New metoclopramide impurity and preparation method thereof

Abstract

The new metoclopramide impurity is disclosed for the first time, the liquid phase purity of the prepared new metoclopramide impurity is larger than 95%, and the new metoclopramide impurity can be directly used as a reference substance for quality research of metoclopramide. The impurity can be directly used as an impurity reference substance when related substances of metoclopramide or metoclopramide hydrochloride raw material medicines and preparations are detected, so that more strict quality control on the metoclopramide raw material medicines and preparations is realized.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemical preparation, and in particular to a new impurity of metoclopramide and a preparation method thereof. Background Art

[0002] Metoclopramide, for the treatment of Stomach and esophagus The drug in question belongs to Dopamine receptor antagonists This product is mainly used to treat nausea and Vomit , and can assist Gastric discharge Patients with impaired emptying of the stomach and treatment Gastroesophageal reflux and Light stomach Paralysis , can also be used to treat migraines.

[0003] Metoclopramide is a white crystalline powder. Its English name is Metoclopramide. Its Chinese chemical name is N-[(2-diethylamino)ethyl]-4-amino-2-methoxy-5-chloro-benzamide. Its CAS registration number is 364-62-5. Its molecular formula is C 14 H 22 ClN3O2, molecular weight is 299.80.

[0004] The synthetic route of metoclopramide bulk drug used by the applicant of the present invention is as follows:

[0005]

[0006] Step 1: isopropyl alcohol, acetic acid, N,N-diethylethylenediamine;

[0007] Step 2: NaOH aqueous solution

[0008] Refining: Isopropyl alcohol.

[0009] During the synthesis process, it was found that there were unknown impurities in INT-2. The inventor searched for all impurities in the current literature and pharmacopoeia about metoclopramide and found that they were inconsistent with the impurity information. Therefore, it is necessary to investigate the source of the impurity, analyze its structure, and prepare an impurity reference substance for subsequent quality research and process improvement of metoclopramide.

[0010] By concentrating and enriching the crystallization mother liquor of INT-2 material, a new impurity is obtained, as shown in the following formula I:

[0011]

[0012] It is known in the art that, for the sake of safety of human administration, before an effective pharmaceutical ingredient (API) product is commercialized, national and international management is required to establish extremely low limits for the identification of non-characteristic impurities in toxicology. Usually the limit of each impurity is less than 0.15% by weight. The limit of unidentified and / or non-characteristic impurities is significantly lower, usually less than 0.1% by weight. Therefore, the present invention develops suitable analytical detection methods for new impurities of metoclopramide and formulates impurity limits in order to achieve stricter quality control of drugs. Summary of the invention

[0013] The invention discloses for the first time a new impurity of metoclopramide and a preparation method thereof, and provides an HPLC method for effectively detecting the impurity.

[0014] First, the structure of the new impurity in metoclopramide was determined by liquid chromatography-mass spectrometry (LC-MS), and the impurity was not included in any official pharmacopoeia or literature reports. The provided new impurity of metoclopramide, i.e., the compound of formula I (4-amino-N-(2-(diethylamino)ethyl)-5-(2-(diethylamino)ethyl)amino)-2-methoxybenzamide), has the following chemical structure:

[0015]

[0016] In a second aspect, the present invention provides a method for preparing a compound of formula I, providing a qualified reference substance for the quality control of metoclopramide, comprising the following steps:

[0017]

[0018] Metoclopramide is directly alkylated with N,N-diethylethylenediamine in an organic solvent under the action of an acid-binding agent to obtain a compound of formula I.

[0019] The above synthesis method is further

[0020] The solvent is N,N-dimethylformamide, N,N-dimethylformamide, toluene, 1,4-dioxane, and more preferably N,N-dimethylformamide;

[0021] The above synthesis method is further

[0022] The molar ratio of metoclopramide to N,N-diethylethylenediamine is 1:1 to 1:5, and the more preferred molar ratio is 1:4 to 1:1.6;

[0023] The above synthesis method is further

[0024] The acid binding agent is potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, and more preferably potassium carbonate;

[0025] The above synthesis method is further

[0026] The reaction time is not less than 2 hours, preferably 2 to 5 hours; the reaction temperature is 90 to 120°C;

[0027] The above synthesis steps are further performed.

