Preparation method of metoclopramide intermediate

Abstract

The invention relates to the field of medicinal chemistry, and provides a preparation method of metoclopramide intermediate methyl 2-methoxy-4-acetamidobenzoate, which comprises the following steps: mixing methyl 2-methoxy-4-acetamidobenzoate and acetic anhydride in a molar ratio of 1: (1.2-2.0) in the absence of a solvent, and reacting at the temperature of 50-80 DEG C; and after the reaction, adding methyl tert-butyl ether for crystallization, cooling and filtering to obtain a product. The method has the advantages that acetic anhydride is used as an acylation reagent; on one hand, compared with acetyl chloride, the reaction is more stable, the reaction controllability is better, and the product purity is high; on the other hand, acetic anhydride is liquid and can serve as a solvent, no extra solvent needs to be added, and cost is saved; meanwhile, no solvent is added, so that the post-treatment process is simplified, the operation is simple, and the yield is higher. The 2-methoxy-4-acetamidobenzoic acid methyl ester prepared on the basis of the method has the purity of 99.8% or above and the yield of 90% or above, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and particularly to a method for preparing methyl 2-methoxy-4-acetamidobenzoate, an intermediate of metoclopramide. Background Art

[0002] Metoclopramide hydrochloride is a dopamine receptor antagonist, mainly used for treating symptoms such as nausea, vomiting, gastroesophageal reflux, and gastroparesis.

[0003] Methyl 2-methoxy-4-acetamidobenzoate is an important intermediate for the preparation of metoclopramide hydrochloride. It is prepared by acetylating the amino group of methyl 2-methoxy-4-aminobenzoate, as shown below:

[0004]

[0005] Currently, for the acetylation of the amino group of methyl 2-methoxy-4-aminobenzoate, acetyl chloride is mainly used as the acylating agent, triethylamine as the acid-binding agent, and dichloromethane as the solvent. Among them, "acetyl chloride" has active chemical properties and many side reactions, so the purity of the prepared product is relatively poor. At the same time, due to the introduction of the solvent, the post-treatment process is relatively complex and the yield is low.

[0006] Therefore, there is an urgent need to improve the existing process and design a new preparation method for methyl 2-methoxy-4-acetamidobenzoate, an intermediate of metoclopramide. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a method for preparing methyl 2-methoxy-4-acetamidobenzoate, an intermediate of metoclopramide, which has simple operation, high product purity, high yield, and is suitable for industrial production.

[0008] The present invention adopts the following technical solutions to solve the above technical problems:

[0009] A method for preparing methyl 2-methoxy-4-acetamidobenzoate, an intermediate of metoclopramide, comprises the following steps:

[0010] (1) Under solvent-free conditions, methyl 2-methoxy-4-aminobenzoate and acetic anhydride are mixed in a molar ratio of 1:(1.2 - 2.0), and the reaction occurs at a temperature of 50 - 80 °C;

[0011] (2) After the reaction, methyl tert-butyl ether is added for crystallization, and after cooling, filtration is carried out to obtain the product.

[0012] As one of the preferred embodiments of the present invention, the specific process of step (1) is as follows: Methyl 2-methoxy-4-aminobenzoate and acetic anhydride are added into a reaction flask or a reaction kettle, and the molar ratio is 1:(1.2 - 2.0) respectively; subsequently, stir to dissolve and heat up to 50 - 80°C for reaction for 1 - 2 h.

[0013] As one of the preferred embodiments of the present invention, the reaction temperature is specifically selected as 65 - 80°C.

[0014] As one of the preferred embodiments of the present invention, the specific process of step (2) is as follows: After the reaction is completed, methyl tert-butyl ether is added, and the temperature is lowered to 0 - 5°C and stirred for 1 h for crystallization; subsequently, filter, wash with methyl tert-butyl ether, and dry to obtain the product.

[0015] As one of the preferred embodiments of the present invention, the addition amount of methyl tert-butyl ether is 0.3 - 0.4 times the volume of the reaction product.

[0016] As one of the preferred embodiments of the present invention, after adding methyl tert-butyl ether, the temperature is specifically lowered to 4°C for stirring and crystallization.

[0017] As one of the preferred embodiments of the present invention, the yield of the product reaches more than 90%, and the HPLC purity reaches more than 99.8%.

[0018] The advantages of the present invention compared with the prior art are as follows:

[0019] The present invention uses "acetic anhydride" as an acylating agent; on the one hand, in terms of chemical properties, it is more stable than "acetyl chloride", and the reaction controllability is better, avoiding the problem of poor product purity caused by more side reactions; on the other hand, since "acetic anhydride" is a liquid, acetic anhydride itself can be used as a solvent, without the need to add an additional solvent, saving costs; at the same time, since no solvent is added in the reaction, the post-treatment process is simplified, making the reaction operation simple and the yield higher.

[0020] The methyl 2-methoxy-4-acetamidobenzoate product prepared based on the method of the present invention has a final purity of more than 99.8% and a yield of more than 90%, which is suitable for industrial production. Description of the Drawings

[0021] Figure 1 It is the HPLC chart of methyl 2-methoxy-4-acetamidobenzoate in Example 1;

[0022] Figure 2 It is the HPLC chart of methyl 2-methoxy-4-acetamidobenzoate in Example 2;

[0023] Figure 3 It is the HPLC chart of methyl 2-methoxy-4-acetamidobenzoate in Example 3;

[0024] Figure 4 It is the HPLC chart of methyl 2-methoxy-4-acetamidobenzoate in Example 4. Detailed implementation manners

[0025] The embodiments of the present invention will be described in detail below. These embodiments are implemented on the premise of the technical solutions of the present invention, and detailed implementation manners and specific operation processes are given. However, the protection scope of the present invention is not limited to the following embodiments. At the same time, the raw materials, reagents, equipment and experimental methods used in the following embodiments, unless otherwise specified, are all conventional raw materials, reagents, equipment and methods in the art and will not be elaborated.

