Metoclopramide intermediate as well as preparation method and application thereof

Abstract

The invention provides a metoclopramide intermediate and a preparation method and application thereof, the molecular formula of the metoclopramide intermediate is C9H10ClNO3, and the metoclopramide intermediate can be used for quality detection and control in the synthesis process of metoclopramide and can also be used for formulating a central control standard of a metoclopramide ammonolysis reaction product.

Description

Technical Field

[0001] The invention relates to the technical field of metoclopramide preparation, in particular to a metoclopramide intermediate and a preparation method and application thereof. 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] But 5-chloro-4-amino-2-methoxybenzoic acid methyl ester and N, N diethylethylenediamine reaction process is slower, and after 5-chloro-4-acetylamino-2-methoxybenzoic acid methyl ester conversion is complete, 5-chloro-4-amino-2-methoxybenzoic acid methyl ester still has residue.If using 5-chloro-4-acetylamino-2-methoxybenzoic acid methyl ester relative peak area as the ammonolysis reaction endpoint judgment basis, the metoclopramide yield can be affected.Control the generation of 5-chloro-4-amino-2-methoxybenzoic acid methyl ester, the yield of metoclopramide can be improved. Summary of the invention

[0008] The invention provides a metoclopramide intermediate and a preparation method and application thereof.

[0009] The technical solution of the present invention is achieved as follows: a metoclopramide intermediate, the molecular formula of which is C9H 10 ClNO3, its structural formula is:

[0010]

[0011] A method for preparing a metoclopramide intermediate comprises the following steps:

[0012] (1) 25 g to 26 g of methyl 5-chloro-4-acetylamino-2-methoxybenzoate, 120 g to 130 g of methanol, 8.5 g to 9.5 g of sodium hydroxide, and 65 g to 75 g of water are mixed, and then heated to react to obtain a reaction solution A;

[0013] (2) Reaction solution A is concentrated under reduced pressure to remove methanol, and then 150 g to 200 g of water is added and heated to dissolve, thereby obtaining reaction solution B.

[0014] (3) adjusting the pH value of the reaction solution B to 4-5 with hydrochloric acid, filtering, washing the filter cake with water until neutral, and drying the filter cake to obtain 5-chloro-4-amino-2-methoxybenzoic acid;

[0015] (4) 19.5 g to 20.5 g of 5-chloro-4-amino-2-methoxybenzoic acid and 120 g to 130 g of methanol are mixed, and 14.5 g to 15.5 g of thionyl chloride is added dropwise; after the addition is completed, the mixture is heated to react, and after the reaction is completed, the mixture is concentrated under reduced pressure to dryness and substantially no fraction is obtained, to obtain solid C;

[0016] (5) Add 70 g to 80 g of methanol to solid C, heat to dissolve, cool, filter, and dry to obtain 5-chloro-4-amino-2-methoxybenzoic acid methyl ester hydrochloride;

[0017] (6) 6.5 g to 7.5 g of 5-chloro-4-amino-2-methoxybenzoic acid methyl ester hydrochloride, 40 g to 50 g of water, and 40 g to 50 g of dichloromethane were mixed, cooled to 0° C. to 10° C., and then the pH value was adjusted to 8 to 9. The liquids were separated, and the organic phase was concentrated under reduced pressure until there was no solvent to obtain a metoclopramide intermediate (5-chloro-4-amino-2-methoxybenzoic acid methyl ester).

[0018] Furthermore, in step (1), the conditions for the heating reaction are: heating to 60°C to 65°C and reacting for 2h to 2.5h.

[0019] Furthermore, in step (2), the heating and dissolving conditions are 30°C to 60°C.

[0020] Furthermore, in step (4), the heating reaction conditions are: heating to 60°C to 65°C and reacting for 3h to 4h.

[0021] Furthermore, in step (5), the conditions for thermal dissolution are: heating to 60°C to 65°C.

[0022] A metoclopramide intermediate is prepared by the preparation method.

[0023] A metoclopramide intermediate is used as a reference substance for quality control in the process of preparing metoclopramide. For example, it can be used as a reference substance for quality control of metoclopramide and can be used to formulate in-process control standards for metoclopramide ammonolysis reaction products.