[0028] Metoclopramide, N,N-diethylethylenediamine, solvent and acid binding agent were added into a pot, heated for reaction, and the reaction of metoclopramide was completed under HPLC monitoring;

[0029] After the reaction is completed, the excess acid-binding agent is directly filtered out, the filtrate is directly concentrated to dryness, and isopropanol is added for recrystallization to obtain the target product, compound of formula I.

[0030] The technical solution used in the invention is simple to operate, the reaction conditions are mild and controllable, and the product has high yield and high purity.

[0031] The third aspect of the present invention provides a method for detecting new impurities of metoclopramide;

[0032] The chromatographic conditions are:

[0033] Octadecylsilane bonded silica gel was used as filler (4.6×150 mm; 3.5 μm);

[0034] Mobile phase A: 5 g / L ammonium acetate solution (adjust pH to 7.0 with glacial acetic acid or ammonia water);

[0035] Mobile phase B: acetonitrile;

[0036] Detection wavelength: 275nm;

[0037] Flow rate: 0.9ml / min;

[0038] Column temperature: 37°C.

[0039] Further, the gradient elution procedure is as follows:

[0040] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 95 5 1.5 95 5 16.5 42.5 57.5 20 95 5 25 95 5 .

[0041] The invention discloses for the first time a new impurity of metoclopramide (compound of formula I) and a preparation method thereof. The prepared new impurity of the compound of formula I has an HPLC purity of more than 95%, and provides an HPLC method for controlling the impurity. The compound of formula I can provide an impurity reference substance that meets the requirements for quality control of metoclopramide, and can be used for quality research of a metoclopramide bulk drug and a preparation thereof, so that the metoclopramide bulk drug and the preparation thereof can better control the quality standards of related substances.

[0042] Specific implementation cases

[0043] The synthesis process of the compound of formula I (4-amino-N-(2-(diethylamino)ethyl)-5-(2-(diethylamino)ethyl)amino)-2-methoxybenzamide) is:

[0044]

[0045] Example 1: Preparation of Compounds of Formula I

[0046] N, N-dimethylformamide (50 mL) and anhydrous potassium carbonate (10.4 g, 0.075 mol) were added to a 250 mL three-necked flask in sequence. After stirring for several minutes, N, N-diethylethylenediamine (11.6 g, 0.1 mol) and metoclopramide (15.0 g, 0.05 mol) were added. The temperature was raised to 100 ° C and reacted for 3 h. The reaction of metoclopramide in the reaction solution was monitored by HPLC. After the temperature was slightly lowered to 40-50 ° C, potassium carbonate salt was directly removed by vacuum filtration. The filtrate was concentrated at 80 ° C under reduced pressure until no obvious liquid flowed out. 100 mL of isopropanol was added to the residue for recrystallization to obtain 11.4 g of white solid, yield: 60.1%, HPLC purity 99.32% (HPLC normalization method), ESI-MS (m / z): 380.3029 [M+H] + .

[0047] 1 H-NMR (δ-DMSO, 400MHz) δ: 8.117~8.141 (m, 1H), 7.744 (s, 1H), 6.496 (s, 1H), 5.926 (s, 2H), 4. 102 (s, 1H), 3.837 (s, 3H), 3.285~3.344 (m, 4H), 2.466~2.526 (m, 12H), 0.959~1.056 (dd, 12H).

