methanol (1.1 L) and 36 wt% hydrochloric acid (90 ml) were added to the intermediate Ⅱ, and the temperature was maintained at 20°C. The reaction was stirred for 12 h, and the pH value was adjusted to 11 with a 0.5 M sodium hydroxide aqueous solution. The organic phase was allowed to stand and removed. The aqueous phase was adjusted to pH 3 with a 0.5 M phosphoric acid aqueous solution. Dichloromethane (2 L) was added for extraction. The layers were separated. The organic phase was concentrated to dryness. Ethyl acetate (600 ml) was first added to the organic phase, and then methyl tert-butyl ether (600 ml) was added dropwise. The temperature was maintained at 20 ° C. After stirring and crystallization for 1 h, the filter cake was collected after filtration and vacuum dried to obtain a solid triazine dione compound (25.00 g) with high chiral purity. Its chiral chromatogram is as follows: Figure 1 As shown, it was calculated that the ee% value was 98.26% and no diastereoisomer impurities were detected.

[0025] Example 2 The starting compound Ⅰ (29.75g, 85.40mmol) was added to anhydrous tetrahydrofuran (200ml), and (R)-1-methyl, 3,3-diphenyl-tetrahydro-pyrrolo(1,2-c)(1,3,2)oxazolidinone (3.55g, 12.81mmol) was added at a temperature of -10°C, and the temperature was kept at -10°C, and borane-tetrahydrofuran complex (1mol / L, 426.98ml, 427mmol) was slowly added, and the temperature was controlled at -10°C. After stirring for 2.5h, potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution with a pH of 7.4 was slowly added to quench the reaction, and anhydrous tetrahydrofuran was added to the mixture for extraction twice (200ml×2), and the organic layer mixture was collected and dried with anhydrous magnesium sulfate, and filtered to obtain a tetrahydrofuran solution containing intermediate Ⅰ, i.e., organic solution Ⅰ, which was directly used in the next step reaction; Compound Ⅱ (25.00 g, 44.03 mmol) and n-butylphosphonic anhydride (50 wt% ethyl acetate solution) (31.73 g, 88.07 mmol) were added to the organic solution Ⅰ, mixed evenly, stirred and reacted at 25°C for 15 h, purified water was added to the reaction solution for quenching, extracted with tetrahydrofuran twice (200 ml×2), all the tetrahydrofuran mixture was collected, and concentrated to dryness under reduced pressure to obtain intermediate Ⅱ, anhydrous methanol (300 ml) and 36 wt% hydrochloric acid (37 ml) were added to the intermediate Ⅱ, and the temperature was maintained at 40 °C for 2 hours. The mixture was stirred at 25°C for 12 hours, and the pH value was adjusted to 12 with a 0.5M sodium hydroxide solution. The organic phase was allowed to stand and separated. The pH value of the aqueous phase was adjusted to 5 with 0.5M phosphoric acid. Dichloromethane (1L) was added for extraction. The layers were separated. After the organic phase was concentrated to dryness, ethyl acetate (300ml) was first added to the organic phase, and then methyl tert-butyl ether (300ml) was added dropwise. The temperature was maintained at 30°C. After stirring and crystallizing for 1 hour, the filter cake was collected after filtration and vacuum dried to obtain a solid triazinedione compound (16.00 g) with high chiral purity. Its chiral chromatogram is as follows: Figure 2 As shown, it was calculated that the ee% value was 97.50% and no diastereoisomer impurities were detected.

[0026] Example 3 The starting compound Ⅰ (22.31g, 64.05mmol) was added to toluene (150ml), and (R)-1-methyl, 3,3-diphenyl-tetrahydro-pyrrolo(1,2-c)(1,3,2)oxazolidinone (5.33g, 19.21mmol) was added at a temperature of -10°C, and the temperature was kept at -10°C, and borane-dimethyl sulfide complex (10mol / L, 12.8ml, 128mmol) was slowly added. After mixing evenly, the mixture was stirred for reaction for 5h, and the temperature was controlled not to exceed -10°C. A potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution with a pH of 7.4 was slowly added to quench the reaction, and toluene was added for extraction twice (200ml×2), and the organic layer mixture was collected and dried with anhydrous magnesium sulfate, and filtered to obtain a toluene solution containing the intermediate Ⅰ, i.e., the organic solution Ⅰ, which was directly used for the next step reaction; Compound II (20.00 g, 35.23 mmol) and n-butylphosphonic anhydride (50% ethyl acetate solution) (126.91 g, 176.13 mmol) were added to the organic solution I and mixed evenly. After stirring for 15 h at 30°C, purified water was added to the reaction solution for quenching, and the solution was extracted twice with toluene (400 ml × 2). Collect all the toluene mixture, concentrate to dryness under reduced pressure to obtain intermediate II, add anhydrous methanol (400 ml) and 36 wt% hydrochloric acid (30 ml) to the intermediate II, keep the temperature at 30°C, stir and react for 12 h, adjust the pH value to 11.5 with 0.5 M potassium hydroxide solution, remove the organic phase after standing, adjust the pH value of the aqueous phase to 4 with 0.5 M phosphoric acid aqueous solution, add dichloromethane (600 ml) for extraction, separate the layers, concentrate the organic phase to dryness, first add ethyl acetate (200 ml) to the organic phase, and then add methyl tert-butyl ether (200 ml) dropwise, keep the temperature at 25°C, stir and crystallize for 1.5 h, filter and collect the filter cake, and vacuum dry the filter cake to obtain a solid triazine dione compound (12.00 g) with high chiral purity, and its chiral chromatogram is as follows: Figure 3 As shown, it was calculated that the ee% value was 98.64% and no diastereoisomer impurities were detected.

