CN113979908A - Acotiamide hydrochloride impurity and preparation method thereof - Google Patents
Acotiamide hydrochloride impurity and preparation method thereof Download PDFInfo
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Abstract
The invention relates to acotiamide hydrochloride impurities and a preparation method thereof, wherein the acotiamide hydrochloride impurities shown in formulas II and III have the structural formulas shown in the specification. The invention also provides a preparation method of the acotiamide hydrochloride impurity shown in the formula II (formula III), which comprises the following steps: (1) dissolving a compound IV (compound V) in a solvent at the temperature of 30-90 ℃; (2) adding alkali into the mixed solution obtained in the step (1), and performing hydrolysis reaction at the temperature of 60-90 ℃ to prepare impurities shown in a formula II (formula III); the specific synthetic route is as follows. The acotiamide hydrochloride impurity provided by the invention provides a new reference substance for detecting impurities in the acotiamide hydrochloride bulk drug, can be used for calibrating the content of the acotiamide hydrochloride bulk drug, and is more beneficial to development of a method for detecting related substances in the acotiamide hydrochloride bulk drug, so that the product is controlledAnd (4) quality.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a novel acotiamide hydrochloride impurity and a preparation method thereof.
Background
Functional Dyspepsia (FD), also known as dyspepsia, is a symptom that originates in the stomach and duodenum area and is a common clinical syndrome. According to the Roman III diagnosis standard, metabolic, systemic or organic lesions are not found in routine examination, and one or more symptoms of epigastric pain, postprandial fullness and discomfort, epigastric burning sensation and early satiety appear in more than three months in six months, namely functional dyspepsia.
Acotiamide hydrochloride was developed by association of the astelane (Astellas) pharmaceutical and zeristine co, approved for the treatment of Functional Dyspepsia (FD) in japan in 2013, 2 months. The main action mechanism is that the quantity of acetylcholine in cholinergic nerve endings is increased by selectively inhibiting the activity of acetylcholinesterase, thereby promoting gastrointestinal peristalsis and improving gastric emptying. The drug is the first FD therapeutic drug in the world and has good market prospect.
Acotiamide hydrochloride (CAS number: 773092-05-0) having the chemical name N- {2- [ bis (1-methylethyl) amino ] ethyl } -2- [ (2-hydroxy-4, 5-dimethoxybenzoyl) amino ] -thiazole-4-carboxamide monohydrochloride trihydrate and having the structure shown below:
new impurities are found in the research of the synthesis process of acotiamide hydrochloride, but the research report of the impurities of the acotiamide hydrochloride process is not described, and the structural information of the acotiamide hydrochloride is not searched in SCIFINDER at present. According to the requirements of international harmonization (ICH) for registration standards of human drugs, in order to ensure the safety of drugs, it is necessary to perform safety evaluation on each impurity in Active Pharmaceutical Ingredients (API), and establish the limit of impurity content for ensuring the safety thereof, in addition, different API produced by different starting materials and preparation processes also have the safety risk of introducing different new impurities, and it is further necessary to perform structure confirmation on the generated new impurities to provide a basis for toxicological research, thereby establishing the limit of safety content, which can not only provide reference for the control of API process synthesis conditions, but also meet the requirements of drug preparation. Therefore, it is necessary to research new impurities found in the synthesis process of acotiamide hydrochloride bulk drug.
Disclosure of Invention
The invention aims to provide novel acotiamide hydrochloride impurities with structures shown in formula II and formula III on the basis of the prior art.
The invention also aims to provide a preparation method of the acotiamide hydrochloride impurity shown in the formula II.
The third purpose of the invention is to provide a preparation method of acotiamide hydrochloride impurity shown in the formula III.
The fourth purpose of the invention is to provide the application of the acotiamide hydrochloride impurities shown in the formulas II and III in the aspect of detecting the acotiamide hydrochloride.
The technical scheme of the invention is as follows:
the acotiamide hydrochloride impurity shown in the formula II and the formula III has the following structural formula:
wherein the acotiamide hydrochloride impurity shown in the formula II has the name: (Z) -S- (2-amino-3- ((2- (diisopropylamino) ethyl) amino) -3-oxoprop-1-en-1-yl) (2-hydroxy-4, 5-dimethoxybenzoyl) carbamate; the acotiamide hydrochloride impurity shown in the formula III is named as: (Z) -2-amino-3- (((2-hydroxy-4, 5-dimethoxybenzoyl) carbamoyl) thio) acrylic acid.