[0024] Beneficial effects of the present invention:

[0025] The metoclopramide intermediate prepared by the invention is an intermediate in the process of the aminolysis reaction of metoclopramide, and its chemical formula and structural formula are clarified, which is convenient for pathological research; meanwhile, the intermediate can be used as a quality control in the process of the aminolysis reaction of metoclopramide, and is used for formulating the intermediate control standard of the product of the aminolysis reaction of metoclopramide, controlling the content of the intermediate in the aminolysis reaction liquid, and improving the yield of metoclopramide. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] 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.

[0027] Figure 1 is the mass spectrum of metoclopramide intermediate;

[0028] Figure 2 It is an intermediate of metoclopramide 1 H NMR spectroscopy;

[0029] Figure 3 This is the HPLC spectrum of the metoclopramide intermediate.

[0030] Figure 4 It is a detection spectrum of the aminolysis reaction solution (metoclopramide crude product reaction solution) under the conditions of 4.00eq of N,N-diethylethylenediamine and a reaction temperature of 120°C to 125°C. After reacting for 5.5h under this condition, the relative peak area of ​​the metoclopramide intermediate is 8.69%.

[0031] Figure 5 It is a detection spectrum of the ammonolysis reaction solution (metoclopramide crude product reaction solution) under the conditions of 1.00eq of glacial acetic acid, 4.00eq of N,N-diethylethylenediamine and a reaction temperature of 120°C to 125°C. After reacting for 3.5h under this condition, the relative peak area of ​​the metoclopramide intermediate is 1.59%.

[0032] Figure 6 This is the detection spectrum of crude metoclopramide. The metoclopramide intermediate enters the water phase after hydrolysis and is not detected in the crude metoclopramide. 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] A method for preparing a metoclopramide intermediate comprises the following steps:

[0035] (1) 25.77 g of methyl 5-chloro-4-acetylamino-2-methoxybenzoate, 130 g of methanol, 8.8 g of sodium hydroxide, and 66 g of water were mixed, and the mixture was heated to 60° C. to 65° C. and reacted for 2 h to 2.5 h to obtain a reaction solution A;

[0036] (2) After the reaction is completed, the reaction solution A is concentrated under reduced pressure to remove methanol, and then 170 g of water is added and heated to 50° C. to 60° C. to dissolve, thereby obtaining a reaction solution B;

[0037] (3) adjusting the pH value of the reaction solution B to 5 with hydrochloric acid, filtering, washing the filter cake with water until neutral, and drying the filter cake to obtain 5-chloro-4-amino-2-methoxybenzoic acid;

[0038] (4) 20 g of 5-chloro-4-amino-2-methoxybenzoic acid and 130 g of methanol were mixed, 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. for reaction for 3 h to 4 h; after the reaction was completed, the mixture was concentrated under reduced pressure until almost no fraction was obtained, to obtain solid C;

[0039] (5) Add 70 g to 80 g of methanol to solid C, 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;

[0040] (6) 7 g of 5-chloro-4-amino-2-methoxybenzoic acid methyl ester hydrochloride, 40 g of purified water, and 50 g of dichloromethane were mixed, stirred, and cooled to 0°C to 10°C; then, aqueous ammonia was added dropwise to adjust the pH value to 8 to 9, and the mixture was stirred for 10 min at the same temperature; finally, the liquids were separated, and the organic phase was concentrated under reduced pressure until there was no solvent, thereby obtaining a metoclopramide intermediate (5-chloro-4-amino-2-methoxybenzoic acid methyl ester).

[0041] The synthesis equation of the metoclopramide intermediate is as follows:

[0042]

[0043] like Figure 1 and 2 As shown, the molecular formula of the metoclopramide intermediate is C9H 10ClNO3, molecular weight is 215.63, chemical structure formula:

[0044]

[0045] like Figure 3 As shown, the relative peak area of ​​the metoclopramide intermediate prepared in this example is 99.08% (retention time 30.227 min). In addition, the metoclopramide intermediate is a white to off-white crystalline powder; odorless.

