Synthesis method of dimer impurity i and dimer impurity ii in methoclopramide injection

Abstract

The present application relates to the chemical technology field, specifically disclose the synthesis method of methoxychlorpromazine injection two dimer impurities I and II, methoxychlorpromazine, catalyst, ligand and base are dissolved in organic solvent, two dimer can be generated through one step catalytic coupling reaction, route is simple, two new dimer impurities in methoxychlorpromazine injection are synthesized, the mild synthesis reaction condition, low requirement to equipment, simple operation, easy to implement, optimization reaction condition and post-processing purification method, can obtain high purity target impurity, fully meet the requirement as chromatographic analysis chemical reference substance, provide key impurity reference substance for methoxychlorpromazine injection quality control, help pharmaceutical production enterprises more comprehensive impurity spectrum research, develop reasonable impurity control strategy, so as to improve the safety and quality consistency of drug.

Description

Technical Field

[0001] This invention relates to the field of chemical technology, specifically to a method for synthesizing dimer impurity I and dimer impurity II in metoclopramide injection. Background Technology

[0002] Metoclopramide is a dopamine D2 receptor antagonist that also possesses 5-HT4 receptor agonist activity and mild 5-HT3 receptor inhibitory activity. Its mechanism of action involves blocking dopamine receptors in the medullary chemoreceptor trigger zone (CTZ) to exert a central antiemetic effect. It also promotes gastrointestinal motility and gastric emptying, making it a commonly used drug in clinical digestive system therapy and as an adjuvant in antitumor treatment. Since its initial market launch in 1964, it has been widely used to treat vomiting induced by chemotherapy / radiotherapy, symptomatic treatment of diabetic gastroparesis, and as an adjunct to gastrointestinal examinations, demonstrating significant clinical value.

[0003] There are two key technical problems with the domestically marketed metoclopramide hydrochloride injection: first, insufficient stability, as the traditional process does not fully form salts of metoclopramide, which easily precipitates crystals during storage, resulting in excessive visible foreign matter and affecting medication safety; second, poor patient compliance, as the pH range of the injection solution is too low (2.5-4.5), which may cause local irritation or discomfort during injection.

[0004] To address the aforementioned issues, the industry has been continuously conducting research on formulation optimization and process improvement for metoclopramide injection in recent years, thereby enhancing the storage stability of the formulation and reducing clinical injection side effects. Consequently, quality research on the raw material and formulation manufacturing processes has become increasingly stringent. Currently, metoclopramide impurity research can refer to the European Pharmacopoeia 11.0, which identifies EP impurities A, B, C, D, E, F, G, and H. However, in actual research, many unidentified and structurally ambiguous impurities remain, particularly polymeric impurities. These can reduce the therapeutic effect of the drug and increase the risk of adverse reactions. Dimeric impurities are the most representative and critical type of polymeric impurities.

[0005] Therefore, the structural identification and synthesis methods for unknown polymer impurities in metoclopramide injection are key to achieving precise control of drug impurities and improving drug quality, and have important clinical significance and application value. Summary of the Invention

[0006] (a) Technical problems to be solved To address the shortcomings of existing technologies, this invention provides a metoclopramide dimer impurity and its preparation method, solving the problems in existing technologies where there is a lack of clear synthesis methods for unknown dimer impurities in metoclopramide injection and the inability to provide high-purity reference standards for quality control.

[0007] (II) Technical Solution To achieve the above objectives, this invention discloses a method for synthesizing dimer impurity I and dimer impurity II in metoclopramide injection, comprising the following steps: Step 1: Under nitrogen gas protection, metoclopramide, catalyst, ligand and base are dissolved in an organic solvent, stirred and mixed, and the reaction is carried out to obtain a reaction solution; Step 2: Extract the reaction solution from Step 1, combine the organic phases, concentrate and purify by column chromatography, and dry to obtain dimer impurity I and dimer impurity II in metoclopramide injection.