The acotiamide hydrochloride impurities shown in the formulas II and III are unknown impurities found in the related substance maps of a plurality of batches of acotiamide hydrochloride by the inventor of the invention, the unknown impurities are separated, and structural identification is carried out respectively, for example,1H-NMR、13C-NMR and TOF MS ES confirm the chemical structural formulas of the acotiamide hydrochloride impurities shown in the formulas II and III. The method for reducing generation and removing the acotiamide hydrochloride raw material medicine is established in a targeted mode in the preparation process of the acotiamide hydrochloride raw material medicine, and is used as an impurity reference substance, the content limit of the acotiamide hydrochloride raw material medicine in a finished product is monitored, so that the content limit of the acotiamide hydrochloride raw material medicine in the acotiamide hydrochloride raw material medicine is smaller than 0.05%, and the safety of the acotiamide hydrochloride raw material medicine is guaranteed.
At present, the two compounds shown in the formulas II and III are not described in reports related to acotiamide hydrochloride, no search result is found in the scifrinder, and the acotiamide hydrochloride impurities shown in the formulas II and III can be deduced to be two new compounds. In the preparation process of acotiamide hydrochloride, the thiazole ring in the structure of the acotiamide hydrochloride is likely to be subjected to ring opening, and a new byproduct is generated. In order to further understand the acotiamide hydrochloride impurities shown in the formulas II and III, the inventor takes a compound IV (acotiamide) and a compound V (an acotiamide intermediate) as raw materials to perform hydrolysis reaction on the basis of the prior art to obtain the acotiamide hydrochloride impurities shown in the formulas II and III, which can be used for calibrating the content of the acotiamide hydrochloride impurities in an acotiamide hydrochloride raw material medicine and can provide a direction for controlling a synthesis method of the acotiamide hydrochloride, so that the safety of the acotiamide hydrochloride medicine is ensured.
The invention also provides a preparation method of the acotiamide hydrochloride impurity shown in the formula II, and the synthetic route is as follows:
in a preferred embodiment, the preparation method of the acotiamide hydrochloride impurity shown in the formula II comprises the following steps:
(1) dissolving a compound IV in a solvent at the temperature of 30-90 ℃;
(2) and (2) adding alkali into the mixed solution obtained in the step (1), and performing hydrolysis reaction at the temperature of 60-90 ℃ to prepare the impurity shown in the formula II.
For the present invention, in step (1), the solvent is dichloromethane, ethyl acetate, acetonitrile, methanol, ethanol, isopropanol, aqueous methanol, aqueous ethanol, or aqueous isopropanol. Preferably, the solvent is methanol, ethanol, isopropanol, aqueous methanol, aqueous ethanol or aqueous isopropanol. More preferably, the solvent is an aqueous isopropanol solution.
Further, the volume fraction of the aqueous isopropanol solution is 20-90%, and may be, but is not limited to, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 85%, or 90%, and further, the volume fraction of the aqueous isopropanol solution is 80%.
Furthermore, the mass-volume ratio of the compound IV to the isopropanol aqueous solution is 1: 4-20 g/ml; can be but is not limited to 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:13, 1:15, 1:17, 1:19 or 1:20, and further, the mass-to-volume ratio of the compound IV to the isopropanol water solution is 1:6 g/ml.
For the present invention, in the step (1), the compound IV is dissolved at a temperature of 30 to 90 ℃, but not limited to 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃ or 90 ℃ and between two temperature nodes, for example, 50 to 70 ℃, 50 to 60 ℃ or 60 to 70 ℃. In a preferable scheme, the dissolving temperature is 60-70 ℃.
In the step (2), the alkali is one or more of sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or potassium hydroxide, and preferably, the alkali is sodium hydroxide.
In the step (2), when the impurities shown in the formula II are prepared, the dosage of the alkali is strictly controlled, so that better yield can be obtained, and the generation of byproducts is reduced. Further, the molar ratio of the compound IV to the alkali is 1: 0.1-4.0; may be, but is not limited to, 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.8, 1:1.0, 1:1.5, 1:2.0, 1:2.5, 1:3.0, 1:3.5 or 1:4.0, and further, the molar ratio of compound IV to base is 1: 0.5.
In the step (2), when the impurities shown in the formula II are prepared, the reaction temperature is strictly controlled, so that better yield can be obtained, and the generation of byproducts is reduced. In a preferred embodiment, the reaction temperature is 30-90 ℃, and can be, but is not limited to, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃ or 90 ℃, and between two temperature nodes, for example, 50-80 ℃, 50-70 ℃, 60-70 ℃ or 70-80 ℃. In a preferable scheme, the reaction temperature is 70-80 ℃.
