Mosapride citrate impurity compound and preparation method thereof

Abstract

The present application provides a kind of mosapride citrate impurity compound, with formula I or formula II structure.The impurity provided by the present application is the process impurity of mosapride citrate, which is highly similar to the structure of mosapride citrate compound, and may have potential safety problems.The above-mentioned impurity compound can be used as the impurity control sample in the detection standard of mosapride citrate intermediate and finished product, for the quantitative analysis of impurities in the production process of mosapride citrate, which helps the quality research of mosapride citrate bulk drug, and provides a new direction for obtaining more safe and reliable, curative mosapride citrate.The synthesis route design is reasonable, the reaction condition is mild, the post-treatment is simple, and the sample with high purity can be obtained.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to a mosapride citrate impurity compound and its preparation method. Background Technology

[0002] Mosapride citrate, developed by Dai Nippon Pharmaceutical Co., Ltd., is primarily used for functional dyspepsia accompanied by gastrointestinal symptoms such as heartburn, belching, nausea, vomiting, early satiety, and upper abdominal distension. It can also be used for gastroesophageal reflux disease, diabetic gastroparesis, and gastric dysfunction in patients who have undergone partial gastrectomy. It is a selective serotonin receptor agonist. Chemical name: (±)-4-amino-5-chloro-2-ethoxy-N-{[4-(4-fluorobenzyl)-2-morpholine]methyl}benzamide citrate dihydrate.

[0003] Its structural formula is:

[0004]

[0005] The quality of active pharmaceutical ingredients (APIs) is the key and source of drug quality control. Among them, the research and control of impurities are related to the clinical safety of drugs. As a key quality attribute of drugs, impurities are an important research content that runs through the entire research and development process.

[0006] With the progress of the times and the improvement of technology, people have placed higher demands on the safety, efficacy, and controllability of medicines. Therefore, various pharmaceutical-related departments are paying increasing attention to the research and control of drug impurities. Summary of the Invention

[0007] In view of this, the technical problem to be solved by the present invention is to provide a mosapride citrate impurity compound and a method for preparing the same, thereby providing a new mosapride citrate impurity compound.

[0008] This invention provides a mosapride citrate impurity compound having the structure shown in Formula I or Formula II:

[0009]

[0010] This invention has discovered that when the starting material 005 contains a meta-fluorinated impurity compound d, it will participate in the amidation reaction to derive impurity formula I (process as follows):

[0011]

[0012] When starting material 005 contains defluorinated impurity compound D, it will participate in the amidation reaction to derive impurity formula II (process as follows):

[0013]

[0014] The two compounds of this invention differ from mosapride in their structural formulas in the position of the fluorine element on the benzene ring. Formula I is meta-fluorine, Formula II is fluorine-free, and mosapride is para-fluorine. Their structures are similar, and due to the stability and polarity of the compounds themselves, they are difficult to remove from the finished product. Quantitative detection of these two impurities is required to control their limits. Moreover, these two impurities are process impurities introduced in the final synthesis reaction and are detected in the finished product. As a marketable drug, its quality must be effectively controlled. Therefore, it is necessary to synthesize the corresponding impurities as impurity reference standards for impurity localization and quality control studies.

[0015] This invention provides a method for preparing the compound represented by Formula I above, comprising the following steps:

[0016] Compound d and compound e undergo an amidation reaction to give the compound shown in Formula I;

[0017]

[0018] Preferably, the amidation reaction is carried out in an organic solvent.

[0019] The organic solvent is preferably dichloromethane.

[0020] The preferred temperature for the amidation reaction is -5 to 5°C.

[0021] The preferred time for the amidation reaction is 2 to 4 hours.

[0022] Preferably, an acid-binding agent and a condensing agent are added to the amidation reaction.

[0023] The acid-binding agent is preferably triethylamine.

[0024] The condensing agent is preferably isobutyl chloroformate.

[0025] Preferably, the mass ratio of compound e, isobutyl chloroformate, and compound d is (1.3-1.8):1:(1.5-2.0).

