Mosapride citrate impurity compound and preparation method thereof

Abstract

The invention relates to the technical field of medicine synthesis, in particular to a mosapride citrate impurity compound and a preparation method thereof. The mosapride citrate impurity compound has a structure as shown in a formula I-1 or a formula I-2. The impurity compound can be used as an impurity reference substance and is used for detecting mosapride citrate intermediates, raw material medicines and / or preparations in the production process. The synthesis method is short in route and simple to operate. # imgabs0 #

Description

Technical Field

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

[0002] Mosapride citrate is a potent and selective 5-hydroxytryptamine 4 (5-HT4) receptor agonist that can promote the release of acetylcholine and enhance gastric and duodenal motility. It is a new safe and effective gastrointestinal motility drug. Because it has no affinity with dopamine D2 receptors, adrenaline α1 receptors, 5-HT1 and 5-HT2 receptors on the synaptic membranes of brain nerve cells, it will not cause extrapyramidal syndrome and adverse cardiovascular reactions. Clinically, it is mainly used to relieve digestive system symptoms associated with chronic gastritis. It can also be used for gastroesophageal reflux disease, diabetic gastroparesis and gastric dysfunction in patients with partial gastrectomy. Due to its good clinical efficacy and low side effects, it has been widely used at home and abroad, providing options and help for patients to relieve pain and restore health.

[0003] The research and control of drug impurities is one of the important aspects of controlling drug quality risks. With the progress of the times and the improvement of scientific and technological levels, people have put forward higher requirements for the safety, effectiveness and controllability of drugs. Therefore, various medical-related departments are paying more and more attention to the research and control of drug impurities. Summary of the invention

[0004] 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.

[0005] The present invention provides a mosapride citrate impurity compound having a structure shown in Formula I-1 or Formula I-2:

[0006]

[0007] The present invention has been found through research that when the starting material 002 contains impurity compound B, it will be derived into compound C during the hydrolysis process, and further derived into impurity formula I-1 (flow chart as follows) during the amidation reaction. In the process of preparing mosapride citrate from mosapride, the impurity will be transferred downward in the original form, so it is necessary to control the impurity during the synthesis of mosapride citrate.

[0008]

[0009] When the starting material 002 contains impurity compound E, it will be derived into compound F during the hydrolysis process, and further derived into impurity formula I-2 (flow chart below) during the amidation reaction. In the process of preparing mosapride citrate from mosapride, the impurity will be transferred downward in the original form, so it is necessary to control the impurity during the synthesis of mosapride citrate.

[0010]

[0011] Through the analysis of the synthesis process of the starting material 002, there may be impurities of formula I-1 and I-2, and these two impurities will be derived and transmitted along with the synthesis process of mosapride. These two impurities are the main impurities in the process. As a drug on the market, its quality must be effectively controlled. Once the impurities exceed the standard, it may affect the quality of the drug and cause serious adverse drug reactions. In order to ensure that the impurities can be detected in the drug, it is necessary to synthesize the corresponding impurities as impurity reference substances for impurity location and quality control research.

[0012] The present invention provides a method for preparing the compound represented by the above formula I-1, comprising the following steps:

[0013] Compound A is subjected to bromination reaction with NBS to obtain compound B;

[0014] Allow compound B to undergo a hydrolysis reaction under alkaline conditions to obtain compound C;

[0015] Compound C and compound G are subjected to a condensation reaction to obtain a compound represented by formula Ⅰ-1;

[0016]

[0017] Formula Ⅰ-1.

[0018] Preferably, the solvent for the bromination reaction is DMF.

[0019] The temperature of the bromination reaction is preferably 65-75°C, more preferably 70°C.

[0020] The bromination reaction time is preferably 2-3 h, more preferably 2.5 h.

[0021] The mass ratio of the compound A to NBS is preferably 50:(40-50), more preferably 50:45.

[0022] Preferably, after the bromination reaction is completed, the temperature of the reaction system is lowered to room temperature, purified water is added, stirred, filtered, and dried to obtain compound B.

[0023] The drying temperature is preferably 50-70°C, more preferably 60°C.

[0024] The drying time is preferably 3-5 hours, more preferably 4 hours.

[0025] The temperature of the hydrolysis reaction is preferably 75-85°C, more preferably 80°C.

[0026] The hydrolysis reaction time is preferably 3.5-4.5 h, more preferably 4 h.