[0048] Implementation Case 2: Preparation of Impurity I with Different Feed Molar Ratios

[0049] N, N-dimethylformamide (50 mL) and anhydrous potassium carbonate (10.4 g, 0.075 mol) were added to a 250 mL three-necked flask in sequence. After stirring for several minutes, N, N-diethylethylenediamine (9.3 g, 0.08 mol) and metoclopramide (15.0 g, 0.05 mol) were added. The temperature was raised to 100 ° C and reacted for 3 h. The reaction of metoclopramide in the reaction solution was monitored by HPLC. After the temperature was slightly lowered to 40-50 ° C, the potassium carbonate salt was directly removed by vacuum filtration. The filtrate was concentrated at 80 ° C under reduced pressure until no obvious liquid flowed out. 100 mL of isopropanol was added to the residue for recrystallization to obtain 13.1 g of a white solid with a yield of 69.3% and a HPLC purity of 99.54% (HPLC normalization method). The NMR data is shown in Example 1.

[0050] Implementation Case 3: Preparation of Impurity I Using Sodium Bicarbonate as Acid Binding Agent

[0051] N, N-dimethylformamide (50 mL) and sodium bicarbonate (6.3 g, 0.075 mol) were added to a 250 mL three-necked flask in sequence. After stirring for several minutes, N, N-diethylethylenediamine (11.6 g, 0.1 mol) and metoclopramide (15.0 g, 0.05 mol) were added. The temperature was raised to 100 ° C. and the reaction was carried out for 3 h. The reaction of metoclopramide in the reaction solution was monitored by HPLC. After the temperature was slightly lowered to 40-50 ° C., potassium carbonate was directly removed by vacuum filtration. The filtrate was concentrated at 80 ° C. until no obvious liquid flowed out. 100 mL of isopropanol was added to the residue for recrystallization to obtain 10.8 g of a white solid with a yield of 57.2% and a HPLC purity of 98.27% (HPLC normalization method). The NMR data is shown in Example 1.

[0052] Implementation Case 4: Detection Method of New Impurities in Metoclopramide

[0053] Take an appropriate amount of the product for test solution, weigh it accurately, dissolve it in solvent and quantitatively dilute it to make a solution containing about 1 mg of metoclopramide new impurity per 1 ml.

[0054] For the control solution, accurately measure an appropriate amount of the test solution and quantitatively dilute it with a solvent to produce a solution containing approximately 1 μg of the new impurity of metoclopramide per 1 ml.

[0055] Reference solution Take appropriate amount of metoclopramide new impurity and metoclopramide, dissolve them in appropriate amount of acetonitrile, dissolve and dilute with solvent to make a solution containing about 1 μg of the new impurity and metoclopramide per 1 ml (according to C 14 H 22 A mixed solution of 10 μg of ClN3O2.

[0056] Chromatographic conditions: octadecylsilane bonded silica gel was used as filler (4.6×150 mm; 3.5 μm); mobile phase A was 5 g / L ammonium acetate solution (pH value was adjusted to 7.0 with glacial acetic acid or ammonia water), mobile phase B was acetonitrile, detection wavelength was 275 nm; flow rate was 0.9 ml per minute; column temperature was 37°C; gradient elution was performed according to the following table:

[0057] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 95 5 1.5 95 5 16.5 42.5 57.5 20 95 5 25 95 5 .

[0058] System suitability requires that in the chromatogram of the reference solution, the retention time of the metoclopramide peak is about 10 minutes, and the separation degree between the new impurity peak and the metoclopramide peak should be greater than 2.0.

[0059] Determination method: Accurately measure the test solution, control solution and reference substance solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0060] Relative retention time and limit of new impurities in metoclopramide

[0061]

[0062] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A new impurity of metoclopramide was disclosed for the first time, and its structural formula is shown in the figure below:

2. A method for detecting new impurities of metoclopramide according to claim 1, wherein the chromatographic conditions are: using octadecylsilane bonded silica gel as a filler (4.6×150 mm; 3.5 μm); mobile phase A is 5 g / L ammonium acetate solution (adjusting the pH value to 7.0 with glacial acetic acid or ammonia water), mobile phase B is acetonitrile, and gradient elution is performed according to the table below; the detection wavelength is 275 nm; the flow rate is 0.9 ml per minute; and the column temperature is 37° C.

3. The method for detecting new impurities of metoclopramide according to claim 2, characterized in that, The procedure of the gradient elution is as follows: 。

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