[0026] Preferably, in this invention, the above-mentioned amidation reaction specifically comprises:

[0027] First, compound e is mixed with an acid-binding agent in an organic solvent, preferably at room temperature. Then, the reaction system is cooled to -5°C, a condensing agent is added, and the reaction is carried out at low temperature for 0.5 to 1.5 hours. Then, compound d is added to carry out an amidation reaction.

[0028] After the reaction is complete, post-processing is performed, preferably:

[0029] The system was washed with saturated sodium bicarbonate, then washed with pure water, the organic phase was separated, the solvent was separated after drying, anhydrous ethanol was added to the residue, and the mixture was heated to reflux and then cooled to precipitate the product.

[0030] Preferably, in this invention, compound d is prepared according to the following method:

[0031] Compound c undergoes hydrolysis under acidic conditions to yield compound d;

[0032]

[0033] The acidic conditions are preferably provided by acidic compounds.

[0034] The acidic compound may be an acidic compound well known to those skilled in the art, including but not limited to concentrated hydrochloric acid, concentrated sulfuric acid, etc.

[0035] The preferred temperature for the reduction reaction is 85–95°C.

[0036] The reduction reaction is preferably carried out over a period of 3 to 5 hours.

[0037] The solvent for the reduction reaction is preferably water.

[0038] The mass-to-volume ratio of compound c to solvent is preferably 0.3:1 to 0.5:1 (g / mL).

[0039] After the reduction reaction is complete, post-processing is performed, preferably:

[0040] Cool the reaction system to room temperature and adjust the pH to alkaline, preferably to around 11. Extract the system with chloroform, separate the liquid from the liquid, dry the organic phase and remove the solvent. The remaining oily substance is compound d.

[0041] Preferably, in this invention, compound c is prepared according to the following method:

[0042] Compound a and compound b react under acidic conditions, and then, in the presence of acetic anhydride, compound c is obtained.

[0043]

[0044] Specifically, compounds a and b first undergo a nucleophilic reaction, then cyclize under acidic conditions, and are subsequently processed to obtain compound c.

[0045] The molar ratio of compound a to compound b is preferably 1:1 to 1:1.5.

[0046] The preferred temperature for the nucleophilic reaction is 70–90°C.

[0047] The preferred time for the nucleophilic reaction is 3 to 5 hours.

[0048] The acidic conditions are provided by acidic compounds.

[0049] The acidic compound can be any acidic compound well known to those skilled in the art, preferably concentrated sulfuric acid.

[0050] The preferred volume-to-mass ratio of the acidic compound to compound a is 1:(20-40)(mL / g).

[0051] The preferred temperature for the ring closure is 130–150°C.

[0052] The preferred time for the ring to close is 2 to 4 hours.

[0053] After the reaction is complete, the reaction system is cooled to room temperature, the pH is adjusted to alkaline, preferably around 11, and then extracted with chloroform. After drying, the solvent is removed.

[0054] The solvent-removed residue was dissolved in acetonitrile, acetic anhydride was added, and the mixture was reacted at room temperature to obtain compound c.

[0055] The preferred reaction time at room temperature is 5 to 7 hours.

[0056] After the reaction was completed, a solid product was generated in the system. After filtration and drying, the filter cake was dried to obtain compound c.

[0057] The equation for the above reaction is as follows:

[0058]

[0059] The present invention also provides a method for preparing the compound represented by Formula II above, comprising the following steps:

[0060] Compound D and compound e undergo an amidation reaction to give the compound shown in formula II;

[0061]

[0062] Preferably, the amidation reaction is carried out in an organic solvent.

[0063] The organic solvent is preferably dichloromethane.

[0064] The preferred temperature for the amidation reaction is -5 to 5°C.

[0065] The preferred time for the amidation reaction is 2 to 4 hours.

[0066] Preferably, an acid-binding agent and a condensing agent are added to the amidation reaction.

[0067] The acid-binding agent is preferably triethylamine.

[0068] The condensing agent is preferably isobutyl chloroformate.

[0069] Preferably, the mass ratio of compound e, isobutyl chloroformate, and compound D is (1.3-1.8):1:(1.5-2.0).