[0027] Preferably, the alkaline conditions of the hydrolysis reaction are provided by an alkaline compound. The present invention has no particular limitation on the alkaline compound, which may be an applicable alkaline compound well known to those skilled in the art, including but not limited to KOH, NaOH, and the like.

[0028] The mass ratio of the compound B to the basic compound is preferably 45:(10-20), more preferably 45:17.

[0029] The solvent for the hydrolysis reaction is preferably ethanol.

[0030] Preferably, after the hydrolysis reaction is completed, the reaction solution is cooled to room temperature, and the reaction system is adjusted to acidity with concentrated hydrochloric acid, preferably the pH value is adjusted to about 3, and the solution is filtered and dried to obtain compound C.

[0031] The drying temperature is preferably 50-70°C, more preferably 60°C.

[0032] The drying time is preferably 3-5 hours, more preferably 4 hours.

[0033] The solvent for the condensation reaction is preferably dichloromethane.

[0034] The temperature of the condensation reaction is preferably -5 to 5°C, more preferably 0°C.

[0035] The condensation reaction time is preferably 2.5-3.5 h, more preferably 3 h.

[0036] Preferably, an acid binding agent and a condensing agent are added in the condensation reaction.

[0037] The acid binding agent is preferably triethylamine.

[0038] The condensing agent is preferably isobutyl chloroformate.

[0039] The mass ratio of the compound C to the acid binding agent is preferably 30:(15-20), more preferably 30:18.

[0040] The mass ratio of the compound C to the condensing agent is preferably 30:(15-25), more preferably 30:20.

[0041] The mass ratio of the compound C to the compound G is preferably 30:(30-35), more preferably 30:31.

[0042] Preferably, after the reaction is completed, purified water is added to the reaction system and the system is filtered and dried to obtain a compound represented by formula Ⅰ-1.

[0043] The drying temperature is preferably 50-70°C, more preferably 60°C.

[0044] The drying time is preferably 3-5 hours, more preferably 4 hours.

[0045] The reaction equation of the above preparation method is as follows:

[0046]

[0047] The present invention provides a method for preparing the compound represented by the above formula I-2, comprising the following steps:

[0048] Compound A is subjected to chlorination reaction with NCS to obtain compound E;

[0049] Allowing compound E to undergo a hydrolysis reaction under alkaline conditions to obtain compound F;

[0050] Reacting compound F with compound G to obtain a compound represented by formula Ⅰ-2;

[0051]

[0052] Preferably, the solvent for the chlorination reaction is DMF.

[0053] The temperature of the chlorination reaction is preferably 85-95°C. In some specific embodiments of the present invention, the temperature of the chlorination reaction includes but is not limited to 85°C, 90°C, and 95°C.

[0054] The chlorination reaction time is preferably 2-4 hours, more preferably 3 hours.

[0055] The mass ratio of the compound A to NCS is preferably 50:(80-90).

[0056] Preferably, after the chlorination reaction is completed, the temperature of the reaction system is lowered to room temperature, purified water is added, stirred, filtered, and dried to obtain compound E.

[0057] The drying temperature is preferably 50-70°C, more preferably 60°C.

[0058] The drying time is preferably 3-5 hours, more preferably 4 hours.

[0059] The temperature of the hydrolysis reaction is preferably 75-85°C, more preferably 75-80°C.

[0060] The hydrolysis reaction time is preferably 3.5-4.5 h, more preferably 4 h.

[0061] Preferably, the alkaline conditions of the hydrolysis reaction are provided by an alkaline compound. The present invention has no particular limitation on the alkaline compound, which may be an applicable alkaline compound well known to those skilled in the art, including but not limited to KOH, NaOH, and the like.

[0062] The mass ratio of the compound E to the basic compound is preferably 1:(0.3-0.5), more preferably 1:0.4.

[0063] The solvent for the hydrolysis reaction is preferably ethanol.

[0064] Preferably, after the hydrolysis reaction is completed, the reaction solution is cooled to room temperature, and the reaction system is adjusted to acidity with concentrated hydrochloric acid, preferably the pH value is adjusted to about 3, and the solution is filtered and dried to obtain compound F.

[0065] The drying temperature is preferably 50-70°C, more preferably 60°C.

[0066] The drying time is preferably 3-5 hours, more preferably 4 hours.

[0067] The solvent for the condensation reaction is preferably dichloromethane.

[0068] The temperature of the condensation reaction is preferably -5 to 5°C, more preferably 0°C.

