Preparation method of metoclopramide

Abstract

The invention provides a preparation method of metoclopramide, which comprises the following steps: mixing 5-chloro-4-amino-2-methoxybenzoic acid methyl ester hydrochloride and N, N-diethylethylenediamine, and heating to react, so as to obtain a metoclopramide crude product reaction solution; dissociating the metoclopramide crude product reaction solution by using a sodium hydroxide solution, filtering, washing a filter cake to be neutral by using water, and drying to obtain a metoclopramide crude product. According to the method, the methyl 5-chloro-4-amino-2-methoxybenzoate hydrochloride is used as the raw material to prepare the metoclopramide, so that the reaction impurities are reduced, the conversion rate is increased, and the relative peak area of the methyl 5-chloro-4-amino-2-methoxybenzoate is only 0.11% in the prepared crude product reaction liquid of the metoclopramide.

Description

Technical Field

[0001] The invention relates to the technical field of metoclopramide, in particular to a preparation method of metoclopramide. Background Art

[0002] The commonly used process routes for metoclopramide are as follows:

[0003]

[0004] According to the synthetic route, 5-chloro-4-acetylamino-2-methoxybenzoic acid methyl ester and N,N-diethylethylenediamine are subjected to an aminolysis reaction to obtain 4-acetylamino-5-chloro-N-[(2-diethylamino)ethyl]-2-methoxybenzamide, which is then hydrolyzed with sodium hydroxide to remove the acetyl group, and the product is crystallized to obtain a crude product of metoclopramide.

[0005] In the process of testing the reaction liquid of crude metoclopramide, it was found that during the aminolysis reaction, 5-chloro-4-acetylamino-2-methoxybenzoic acid methyl ester would be converted into 5-chloro-4-amino-2-methoxybenzoic acid methyl ester, and 5-chloro-4-amino-2-methoxybenzoic acid methyl ester would then react with N, N-diethylethylenediamine to generate metoclopramide. The actual reaction process is as follows:

[0006]

[0007] However, the reaction process of methyl 5-chloro-4-amino-2-methoxybenzoate and N, N-diethylethylenediamine was slow and the conversion rate was low. After reacting at 120°C to 125°C for 5.5 hours, the relative peak area of ​​methyl 5-chloro-4-amino-2-methoxybenzoate in the reaction solution was still 8.69% (see Figure 2 , peak time 30.083min). Summary of the invention

[0008] The invention provides a preparation method of metoclopramide. 5-chloro-4-amino-2-methoxybenzoic acid methyl ester hydrochloride is used as a raw material to prepare metoclopramide, thereby reducing reaction impurities and improving conversion rate.

[0009] The technical solution of the present invention is achieved in this way: a method for preparing metoclopramide comprises the following steps:

[0010] (1) 2.5 g to 2.6 g of 5-chloro-4-amino-2-methoxybenzoic acid methyl ester hydrochloride and 3 g to 5 g of N,N-diethylethylenediamine are mixed and then heated to react to obtain a reaction solution A;

[0011] (2) adding 10 g to 20 g of water and 0.5 g to 1.0 g of sodium hydroxide to the reaction solution A, and then heating and hydrolyzing to obtain a reaction solution B;

[0012] (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 crude product of metoclopramide.

[0013] Further, in step (1), the preparation method of 5-chloro-4-amino-2-methoxybenzoic acid methyl ester hydrochloride is as follows:

[0014] 1) Mix 19.5g-20.5g of 5-chloro-4-amino-2-methoxybenzoic acid with 120g-130g of methanol, and dropwise add 14.5g-15.5g of thionyl chloride; after the dropwise addition, heat to 60°C-65°C and react for 3h-4h; after the reaction, concentrate under reduced pressure until almost no fraction is produced;

[0015] 2) Add 70 g to 80 g of methanol to the solid obtained in step 1), heat to 60° C. to 65° C. to dissolve, then cool to 0° C. to 5° C., filter and dry to obtain 5-chloro-4-amino-2-methoxybenzoic acid methyl ester hydrochloride.