[0070] Preferably, in this invention, the above-mentioned amidation reaction specifically comprises:

[0071] First, compound e is mixed with an acid-binding agent in an organic solvent, preferably at room temperature. Then, the reaction system is cooled to -5°C, a condensing agent is added, and the reaction is carried out at low temperature for 0.5 to 1.5 hours. Then, compound D is added to carry out an amidation reaction.

[0072] After the reaction is complete, post-processing is performed, preferably:

[0073] The system was washed with saturated sodium bicarbonate, then washed with pure water, the organic phase was separated, the solvent was separated after drying, anhydrous ethanol was added to the residue, and the mixture was heated to reflux and then cooled to precipitate the product.

[0074] Preferably, in this invention, compound D is prepared according to the following method:

[0075] Compound C undergoes hydrolysis under acidic conditions to yield compound D;

[0076]

[0077] The acidic conditions are preferably provided by acidic compounds.

[0078] The acidic compound may be an acidic compound well known to those skilled in the art, including but not limited to concentrated hydrochloric acid, concentrated sulfuric acid, etc.

[0079] The preferred temperature for the reduction reaction is 85–95°C.

[0080] The reduction reaction is preferably carried out over a period of 3 to 5 hours.

[0081] The solvent for the reduction reaction is preferably water.

[0082] The preferred mass-to-volume ratio of compound C to solvent is 0.3:1 to 0.5:1 (g / mL).

[0083] After the reduction reaction is complete, post-processing is performed, preferably:

[0084] Cool the reaction system to room temperature and adjust the pH to alkaline, preferably to around 11. Extract the system with chloroform, separate the liquid from the liquid, dry the organic phase and remove the solvent. The remaining oily substance is compound D.

[0085] Preferably, in this invention, compound C is prepared according to the following method:

[0086] Compound a and compound B react under acidic conditions, and then, in the presence of acetic anhydride, compound C is obtained.

[0087]

[0088] Specifically, compound a and compound B first undergo a nucleophilic reaction, and then under acidic conditions, they undergo cyclization, followed by post-treatment to obtain compound C.

[0089] The molar ratio of compound a to compound B is preferably 1:1.4 to 1:1.8.

[0090] The preferred temperature for the nucleophilic reaction is 70–90°C.

[0091] The preferred time for the nucleophilic reaction is 3 to 5 hours.

[0092] The acidic conditions are provided by acidic compounds.

[0093] The acidic compound can be any acidic compound well known to those skilled in the art, preferably concentrated sulfuric acid.

[0094] The preferred volume-to-mass ratio of the acidic compound to compound a is 1:(20-40)(mL / g).

[0095] The preferred temperature for the ring closure is 130–150°C.

[0096] The preferred time for the ring to close is 2 to 4 hours.

[0097] After the reaction is complete, the reaction system is cooled to room temperature, the pH is adjusted to alkaline, preferably around 11, and then extracted with chloroform. After drying, the solvent is removed.

[0098] The solvent-removed residue was dissolved in acetonitrile, acetic anhydride was added, and the mixture was reacted at room temperature to obtain compound C.

[0099] The preferred reaction time at room temperature is 5 to 7 hours.

[0100] After the reaction was completed, a solid product was generated in the system. After filtration and drying, the filter cake was dried to obtain compound C.

[0101] The equation for the above reaction is as follows:

[0102]

[0103] Compared with existing technologies, this invention provides an impurity compound of mosapride citrate, having the structure shown in Formula I or Formula II. The impurity provided by this invention is a process impurity of mosapride citrate, which is highly similar in structure to the mosapride citrate compound and may pose potential safety issues.

[0104] The aforementioned impurity compounds can be used as impurity reference standards in the testing standards for mosapride citrate intermediates and finished products. They can be used for quantitative analysis of impurities in the production process of mosapride citrate, which will help in the quality research of mosapride citrate raw materials and provide a new direction for obtaining safer, more reliable, and more effective mosapride citrate.

