Mosapride citrate impurity compound and preparation method thereof

Abstract

The invention relates to the technical field of biological medicine, in particular to a mosapride citrate impurity compound and a preparation method thereof. The impurity compound of mosapride citrate has a structure as shown in a formula I. The impurity compound can be used as a mosapride intermediate and an impurity reference substance in a finished product detection standard, and is used for a quality control link of qualitative and quantitative analysis of impurities in a mosapride production process. The preparation method is reasonable in synthetic route design, mild in reaction condition, low in production cost, simple in post-treatment, stable in process, good in reproducibility, high in operability and relatively high in sample yield and purity. # 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 raw material is already on the market and is widely used clinically for patients with functional dyspepsia with symptoms such as upper abdominal fullness, nausea, vomiting, acid reflux, heartburn, etc. It can also be used for patients with reflux esophagitis, gastroparesis, and dyspepsia symptoms after partial gastrectomy.

[0003] At present, the research and control of drug impurities is one of the important tasks to control 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 pay 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:

[0006]

[0007] The present invention provides a method for preparing the compound represented by the above formula I, comprising the following steps:

[0008] Condensation reaction is carried out between compound III and compound II to obtain a compound represented by formula I;

[0009]

[0010] The solvent for the condensation reaction is preferably dichloromethane.

[0011] The temperature of the condensation reaction is preferably -5 to 5°C. In some specific embodiments of the present invention, the temperature of the condensation reaction is -5°C, 0°C or 5°C.

[0012] The condensation reaction time is preferably 2.5-3.5 h, more preferably 3 h.

[0013] Preferably, an acid binding agent and a condensing agent are added in the condensation reaction.

[0014] The acid binding agent is preferably triethylamine.

[0015] The condensing agent is preferably isobutyl chloroformate.

[0016] The mass ratio of the acid binding agent to the compound III is preferably 1:(1.45-1.85), more preferably 1:(1.55-1.75).

[0017] The mass ratio of the condensing agent to the compound III is preferably 1:(1.05-1.35), and more preferably 1:(1.15-1.25).

[0018] The mass ratio of the compound II to the compound III is preferably 1:(0.65-0.85), and more preferably 1:(0.70-0.80).

[0019] 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.

[0020] Preferably, the compound III is prepared according to the following method:

[0021] Allowing compound IV to undergo a hydrolysis reaction under alkaline conditions to obtain compound III;

[0022]

[0023] The temperature of the hydrolysis reaction is preferably 75-85°C, more preferably 75-80°C.

[0024] The hydrolysis reaction time is preferably 3.5-4.5 h, more preferably 4 h.

[0025] 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.

[0026] The mass ratio of the compound IV to the basic compound is preferably 1:(0.15-0.25), more preferably 1:(0.18-0.20).

[0027] The solvent for the hydrolysis reaction is preferably ethanol.

[0028] Preferably, after the hydrolysis reaction is completed, the reaction solution is cooled to room temperature, and the reaction system is adjusted to acidity with hydrochloric acid, preferably the pH value is adjusted to about 2-3, and a white solid is precipitated, and the white solid is compound III.

[0029] Preferably, the compound IV is prepared according to the following method:

[0030] Compound V is subjected to chlorination reaction with NCS to obtain compound IV;

[0031]

[0032] The solvent for the chlorination reaction is preferably DMF.

[0033] The temperature of the chlorination reaction is preferably 60-80°C. In some specific embodiments of the present invention, the temperature of the chlorination reaction is 60°C, 70°C or 80°C.

[0034] The chlorination reaction time is preferably 2-4 hours, more preferably 3 hours.

[0035] Preferably, the mass ratio of the NCS to the compound V is 2:(2.5-3.5), more preferably 2:3.

[0036] The reaction equation of the above preparation method is as follows:

[0037]

[0038] Compared with the prior art, the present invention provides an impurity compound of mosapride citrate, which has a structure shown in formula I. The impurity compound can be used as an impurity reference substance in the detection standards of mosapride intermediates and finished products, and is used in the quality control link of qualitative and quantitative analysis of impurities in the production process of mosapride. The preparation method thereof has a reasonable synthetic route design, mild reaction conditions, low production cost, simple post-treatment, stable process, good reproducibility, strong operability, and high sample yield and purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 HPLC spectrum of compound I prepared in Example 1;

[0040] Figure 2 NMR spectrum of compound I prepared in Example 1;

[0041] Figure 3 The MS spectrum of compound I prepared in Example 1;

[0042] Figure 4 NMR spectrum of compound IV prepared in Example 1;

[0043] Figure 5 This is the MS spectrum of compound IV prepared in Example 1. DETAILED DESCRIPTION

[0044] 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.