[0008] Preferably, the catalyst in step one includes any one of palladium acetate, palladium chloride, bis(triphenylphosphine)palladium dichloride, bis(pyridine)palladium dichloride, allyl palladium chloride dimer, ethylenediamine palladium chloride, (2,2-bipyridine)palladium dichloride, bis(acetylacetone)palladium, tris(dibenzylideneacetone)palladium, tetra(triphenylphosphine)palladium, and tetra(triphenyl phosphite)palladium.

[0009] Preferably, the ligand in step one includes any one of triphenylphosphine, bipyridine, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, tri-tert-butylphosphine, BINAP, XantPhos, DPPF, BrettPhos, DavePhos, RuPhos, XPhos, SPhos, JohnPhos, and BippyPhos.

[0010] Preferably, the structural formulas of BINAP, XantPhos, DPPF, BrettPhos, DavePhos, RuPhos, XPhos, SPhos, JohnPhos, and BippyPhos are as follows: .

[0011] Preferably, the alkali in step one includes any one of sodium hydroxide, potassium hydroxide, pyridine, triethylamine, potassium carbonate, and cesium carbonate.

[0012] Preferably, the reaction solvent in step one includes any one of 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, and toluene.

[0013] Preferably, in step one, the molar ratio of metoclopramide, catalyst, ligand, and base is 1:(0.01~0.10):(0.01~0.30):(1.0~3.0), the reaction temperature is 70~120℃, and the reaction time is 10~24h.

[0014] Preferably, in step one, the mass-to-volume ratio of metoclopramide to organic solvent is 1.0:(10~100).

[0015] Preferably, the organic solvent used for extraction in step two includes either dichloromethane or ethyl acetate.

[0016] Preferably, the structural formulas of dimer impurity I and dimer impurity II in the metoclopramide injection solution in step two are shown in Figures I and II: .

[0017] (iii) Beneficial technical effects Compared with the prior art, the beneficial effects of the present invention are as follows: (1) The synthesis method provided in this invention uses readily available metoclopramide raw material as the starting material, and two dimers can be generated through a one-step catalytic coupling reaction, which is a simple route. Two novel dimer impurities in metoclopramide injection were synthesized. Impurity I is 4-amino-5-((2-chloro-4-((2-(diethylamino)ethyl)carbamoyl)-5-methoxyphenyl)amino)-N-(2-(diethylamino)ethyl)-2-methoxybenzamide, and impurity II is N2,N7-bis(2-(diethylamino)ethyl)-3,8-dimethoxyphenazine-2,7-dicarboxamide.

[0018] (2) The synthesis reaction conditions in this invention are mild, have low equipment requirements, are simple to operate, and are easy to implement. By optimizing the reaction conditions and post-processing purification methods, high-purity target impurities can be obtained, fully meeting the requirements for use as chemical reference standards in chromatographic analysis. This provides a key impurity reference standard for the quality control of metoclopramide injection, helping pharmaceutical manufacturers to conduct more comprehensive impurity profile studies and formulate reasonable impurity control strategies, thereby improving the safety and quality consistency of the drug. Detailed Implementation

[0019] The following specific embodiments illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0020] It should be noted that, unless otherwise stated, the technical or scientific terms used in this application should have the ordinary meaning understood by those skilled in the art. Unless otherwise stated, the experimental materials in the following embodiments are all from commercial sources, and the experimental methods described are all general experimental methods.

[0021] In view of the shortcomings of the prior art, the inventors of this invention have proposed the technical solution of the present invention through long-term research and extensive practice. The following will further explain the technical solution, its implementation process and principle.