[0016] Further, the preparation method of 5-chloro-4-amino-2-methoxybenzoic acid is as follows:

[0017] A. Mix 25g-26g of methyl 5-chloro-4-acetylamino-2-methoxybenzoate, 120g-130g of methanol, 8.5g-9.5g of sodium hydroxide, and 65g-75g of purified water, and heat to 60°C-65°C for 2h-2.5h;

[0018] B. After the reaction is completed, the methanol is removed by concentration under reduced pressure, and then water is added to dissolve it. Finally, the pH value is adjusted to 4-5 with hydrochloric acid, filtered, and the filter cake is washed with water until it is neutral. The filter cake is dried to obtain 5-chloro-4-amino-2-methoxybenzoic acid.

[0019] Furthermore, in step (1), the heating reaction method is as follows: the oil bath is heated to 90°C to 95°C and reacted for 2h to 3h.

[0020] Furthermore, in step B, the conditions for adding water to dissolve are: adding 150g to 200g of water and heating to 30°C to 60°C to dissolve.

[0021] Furthermore, in step (2), the conditions for heating hydrolysis are: heating to 90°C to 95°C and hydrolyzing for 1 hour.

[0022] Furthermore, in step (3), solution B is cooled to 25°C to 30°C.

[0023] Furthermore, in step (3), the drying conditions are: vacuum drying at 50°C to 60°C.

[0024] Metoclopramide is prepared by the preparation method.

[0025] Reaction process:

[0026]

[0027] Beneficial effects of the present invention:

[0028] The invention uses 5-chloro-4-amino-2-methoxybenzoic acid methyl ester hydrochloride as a raw material to prepare metoclopramide, reduces reaction impurities, improves conversion rate, and in the reaction liquid of the crude metoclopramide, the relative peak area of ​​5-chloro-4-amino-2-methoxybenzoic acid methyl ester is only 0.11%.

[0029] The 5-chloro-4-amino-2-methoxybenzoic acid methyl ester hydrochloride of the invention uses 5-chloro-4-amino-2-methoxybenzoic acid as a raw material. The 5-chloro-4-amino-2-methoxybenzoic acid can be prepared from 5-chloro-4-acetylamino-2-methoxybenzoic acid methyl ester or through other processes, and the source is wider. Moreover, the 5-chloro-4-amino-2-methoxybenzoic acid can also be used as a cisapride intermediate. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] 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.

[0031] Figure 1 The chromatogram of the crude metoclopramide reaction solution prepared in Example 1;

[0032] Figure 2 The chromatogram of the reaction solution of the crude metoclopramide prepared in Comparative Example 1 is shown. DETAILED DESCRIPTION

[0033] 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.

[0034] Example 1

[0035] A preparation process of metoclopramide comprises the following steps:

[0036] (1) Add 25.77 g of methyl 5-chloro-4-acetylamino-2-methoxybenzoate, 130 g of methanol, 8.80 g of sodium hydroxide, and 66 g of purified water into a 250 mL three-necked flask, heat the oil bath to 60° C. to 65° C., and reflux for 2 h to 2.5 h;

[0037] (2) After the reaction is completed, the methanol is removed by concentration under reduced pressure, and then 170 g of water is added, and the temperature is raised to 50°C to 60°C to dissolve, and the pH value is adjusted to 5 with about 3 mol / L hydrochloric acid, and the filter cake is filtered and washed with water until it is neutral. The filter cake is dried with forced air at 50°C to obtain 5-chloro-4-amino-2-methoxybenzoic acid;

[0038] (3) 20 g of 5-chloro-4-amino-2-methoxybenzoic acid and 130 g of methanol were added to a 250 mL three-necked flask, and 14.87 g of thionyl chloride was added dropwise. After the addition was completed, the temperature was raised to 60° C. to 65° C., and the reaction was refluxed for 3 h to 4 h. After the reaction was completed, the reaction was concentrated to dryness under reduced pressure, and the obtained solid was recrystallized from methanol to obtain 5-chloro-4-amino-2-methoxybenzoic acid methyl ester hydrochloride;

[0039] (4) Add 2.52 g of 5-chloro-4-amino-2-methoxybenzoic acid methyl ester hydrochloride and 3.49 g of N,N-diethylethylenediamine into a 25 mL single-necked bottle, heat the oil bath to 90° C. to 95° C., and react for 2 h to 3 h to obtain a crude metoclopramide reaction solution (reaction solution A);

[0040] (5) Add 15 g of water and 0.6 g of sodium hydroxide to the crude metoclopramide reaction solution, then heat the solution to 90° C. to 95° C. and hydrolyze for 1 hour to obtain a reaction solution B; cool the reaction solution B, filter it, and wash the filter cake with water until it is neutral; and dry the filter cake at 50° C. to 60° C. to obtain a crude metoclopramide product.