Further, in the step (2), the reaction time is 12 to 72 hours, but not limited to 12 hours, 24 hours, 36 hours, 48 hours, 54 hours, 60 hours, 66 hours or 72 hours, and between two time nodes, for example, 36 to 60 hours, 48 to 54 hours, 48 to 60 hours or 54 to 60 hours. In a preferable scheme, the reaction time is 48 to 54 hours.
The invention also provides a preparation method of the acotiamide hydrochloride impurity shown in the formula III, and the synthetic route is as follows:
in a preferred embodiment, the preparation method of the acotiamide hydrochloride impurity shown in the formula III comprises the following steps:
(1) dissolving a compound V in a solvent at the temperature of 30-90 ℃;
(2) and (2) adding alkali into the mixed solution obtained in the step (1), and performing hydrolysis reaction at the temperature of 60-90 ℃ to prepare the impurity shown in the formula III.
For the present invention, in step (1), the solvent is dichloromethane, ethyl acetate, acetonitrile, methanol, ethanol, isopropanol, aqueous methanol, aqueous ethanol, or aqueous isopropanol. Preferably, the solvent is methanol, ethanol, isopropanol, aqueous methanol, aqueous ethanol or aqueous isopropanol. More preferably, the solvent is an aqueous isopropanol solution.
Further, the volume fraction of the aqueous isopropanol solution is 20-90%, and may be, but is not limited to, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 85%, or 90%, and further, the volume fraction of the aqueous isopropanol solution is 80%.
Furthermore, the mass-to-volume ratio of the compound V to the isopropanol aqueous solution is 1: 4-20 g/ml; can be but is not limited to 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:13, 1:15, 1:17, 1:19 or 1:20, and further, the mass-to-volume ratio of the compound V to the isopropanol aqueous solution is 1:10 g/ml.
For the present invention, in the step (1), when the compound V is dissolved, the dissolving temperature is 30 to 90 ℃, and may be, but is not limited to, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃ or 90 ℃, and between two temperature nodes, for example, 50 to 70 ℃, 50 to 60 ℃ or 60 to 70 ℃. In a preferable scheme, the dissolving temperature is 50-60 ℃.
In the step (2), the alkali is one or more of sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or potassium hydroxide, and preferably, the alkali is sodium hydroxide.
In the step (2), when the impurities shown in the formula III are prepared, the dosage of the alkali is strictly controlled, so that better yield can be obtained, and the generation of byproducts is reduced. Further, the molar ratio of the compound V to the base is 1: 3.5-6.5; can be but is not limited to 1:3.5, 1:4.0, 1:4.5, 1:5.0, 1:5.5, 1:6.0 or 1:6.5, further, the molar ratio of compound V to base is 1:5.
In the step (2), when the impurities shown in the formula III are prepared, the reaction temperature is strictly controlled, so that better yield can be obtained, and the generation of byproducts is reduced. In a preferred embodiment, the reaction temperature is 30-90 ℃, and can be, but is not limited to, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃ or 90 ℃, and between two temperature nodes, for example, 50-80 ℃, 50-70 ℃, 60-70 ℃ or 70-80 ℃. In a preferable scheme, the reaction temperature is 70-80 ℃.
Further, in the step (2), the reaction time is 12 to 72 hours, but not limited to 12 hours, 24 hours, 36 hours, 48 hours, 54 hours, 60 hours, 66 hours or 72 hours, and between two time nodes, for example, 36 to 60 hours, 48 to 54 hours, 48 to 60 hours or 54 to 60 hours. In a preferable scheme, the reaction time is 48 to 54 hours.
By adopting the technical scheme of the invention, the advantages are as follows:
(1) the novel acotiamide hydrochloride impurities with the structures of the formula II and the formula III generated in the acotiamide hydrochloride raw material medicine are beneficial to the quality control of the acotiamide hydrochloride product, so that the safety of the acotiamide hydrochloride raw material medicine is ensured.
(2) The invention provides a preparation method of novel acotiamide hydrochloride impurities with structures of a formula II and a formula III, which has the advantages of mild reaction conditions, simple post-treatment and high yield and purity of target products.
(3) The novel acotiamide hydrochloride impurities with the structures of the formula II and the formula III, which are prepared by the invention, provide a novel reference substance for detecting the impurities in the acotiamide hydrochloride raw material medicine, can be used for calibrating the content of the impurities in the acotiamide hydrochloride raw material medicine, provide a direction for controlling a synthesis method of the acotiamide hydrochloride, and are more beneficial to the development of a detection method of related substances in the acotiamide hydrochloride raw material medicine, thereby controlling the product quality.
