Fused ring pyridone compound, preparation method and application

[0110] Embodiment General preparation method two

[0111]

[0112] Step 1: Dissolve the fused ring pyridone intermediate (1eq.) in anhydrous tetrahydrofuran, add DIPEA (1.6eq.) and piperazine intermediate (1.5eq.) in sequence, and heat to reflux for 18 hours under nitrogen protection . The reaction was complete as monitored by TLC, cooled to room temperature, and concentrated under reduced pressure. The residue was separated by adding water and dichloromethane. The aqueous phase was extracted three times with dichloromethane. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The target product was obtained by chromatography separation and purification, and its structure was confirmed by NMR and mass spectrometry.

[0113] The second step: dissolve the above-mentioned first step product (1eq.) in anhydrous glacial acetic acid, slowly add reduced iron powder (3eq.), and heat to 80 degrees under nitrogen protection and stir for 0.5 hours. After the reaction was completed, it was filtered through celite, washed with ethyl acetate, and the filtrate was concentrated. The residue was diluted with dichloromethane, washed successively with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain the target product. Confirm the structure.

[0114]The third step: Dissolve the above-mentioned second-step product (1eq.) in DMF, add sodium hydrogen (1.5eq.) at 0°C, stir for 0.5 hours, add iodomethane (1.1eq.), and react overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was diluted with dichloromethane, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography. The target product was purified, and its structure was confirmed by NMR and mass spectrometry.

[0115] Step 4: Dissolve the above-mentioned third step product (1eq.) in a mixed solvent of anhydrous dioxane/water (4/1), add boric acid or trifluoroborate potassium salt (2eq.) successively, and anhydrous Potassium carbonate powder (2.5eq.) and Pd(dppf)Cl 2 (0.1eq.), heated to reflux under nitrogen protection for 2 hours. The reaction was complete as monitored by TLC, cooled to room temperature, concentrated under reduced pressure, the residue was diluted with dichloromethane, washed successively with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was washed with silica gel The target product was obtained by separation and purification by column chromatography, and its structure was confirmed by NMR and mass spectrometry.

[0116] Step 5: Dissolve the product (1 eq.) of the fourth step above in methanol, add 4M hydrogen chloride/methanol solution (20 eq.), and stir at room temperature for 3 hours. The completion of the reaction was monitored by TLC, concentrated under reduced pressure, and the residue was dissolved in dichloromethane, and DIPEA (3eq.) and acryloyl chloride (1eq.) were added successively at 0°C, stirred for 0.5 hours, and the reaction solution was washed with saturated ammonium chloride solution and saturated Washed with saline, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the target compound, whose structure was confirmed by NMR and mass spectrometry.

[0117] Embodiment General preparation method three

[0118]

[0119] Step 1: Dissolve the fused ring pyridone amide intermediate (1eq.) in a mixed solvent of acetonitrile/triethylamine (3/1), add phosphorus pentasulfide (1eq.) in batches, and heat to reflux for 3 hours under nitrogen protection . After the reaction was completed, cooled to room temperature, a solid precipitated out, filtered, and the filter cake was vacuum-dried to obtain the target product, whose structure was confirmed by NMR and mass spectrometry.

[0120] The second step: dissolve the above-mentioned first step product (1eq.) in a mixed solvent of ethanol/DIPEA (5/1), add 2,2-dimethoxyethylamine (1eq.), and heat to reflux under nitrogen protection 6 hours. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in glacial acetic acid, heated to 100°C and stirred for 2 hours. Cool to room temperature, concentrate under reduced pressure, dilute the residue with dichloromethane, wash with saturated sodium bicarbonate solution and saturated brine successively, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate and purify the residue by silica gel column chromatography The target product was obtained, and its structure was confirmed by NMR and mass spectrometry.

[0121] The third step: dissolve the above-mentioned second step product (1eq.) in the mixed solvent of anhydrous dioxane/water (4/1), add boric acid or trifluoroborate potassium salt (2eq.) successively, anhydrous Potassium carbonate powder (2.5eq.) and Pd(dppf)Cl 2 (0.1eq.), heated to reflux under nitrogen protection for 2 hours. The reaction was complete as monitored by TLC, cooled to room temperature, concentrated under reduced pressure, the residue was diluted with dichloromethane, washed successively with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was washed with silica gel The target product was obtained by separation and purification by column chromatography, and its structure was confirmed by NMR and mass spectrometry.

[0122] Step 4: Dissolve the product (1 eq.) of the third step above in methanol, add 4M HCl methanol solution (20 eq.), and stir at room temperature for 3 hours. The completion of the reaction was monitored by TLC, concentrated under reduced pressure, and the residue was dissolved in dichloromethane, and DIPEA (3eq.) and acryloyl chloride (1eq.) were added successively at 0°C, stirred for 0.5 hours, and the reaction solution was washed with saturated ammonium chloride solution and saturated Washed with saline, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the target compound, whose structure was confirmed by NMR and mass spectrometry.