[0026] Example 1

[0027] A preparation method of methyl 2-methoxy-4-acetamidobenzoate, an intermediate of metoclopramide, in this example includes the following steps:

[0028] Add methyl 2-methoxy-4-aminobenzoate and acetic anhydride into a reaction flask, with a molar ratio of 1:1.2 respectively; stir to dissolve and heat up to 80 °C for reaction for 1 h.

[0029] After the reaction is completed, add 0.3 times the volume (relative to the reaction product) of methyl tert-butyl ether, cool down to 4 °C and stir for 1 h for crystallization, filter, wash with methyl tert-butyl ether, and dry to obtain the product methyl 2-methoxy-4-acetamidobenzoate, with a yield of 92.8% and an HPLC purity of 99.88% ( Figure 1 ).

[0030] Example 2

[0031] A preparation method of methyl 2-methoxy-4-acetamidobenzoate, an intermediate of metoclopramide, in this example includes the following steps:

[0032] Add methyl 2-methoxy-4-aminobenzoate and acetic anhydride into a reaction flask, with a molar ratio of 1:1.6 respectively; stir to dissolve and heat up to 50 °C for reaction for 2 h.

[0033] After the reaction is completed, add 0.4 times the volume (relative to the reaction product) of methyl tert-butyl ether, cool down to 4 °C and stir for 1 h for crystallization, filter, wash with methyl tert-butyl ether, and dry to obtain the product methyl 2-methoxy-4-acetamidobenzoate, with a yield of 90% and an HPLC purity of 99.89% ( Figure 2 ).

[0034] Example 3

[0035] A preparation method of methyl 2-methoxy-4-acetamidobenzoate, an intermediate of metoclopramide, in this example includes the following steps:

[0036] Methyl 2-methoxy-4-aminobenzoate and acetic anhydride were added to a reaction flask, with a molar ratio of 1:2.0 respectively; stirred to dissolve, and the temperature was raised to 70 °C and reacted for 1.5 h.

[0037] After the reaction was completed, methyl tert-butyl ether with a volume 0.3 times that of the reaction product (relative to the reaction product) was added, the temperature was lowered to 4 °C, stirred for 1 h to crystallize, filtered, washed with methyl tert-butyl ether, and dried to obtain the product methyl 2-methoxy-4-acetamidobenzoate, with a yield of 92% and an HPLC purity of 99.88% ( Figure 3 ).

[0038] Example 4

[0039] A preparation method of methyl 2-methoxy-4-acetamidobenzoate, an intermediate of metoclopramide in this example, includes the following steps:

[0040] Methyl 2-methoxy-4-aminobenzoate and acetic anhydride were added to a reaction kettle, with a molar ratio of 1:1.2 respectively; stirred to dissolve, and the temperature was raised to 65 °C and reacted for 1 h.

[0041] After the reaction was completed, methyl tert-butyl ether with a volume 0.3 times that of the reaction product (relative to the reaction product) was added, the temperature was lowered to 4 °C, stirred for 1 h to crystallize, filtered, washed with methyl tert-butyl ether, and dried to obtain the product methyl 2-methoxy-4-acetamidobenzoate, with a yield of 91% and a purity of 99.96% ( Figure 4 ).

[0042] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for preparing a metoclopramide intermediate, characterized in that: The intermediate is methyl 2-methoxy-4-acetylaminobenzoate, and the preparation method is as follows: (1) in the absence of a solvent, methyl 2-methoxy-4-aminobenzoate and acetic anhydride are mixed in a molar ratio of 1:(1.2-2.0) and reacted at a temperature of 50-80° C.; (2) After the reaction, methyl tert-butyl ether was added for crystallization, and the mixture was cooled and filtered to obtain the product.

2. The method for preparing a metoclopramide intermediate according to claim 1, wherein The specific process of step (1) is: adding methyl 2-methoxy-4-aminobenzoate and acetic anhydride in a reaction bottle or a reaction kettle, with a molar ratio of 1:(1.2-2.0); then, stirring to dissolve, and heating to 50-80° C. to react for 1-2 hours.

3. The method for preparing a metoclopramide intermediate according to claim 2, wherein The reaction temperature is specifically selected to be 65-80°C.

4. The method for preparing a metoclopramide intermediate according to claim 1, wherein The specific process of step (2) is as follows: after the reaction is completed, methyl tert-butyl ether is added, the temperature is lowered to 0-5° C., stirred for 1 hour, and crystallized; then, the mixture is filtered, washed with methyl tert-butyl ether, and dried to obtain the product.

5. The method for preparing a metoclopramide intermediate according to claim 4, characterized in that: The added amount of the methyl tert-butyl ether is 0.3 to 0.4 times the volume of the reaction product.

6. The method for preparing a metoclopramide intermediate according to any one of claims 1 to 5, characterized in that: The yield of the product is over 90%, and the HPLC purity is over 99.8%.

Images