Drawings
FIG. 1 is a schematic diagram showing the confirmation of the structure of the impurity of the formula II in example 11H-NMR chart;
FIG. 2 is a structural confirmation of the impurity of the formula II in example 113C-NMR chart;
FIG. 3 is a view of TOF MS ES-for structural confirmation of the impurity represented by the formula II in example 1;
FIG. 4 is a structural confirmation of the impurity of the formula III in example 21H-NMR chart;
FIG. 5 is a structural confirmation of the impurity of the formula III in example 213C-NMR chart;
FIG. 6 is a structure confirmation TOF MS ES-diagram of the impurity represented by the formula III in example 2;
FIG. 7 is a LC-MS diagram of the compound of formula II in the final product acotiamide hydrochloride;
FIG. 8 is a LC-MS diagram of the compound of formula III in the final product of acotiamide hydrochloride.
Detailed Description
The novel impurities and the process for their preparation according to the invention are further illustrated by the following examples in conjunction with the drawing, which are not intended to limit the invention in any way.
Example 1: preparation of (Z) -S- (2-amino-3- ((2- (diisopropylamino) ethyl) amino) -3-oxoprop-1-en-1-yl) (2-hydroxy-4, 5-dimethoxybenzoyl) carbamate (impurity shown in formula II)
Adding compound IV (10.00g, 22.20mmol) and 60mL of 80% isopropanol aqueous solution in volume fraction into a 250mL reaction flask, uniformly stirring, and heating to 60-70 ℃ to completely dissolve the solid. Then, sodium hydroxide (0.44g, 11.00mmol) is added into the mixed solution, the temperature is raised to 70-80 ℃ while stirring, the reaction is continued to be kept for stirring and reacted for 48h, and the TLC monitors that the compound IV is completely reacted. And after the reaction is finished, stopping stirring, cooling to 20-30 ℃, stirring for crystallization for 4h, separating out a large amount of solids, performing suction filtration, leaching a filter cake with 20mL of purified water, and performing vacuum drying on the obtained solids at 50 ℃ and-0.09 MPa to obtain 9.56g of the compound shown in the formula II, wherein the yield is 91.92% and the purity is 99.84%.
The relevant structure validation data are as follows:1HNMR(500MHZDMSO), δ 12.0555ppm (1H, br), δ 11.7606ppm (1H, br), δ 09.7208ppm (1H, br), δ 18.7040ppm (2H, br), δ 7.8626ppm (1H, s), δ 7.4554ppm (1H, s), δ 6.8393ppm (1H, s), δ 3.7936ppm (3H, s), δ 3.7446ppm (3H, s), δ 3.6041-3.6295ppm (4H, t), δ 3.1369-3.1656ppm (2H, m), δ 1.3061-1.3263ppm (12H, d), see fig. 1;13CNMR(500MHZDMSO) is shown in figure 2; MS (M/Z) 469.2[ M + H ]]+See fig. 3.
Example 2: preparation of (Z) -2-amino-3- (((2-hydroxy-4, 5-dimethoxybenzoyl) carbamoyl) thio) acrylic acid (impurity shown in formula III)
Adding the compound V (10.00g, 30.83mmol) and 100mL of 80% isopropanol aqueous solution in volume fraction into a 250mL reaction flask, uniformly stirring, and heating to 50-60 ℃ to completely dissolve the solid. Then, sodium hydroxide (0.25g, 6.25mmol) was added to the resulting mixed solution, the temperature was raised to 70-80 ℃ with stirring, the reaction was continued with stirring for 50 hours with keeping the temperature, and the completion of the reaction of compound V was monitored by TLC. And after the reaction is finished, stopping stirring, cooling to 20-30 ℃, stirring for crystallization for 4h, separating out a large amount of solids, performing suction filtration, leaching a filter cake with 20mL of purified water, and performing vacuum drying on the obtained solids at 50 ℃ and-0.09 MPa to obtain 9.82g of the compound shown in the formula III, wherein the yield is 93.03%, and the purity is 99.76%.
The relevant structure validation data are as follows:1HNMR(300MHZDMSO), δ 12.0547ppm (2H, br), δ 7.9860ppm (1H, s), δ 7.5487ppm (1H, s), δ 6.6597ppm (1H, s), δ 5.3592ppm (4H, br), δ 3.7320-3.7706ppm (6H, d), see fig. 4;13CNMR(500MHZDMSO) is shown in figure 5; MS (M/Z):343.0[ M + H]+See fig. 6.
