Mosapride citrate impurity compound and preparation method thereof

Abstract

The invention provides an impurity compound of mosapride citrate. The impurity compound has a structure as shown in a formula I or a formula II. The impurity provided by the invention is a mosapride citrate process impurity, is highly similar to a mosapride citrate compound in structure, and possibly has a potential safety problem. The impurity compound can be used as an impurity reference substance in a mosapride citrate intermediate and a finished product detection standard, is used for impurity quantitative analysis research in a mosapride citrate production process, and is beneficial to quality research of a mosapride citrate raw material medicine; and a new direction is provided for obtaining the mosapride citrate which is safer and more reliable and has an exact curative effect. The synthesis route is reasonable in design, the reaction condition is mild, the post-treatment is simple, and a sample with higher purity can be obtained. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to a mosapride citrate impurity compound and a preparation method thereof. Background Art

[0002] Mosapride Citrate was developed by Dainippon Pharmaceutical Co., Ltd. It is mainly used for functional dyspepsia accompanied by digestive symptoms such as heartburn, belching, nausea, vomiting, early satiety, upper abdominal distension, etc. It can also be used for gastroesophageal reflux disease, diabetic gastroparesis and gastric dysfunction in patients with partial gastrectomy. It is a selective 5-hydroxytryptamine receptor agonist. Chemical name: (±)-4-amino-5-chloro-2-ethoxy-N-{[4-(4-fluorobenzyl)-2-morpholino]methyl}benzamide citrate dihydrate.

[0003] Its structural formula is:

[0004]

[0005] The quality of raw materials is the key and source of drug quality control. Among them, the research and control of impurities is related to the clinical safety of drugs. Impurities, as a key quality attribute of drugs, are an important research content throughout the research and development.

[0006] With the progress of the times and the improvement of science and technology, people have put forward higher requirements for the safety, effectiveness and controllability of drugs. Therefore, various pharmaceutical-related departments pay more and more 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 preparation method thereof, and to provide a new mosapride citrate impurity compound.

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

[0009]

[0010] The present invention has been found through research that when the starting material 005 contains a meta-fluorine impurity compound d, it will participate in the amidation reaction to derive into an impurity of formula I (the process is as follows):

[0011]

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

[0013]

[0014] The difference between the two compounds of the present invention and mosapride in the structural formula lies in the position of the fluorine element on the benzene ring, which is meta-position in formula I, fluorine-free in formula II, and para-position in mosapride. The structures are similar and are difficult to be removed from the finished product due to the influence of the stability and polarity of the compounds themselves. It is necessary to carry out quantitative detection of the two impurities to control their limits. Moreover, the two impurities are process impurities introduced in the last step of the synthesis reaction and are detected in the finished product. As a drug for sale on the market, its quality must be effectively controlled. Therefore, it is necessary to synthesize the corresponding impurities as impurity reference substances to facilitate impurity location and quality control research.

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

[0016] Compound d and compound e are subjected to amidation reaction to obtain a compound represented by formula I;

[0017]

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

[0019] The organic solvent is preferably dichloromethane.

[0020] The temperature of the amidation reaction is preferably -5 to 5°C.

[0021] The amidation reaction time is preferably 2 to 4 hours.

[0022] Preferably, an acid binding agent and a condensation agent are added in 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 the compound e, isobutyl chloroformate and compound d is (1.3-1.8):1:(1.5-2.0).

[0026] Preferably, the amidation reaction is as follows:

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

[0028] After the reaction is completed, post-treatment is performed, preferably:

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

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

[0031] Compound c is hydrolyzed under acidic conditions to obtain compound d;

[0032]

[0033] The acidic conditions are preferably provided by an acidic compound.

[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, and the like.

[0035] The temperature of the reduction reaction is preferably 85-95°C.

[0036] The reduction reaction time is preferably 3 to 5 hours.

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

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

[0039] After the reduction reaction is completed, post-treatment is performed, preferably:

[0040] The reaction system is cooled to room temperature, and the pH value is adjusted to alkaline, preferably, the pH value is adjusted to about 11. The system is extracted with chloroform, and after separation, the organic phase is dried and the solvent is removed, and the residual oily substance is compound d.