[0045] Example 1

[0046] Step (1): Compound V, i.e. methyl 4-acetamido-2-hydroxybenzoate, is added to a 250 ml three-necked flask, 85 ml of DMF is slowly added and stirring is started, an appropriate amount of NCS (with a mass ratio of about 2:3 (g / g) to compound V) is added and stirring is continued, the three-necked flask is heated and stirred at 70° C. and the reaction is carried out for 3 hours to obtain compound IV, i.e. methyl 4-acetamido-5-chloro-2-hydroxybenzoate;

[0047] Step (2): Add compound IV to a NaOH aqueous solution (take 10 ml of purified water in a 100 ml three-necked flask and stir, add about 0.1 mol of NaOH, rinse with 14 ml of purified water, and stir until completely dissolved), and set the temperature to 80°C. When the system is about 50°C, add an appropriate amount of anhydrous ethanol (the volume mass ratio with compound IV is about 8:5 (ml / g)). Keep the reaction at 80°C for 4 hours and then cool to room temperature. Adjust the pH to about 2 with hydrochloric acid, and a white solid will precipitate. The white solid is compound III (4-amino-5-chloro-2-hydroxybenzoic acid); add 50 ml of dichloromethane, the solid will dissolve, separate the liquids, collect the lower organic phase with a reactor, add an appropriate amount of triethylamine (the mass ratio with compound III is about 5:8 (g / g)), place the reactor in a reaction bath with a cooling effect, set the temperature to -5°C, and start cooling. At -5°C, add an appropriate amount of isobutyl chloroformate (with a mass ratio of about 5:6 (g / g) to compound III), react at low temperature for 1 hour, add an appropriate amount of compound II, namely 2-aminomethyl-4-(4-fluorobenzyl)morpholine (with a mass ratio of about 4:3 (g / g) to compound III), and continue stirring and reacting for 3 hours. After the reaction is completed, add 40 ml of purified water, wash with 25 ml of saturated sodium bicarbonate solution, and then rinse with 20 ml of purified water, separate the organic phase, add about 0.03 mol of anhydrous sodium sulfate to the organic phase for drying, filter out the desiccant, concentrate and evaporate to dryness, add 15 ml of anhydrous ethanol, heat under reflux at 80°C, cool to precipitate the product, and obtain compound I, namely (±)-4-amino-5-chloro-N-((4-(4-fluorobenzyl)morpholin-2-yl)methyl)-2-hydroxybenzamide after drying.

[0048] Example 2

[0049] Step (1): Compound V, i.e. methyl 4-acetamido-2-hydroxybenzoate, is added to a 250 ml three-necked flask, 80 ml of DMF is slowly added and stirring is started, an appropriate amount of NCS (with a mass ratio of about 2:3 (g / g) to compound V) is added and stirring is continued, the three-necked flask is heated and stirred at 60° C. and the reaction is carried out for 3 h to obtain compound IV, i.e. methyl 4-acetamido-5-chloro-2-hydroxybenzoate;

[0050] Step (2): Add compound IV to a NaOH aqueous solution (take 10 ml of purified water in a 50 ml three-necked flask, start stirring, add about 0.1 mol of NaOH, then rinse with 14 ml of purified water, and stir until completely dissolved), and set the temperature to 80°C. When the system is about 50°C, add an appropriate amount of anhydrous ethanol (the volume mass ratio with compound IV is about 8:5 (ml / g)). Keep the reaction at 80°C for 4 hours and then cool to room temperature. Adjust the pH to about 2 with hydrochloric acid, and a white solid will precipitate. The white solid is compound III (4-amino-5-chloro-2-hydroxybenzoic acid); add 50 ml of dichloromethane, the solid will dissolve, separate the liquids, collect the lower organic phase with a reactor, add an appropriate amount of triethylamine (the mass ratio with compound III is about 5:8 (g / g)), place the reactor in a reaction bath with a cooling effect, set the temperature to 0°C, and start cooling. At 0°C, add an appropriate amount of isobutyl chloroformate (with a mass ratio of about 5:6 (g / g) to compound III), react at low temperature for 1 hour, add an appropriate amount of compound II, namely 2-aminomethyl-4-(4-fluorobenzyl)morpholine (with a mass ratio of about 4:3 (g / g) to compound III), and continue stirring and reacting for 3 hours. After the reaction is completed, add 40 ml of purified water, wash with 25 ml of saturated sodium bicarbonate solution, and then rinse with 20 ml of purified water, separate the organic phase, add about 0.03 mol of anhydrous sodium sulfate to the organic phase for drying, filter out the desiccant, concentrate and evaporate to dryness, add 10 ml of anhydrous ethanol, heat under reflux at 70°C, cool to precipitate the product, and obtain compound I, namely (±)-4-amino-5-chloro-N-((4-(4-fluorobenzyl)morpholin-2-yl)methyl)-2-hydroxybenzamide after drying.