[0105] Its synthetic route is reasonably designed, the reaction conditions are mild, and the post-processing is simple, which can yield samples with high purity. Attached Figure Description

[0106] Figure 1 The Ms spectrum of compound d prepared in Example 1;

[0107] Figure 2 The 1H NMR spectrum of compound d prepared in Example 1;

[0108] Figure 3 The 1H NMR spectrum of compound I prepared in Example 1;

[0109] Figure 4 The Ms spectrum of compound I prepared in Example 1;

[0110] Figure 5 The 1H NMR spectrum of compound C prepared in Example 4;

[0111] Figure 6 The Ms spectrum of compound C prepared in Example 4;

[0112] Figure 7 The 1H NMR spectrum of compound D prepared in Example 4;

[0113] Figure 8 The 1H NMR spectrum of compound II prepared in Example 4;

[0114] Figure 9 The Ms-ESI+ and Ms-ESI- spectra of compound II prepared in Example 4;

[0115] Figure 10 The liquid chromatograms of the target compounds (formulas I and II) in mosapride citrate are shown. Detailed Implementation

[0116] To further illustrate the present invention, the following detailed description of the mosapride citrate impurity compound and its preparation method provided by the present invention is provided in conjunction with embodiments.

[0117] Example 1

[0118] Preparation of compound c: 50.14 g of compound a and 52.28 g of compound b were added to a 250 mL three-necked flask, heated to 80 °C, and reacted at 80 °C for 4 hours. Then, 1.5 mL of concentrated sulfuric acid was slowly added dropwise, and the reaction was maintained at 140 °C for 3 hours. After the reaction was complete, the reaction system was cooled to room temperature, 100 mL of purified water was added, and the pH of the system was adjusted to approximately 11 with sodium hydroxide. Then, the mixture was extracted with 300 mL of chloroform, and anhydrous sodium sulfate was added and the mixture was stirred and dried for 2 hours. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure and evaporated to dryness.

[0119] The concentrated and evaporated residue was dissolved in 100 mL of acetonitrile, and 38.41 g of acetic anhydride was added. The mixture was stirred at room temperature for 6 hours, and a solid product was formed. The product was filtered, dried under vacuum, and the filter cake was dried at 60 °C to obtain an off-white powder (compound c).

[0120] Preparation of compound d: 200 mL of purified water was added to the reaction vessel at room temperature; stirring was started, and 80 mL of concentrated hydrochloric acid was slowly added; then 45.31 g of compound c was added. After the addition was complete, the system was heated to approximately 90 ± 5 °C and reacted at 90 °C for 4 hours.

[0121] After the reaction was complete, the reaction system was cooled to room temperature; the pH of the system was adjusted to approximately 11 with sodium hydroxide. The system was extracted with 200 mL of chloroform and separated; the organic phase was washed with saturated brine; separated, the organic phase was dried with anhydrous sodium sulfate under stirring for 2 hours; the drying agent was filtered off, and the filtrate was concentrated under reduced pressure and evaporated to dryness to obtain a colorless oily substance (compound d).

[0122] Figure 1 The Ms spectrum of compound d is shown. Figure 2 This is the 1H NMR spectrum of compound d.

[0123] Preparation of Compound I: 200 mL of dichloromethane was added to a 500 mL three-necked flask, along with 15.04 g of compound e. The mixture was stirred at room temperature, followed by 7.15 g of triethylamine. The reactor was placed in a cooling reaction bath at -5 °C, and the temperature was lowered. At -5 °C, 10.04 g of isobutyl chloroformate was added. After reacting at low temperature for 1 hour, 16.28 g of compound d was added, and the reaction was continued with stirring for another 3 hours.

[0124] After the reaction was complete, the system was washed with 150 mL of saturated sodium bicarbonate solution and then rinsed with 100 mL of purified water. The organic phase was separated, and anhydrous sodium sulfate was added to the organic phase for drying. After filtering out the desiccant, the mixture was concentrated and evaporated to dryness. 100 mL of anhydrous ethanol was added, and the mixture was heated to reflux at 80 °C and then cooled to precipitate the product. After drying, the target substance was obtained with a purity of 99.75% and a yield of 99.56%.