[0041] Preferably, the compound C is prepared according to the following method:

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

[0043]

[0044] Specifically, the compound a and the compound b are first subjected to a nucleophilic reaction, and then cyclized under acidic conditions, and then post-treated to obtain the compound c.

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

[0046] The temperature of the nucleophilic reaction is preferably 70-90°C.

[0047] The time of the nucleophilic reaction is preferably 3 to 5 hours.

[0048] The acidic conditions are provided by an acidic compound.

[0049] The acidic compound may be an acidic compound well known to those skilled in the art, and is preferably concentrated sulfuric acid.

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

[0051] The ring closing temperature is preferably 130-150°C.

[0052] The ring closing time is preferably 2 to 4 hours.

[0053] After the reaction is completed, the reaction system is cooled to room temperature, the pH value is adjusted to alkaline, preferably to about 11, and then extracted with chloroform, dried and the solvent is removed.

[0054] The residue after removing the solvent is dissolved in acetonitrile, and acetic anhydride is added thereto, and the mixture is reacted at room temperature to obtain compound c.

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

[0056] After the reaction is completed, a solid product is generated in the system, which is filtered and dried, and the filter cake is 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 the above formula II, comprising the following steps:

[0060] Compound D and compound e undergo an amidation reaction to obtain a compound represented by formula II;

[0061]

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

[0063] The organic solvent is preferably dichloromethane.

[0064] The temperature of the amidation reaction is preferably -5 to 5°C.

[0065] The amidation reaction time is preferably 2 to 4 hours.

[0066] Preferably, an acid binding agent and a condensation agent are added in 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 the compound e, isobutyl chloroformate and compound D is (1.3-1.8):1:(1.5-2.0).

[0070] Preferably, the amidation reaction is as follows:

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

[0072] After the reaction is completed, post-treatment is performed, preferably:

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

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

[0075] Compound C is hydrolyzed under acidic conditions to obtain compound D;

[0076]

[0077] The acidic conditions are preferably provided by an acidic compound.

[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, and the like.

[0079] The temperature of the reduction reaction is preferably 85-95°C.

[0080] The reduction reaction time is preferably 3 to 5 hours.

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

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

[0083] After the reduction reaction is completed, post-treatment is performed, preferably:

[0084] The reaction system is cooled to room temperature, and the pH value is adjusted to alkaline, preferably, the pH value is adjusted to about 11. The system is extracted with chloroform. After separation, the organic phase is dried and the solvent is removed. The residual oily substance is compound D.

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

[0086] Compound A and compound B react under acidic conditions, and then under the action of acetic anhydride, compound C is obtained;

[0087]

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

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

[0090] The temperature of the nucleophilic reaction is preferably 70-90°C.

[0091] The time of the nucleophilic reaction is preferably 3 to 5 hours.

[0092] The acidic conditions are provided by an acidic compound.

[0093] The acidic compound may be an acidic compound well known to those skilled in the art, and is preferably concentrated sulfuric acid.

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

[0095] The ring closing temperature is preferably 130-150°C.

[0096] The ring closing time is preferably 2 to 4 hours.

[0097] After the reaction is completed, the reaction system is cooled to room temperature, the pH value is adjusted to alkaline, preferably to about 11, and then extracted with chloroform, dried and the solvent is removed.

[0098] The residue after removing the solvent is dissolved in acetonitrile, and acetic anhydride is added thereto, and the mixture is reacted at room temperature to obtain compound C.

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

[0100] After the reaction is completed, a solid product is generated in the system, which is filtered and dried, and the filter cake is dried to obtain compound C.

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

[0102]

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

[0104] The above impurity compounds can be used as impurity reference substances in the detection standards of mosapride citrate intermediates and finished products, and can be used for the quantitative analysis of impurities in the production process of mosapride citrate, which is helpful for the quality research of mosapride citrate raw materials and provides a new direction for obtaining safer, more reliable and more effective mosapride citrate.