[0069] The condensation reaction time is preferably 2.5-3.5 h, more preferably 3 h.

[0070] Preferably, an acid binding agent and a condensing agent are added in the condensation reaction.

[0071] The acid binding agent is preferably triethylamine.

[0072] The condensing agent is preferably isobutyl chloroformate.

[0073] The mass ratio of the compound F to the acid binding agent is preferably 1:(0.5-0.8), more preferably 1:(0.4-0.5).

[0074] The mass ratio of the compound F to the condensing agent is preferably 1:(0.6-1), more preferably 1:(0.6-0.8).

[0075] The mass ratio of the compound F to the compound G is preferably 1:(0.6-0.8), more preferably 1:(0.65-0.75).

[0076] Preferably, after the reaction is completed, purified water is added to the reaction system, washed with an alkaline compound until neutral, the organic phase is separated, the organic solvent is removed after drying, the residue is mixed with anhydrous ethanol, heated under reflux, cooled to precipitate a solid product, and dried to obtain the compound shown in formula Ⅰ-2.

[0077] The reaction equation of the above preparation method is as follows:

[0078]

[0079] Compared with the prior art, the present invention provides an impurity compound of mosapride citrate, which has a structure shown in Formula I-1 or Formula I-2. The impurity compound can be used as an impurity reference substance for detecting mosapride citrate intermediates, raw materials and / or preparations in the production process. The synthesis method thereof has a short route and is simple to operate. BRIEF DESCRIPTION OF THE DRAWINGS

[0080] Figure 1 The H NMR spectrum of compound B prepared in Example 1;

[0081] Figure 2 The mass spectrum of compound B prepared in Example 1;

[0082] Figure 3 The H NMR spectrum of compound C prepared in Example 1;

[0083] Figure 4 is the mass spectrum of compound C prepared in Example 1;

[0084] Figure 5 The H NMR spectrum of compound D (Formula I-1) prepared in Example 1;

[0085] Figure 6 The mass spectrum of compound D (Formula I-1) prepared in Example 1;

[0086] Figure 7 The H NMR spectrum of compound E prepared in Example 4;

[0087] Figure 8 is the mass spectrum of compound E prepared in Example 4;

[0088] Fig. 9 The H NMR spectrum of compound F prepared in Example 4;

[0089] Fig.10 is the mass spectrum of compound F prepared in Example 4;

[0090] Fig.11 The H NMR spectrum of compound H (Formula I-2) prepared in Example 4;

[0091] Fig.12 The mass spectrum of compound H (Formula I-2) prepared in Example 4;

[0092] Fig.13 It is the liquid chromatogram of compound B and compound E in the starting material 002;

[0093] Fig.14 It is the liquid chromatogram of the target compound (Formula I-1 and I-2) in mosapride citrate. DETAILED DESCRIPTION

[0094] 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.

[0095] Example 1

[0096] 1. Preparation of Compound B

[0097] Compound A (50.09 g) was added to DMF, and then NBS (44.90 g) was added. Stirring was started and the reaction was carried out at 70° C. for 2.5 h.

[0098] After the reaction was complete, the solution was cooled to room temperature, purified water (150 ml) was added and stirring was continued for 3 hours, the product was filtered, the filter cake was rinsed with purified water, and dried by suction, and the filter cake was dried by air at 60° C. for 4 hours to obtain an off-white powder (54.42 g).

[0099] 2. Preparation of Compound C

[0100] Sodium hydroxide (17.12 g) was dissolved in purified water (100 ml), and stirring was started. After dissolution, the temperature was cooled to room temperature, and compound B (45.54 g) was added, followed by ethanol (50 ml), and the reaction was carried out at 80° C. for 4 h.

[0101] After the reaction was completed, the reaction solution was cooled to room temperature, and the reaction system was adjusted to a pH of about 3 with concentrated hydrochloric acid. The solution was filtered, and the filter cake was rinsed with purified water (100 ml) and dried. The filter cake was dried at 60° C. for 4 h to obtain an off-white powder (46.12 g).

[0102] 3. Preparation of Compound D (Formula I-1)

[0103] Dissolve compound C (30.51 g) in dichloromethane (300 ml), start stirring, add triethylamine (18.43 g), cool the reaction system to 0°C, add isobutyl chloroformate (20.90 g) and react for 1 h, then add 2-aminomethyl-4-(4-fluorobenzyl)morpholine (31.02 g) and continue the reaction for 3 h.