[0125] Figure 3 This is the 1H NMR spectrum of compound I. Figure 4 This is the Ms spectrum of compound I.

[0126] Example 2

[0127] Preparation of compound c: 50.14 g of compound a and 41.69 g of compound b were added to a 250 mL three-necked flask, heated to 70 °C, and reacted at 70 °C for 4 hours. Then, 1.5 mL of concentrated sulfuric acid was slowly added dropwise, and the reaction was maintained at 130 °C for 3 hours. After the reaction was complete, the reaction system was cooled to room temperature, 100 mL of purified water was added, and the pH of the system was adjusted to approximately 11 with sodium hydroxide. Then, the mixture was extracted with 300 mL of chloroform, and anhydrous sodium sulfate was added and the mixture was stirred and dried for 2 hours. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure and evaporated to dryness.

[0128] The concentrated and evaporated residue was dissolved in 100 mL of acetonitrile, and 36.54 g of acetic anhydride was added. The mixture was stirred at room temperature for 6 hours, resulting in the formation of a solid product. The product was filtered, dried under vacuum, and the filter cake was dried at 60 °C to obtain an off-white powder (compound c).

[0129] Preparation of compound d: 200 mL of purified water was added to the reaction vessel at room temperature; stirring was started, and 80 mL of concentrated hydrochloric acid was slowly added; then 30.65 g of compound c was added. After the addition was complete, the system was heated to approximately 90 ± 5 °C and reacted at 90 °C for 4 hours.

[0130] After the reaction was complete, the reaction system was cooled to room temperature; the pH of the system was adjusted to approximately 11 with sodium hydroxide. The system was extracted with 200 mL of chloroform and separated; the organic phase was washed with saturated brine; separated, the organic phase was dried with anhydrous sodium sulfate under stirring for 2 hours; the drying agent was filtered off, and the filtrate was concentrated under reduced pressure and evaporated to dryness to obtain a colorless oily substance (compound d).

[0131] Preparation of Compound I: 200 mL of dichloromethane was added to a 500 mL three-necked flask, along with 13.25 g of compound e. The mixture was stirred at room temperature, followed by 6.47 g of triethylamine. The reactor was placed in a cooling reaction bath at -5 °C, and the temperature was lowered. At -5 °C, 10.11 g of isobutyl chloroformate was added. After reacting at low temperature for 1 hour, 15.03 g of compound d was added, and the reaction was continued with stirring for another 3 hours.

[0132] After the reaction was complete, the system was washed with 150 mL of saturated sodium bicarbonate solution and then rinsed with 100 mL of purified water. The organic phase was separated, and anhydrous sodium sulfate was added to the organic phase for drying. After filtering out the desiccant, the mixture was concentrated and evaporated to dryness. 100 mL of anhydrous ethanol was added, and the mixture was heated to reflux at 80 °C and then cooled to precipitate the product. After drying, the target substance was obtained with a purity of 99.23% and a yield of 99.17%.

[0133] Example 3

[0134] Preparation of compound c: 50.14 g of compound a and 62.83 g of compound b were added to a 250 mL three-necked flask, heated to 90 °C, and reacted at 90 °C for 4 hours. Then, 1.5 mL of concentrated sulfuric acid was slowly added dropwise, and the reaction was maintained at 150 °C for 3 hours. After the reaction was complete, the reaction system was cooled to room temperature, 100 mL of purified water was added, and the pH of the system was adjusted to approximately 11 with sodium hydroxide. Then, the mixture was extracted with 300 mL of chloroform, and anhydrous sodium sulfate was added and the mixture was stirred and dried for 2 hours. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure and evaporated to dryness.

[0135] The concentrated and evaporated residue was dissolved in 100 mL of acetonitrile, and 39.03 g of acetic anhydride was added. The mixture was stirred at room temperature for 6 hours, resulting in the formation of a solid product. The product was filtered, dried under vacuum, and the filter cake was dried at 60 °C to obtain an off-white powder (compound c).