[0123] Embodiment General preparation method four

[0124]

[0125] Step 1: Dissolve the fused ring pyridone sulfamide intermediate (1eq.) in tetrahydrofuran, add hydrazine hydrate (1.5eq.), and heat to reflux for 6 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, a solid precipitated out, filtered, and the filter cake was vacuum-dried to obtain the target product. The structure was confirmed by NMR and mass spectrometry.

[0126] The second step: dissolve the above-mentioned first step product (1eq.) in dichloromethane, add trimethyl orthoformate (4eq.), stir for ten minutes, and then add trifluoroacetic acid (1eq.). After continuing to stir at room temperature for one hour, it was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the target product, whose structure was confirmed by NMR and mass spectrometry.

[0127] The third step: dissolve the above-mentioned second step product (1eq.) in the mixed solvent of anhydrous dioxane/water (4/1), add boric acid or trifluoroborate potassium salt (2eq.) successively, anhydrous Potassium carbonate powder (2.5eq.) and Pd(dppf)Cl 2 (0.1eq.), heated to reflux under nitrogen protection for 2 hours. The reaction was complete as monitored by TLC, cooled to room temperature, concentrated under reduced pressure, the residue was diluted with dichloromethane, washed successively with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was washed with silica gel The target product was obtained by separation and purification by column chromatography, and its structure was confirmed by NMR and mass spectrometry.

[0128] Step 4: Dissolve the product (1 eq.) of the third step above in methanol, add 4M HCl methanol solution (20 eq.), and stir at room temperature for 3 hours. The completion of the reaction was monitored by TLC, concentrated under reduced pressure, and the residue was dissolved in dichloromethane, and DIPEA (3eq.) and acryloyl chloride (1eq.) were added successively at 0°C, stirred for 0.5 hours, and the reaction solution was washed with saturated ammonium chloride solution and saturated Washed with saline, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the target compound, whose structure was confirmed by NMR and mass spectrometry.

[0129] Embodiment General preparation method five

[0130]

[0131] The first step: dissolve the fused ring pyridone sulfamide intermediate (1eq.) in a mixed solvent of methanol/concentrated ammonia water (1/1), place it in a stuffy tank, add a catalytic amount of p-toluenesulfonic acid, and heat to Stir at 100 degrees for 6 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was diluted with dichloromethane, washed successively with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was directly used in the next reaction.

[0132] The second step: Suspend the crude product (1 eq.) of the first step above in isopropanol, and add dimethylformamide-dimethyl acetal (1.2 eq.) dropwise at room temperature. After the dropwise addition, the reaction solution was heated to reflux for three hours, cooled to room temperature, and hydroxylamine hydrochloride (1.2 eq.) was added to the reaction solution, and heated and stirred overnight at 50°C. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and dried. The residue was suspended in anhydrous THF, cooled in an ice bath, and then trifluoroacetic anhydride (1.5 eq.) was slowly added dropwise. After the dropwise addition was completed, the ice bath was removed, and the mixture was stirred overnight at room temperature. Slowly add saturated sodium bicarbonate solution dropwise to the above reaction solution, extract with dichloromethane, wash with water and saturated brine successively, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and the residue is separated and purified by silica gel column chromatography to obtain The structure of the target product was confirmed by NMR and mass spectrometry.

[0133] The third step: dissolve the above-mentioned second step product (1eq.) in the mixed solvent of anhydrous dioxane/water (4/1), add boric acid or trifluoroborate potassium salt (2eq.) successively, anhydrous Potassium carbonate powder (2.5eq.) and Pd(dppf)Cl 2 (0.1eq.), heated to reflux under nitrogen protection for 2 hours. The reaction was complete as monitored by TLC, cooled to room temperature, concentrated under reduced pressure, the residue was diluted with dichloromethane, washed successively with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was washed with silica gel The target product was obtained by separation and purification by column chromatography, and its structure was confirmed by NMR and mass spectrometry.

[0134] Step 4: Dissolve the product (1 eq.) of the third step above in methanol, add 4M HCl methanol solution (20 eq.), and stir at room temperature for 3 hours. The completion of the reaction was monitored by TLC, concentrated under reduced pressure, and the residue was dissolved in dichloromethane, and DIPEA (3eq.) and acryloyl chloride (1eq.) were added successively at 0°C, stirred for 0.5 hours, and the reaction solution was washed with saturated ammonium chloride solution and saturated Washed with saline, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the target compound, whose structure was confirmed by NMR and mass spectrometry.

[0135] Example

[0136] Using intermediates 1-2 and other commercially available reagents as raw materials, the compounds of the following examples were prepared by using the synthesis methods of the general preparation methods 1 to 5 of the examples, respectively.

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