[0041] like Figure 1 As shown, in the reaction solution of crude metoclopramide prepared with 5-chloro-4-amino-2-methoxybenzoic acid methyl ester hydrochloride as raw material, the relative peak area of ​​5-chloro-4-amino-2-methoxybenzoic acid methyl ester was 0.11% (retention time 30.383 min).

[0042] Comparative Example 1

[0043]

[0044] Metoclopramide was prepared using the above process route using 5-chloro-4-acetylamino-2-methoxybenzoic acid methyl ester as raw material. Figure 2 As shown, in the prepared reaction solution of crude metoclopramide, the relative peak area of ​​methyl 5-chloro-4-amino-2-methoxybenzoate was 8.69% (retention time 30.083 min).

[0045] 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 method for preparing metoclopramide, characterized in that, The following steps are involved: (1) 2.5 g to 2.6 g of 5-chloro-4-amino-2-methoxybenzoic acid methyl ester hydrochloride and 3 g to 5 g of N,N-diethylethylenediamine are mixed and then heated to react to obtain a reaction solution A; (2) adding 10 g to 20 g of water and 0.5 g to 1.0 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 crude product of metoclopramide.

2. A method for preparing metoclopramide according to claim 1, characterized in that, In step (1), the preparation method of 5-chloro-4-amino-2-methoxybenzoic acid methyl ester hydrochloride is as follows: 1) Mix 19.5g-20.5g of 5-chloro-4-amino-2-methoxybenzoic acid with 120g-130g of methanol, and dropwise add 14.5g-15.5g of thionyl chloride; after the dropwise addition, heat to 60°C-65°C and react for 3h-4h; after the reaction, concentrate under reduced pressure until almost no fraction is produced; 2) Add 70 g to 80 g of methanol to the solid obtained in step 1), heat to 60° C. to 65° C. to dissolve, then cool to 0° C. to 5° C., filter and dry to obtain 5-chloro-4-amino-2-methoxybenzoic acid methyl ester hydrochloride.

3. A method for preparing metoclopramide according to claim 2, characterized in that, The preparation method of 5-chloro-4-amino-2-methoxybenzoic acid is as follows: A. Mix 25g-26g of methyl 5-chloro-4-acetylamino-2-methoxybenzoate, 120g-130g of methanol, 8.5g-9.5g of sodium hydroxide, and 65g-75g of purified water, and heat to 60°C-65°C for 2h-2.5h; B. After the reaction is completed, the methanol is removed by concentration under reduced pressure, and then water is added to dissolve it. Finally, the pH value is adjusted to 4-5 with hydrochloric acid, filtered, and the filter cake is washed with water until it is neutral. The filter cake is dried to obtain 5-chloro-4-amino-2-methoxybenzoic acid.

4. A method for preparing metoclopramide according to claim 1, characterized in that, In step (1), the heating reaction method is as follows: the oil bath is heated to 90°C to 95°C and reacted for 2h to 3h.

5. A method for preparing metoclopramide according to claim 3, characterized in that, In step B, the conditions for adding water to dissolve are: adding 150 g to 200 g of water and heating to 30° C. to 60° C. to dissolve.

6. A method for preparing metoclopramide according to claim 1, characterized in that, In step (2), the conditions for heating hydrolysis are: heating to 90°C to 95°C and hydrolyzing for 1 hour.

7. A method for preparing metoclopramide according to claim 1, characterized in that, In step (3), solution B is cooled to 25°C to 30°C.

8. A method for preparing metoclopramide according to claim 1, characterized in that, In step (3), the drying conditions are: vacuum drying at 50°C to 60°C.

9. Metoclopramide prepared by the preparation method according to any one of claims 1 to 8.

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