[0136] Preparation of compound d: 200 mL of purified water was added to the reaction vessel at room temperature; stirring was started, and 80 mL of concentrated hydrochloric acid was slowly added; then 49.89 g of compound c was added. After the addition was complete, the system was heated to approximately 90 ± 5 °C and reacted at 90 °C for 4 hours.

[0137] After the reaction was complete, the reaction system was cooled to room temperature; the pH of the system was adjusted to approximately 11 with sodium hydroxide. The system was extracted with 200 mL of chloroform and separated; the organic phase was washed with saturated brine; separated, the organic phase was dried with anhydrous sodium sulfate under stirring for 2 hours; the drying agent was filtered off, and the filtrate was concentrated under reduced pressure and evaporated to dryness to obtain a colorless oily substance (compound d).

[0138] Preparation of Compound I: 200 mL of dichloromethane was added to a 500 mL three-necked flask, along with 18.12 g of compound e. The mixture was stirred at room temperature, followed by 7.93 g of triethylamine. The reactor was placed in a cooling reaction bath at -5 °C, and the temperature was lowered. At -5 °C, 10.12 g of isobutyl chloroformate was added. After reacting at low temperature for 1 hour, 19.67 g of compound d was added, and the reaction was continued with stirring for another 3 hours.

[0139] After the reaction was complete, the system was washed with 150 mL of saturated sodium bicarbonate solution and then rinsed with 100 mL of purified water. The organic phase was separated, and anhydrous sodium sulfate was added to the organic phase for drying. After filtering out the desiccant, the mixture was concentrated and evaporated to dryness. 100 mL of anhydrous ethanol was added, and the mixture was heated to reflux at 80 °C and then cooled to precipitate the product. After drying, the target substance was obtained with a purity of 99.56% and a yield of 99.34%.

[0140] Example 4

[0141] Preparation of compound C: 40.03 g of compound a and 50.03 g of compound B were added to a 250 mL three-necked flask, heated to 80 °C, and reacted at 80 °C for 4 hours. Then, 1.5 mL of concentrated sulfuric acid was slowly added dropwise, and the reaction was maintained at 140 °C for 3 hours. After the reaction was complete, the reaction system was cooled to room temperature, 100 mL of purified water was added, and the pH of the system was adjusted to approximately 11 with sodium hydroxide. Then, the mixture was extracted with 300 mL of chloroform, and anhydrous sodium sulfate was added and the mixture was stirred and dried for 2 hours. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure and evaporated to dryness.

[0142] The concentrated and evaporated residue was dissolved in 100 mL of acetonitrile, and 37.69 g of acetic anhydride was added. The mixture was stirred at room temperature for 6 hours, resulting in the formation of a solid product. The product was filtered, dried under vacuum, and the filter cake was dried at 60 °C to obtain an off-white powder (compound C).

[0143] Figure 5 This is the 1H NMR spectrum of compound C. Figure 6 This is the Ms spectrum of compound C.

[0144] Preparation of compound D: 200 mL of purified water was added to the reaction vessel at room temperature; stirring was started, and 80 mL of concentrated hydrochloric acid was slowly added; then 44.06 g of compound C was added. After the addition was complete, the system was heated to approximately 90 ± 5 °C and reacted at 90 °C for 4 hours.

[0145] After the reaction was complete, the reaction system was cooled to room temperature; the pH of the system was adjusted to approximately 11 with sodium hydroxide. The system was extracted with 200 mL of chloroform and separated; the organic phase was washed with saturated brine; separated, the organic phase was dried with anhydrous sodium sulfate under stirring for 2 hours; the drying agent was filtered off, and the filtrate was concentrated under reduced pressure and evaporated to dryness to obtain a colorless oily substance (compound D).

[0146] Figure 7 This is the 1H NMR spectrum of compound D.

[0147] Preparation of Compound II: 200 mL of dichloromethane was placed in a 500 mL three-necked flask, and 15.21 g of compound e was added. The mixture was stirred at room temperature, followed by the addition of 7.44 g of triethylamine. The reactor was placed in a cooling reaction bath at -5 °C, and the temperature was lowered. At -5 °C, 10.21 g of isobutyl chloroformate was added. After reacting at low temperature for 1 hour, 17.24 g of compound D was added, and the reaction was continued with stirring for another 3 hours.