[0022] Example 1 This embodiment provides a method for synthesizing dimer impurity I and dimer impurity II in metoclopramide injection. The specific synthesis steps are as follows: Under nitrogen protection, 1.25 g of metoclopramide, 38 mg of palladium acetate, 80 mg of 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, and 1.6 g of cesium carbonate were dissolved in 15 mL of 1,4-dioxane solvent. After nitrogen purging, the reaction was carried out at 100 °C for 24 h. The reaction was stopped by TLC monitoring. After three extractions with dichloromethane and water, the organic phases were combined, concentrated, and purified by column chromatography to obtain dimer impurity I in 400 mg metoclopramide injection solution, a yellow solid with a yield of 17.04% and a purity of 97.0%. LC / MS ( m / z 563.31[M+H] + ; 1 ¹H NMR (600MHz, DMSO-d⁶) δ 8.15 (dt, J=24.0, 5.1Hz, 2H), 7.82 (s, 1H), 7.63 (s, 1H), 7.32 (s, 1H), 6.49 (s, 1H), 5.93 (s, 1H), 5.53 (s, 2H), 3.86 (s, 3H), 3.62 (s, 3H), 3.31 (d, J=6.0Hz, 4H), 2.53–2.50 (m, 12H), 0.98 (dt, J=18.3, 7.1Hz, 12H); Dimer impurity II in 600mg metoclopramide injection, yellow solid, yield 27.43%, purity 98.9%, LC / MS ( m / z 525.32[M+H] + ; 1 HNMR(600MHz,Chloroform-d)δ8.98(s,1H),8.44(s,1H),7.56(s,1H),4.16(s ,3H),3.63(d,J=5.7Hz,2H),2.73(s,2H),2.64(d,J=7.2Hz,4H),1.10(s,6H).

[0023] Example 2 This embodiment provides a method for synthesizing dimer impurity I and dimer impurity II in metoclopramide injection. The specific synthesis steps are as follows: Under nitrogen protection, 1.25 g of metoclopramide, 32 mg of palladium chloride, 40 mg of triphenylphosphine, and 1.0 g of potassium carbonate were dissolved in 15 mL of 1,4-dioxane solvent. After nitrogen purging, the reaction was carried out at 120 °C for 10 h. The reaction was stopped after TLC monitoring. After three extractions with dichloromethane and water, the organic phases were combined, concentrated, and purified by column chromatography to obtain dimer impurity I in 320 mg metoclopramide injection, a yellow solid with a yield of 13.63% and a purity of 96.2%; and dimer impurity II in 210 mg metoclopramide injection, a yellow solid with a yield of 9.60% and a purity of 95.6%.

[0024] Example 3 This embodiment provides a method for synthesizing dimer impurity I and dimer impurity II in metoclopramide injection. The specific synthesis steps are as follows: Under nitrogen protection, 1.25 g of metoclopramide, 43 mg of bis(acetylacetone)palladium, 45 mg of DPPF, and 0.38 g of sodium hydroxide were dissolved in 15 mL of tetrahydrofuran solvent. After nitrogen purging, the reaction was carried out at 70 °C for 24 h. The reaction was stopped after TLC monitoring. After three extractions with dichloromethane and water, the organic phases were combined, concentrated, and purified by column chromatography to obtain dimer impurity I in 150 mg metoclopramide injection, a yellow solid with a yield of 6.36% and a purity of 95.5%; and dimer impurity II in 220 mg metoclopramide injection, a yellow solid with a yield of 10.06% and a purity of 98.2%.

[0025] Example 4 This embodiment provides a method for synthesizing dimer impurity I and dimer impurity II in metoclopramide injection. The specific synthesis steps are as follows: Under nitrogen protection, 1.25 g of metoclopramide, 74 mg of tetrakis(triphenylphosphine)palladium, 65 mg of Xantphos, and 1.6 g of cesium carbonate were dissolved in 15 mL of 1,4-dioxane solvent. After nitrogen purging, the mixture was reacted at 100 °C for 24 h. The reaction was stopped after TLC monitoring. The mixture was extracted three times with dichloromethane and water, and the combined organic phases were concentrated and purified by column chromatography. Dimer impurity I in 360 mg metoclopramide injection was obtained as a yellow solid with a yield of 15.25% and a purity of 96.0%. Dimer impurity II in 520 mg metoclopramide injection was obtained as a yellow solid with a yield of 23.78% and a purity of 96.8%.