[0104] After the reaction, purified water (150 ml) was added and the mixture was stirred continuously, filtered, and the filter cake was rinsed with purified water (200 ml) and dried by suction. The filter cake was dried by forced air at 60°C for 4 h to obtain an off-white powder (31.41 g).

[0105] Example 2

[0106] 1. Preparation of Compound B

[0107] Compound A (45.18 g) was added to DMF, and then NBS (40.49 g) was added. Stirring was started and the reaction was carried out at 65° C. for 2.5 h.

[0108] After the reaction was complete, the solution was cooled to room temperature, purified water (150 ml) was added and stirring was continued for 3 hours, the product was filtered, the filter cake was rinsed with purified water, and dried by suction, and the filter cake was dried by air at 60° C. for 4 hours to obtain an off-white powder (49.56 g).

[0109] 2. Preparation of Compound C

[0110] Sodium hydroxide (12.16 g) was dissolved in purified water (100 ml), and stirring was started. After dissolution, the temperature was cooled to room temperature, and compound B (40.06 g) was added, followed by ethanol (50 ml), and the reaction was carried out at 75° C. for 4 h.

[0111] After the reaction was completed, the reaction solution was cooled to room temperature, and the reaction system was adjusted to a pH of about 3 with concentrated hydrochloric acid. The solution was filtered, and the filter cake was rinsed with purified water (100 ml) and dried. The filter cake was dried at 60° C. for 4 h to obtain an off-white powder (41.52 g).

[0112] 3. Preparation of Compound D (Formula I-1)

[0113] Dissolve compound C (25.62 g) in dichloromethane (300 ml), start stirring, add triethylamine (13.68 g), cool the reaction system to 0°C, add isobutyl chloroformate (15.69 g) and react for 1 h, then add 2-aminomethyl-4-(4-fluorobenzyl)morpholine (26.03 g) and continue the reaction for 3 h.

[0114] After the reaction, purified water (150 ml) was added and the mixture was stirred continuously, filtered, and the filter cake was rinsed with purified water (200 ml) and dried by suction. The filter cake was dried by forced air at 60°C for 4 h to obtain an off-white powder (26.45 g).

[0115] Example 3

[0116] 1. Preparation of Compound B

[0117] Compound A (55.08 g) was added to DMF, and then NBS (49.37 g) was added. Stirring was started and the reaction was carried out at 75° C. for 2.5 h.

[0118] After the reaction was complete, the solution was cooled to room temperature, purified water (150 ml) was added and stirring was continued for 3 hours, the product was filtered, the filter cake was rinsed with purified water, and dried by suction, and the filter cake was dried by air at 60° C. for 4 hours to obtain an off-white powder (59.12 g).

[0119] 2. Preparation of Compound C

[0120] Sodium hydroxide (22.23 g) was dissolved in purified water (100 ml), and stirring was started. After dissolution, the temperature was cooled to room temperature, and compound B (50.54 g) was added, followed by ethanol (50 ml), and the reaction was carried out at 85° C. for 4 h.

[0121] After the reaction was completed, the reaction solution was cooled to room temperature, and the reaction system was adjusted to a pH of about 3 with concentrated hydrochloric acid. The solution was filtered, and the filter cake was rinsed with purified water (100 ml) and dried. The filter cake was dried at 60° C. for 4 h to obtain an off-white powder (51.31 g).

[0122] 3. Preparation of Compound D (Formula I-1)

[0123] Dissolve compound C (35.11 g) in dichloromethane (300 ml), start stirring, add triethylamine (23.36 g), cool the reaction system to 0°C, add isobutyl chloroformate (20.90 g) and react for 1 h, then add 2-aminomethyl-4-(4-fluorobenzyl)morpholine (36.24 g) and continue the reaction for 3 h.

[0124] After the reaction, purified water (150 ml) was added and the mixture was stirred continuously, filtered, the filter cake was rinsed with purified water (200 ml), and dried by suction. The filter cake was dried by forced air at 60°C for 4 h to obtain an off-white powder (36.41 g).

[0125] Example 4

[0126] 1. Preparation of Compound E

[0127] Compound A (53.19 g) was dissolved in DMF (150 ml), and NCS (89.77 g) was added. After the addition was completed, the reaction system was reacted at 90° C. for 3 h.