[0148] After the reaction was complete, the system was washed with 150 mL of saturated sodium bicarbonate solution and then rinsed with 100 mL of purified water. The organic phase was separated, and anhydrous sodium sulfate was added to the organic phase for drying. After filtering out the desiccant, the mixture was concentrated and evaporated to dryness. 100 mL of anhydrous ethanol was added, and the mixture was heated to reflux at 80 °C and then cooled to precipitate the product. After drying, the target compound was obtained with a purity of 99.67% and a yield of 99.13%.

[0149] Figure 8 This is the 1H NMR spectrum of compound II. Figure 9 These are the Ms-ESI+ and Ms-ESI- spectra of compound II.

[0150] Example 5

[0151] Preparation of compound C: 40 g of compound a and 43.8 g of compound B were added to a 250 mL three-necked flask, heated to 60 °C, and reacted at 60 °C for 4 hours. Then, 1.5 mL of concentrated sulfuric acid was slowly added dropwise, and the reaction was maintained at 130 °C for 3 hours. After the reaction was complete, the reaction system was cooled to room temperature, 100 mL of purified water was added, and the pH of the system was adjusted to approximately 11 with sodium hydroxide. Then, the mixture was extracted with 300 mL of chloroform, and anhydrous sodium sulfate was added and the mixture was stirred and dried for 2 hours. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure and evaporated to dryness.

[0152] The concentrated and evaporated residue was dissolved in 85 mL of acetonitrile, and 35.13 g of acetic anhydride was added. The mixture was stirred at room temperature for 5 hours, resulting in the formation of a solid product. The product was filtered, dried under vacuum, and the filter cake was dried at 60 °C to obtain an off-white powder (compound C).

[0153] Preparation of compound D: 200 mL of purified water was added to the reaction vessel at room temperature; stirring was started, and 80 mL of concentrated hydrochloric acid was slowly added; then 30.15 g of compound C was added. After the addition was complete, the system was heated to approximately 90 ± 5 °C and reacted at 90 °C for 4 hours.

[0154] After the reaction was complete, the reaction system was cooled to room temperature; the pH of the system was adjusted to approximately 11 with sodium hydroxide. The system was extracted with 200 mL of chloroform and separated; the organic phase was washed with saturated brine; separated, the organic phase was dried with anhydrous sodium sulfate under stirring for 2 hours; the drying agent was filtered off, and the filtrate was concentrated under reduced pressure and evaporated to dryness to obtain a colorless oily substance (compound D).

[0155] Preparation of Compound II: 200 mL of dichloromethane was placed in a 500 mL three-necked flask, and 13.08 g of compound e was added. The mixture was stirred at room temperature, followed by the addition of 6.45 g of triethylamine. The reactor was placed in a cooling reaction bath at -5 °C, and the temperature was lowered. At -5 °C, 10.16 g of isobutyl chloroformate was added. After reacting at low temperature for 1 hour, 15.14 g of compound D was added, and the reaction was continued with stirring for another 3 hours.

[0156] After the reaction was complete, the system was washed with 150 mL of saturated sodium bicarbonate solution and then rinsed with 100 mL of purified water. The organic phase was separated, and anhydrous sodium sulfate was added to the organic phase for drying. After filtering out the desiccant, the mixture was concentrated and evaporated to dryness. 100 mL of anhydrous ethanol was added, and the mixture was heated to reflux at 80 °C and then cooled to precipitate the product. After drying, the target compound was obtained with a purity of 99.24% and a yield of 98.96%.

[0157] Example 6

[0158] Preparation of compound C: 40 g of compound a and 56.42 g of compound B were added to a 250 mL three-necked flask, heated to 90 °C, and reacted at 90 °C for 4 hours. Then, 1.5 mL of concentrated sulfuric acid was slowly added dropwise, and the reaction was maintained at 150 °C for 3 hours. After the reaction was complete, the reaction system was cooled to room temperature, 100 mL of purified water was added, and the pH of the system was adjusted to approximately 11 with sodium hydroxide. Then, the mixture was extracted with 300 mL of chloroform, and anhydrous sodium sulfate was added and stirred and dried for 2 hours. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure and evaporated to dryness.