Example 3: detection of acotiamide hydrochloride finished product
Taking a proper amount of acotiamide hydrochloride finished products, precisely weighing, dissolving with a proper amount of diluent (mobile phase A-mobile phase B (85:15)), and diluting to prepare a solution containing about 0.5mg in each 1ml as a test solution. Performing high performance liquid chromatography (0512 in the four-part general regulation of the Chinese pharmacopoeia 2015) test by using pentafluorophenyl bonded silica gel as a filler (250 × 4.6mm, 5 μm); gradient elution is carried out by taking 20nmol/L ammonium formate solution (1.26 g ammonium formate, 1000ml water is added for dissolution, and the pH value is adjusted to 3.0 by formic acid) as a mobile phase A and acetonitrile as a mobile phase B according to the following table; the detection wavelength is 280nm, and the column temperature is 30 ℃. Precisely measuring 20 μ l of the test solution, injecting into a mass spectrometer, and recording the spectrogram.
And (4) analyzing results: 11.817min is a compound represented by formula II, MS (M/Z):469.18[ M + H ] +, as shown in FIG. 7; the peak impurity at 3.779min is a compound shown in formula III, MS (M/Z):343.14[ M + H ] +, as shown in FIG. 8.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: modifications of the technical solutions described in the foregoing embodiments are still possible, or some technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. The acotiamide hydrochloride impurity shown in the formula II and the formula III has the following structural formula:
2. the method for preparing acotiamide hydrochloride impurity shown in formula II in claim 1, is characterized in that the synthetic route is as follows:
3. the method for preparing acotiamide hydrochloride impurity represented by formula II according to claim 2, characterized in that it comprises the steps of:
(1) dissolving a compound IV in a solvent at the temperature of 30-90 ℃;
(2) and (2) adding alkali into the mixed solution obtained in the step (1), and performing hydrolysis reaction at the temperature of 60-90 ℃ to prepare the impurity shown in the formula II.
4. The method for preparing acotiamide hydrochloride impurities shown in formula II according to claim 3, wherein in the step (1), the dissolving temperature is 60-70 ℃; the solvent is dichloromethane, ethyl acetate, acetonitrile, methanol, ethanol, isopropanol, methanol water solution, ethanol water solution or isopropanol water solution, preferably isopropanol water solution; more preferably an aqueous isopropanol solution with a volume fraction of 20-90%, and particularly preferably an aqueous isopropanol solution with a volume fraction of 80%.
5. The method for preparing acotiamide hydrochloride impurities shown in formula II according to claim 3, wherein in the step (2), the hydrolysis reaction temperature is 70-80 ℃; the hydrolysis reaction time is 12-72 hours, preferably 48-54 hours; the alkali is one or more of sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or potassium hydroxide, and is preferably sodium hydroxide; the molar ratio of the compound IV to the base is 1: 0.1-4.0, and preferably 1: 0.5.
6. The method for preparing acotiamide hydrochloride impurity shown in formula III in claim 1, is characterized in that the synthetic route is as follows:
7. the method for preparing acotiamide hydrochloride impurity represented by formula III according to claim 6, characterized in that it comprises the steps of:
(1) dissolving a compound V in a solvent at the temperature of 30-90 ℃;
(2) and (2) adding alkali into the mixed solution obtained in the step (1), and performing hydrolysis reaction at the temperature of 60-90 ℃ to prepare the impurity shown in the formula III.
8. The method for preparing acotiamide hydrochloride impurities shown in formula III according to claim 7, wherein in the step (1), the dissolving temperature is 50-60 ℃; the solvent is dichloromethane, ethyl acetate, acetonitrile, methanol, ethanol, isopropanol, methanol water solution, ethanol water solution or isopropanol water solution, preferably isopropanol water solution; more preferably an aqueous isopropanol solution with a volume fraction of 20-90%, and particularly preferably an aqueous isopropanol solution with a volume fraction of 80%.
9. The method for preparing acotiamide hydrochloride impurities shown in formula III according to claim 7, wherein in the step (2), the hydrolysis reaction temperature is 70-80 ℃; the hydrolysis reaction time is 12-72 hours, preferably 48-54 hours; the alkali is one or more of sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or potassium hydroxide, and is preferably sodium hydroxide; the molar ratio of the compound V to the base is 1: 3.5-6.5, preferably 1:5.
10. The use of the acotiamide hydrochloride impurity shown in the formula II and the formula III in claim 1 for detecting the acotiamide hydrochloride.
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