[0051] Example 3

[0052] Step (1): Compound V, i.e., methyl 4-acetamido-2-hydroxybenzoate, is added to a 250 ml three-necked flask, 90 ml of DMF is slowly added and stirring is started, an appropriate amount of NCS (with a mass ratio of about 2:3 (g / g) to compound V) is added and stirring is continued, the three-necked flask is heated and stirred at 80° C. and reacted for 3 h to obtain compound IV, i.e., methyl 4-acetamido-5-chloro-2-hydroxybenzoate;

[0053] Step (2): Add compound IV to a NaOH aqueous solution (take 10 ml of purified water in a 50 ml three-necked flask and stir, add about 0.1 mol of NaOH, rinse with 14 ml of purified water, and stir until completely dissolved), and set the temperature to 80°C. When the system is about 50°C, add an appropriate amount of anhydrous ethanol (the volume mass ratio with compound IV is about 8:5 (ml / g)). Keep the reaction at 80°C for 4 hours, adjust the pH to about 2 with hydrochloric acid, and a white solid will precipitate. The white solid is compound III (4-amino-5-chloro-2-hydroxybenzoic acid); add 50 ml of dichloromethane, the solid will dissolve, separate the liquids, collect the lower organic phase with a reactor, add an appropriate amount of triethylamine (the mass ratio with compound III is about 5:8 (g / g)), place the reactor in a reaction bath with a cooling effect, set the temperature to 5°C, and start cooling. When the temperature is 5°C, add an appropriate amount of isobutyl chloroformate (with a mass ratio of about 5:6 (g / g) to compound III), react for 1 hour, add an appropriate amount of compound II, namely 2-aminomethyl-4-(4-fluorobenzyl)morpholine (with a mass ratio of about 4:3 (g / g) to compound III), and continue to stir and react for 3 hours. After the reaction is completed, add 40 ml of purified water, wash with 25 ml of saturated sodium bicarbonate solution, and then rinse with 20 ml of purified water, separate the organic phase, add about 0.03 mol of anhydrous sodium sulfate to the organic phase for drying, filter out the desiccant, concentrate and evaporate to dryness, add 20 ml of anhydrous ethanol, heat under reflux at 90°C, cool to precipitate the product, and dry to obtain compound I, namely (±)-4-amino-5-chloro-N-((4-(4-fluorobenzyl)morpholin-2-yl)methyl)-2-hydroxybenzamide.

[0054] 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 the structure shown in Formula I:

2. A method for preparing the compound represented by formula I, comprising the following steps: Condensation reaction is carried out between compound III and compound II to obtain a compound represented by formula I; 3. The preparation method according to claim 2, characterized in that: The solvent for the condensation reaction is dichloromethane.

4. The preparation method according to claim 2, characterized in that: The temperature of the condensation reaction is -5 to 5°C.

5. The preparation method according to claim 2, characterized in that: In the condensation reaction, an acid binding agent and a condensing agent are added The acid binding agent is selected from triethylamine; The condensing agent is selected from isobutyl chloroformate.

6. The preparation method according to claim 2, characterized in that: The compound III was prepared according to the following method: Compound IV is hydrolyzed under alkaline conditions to obtain compound III; 7. The preparation method according to claim 6, characterized in that: The temperature of the hydrolysis reaction is 75-85°C.

8. The preparation method according to claim 6, characterized in that: The compound IV was prepared according to the following method: Compound V undergoes chlorination reaction with NCS to obtain compound IV; 9. The preparation method according to claim 8, characterized in that: The solvent of the chlorination reaction is DMF; The temperature of the chlorination reaction is 60-80°C.

10. The preparation method according to claim 8, characterized in that: The mass ratio of the NCS to the compound V is 2:(2.5-3.5).

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