[0105] The synthetic route is reasonably designed, the reaction conditions are mild, the post-treatment is simple, and a sample with high purity can be obtained. BRIEF DESCRIPTION OF THE DRAWINGS

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

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

[0108] Figure 3 The H 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 H 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 H NMR spectrum of compound D prepared in Example 4;

[0113] Figure 8 This is the H NMR spectrum of compound II prepared in Example 4;

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

[0115] Fig.10 It is the liquid chromatogram of the target compound (Formula I and II) in mosapride citrate. DETAILED DESCRIPTION

[0116] In order to further illustrate the present invention, the mosapride citrate impurity compound and the preparation method thereof provided by the present invention are described in detail below in conjunction with the examples.

[0117] Example 1

[0118] Preparation of compound c: Add 50.14 g of compound a and 52.28 g of compound b to a 250 ml three-necked flask, heat to 80°C, react at 80°C for 4 hours, then slowly drop 1.5 ml of concentrated sulfuric acid, and keep warm at 140°C for 3 hours. After the reaction, cool the reaction system to room temperature, add 100 ml of purified water, and adjust the system to a pH of about 11 with sodium hydroxide. Then extract with 300 ml of chloroform, add anhydrous sodium sulfate, stir and dry for 2 hours, filter out the desiccant, and concentrate the filtrate under reduced pressure and evaporate to dryness.

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

[0120] Preparation of compound d: Add 200 ml of purified water to the reaction kettle at room temperature; start stirring and slowly add 80 ml of concentrated hydrochloric acid; then add 45.31 g of compound c. After the addition, heat the system to about 90±5°C and react at 90°C for 4 hours.

[0121] After the reaction, the reaction system was cooled to room temperature; the pH value of the system was adjusted to about 11 with sodium hydroxide. The system was extracted with 200 ml of chloroform and separated; the organic phase was washed with saturated brine; the organic phase was separated, and anhydrous sodium sulfate was added to the organic phase and dried for 2 hours under stirring; the desiccant was filtered out, and the filtrate was concentrated and evaporated to dryness under reduced pressure to obtain a colorless oil (compound d).

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

[0123] Preparation of compound I: 200 ml of dichloromethane was added to a 500 ml three-necked flask, and 15.04 g of compound e was added. The mixture was stirred at room temperature, and 7.15 g of triethylamine was added. The reactor was placed in a reaction bath with a cooling effect, and the temperature was set to -5°C, and the temperature began to drop. At -5°C, 10.04 g of isobutyl chloroformate was added, and the reaction was carried out at low temperature for 1 hour. Then, 16.28 g of compound d was added, and the reaction was continued with stirring for 3 hours.

[0124] After the reaction is completed, the system is washed with 150 ml of saturated sodium bicarbonate solution, and then rinsed with 100 ml of purified water, the organic phase is separated, anhydrous sodium sulfate is added to the organic phase for drying, the desiccant is filtered out, and then concentrated and evaporated to dryness, 100 ml of anhydrous ethanol is added, and the product is precipitated after heating under reflux at 80° C. and cooled, and the target product is obtained after drying, with a purity of 99.75% and a yield of 99.56%.

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

[0126] Example 2

[0127] Preparation of compound c: Add 50.14 g of compound a and 41.69 g of compound b to a 250 ml three-necked flask, heat to 70°C, react at 70°C for 4 hours, then slowly drop 1.5 ml of concentrated sulfuric acid, and keep warm at 130°C for 3 hours. After the reaction, cool the reaction system to room temperature, add 100 ml of purified water, and adjust the system to a pH of about 11 with sodium hydroxide. Then extract with 300 ml of chloroform, add anhydrous sodium sulfate, stir and dry for 2 hours, filter out the desiccant, and concentrate the filtrate under reduced pressure and evaporate to dryness.

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

[0129] Preparation of compound d: Add 200 ml of purified water to the reaction kettle at room temperature; start stirring and slowly add 80 ml of concentrated hydrochloric acid; then add 30.65 g of compound c. After the addition, heat the system to about 90±5°C and react at 90°C for 4 hours.