[0046] The existing metoclopramide process route is adopted, and after the aminolysis reaction of 4.00eq of N,N-diethylethylenediamine and the reaction temperature of 120°C to 125°C for 5.5h, a crude metoclopramide reaction solution is obtained. The chromatogram of the crude metoclopramide reaction solution is as follows: Figure 4 As shown, the relative peak area of ​​the metoclopramide intermediate is 8.69% (retention time: 30.083 min).

[0047]

[0048] In the existing metoclopramide process route, glacial acetic acid is added; 1.00 eq of glacial acetic acid, 4.00 eq of N,N-diethylethylenediamine, and an aminolysis reaction is carried out at a reaction temperature of 120° C. to 125° C. for 3.5 hours to obtain a crude metoclopramide reaction liquid. The chromatogram of the crude metoclopramide reaction liquid is as follows: Figure 5 As shown, the relative peak area of ​​the metoclopramide intermediate is 1.59% (retention time 30.000min). The crude metoclopramide reaction solution prepared by the method is added with sodium hydroxide and water, and then heated for hydrolysis to obtain the crude metoclopramide. The chromatogram of the crude metoclopramide is as shown in Figure 6 As shown, the crude metoclopramide no longer contained the metoclopramide intermediate, and the content of metoclopramide (FP-I, retention time 14.725 min) reached 99.82%.

[0049] 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 intermediate, characterized in that: The molecular formula of the intermediate is C9H 10 ClNO3, its structural formula is:

2. A method for preparing a metoclopramide intermediate, characterized in that: The following steps are involved: (1) 25 g to 26 g of methyl 5-chloro-4-acetylamino-2-methoxybenzoate, 120 g to 130 g of methanol, 8.5 g to 9.5 g of sodium hydroxide, and 65 g to 75 g of water are mixed, and then heated to react to obtain a reaction solution A; (2) Reaction solution A is concentrated under reduced pressure to remove methanol, and then 150 g to 200 g of water is added and heated to dissolve, thereby obtaining reaction solution B. (3) adjusting the pH value of the reaction solution B to 4-5 with hydrochloric acid, filtering, washing the filter cake with water until neutral, and drying the filter cake to obtain 5-chloro-4-amino-2-methoxybenzoic acid; (4) 19.5 g to 20.5 g of 5-chloro-4-amino-2-methoxybenzoic acid and 120 g to 130 g of methanol are mixed, and 14.5 g to 15.5 g of thionyl chloride is added dropwise; after the addition is completed, the mixture is heated to react, and after the reaction is completed, the mixture is concentrated under reduced pressure to dryness and substantially no fraction is obtained, to obtain solid C; (5) Add 70 g to 80 g of methanol to solid C, heat to dissolve, cool, filter, and dry to obtain 5-chloro-4-amino-2-methoxybenzoic acid methyl ester hydrochloride; (6) 6.5 g to 7.5 g of methyl 5-chloro-4-amino-2-methoxybenzoate hydrochloride, 40 g to 50 g of water, and 40 g to 50 g of dichloromethane were mixed, cooled to 0° C. to 10° C., and then the pH value was adjusted to 8 to 9. The liquids were separated, and the organic phase was concentrated under reduced pressure until there was no solvent to obtain a metoclopramide intermediate.

3. The preparation method according to claim 2, characterized in that: In step (1), the heating reaction conditions are: heating to 60°C to 65°C and reacting for 2h to 2.5h.

4. The preparation method according to claim 2, characterized in that: In step (2), the heating and dissolving conditions are 30°C to 60°C.

5. The preparation method according to claim 2, characterized in that: In step (4), the heating reaction conditions are: heating to 60°C to 65°C and reacting for 3h to 4h.

6. The preparation method according to claim 2, characterized in that: In step (5), the conditions for heating and dissolving are: heating to 60°C to 65°C.

7. A metoclopramide intermediate prepared by the preparation method according to claims 2-6.

8. Use of a metoclopramide intermediate according to claim 1 or 7 as a reference substance for quality control in the process of preparing metoclopramide.

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