[0128] After the reaction was complete, the solution was cooled to room temperature, purified water (500 ml) was added and stirring was continued for 2 hours, the solution was filtered, the filter cake was rinsed with purified water, and dried, and the filter cake was dried at 60° C. for 4 hours to obtain an off-white powder (42.12 g).

[0129] 2. Preparation of Compound F

[0130] Add purified water (10 ml) to a three-necked flask (100 ml), start stirring, add NaOH (4.49 g), and then rinse with purified water (10 ml). After complete dissolution, add compound E (10.11 g) and set the temperature to 80°C. When the system is heated to about 50°C, add anhydrous ethanol (10 ml). Keep the reaction at 80°C for 4 hours.

[0131] After the reaction was completed, the pH was adjusted to about 2 with concentrated hydrochloric acid, the precipitated white solid was filtered, washed with purified water, and then dried, and the filter cake was dried at 60° C. to obtain compound F.

[0132] 3. Preparation of Compound H (Formula I-2)

[0133] Take dichloromethane (50ml) and add compound F (4.53g) to a three-necked flask (100ml), stir at room temperature, add triethylamine (2.05g), place the reactor in a cooling reaction bath, set the temperature to -5℃, and start cooling. Add isobutyl chloroformate (3.34g) at -5℃, react at low temperature for 1 hour, then add compound G (3.28g), continue stirring and reacting for 3h. Monitor the reaction by thin layer chromatography, developing solvent: dichloromethane: methanol: glacial acetic acid (15:10:1).

[0134] After the reaction is completed, purified water (30 ml) is added, washed with saturated sodium bicarbonate solution (20 ml), and then rinsed with purified water (20 ml), the organic phase is separated, anhydrous sulfuric acid (3.06 g) is added to the organic phase for drying, the desiccant is filtered out, and the mixture is concentrated and evaporated to dryness, anhydrous ethanol (25 ml) is added, and the product is precipitated after heating under reflux at 80°C and cooled. After drying, the target impurity (4.15 g) is obtained.

[0135] Example 5

[0136] 1. Preparation of Compound E

[0137] Compound A (48.54 g) was dissolved in DMF (150 ml), and NCS (84.22 g) was added. After the addition was completed, the reaction system was reacted at 85° C. for 3 h.

[0138] After the reaction was complete, the solution was cooled to room temperature, purified water (500 ml) was added and stirring was continued for 2 hours, the solution was filtered, the filter cake was rinsed with purified water, and dried, and the filter cake was dried at 60° C. for 4 hours to obtain an off-white powder (37.51 g).

[0139] 2. Preparation of Compound F

[0140] Add purified water (10 ml) to a three-necked flask (100 ml), start stirring, add NaOH (4.01 g), and rinse with purified water (10 ml). After complete dissolution, add compound E (8.06 g) and set the temperature to 75°C. When the system is heated to about 50°C, add anhydrous ethanol (10 ml). Keep the reaction at 75°C for 4 hours.

[0141] After the reaction was completed, the pH was adjusted to about 2 with concentrated hydrochloric acid, the precipitated white solid was filtered, washed with purified water, and then dried, and the filter cake was dried at 60° C. to obtain compound F.

[0142] 3. Preparation of Compound H (Formula I-2)

[0143] Take dichloromethane (50ml) and add compound F (4.05g) to a three-necked flask (100ml), stir at room temperature, add triethylamine (1.95g), place the reactor in a cooling reaction bath, set the temperature to -5℃, and start cooling. Add isobutyl chloroformate (3.26g) at -5℃, react at low temperature for 1 hour, then add compound G (2.81g), continue stirring and reacting for 3h. Monitor the reaction by thin layer chromatography, developing solvent: dichloromethane: methanol: glacial acetic acid (15:10:1).

[0144] After the reaction is completed, purified water (30 ml) is added, washed with saturated sodium bicarbonate solution (20 ml), and then rinsed with purified water (20 ml), the organic phase is separated, anhydrous sulfuric acid (3.01 g) is added to the organic phase for drying, the desiccant is filtered out, and the mixture is concentrated and evaporated to dryness, anhydrous ethanol (25 ml) is added, and the product is precipitated after heating under reflux at 80°C and cooled. After drying, the target impurity (3.86 g) is obtained.

[0145] Example 6

[0146] 1. Preparation of Compound E

[0147] Compound A (58.23 g) was dissolved in DMF (150 ml), and NCS (94.16 g) was added. After the addition was completed, the reaction system was reacted at 95° C. for 3 h.