[0026] Example 5 This embodiment provides a method for synthesizing dimer impurity I and dimer impurity II in metoclopramide injection. The specific synthesis steps are as follows: Under nitrogen protection, 1.25 g of metoclopramide, 65 mg of (2,2-bipyridine) palladium dichloride, 67 mg of BrettPhos, and 1.6 g of cesium carbonate were dissolved in 15 mL of toluene. After nitrogen purging, the mixture was reacted at 110 °C for 18 h. The reaction was stopped after TLC monitoring. The mixture was extracted three times with dichloromethane and water. The combined organic phases were concentrated and purified by column chromatography to obtain dimer impurity I in 340 mg metoclopramide injection, a yellow solid with a yield of 14.41% and a purity of 98.2%; and dimer impurity II in 480 mg metoclopramide injection, a yellow solid with a yield of 21.95% and a purity of 97.6%.

[0027] Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention. All equivalent changes and improvements made within the scope of the present invention should still fall within the scope of the present invention.

Claims

1. A method for synthesizing dimer impurity I and dimer impurity II in metoclopramide injection, characterized in that: Includes the following steps: Step 1: Under nitrogen gas protection, metoclopramide, catalyst, ligand and base are dissolved in an organic solvent, stirred and mixed, and the reaction is carried out to obtain a reaction solution; Step 2: Extract the reaction solution from Step 1, combine the organic phases, concentrate and purify by column chromatography, and dry to obtain dimer impurity I and dimer impurity II in metoclopramide injection.

2. The method for synthesizing dimer impurity I and dimer impurity II in metoclopramide injection according to claim 1, characterized in that: The catalyst in step one includes any one of palladium acetate, palladium chloride, bis(triphenylphosphine)palladium dichloride, bis(pyridine)palladium dichloride, allyl palladium chloride dimer, ethylenediamine palladium chloride, (2,2-bipyridine)palladium dichloride, bis(acetylacetone)palladium, tris(dibenzylacetone)palladium, tetra(triphenylphosphine)palladium, and tetra(triphenyl phosphite)palladium.

3. The method for synthesizing dimer impurity I and dimer impurity II in metoclopramide injection according to claim 1, characterized in that: The ligand in step one includes any one of triphenylphosphine, bipyridine, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, tritert-butylphosphine, BINAP, XantPhos, DPPF, BrettPhos, DavePhos, RuPhos, XPhos, SPhos, JohnPhos, and BippyPhos.

4. The method for synthesizing dimer impurity I and dimer impurity II in metoclopramide injection according to claim 3, characterized in that: The structural formulas of BINAP, Xantphos, DPPF, BrettPhos, DavePhos, RuPhos, XPhos, SPhos, JohnPhos, and BippyPhos are as follows: 。 5. The method for synthesizing dimer impurity I and dimer impurity II in metoclopramide injection according to claim 1, characterized in that: The alkali in step one includes any one of sodium hydroxide, potassium hydroxide, pyridine, triethylamine, potassium carbonate, and cesium carbonate.

6. The method for synthesizing dimer impurity I and dimer impurity II in metoclopramide injection according to claim 1, characterized in that: The reaction solvent in step one includes any one of 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, and toluene.

7. The method for synthesizing dimer impurity I and dimer impurity II in metoclopramide injection according to claim 1, characterized in that: In step one, the molar ratio of metoclopramide, catalyst, ligand, and base is 1:(0.01~0.10):(0.01~0.30):(1.0~3.0), the reaction temperature is 70~120℃, and the reaction time is 10~24h.

8. The method for synthesizing dimer impurity I and dimer impurity II in metoclopramide injection according to claim 1, characterized in that: In step one, the mass-to-volume ratio of metoclopramide to organic solvent is 1.0:(10~100).

9. The method for synthesizing dimer impurity I and dimer impurity II in metoclopramide injection according to claim 1, characterized in that: The organic solvent used for extraction in step two includes either dichloromethane or ethyl acetate.

10. The method for synthesizing dimer impurity I and dimer impurity II in metoclopramide injection according to claim 1, characterized in that: The structural formulas of dimer impurity I and dimer impurity II in the metoclopramide injection solution in step two are shown in Figures I and II, respectively. 。

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