[0159] The concentrated and evaporated residue was dissolved in 85 mL of acetonitrile, and 38.92 g of acetic anhydride was added. The mixture was stirred at room temperature for 5 hours, resulting in the formation of a solid product. The product was filtered, dried under vacuum, and the filter cake was dried at 60 °C to obtain an off-white powder (compound C).

[0160] Preparation of compound D: 200 mL of purified water was added to the reaction vessel at room temperature; stirring was started, and 80 mL of concentrated hydrochloric acid was slowly added; then 50.17 g of compound c was added. After the addition was complete, the system was heated to approximately 90 ± 5 °C and reacted at 90 °C for 4 hours.

[0161] After the reaction was complete, the reaction system was cooled to room temperature; the pH of the system was adjusted to approximately 11 with sodium hydroxide. The system was extracted with 200 mL of chloroform and separated; the organic phase was washed with saturated brine; separated, the organic phase was dried with anhydrous sodium sulfate under stirring for 2 hours; the drying agent was filtered off, and the filtrate was concentrated under reduced pressure and evaporated to dryness to obtain a colorless oily substance (compound D).

[0162] Preparation of Compound II: 200 mL of dichloromethane was placed in a 500 mL three-necked flask, and 18.16 g of compound e was added. The mixture was stirred at room temperature, followed by the addition of 8.25 g of triethylamine. The reactor was placed in a cooling reaction bath at -5 °C, and the temperature was lowered. At -5 °C, 10.33 g of isobutyl chloroformate was added. After reacting at low temperature for 1 hour, 20.24 g of compound D was added, and the reaction was continued with stirring for another 3 hours.

[0163] After the reaction was complete, the system was washed with 150 mL of saturated sodium bicarbonate solution and then rinsed with 100 mL of purified water. The organic phase was separated, and anhydrous sodium sulfate was added to the organic phase for drying. After filtering out the desiccant, the mixture was concentrated and evaporated to dryness. 100 mL of anhydrous ethanol was added, and the mixture was heated to reflux at 80 °C and then cooled to precipitate the product. After drying, the target compound was obtained with a purity of 99.36% and a yield of 99.11%.

[0164] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A method for preparing the compound shown in Formula I, comprising the following steps: Compound d and compound e undergo an amidation reaction to give the compound shown in Formula I; ； Formula I; The solvent for the amidation reaction is dichloromethane; The temperature for the amidation reaction is -5~5℃; The amidation reaction includes an acid-binding agent and a condensing agent. The acid-binding agent is triethylamine; The condensing agent is isobutyl chloroformate; The mass ratio of compound e, isobutyl chloroformate, and compound d is (1.3~1.8):1:(1.5~2.0). Compound d is prepared according to the following method: Compound c undergoes hydrolysis under acidic conditions to yield compound d; ； The hydrolysis reaction is carried out at a temperature of 85~95℃; Compound c is prepared according to the following method: Compound a and compound b react under acidic conditions, and then, in the presence of acetic anhydride, compound c is obtained. 。 2. A method for preparing the compound shown in Formula II, comprising the following steps: Compound D and compound e undergo an amidation reaction to give the compound shown in formula II; ； Formula II; The solvent for the amidation reaction is dichloromethane; The temperature for the amidation reaction is -5~5℃; The amidation reaction includes an acid-binding agent and a condensing agent. The acid-binding agent is triethylamine; The condensing agent is isobutyl chloroformate; The mass ratio of compound e, isobutyl chloroformate, and compound D is (1.3~1.8):1:(1.5~2.0). Compound D was prepared according to the following method: Compound C undergoes hydrolysis under acidic conditions to yield compound D; ； The hydrolysis reaction is carried out at a temperature of 85~95℃; Compound C was prepared according to the following method: Compound a and compound B react under acidic conditions, and then, in the presence of acetic anhydride, compound C is obtained. 。

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