[0130] After the reaction, the reaction system was cooled to room temperature; the pH value of the system was adjusted to about 11 with sodium hydroxide. The system was extracted with 200 ml of chloroform and separated; the organic phase was washed with saturated brine; the organic phase was separated, and anhydrous sodium sulfate was added to the organic phase and dried for 2 hours under stirring; the desiccant was filtered out, and the filtrate was concentrated and evaporated to dryness under reduced pressure to obtain a colorless oil (compound d).

[0131] Preparation of compound I: 200 ml of dichloromethane was added to a 500 ml three-necked flask, and 13.25 g of compound e was added. The mixture was stirred at room temperature, and 6.47 g of triethylamine was added. The reactor was placed in a reaction bath with a cooling effect, and the temperature was set to -5°C, and the temperature began to drop. At -5°C, 10.11 g of isobutyl chloroformate was added, and the reaction was carried out at low temperature for 1 hour. Then, 15.03 g of compound d was added, and the reaction was continued to stir for 3 hours.

[0132] After the reaction was completed, 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, anhydrous sodium sulfate was added to the organic phase for drying, the desiccant was filtered out and concentrated and evaporated to dryness, 100 ml of anhydrous ethanol was added, and the product was precipitated after heating under reflux at 80° C. and cooled. After drying, the target product was obtained with a purity of 99.23% and a yield of 99.17%.

[0133] Example 3

[0134] Preparation of compound c: Add 50.14 g of compound a and 62.83 g of compound b to a 250 ml three-necked flask, heat to 90°C, react at 90°C for 4 hours, then slowly drop 1.5 ml of concentrated sulfuric acid, and keep warm at 150°C for 3 hours. After the reaction, cool the reaction system to room temperature, add 100 ml of purified water, and adjust the system to a pH of about 11 with sodium hydroxide. Then extract with 300 ml of chloroform, add anhydrous sodium sulfate, stir and dry for 2 hours, filter out the desiccant, and concentrate the filtrate under reduced pressure and evaporate to dryness.

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

[0136] Preparation of compound d: Add 200 ml of purified water to the reaction kettle at room temperature; start stirring and slowly add 80 ml of concentrated hydrochloric acid; then add 49.89 g of compound c. After the addition, heat the system to about 90±5°C and react at 90°C for 4 hours.

[0137] After the reaction, the reaction system was cooled to room temperature; the pH value of the system was adjusted to about 11 with sodium hydroxide. The system was extracted with 200 ml of chloroform and separated; the organic phase was washed with saturated brine; the organic phase was separated, and anhydrous sodium sulfate was added to the organic phase and dried for 2 hours under stirring; the desiccant was filtered out, and the filtrate was concentrated and evaporated to dryness under reduced pressure to obtain a colorless oil (compound d).

[0138] Preparation of compound I: 200 ml of dichloromethane was added to a 500 ml three-necked flask, and 18.12 g of compound e was added. The mixture was stirred at room temperature, and 7.93 g of triethylamine was added. The reactor was placed in a reaction bath with a cooling effect, and the temperature was set to -5°C, and the temperature began to drop. At -5°C, 10.12 g of isobutyl chloroformate was added, and the reaction was carried out at low temperature for 1 hour. Then, 19.67 g of compound d was added, and the reaction was continued with stirring for 3 hours.

[0139] After the reaction was completed, 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, anhydrous sodium sulfate was added to the organic phase for drying, the desiccant was filtered out, and the mixture was concentrated and evaporated to dryness. 100 ml of anhydrous ethanol was added, and the mixture was heated under reflux at 80° C. and then cooled to precipitate the product. The target product was obtained after drying with a purity of 99.56% and a yield of 99.34%.

[0140] Example 4

[0141] Preparation of compound C: Add 40.03 g of compound a and 50.03 g of compound B to a 250 ml three-necked flask, heat to 80°C, react at 80°C for 4 hours, then slowly drop 1.5 ml of concentrated sulfuric acid, and keep warm at 140°C for 3 hours. After the reaction, cool the reaction system to room temperature, add 100 ml of purified water, and adjust the system to a pH of about 11 with sodium hydroxide. Then extract with 300 ml of chloroform, add anhydrous sodium sulfate, stir and dry for 2 hours, filter out the desiccant, and concentrate the filtrate under reduced pressure and evaporate to dryness.

