Metoclopramide N-ethyl compound as well as preparation method and application thereof

Abstract

The invention provides a metoclopramide N-ethyl compound as well as a preparation method and application thereof, the molecular formula of the metoclopramide N-ethyl compound is C12H18ClN3O2, and the metoclopramide N-ethyl compound can be used for quality detection and control in the synthesis process of metoclopramide and is used for preparing a metoclopramide starting material N, N-dimethyl formamide. And the content control standard of the impurity N-ethylethylenediamine in the N, N-diethylethylenediamine is met.

Description

Technical Field

[0001] The invention relates to the technical field of metoclopramide preparation, in particular to a metoclopramide N-ethyl compound and a preparation method and application thereof. Background Art

[0002] Metoclopramide can be used for vomiting caused by brain tumor surgery, tumor radiotherapy and chemotherapy, sequelae of brain trauma, acute craniocerebral injury and drugs; in addition, it also has a good effect on indigestion caused by flatulence, loss of appetite, belching, nausea and vomiting, and can also be used for vomiting and motion sickness (ships) caused by sea and air operations. In addition, metoclopramide can also reduce nausea and vomiting reactions during barium meal examination and promote the passage of barium; or it can be taken before duodenal intubation to facilitate smooth intubation; or it can be used as an auxiliary treatment for biliary diseases and chronic pancreatitis.

[0003] As a drug, metoclopramide has high requirements for its purity. The maximum daily dose of metoclopramide preparations is 30 (mg / day). According to the "Chinese Pharmacopoeia: Guidelines for the Analysis of Drug Impurities 9102", the unknown single impurity limit of metoclopramide should be ≤0.10%. When preparing metoclopramide, impurities are usually inspected, and determining which impurities exist is important for quality inspection, which is convenient for controlling the formation of impurities and increasing the yield of metoclopramide; however, there are still impurities whose structures are unclear, which is not convenient for regulation. Summary of the invention

[0004] The invention provides a metoclopramide N-ethyl compound and a preparation method and application thereof. The metoclopramide N-ethyl compound can be used as a quality control in the synthesis process of metoclopramide and used to formulate a content control standard of an impurity N-ethylethylenediamine in N,N-diethylethylenediamine, a starting material of metoclopramide.

[0005] The technical solution of the present invention is achieved in this way: a metoclopramide N-ethyl compound, the molecular formula of the metoclopramide N-ethyl compound is C 12 H 18 ClN3O2, its structural formula is:

[0006]

[0007] A method for preparing a metoclopramide N-ethyl compound comprises the following steps:

[0008] (1) 0.5-1.0 g of glacial acetic acid, 5.00 g of methyl 5-chloro-4-acetylamino-2-methoxybenzoate, and 6-10 g of N-ethylethylenediamine are mixed and then heated to react to obtain a reaction solution A;

[0009] (2) adding 25-30 g of water and 1.3-1.5 g of sodium hydroxide to the reaction solution A, and then heating and hydrolyzing to obtain a reaction solution B;

[0010] (3) cooling the reaction solution B, filtering it to obtain a filter cake, then washing the filter cake with water until it is neutral, and drying it to obtain a metoclopramide N-ethyl compound.

[0011] Furthermore, in step (1), the heating reaction conditions are: the oil bath is heated to 90° C. to 95° C., and the reaction is carried out for 4 h to 5 h.

[0012] Furthermore, in step (2), the conditions for heating hydrolysis are: heating to 90°C to 95°C and hydrolyzing for 1 hour.

[0013] Furthermore, in step (3), the reaction solution B is cooled to 25°C to 30°C.

[0014] Furthermore, in step (3), the drying conditions are: vacuum drying at 50°C to 60°C.

[0015] A metoclopramide N-ethyl compound is prepared by the preparation method.

[0016] A metoclopramide N-ethyl compound is used for quality control in the process of preparing metoclopramide, for example, it can be used as a reference substance for quality control of metoclopramide.

[0017] Beneficial effects of the present invention:

[0018] The metoclopramide N-ethyl compound prepared by the present invention clarifies its chemical formula and structural formula, which is convenient for pathological research; at the same time, it can be used as a quality control in the synthesis process of metoclopramide, and is used to formulate the content control standard of the impurity N-ethylethylenediamine in the metoclopramide starting material N,N-diethylethylenediamine. N,N-diethylethylenediamine is one of the raw materials for preparing metoclopramide. If the content of N-ethylethylenediamine in N,N-diethylethylenediamine reaches 1%, the content of N-ethyl compound in the crude metoclopramide product can reach 1.19%, and after refining, it still has 0.18%, which does not meet the quality standard. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0020] Figure 1 is the mass spectrum of metoclopramide N-ethyl compound;

[0021] Figure 2 Metoclopramide N-ethyl compound 1 H NMR spectroscopy;

[0022] Figure 3 Metoclopramide N-ethyl compound 13 C NMR spectroscopy;

[0023] Figure 4 is the HPLC spectrum of metoclopramide N-ethyl compound;

[0024] Figure 5 is the chromatogram of the mixed reference solution;

[0025] Figure 6 The chromatogram of crude metoclopramide with N-ethylethylenediamine content <0.5%;

[0026] Figure 7 This is the chromatogram of the fine product of metoclopramide with N-ethylethylenediamine content less than 0.5%;

[0027] Figure 8 This is the chromatogram of the crude metoclopramide when the content of N-ethylethylenediamine reaches 1%;