[0148] After the reaction was complete, the solution was cooled to room temperature, purified water (500 ml) was added and stirring was continued for 2 hours, the solution was filtered, the filter cake was rinsed with purified water, and dried, and the filter cake was dried at 60° C. for 4 hours to obtain an off-white powder (47.25 g).

[0149] 2. Preparation of Compound F

[0150] Add purified water (10 ml) to a three-necked flask (100 ml), start stirring, add NaOH (4.63 g), and rinse with purified water (10 ml). After complete dissolution, add compound E (12.03 g) and set the temperature to 85°C. When the system is heated to about 50°C, add anhydrous ethanol (10 ml). Keep the reaction at 80°C for 4 hours.

[0151] After the reaction was completed, the pH was adjusted to about 2 with concentrated hydrochloric acid, the precipitated white solid was filtered, washed with purified water, and then dried, and the filter cake was dried at 60° C. to obtain the target impurity.

[0152] 3. Preparation of Compound H (Formula I-2)

[0153] Take dichloromethane (50ml) and add compound F (5.02g) to a three-necked flask (100ml), stir at room temperature, add triethylamine (2.10g), place the reactor in a cooling reaction bath, set the temperature to 0℃, and start cooling. Add isobutyl chloroformate (3.40g) at 0℃, react at low temperature for 1 hour, then add compound G (3.90g), continue stirring and reacting for 3h. Monitor the reaction by thin layer chromatography, developing solvent: dichloromethane: methanol: glacial acetic acid (15:10:1).

[0154] After the reaction is completed, purified water (30 ml) is added, washed with saturated sodium bicarbonate solution (20 ml), and then rinsed with purified water (20 ml), the organic phase is separated, anhydrous sulfuric acid (3.15 g) is added to the organic phase for drying, the desiccant is filtered out, and the mixture is concentrated and evaporated to dryness, 25 ml of anhydrous ethanol is added, and the mixture is heated to reflux at 80°C and then cooled to precipitate the product, which is then dried to obtain the target impurity (4.61 g).

[0155] Fig.13 It is the liquid chromatogram of compound B and compound E in the starting material 002.

[0156] Fig.14 It is a liquid chromatogram of the target compounds (Formulas I-1 and I-2) in mosapride citrate, wherein the peak at time 14.728 min is the peak of the compound of Formula I-1, and the peak at time 20.092 min is the peak of the compound of Formula I-2.

[0157] 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-1 or Formula I-2:

2. A method for preparing the compound represented by formula I-1, comprising the following steps: Compound A is subjected to bromination reaction with NBS to obtain compound B; Allow compound B to undergo a hydrolysis reaction under alkaline conditions to obtain compound C; Compound C and compound G are subjected to a condensation reaction to obtain a compound represented by formula Ⅰ-1; Formula Ⅰ-1.

3. The preparation method according to claim 2, characterized in that: The solvent for the bromination reaction is DMF; The temperature of the bromination reaction is 65-75°C; The mass ratio of the compound A to NBS is 50:(40-50).

4. The preparation method according to claim 2, characterized in that: The temperature of the hydrolysis reaction is 75-85°C.

5. The preparation method according to claim 2, characterized in that: The solvent for the condensation reaction is dichloromethane; The temperature of the condensation reaction is -5 to 5°C; An acid binding agent and a condensing agent are added in the condensation reaction.

6. A method for preparing the compound represented by formula I-2, comprising the following steps: Compound A is subjected to chlorination reaction with NCS to obtain compound E; Allowing compound E to undergo a hydrolysis reaction under alkaline conditions to obtain compound F; Reacting compound F with compound G to obtain a compound represented by formula Ⅰ-2; Formula Ⅰ-2.

7. The preparation method according to claim 6, characterized in that: The solvent of the chlorination reaction is DMF; The temperature of the chlorination reaction is 85-95°C; The mass ratio of the compound A to NCS is 50:(80-90).

8. The preparation method according to claim 6, characterized in that: The temperature of the hydrolysis reaction is 75-85°C.

9. The preparation method according to claim 6, characterized in that: The solvent for the condensation reaction is dichloromethane; The temperature of the condensation reaction is -5 to 5°C; An acid binding agent and a condensing agent are added in the condensation reaction.

10. The preparation method according to claim 5 or 9, characterized in that: The acid binding agent is selected from triethylamine; The condensing agent is selected from isobutyl chloroformate.

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