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

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

[0144] Preparation of compound D: Add 200 ml of purified water to the reaction kettle at room temperature; start stirring and slowly add 80 ml of concentrated hydrochloric acid; then add 44.06 g of compound C. After the addition, heat the system to about 90±5°C and react at 90°C for 4 hours.

[0145] After the reaction, the reaction system was cooled to room temperature; the pH value of the system was adjusted to about 11 with sodium hydroxide. The system was extracted with 200 ml of chloroform and separated; the organic phase was washed with saturated brine; the organic phase was separated, and anhydrous sodium sulfate was added to the organic phase and dried for 2 hours under stirring; the desiccant was filtered out, and the filtrate was concentrated and evaporated to dryness under reduced pressure to obtain a colorless oil (compound D).

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

[0147] Preparation of compound II: 200 ml of dichloromethane was placed in a 500 ml three-necked flask, 15.21 g of compound e was added, and the mixture was stirred at room temperature. 7.44 g of triethylamine was added, and the reactor was placed in a reaction bath with a cooling effect, and the temperature was set to -5°C, and the temperature was lowered. 10.21 g of isobutyl chloroformate was added at -5°C, and the mixture was reacted at low temperature for 1 hour, and then 17.24 g of compound D was added, and the reaction was continued with stirring for 3 hours.

[0148] After the reaction is completed, the system is washed with 150 ml of saturated sodium bicarbonate solution, and then rinsed with 100 ml of purified water, the organic phase is separated, anhydrous sodium sulfate is added to the organic phase for drying, the desiccant is filtered out, and then concentrated and evaporated to dryness, 100 ml of anhydrous ethanol is added, and the product is precipitated after heating under reflux at 80° C. and cooled, and the target product is obtained after drying, with a purity of 99.67% and a yield of 99.13%.

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

[0150] Example 5

[0151] Preparation of compound C: Add 40 g of compound a and 43.8 g of compound B to a 250 ml three-necked flask, heat to 60°C, react at 60°C for 4 hours, then slowly drop 1.5 ml of concentrated sulfuric acid, and keep warm at 130°C for 3 hours. After the reaction, cool the reaction system to room temperature, add 100 ml of purified water, and adjust the system to a pH of about 11 with sodium hydroxide. Then extract with 300 ml of chloroform, add anhydrous sodium sulfate, stir and dry for 2 hours, filter out the desiccant, and concentrate the filtrate under reduced pressure and evaporate to dryness.

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

[0153] Preparation of compound D: Add 200 ml of purified water to the reaction kettle at room temperature; start stirring and slowly add 80 ml of concentrated hydrochloric acid; then add 30.15 g of compound C. After the addition, heat the system to about 90±5°C and react at 90°C for 4 hours.

[0154] After the reaction, the reaction system was cooled to room temperature; the pH value of the system was adjusted to about 11 with sodium hydroxide. The system was extracted with 200 ml of chloroform and separated; the organic phase was washed with saturated brine; the organic phase was separated, and anhydrous sodium sulfate was added to the organic phase and dried for 2 hours under stirring; the desiccant was filtered out, and the filtrate was concentrated and evaporated to dryness under reduced pressure to obtain a colorless oil (compound D).

[0155] Preparation of compound II: 200 ml of dichloromethane was placed in a 500 ml three-necked flask, 13.08 g of compound e was added, and the mixture was stirred at room temperature. 6.45 g of triethylamine was added, and the reactor was placed in a reaction bath with a cooling effect, and the temperature was set to -5°C, and the temperature was started to drop. 10.16 g of isobutyl chloroformate was added at -5°C, and the mixture was reacted at low temperature for 1 hour, and then 15.14 g of compound D was added, and the reaction was continued with stirring for 3 hours.

[0156] After the reaction was completed, 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, anhydrous sodium sulfate was added to the organic phase for drying, the desiccant was filtered out and concentrated and evaporated to dryness, 100 ml of anhydrous ethanol was added, and the product was precipitated after heating under reflux at 80° C. and cooled. After drying, the target product was obtained with a purity of 99.24% and a yield of 98.96%.