[0028] Fig. 9 This is the chromatogram of metoclopramide concentrate when the N-ethylethylenediamine content reaches 1%. DETAILED DESCRIPTION

[0029] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0030] A method for preparing a metoclopramide N-ethyl compound comprises the following steps:

[0031] (1) 0.58 g of glacial acetic acid, 5.00 g of methyl 5-chloro-4-acetylamino-2-methoxybenzoate, and 6.75 g of N-ethylethylenediamine were added to a 100 mL three-necked flask, and the oil bath was heated to 90° C. to 95° C. for 4 h to 5 h. After the reaction was completed, a reaction solution A was obtained;

[0032] (2) Add 27.50 g of tap water and 1.32 g of sodium hydroxide to reaction solution A, raise the temperature to 90° C. to 95° C. for hydrolysis for 1 h, and after the reaction is completed, obtain reaction solution B;

[0033] (3) The reaction solution B is cooled to 25°C to 30°C, filtered, and the filter cake is washed with tap water until it is neutral. The filter cake is vacuum dried at 50°C to 60°C to obtain a metoclopramide N-ethyl compound.

[0034] The synthesis equation of the metoclopramide N-ethyl compound is as follows:

[0035]

[0036]

[0037] Depend on Figure 1-3 It can be seen that the molecular formula of metoclopramide N-ethyl compound is C 12 H 18 ClN3O2, molecular weight is 271.74, chemical structure formula:

[0038]

[0039] Depend on Figure 4 It can be seen that the purity of metoclopramide N-ethyl compound is 98.84%; and Figure 4 It can be seen that the retention time of metoclopramide N-ethyl compound is 8.763 min, and the retention time of metoclopramide is 16.425 min.

[0040] Metoclopramide N-ethyl compound is a white to off-white crystalline powder; odorless; soluble in chloroform, slightly soluble in ethanol or acetone, very slightly soluble in ether, almost insoluble in water, and soluble in acidic solutions.

[0041] In N, N-diethylethylenediamine, if the content of N-ethylethylenediamine reaches 1%, Figure 8 As shown in FIG. 1 , the content of metoclopramide N-ethyl compound in the crude metoclopramide product can reach 1.19% (retention time 9.093 min). Fig. 9 As shown, after the crude metoclopramide is refined, the metoclopramide N-ethyl compound still contains 0.18% (retention time 9.105 min). It can be seen that the metoclopramide N-ethyl compound can be used as a quality control in the synthesis process of metoclopramide, and is used to formulate the content control standard of the impurity N-ethylethylenediamine in the metoclopramide starting material N,N-diethylethylenediamine.

[0042] like Figure 5 As shown, the mixed reference substance is a mixed sample made of known impurities, and the elution time of each impurity is located. Impurities A to G are all known impurities in the pharmacopoeia, and the elution time of metoclopramide N-ethyl compound (retention time: 9.118min) is inconsistent with impurities A to G, indicating that it is an unknown impurity.

[0043] In N, N-diethylethylenediamine, the content of N-ethylethylenediamine is controlled to be less than 0.5%, and in the prepared crude metoclopramide, Figure 6 As shown in the figure, the content of metoclopramide N-ethyl compound (retention time 8.728min) is 0.19%, and the impurity content is relatively high, which needs to be reduced to below 0.1%. Clarifying the metoclopramide N-ethyl compound is conducive to targeted impurity removal, such as Figure 7 As shown, in the fine product of metoclopramide, the content of metoclopramide N-ethyl compound is controlled at 0.04% (retention time is 8.730 min).

[0044] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A metoclopramide N-ethyl compound, characterized in that: The molecular formula of the metoclopramide N-ethyl compound is C 12 H 18 ClN3O2, its structural formula is:

2. A method for preparing a metoclopramide N-ethyl compound, characterized in that: The following steps are involved: (1) 0.5-1.0 g of glacial acetic acid, 5.00 g of methyl 5-chloro-4-acetylamino-2-methoxybenzoate, and 6-10 g of N-ethylethylenediamine are mixed and then heated to react to obtain a reaction solution A; (2) adding 25-30 g of water and 1.3-1.5 g of sodium hydroxide to the reaction solution A, and then heating and hydrolyzing to obtain a reaction solution B; (3) cooling the reaction solution B, filtering it to obtain a filter cake, then washing the filter cake with water until it is neutral, and drying it to obtain a metoclopramide N-ethyl compound.

3. The method for preparing a metoclopramide N-ethyl compound according to claim 2, characterized in that: In step (1), the heating reaction conditions are: the oil bath is heated to 90°C to 95°C and the reaction is carried out for 4h to 5h.

4. The method for preparing a metoclopramide N-ethyl compound according to claim 2, characterized in that: In step (2), the conditions for heating hydrolysis are: heating to 90°C to 95°C and hydrolyzing for 1 hour.

5. The method for preparing a metoclopramide N-ethyl compound according to claim 2, characterized in that: In step (3), the reaction solution B is cooled to 25°C to 30°C.

6. The method for preparing a metoclopramide N-ethyl compound according to claim 2, characterized in that: In step (3), the drying conditions are: vacuum drying at 50°C to 60°C.

7. A metoclopramide N-ethyl compound prepared by the preparation method according to any one of claims 2 to 6.

8. Use of a metoclopramide N-ethyl compound according to claim 1 or 7 for quality control in the process of preparing metoclopramide.

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