[0027] From Examples 1 to 3, it can be seen that the preparation method provided by the present invention can obtain triazinedione compounds with a chiral purity of 97.50% to 98.64%, and no diastereoisomer impurities are detected.

[0028] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a triazine dione compound with high chiral purity, characterized in that: The structural formula of the triazine dione compound is as follows: ； The steps include: S100, using compound Ⅰ After chiral reduction with a borane reducing agent or chiral resolution with an oxadiazole boron catalyst, intermediate Ⅰ is obtained. ; S200, the intermediate Ⅰ and compound Ⅱ Under the action of phosphoric anhydride condensation agent, a coupling reaction is performed to obtain intermediate II ; S300, intermediate II undergoes a deprotection reaction to remove the trimethylsilyl group, thereby obtaining a crude triazinedione compound; S400, the crude triazinedione compound is extracted and concentrated, and then ethyl acetate and methyl tert-butyl ether are added, stirred and crystallized to obtain a solid triazinedione compound.

2. The method for preparing a triazine dione compound with high chiral purity according to claim 1, characterized in that: The process of step S100 is as follows: Add compound I into organic solvent I to dissolve, then add borane reducing agent or oxazolidinone catalyst, and react at -10 to 30° C. with stirring for 2.5 to 16 hours to obtain organic solution I containing intermediate I; The process of step S200 is as follows: add compound II and a phosphoric anhydride condensing agent to the organic solution I, react at 20-30° C. with stirring for 15±1h, quench, extract, and concentrate the reaction solution to obtain intermediate II; The process of step S300 is as follows: anhydrous alcohol and an acid solution are added to the intermediate II, and the mixture is stirred at 20 to 30° C. for 12±1 h to remove the trimethylsilyl group, thereby obtaining an organic solution II containing a crude triazine dione compound; The process of step S400 is as follows: adjust the pH value of the organic solution II to 11-12 with an alkaline solution, stand and separate, remove the organic phase, adjust the pH value of the aqueous phase to 3-5 with an aqueous phosphoric acid solution, add an organic solvent II for extraction, separate the layers, collect the organic phase and concentrate it to dryness, add ethyl acetate and methyl tert-butyl ether, stir and crystallize at 20-30°C for 1-1.5h, filter, collect the filter cake and dry it to obtain a solid triazine dione compound.

3. The method for preparing a triazine dione compound with high chiral purity according to claim 2, characterized in that: The borane reducing agent in step S100 is at least one selected from borane-tetrahydrofuran complex, borane-dimethyl sulfide complex and (-)-B-diisopinocampheyl chloroborane.

4. The method for preparing a triazine dione compound with high chiral purity according to claim 2, characterized in that: The molar ratio of the borane reducing agent to the compound I added in step S100 is 1:1 to 5:

1.

5. The method for preparing a triazine dione compound with high chiral purity according to claim 2, characterized in that: The oxadiazole boron catalyst in step S100 is selected from (R)-1-methyl, 3,3-diphenyl-tetrahydro-pyrrolo(1,2-c)(1,3,2)oxadiazole borine .

6. The method for preparing a triazine dione compound with high chiral purity according to claim 2, characterized in that: The organic solvent I in step S100 is selected from toluene and / or tetrahydrofuran.

7. The method for preparing a triazine dione compound with high chiral purity according to claim 2, characterized in that: The phosphoric anhydride condensing agent in step S200 is selected from n-butyl phosphoric anhydride.

8. The method for preparing a triazine dione compound with high chiral purity according to claim 2, characterized in that: The molar ratio of the phosphoric anhydride condensing agent to the compound II added in step S200 is 1:1 to 5:

1.

9. The method for preparing a triazine dione compound with high chiral purity according to claim 2, characterized in that: The anhydrous alcohol in step S300 is selected from anhydrous methanol, and the acid solution is selected from 36 wt % hydrochloric acid.

10. The method for preparing a triazine dione compound with high chiral purity according to claim 2, characterized in that: In step S400, the alkaline solution is selected from sodium hydroxide aqueous solution and / or potassium hydroxide aqueous solution, and the organic solvent II is selected from dichloromethane.

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