[0157] Example 6

[0158] Preparation of compound C: Add 40 g of compound a and 56.42 g of compound B to a 250 ml three-necked flask, heat to 90°C, react at 90°C for 4 hours, then slowly drop 1.5 ml of concentrated sulfuric acid, and keep warm at 150°C for 3 hours. After the reaction, cool the reaction system to room temperature, add 100 ml of purified water, and adjust the system to a pH of about 11 with sodium hydroxide. Then extract with 300 ml of chloroform, add anhydrous sodium sulfate, stir and dry for 2 hours, filter out the desiccant, and concentrate the filtrate under reduced pressure and evaporate to dryness.

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

[0160] Preparation of compound D: Add 200 ml of purified water to the reaction kettle at room temperature; start stirring and slowly add 80 ml of concentrated hydrochloric acid; then add 50.17 g of compound C. After the addition, heat the system to about 90±5°C and react at 90°C for 4 hours.

[0161] After the reaction, the reaction system was cooled to room temperature; the pH value of the system was adjusted to about 11 with sodium hydroxide. The system was extracted with 200 ml of chloroform and separated; the organic phase was washed with saturated brine; the organic phase was separated, and anhydrous sodium sulfate was added to the organic phase and dried for 2 hours under stirring; the desiccant was filtered out, and the filtrate was concentrated and evaporated to dryness under reduced pressure to obtain a colorless oil (compound D).

[0162] Preparation of compound II: 200 ml of dichloromethane was placed in a 500 ml three-necked flask, 18.16 g of compound e was added, and the mixture was stirred at room temperature. 8.25 g of triethylamine was added, and the reactor was placed in a reaction bath with a cooling effect, and the temperature was set to -5°C, and the temperature began to drop. At -5°C, 10.33 g of isobutyl chloroformate was added, and the mixture was reacted at low temperature for 1 hour, and then 20.24 g of compound D was added, and the reaction was continued with stirring for 3 hours.

[0163] After the reaction was completed, 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, anhydrous sodium sulfate was added to the organic phase for drying, the desiccant was filtered out and concentrated and evaporated to dryness, 100 ml of anhydrous ethanol was added, and the product was precipitated after heating under reflux at 80° C. and cooled. After drying, the target product was obtained with a purity of 99.36% and a yield of 99.11%.

[0164] The above embodiments are only used to help understand the method and core idea of ​​the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A mosapride citrate impurity compound having a structure shown in Formula I or Formula II:

2. A method for preparing the compound represented by formula I, comprising the following steps: Compound d and compound e are subjected to amidation reaction to obtain a compound represented by formula I; 3. The preparation method according to claim 2, characterized in that: The solvent for the amidation reaction is dichloromethane; The temperature of the amidation reaction is -5 to 5°C; An acid binding agent and a condensation agent are added in the amidation reaction.

4. The preparation method according to claim 2, characterized in that: The compound d was prepared according to the following method: Compound c is hydrolyzed under acidic conditions to obtain compound d; The temperature of the reduction reaction is 85-95°C.

5. The preparation method according to claim 4, characterized in that: The compound C was prepared according to the following method: Compound a and compound b react under acidic conditions, and then under the action of acetic anhydride, compound c is obtained; 6. A method for preparing the compound represented by formula II, comprising the following steps: Compound D and compound e undergo an amidation reaction to obtain a compound represented by formula II; 7. The preparation method according to claim 6, characterized in that: The solvent for the amidation reaction is dichloromethane; The temperature of the amidation reaction is -5 to 5°C; An acid binding agent and a condensation agent are added in the amidation reaction.

8. The preparation method according to claim 7, characterized in that: The compound D was prepared according to the following method: Compound C is hydrolyzed under acidic conditions to obtain compound D; The temperature of the reduction reaction is 85-95°C.

9. The preparation method according to claim 8, characterized in that: The compound C was prepared according to the following method: Compound A and compound B react under acidic conditions, and then under the action of acetic anhydride, compound C is obtained;

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