CN112094239A - Urapidil impurity compound, preparation method and application thereof - Google Patents
Urapidil impurity compound, preparation method and application thereof Download PDFInfo
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- CN112094239A CN112094239A CN202011206428.3A CN202011206428A CN112094239A CN 112094239 A CN112094239 A CN 112094239A CN 202011206428 A CN202011206428 A CN 202011206428A CN 112094239 A CN112094239 A CN 112094239A
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- urapidil
- impurity
- impurity compound
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
Abstract
The invention belongs to the technical field of preparation of medicinal impurities, and discloses an urapidil impurity compound, a preparation method and application thereof, wherein the preparation method of the urapidil impurity compound comprises the following steps: 1) dissolving urapidil in a mixed solvent of an organic solvent and water, heating to completely dissolve the urapidil, and introducing carbon dioxide for pressure reaction; 2) and after the reaction is finished, decompressing, concentrating and drying the reaction solution, and purifying by column chromatography to obtain the urapidil impurity compound. The impurity compound meets the requirement of an impurity reference substance in quality control, can be used for quality control in the synthesis process of urapidil or urapidil hydrochloride, can be used as the impurity reference substance for accurately and quantitatively detecting the urapidil or urapidil hydrochloride, and is beneficial to improvement of quality control of corresponding raw material medicaments.
Description
Technical Field
The invention relates to the technical field of preparation of medicinal impurities, and particularly relates to an urapidil impurity compound, a preparation method and application thereof.
Background
Urapidil (Urapidil), structural formula II, is a high-selectivity alpha receptor blocker, and has dual functions of periphery and center. Peripheral vasodilatation mainly blocks postsynaptic alpha 1 receptors to obviously reduce peripheral resistance, and central action plays a role in reducing blood pressure by activating 5-hydroxytryptamine-1A receptors and reducing sympathetic feedback regulation of medullary cardiovascular center. The Urapidil preparation has two dosage forms of oral administration and injection, wherein the raw material medicine for the oral administration is Urapidil, the raw material medicine for the injection is Urapidil Hydrochloride (Urapidil Hydrochloride), and the structural formula is shown as formula III. The urapidil sustained release tablet is mainly used for essential hypertension, renal hypertension and hypertension caused by pheochromocytoma. The urapidil hydrochloride injection is mainly used for perioperative hypertension, senile hypertensive crisis, pregnancy-induced hypertension syndrome, malignant hypertension after cerebral hemorrhage and hypertension of patients after thoracotomy, and is a first choice medicament for clinically treating severe hypertension.
According to the analysis of the existing synthetic process of urapidil, the 1- [3- [ (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydropyrimidin-4-yl) amino ] propyl ] -4- (2-methoxyphenyl) piperazine-1-onium-1-carboxylic acid (formula I) compound is a possible process impurity. The impurity has not been reported in the literature, and no corresponding reference substance is sold. If the impurities are generated in the process, the impurities may remain in the urapidil bulk drug, thereby affecting the quality and the medication safety of the drug. The urapidil hydrochloride is prepared by salifying urapidil and hydrochloric acid, so that the impurities may remain in the urapidil hydrochloride raw material medicine to influence the quality and the medication safety of the urapidil hydrochloride raw material medicine. In the process of drug research, the drug impurity spectrum must be comprehensively analyzed, and the possible impurities must be systematically researched and strictly controlled, so that the quality and safety of the drug can be ensured.
Based on the defects of the prior art, a preparation method aiming at the impurity of the formula I and an impurity reference substance are needed to be provided, so that the quality control of urapidil or urapidil hydrochloride is improved.
Disclosure of Invention
1. Problems to be solved
Impurities of the compound shown in the formula I can be generated in the urapidil synthesis process, and the impurities can be remained in the raw material medicaments. At present, no standard substance is sold in the market for the impurity, no literature report is available, and whether the detection control can be carried out by the existing analysis method cannot be determined. Aiming at the problem that potential impurities possibly exist in urapidil or urapidil hydrochloride in the prior art and effective quality control cannot be carried out, the invention aims to provide an urapidil impurity compound which is used as a reference substance for quality control of urapidil or urapidil hydrochloride bulk drug and is beneficial to obtaining products with higher quality.
The invention also aims to provide a method for preparing the impurity compound, which has simple process and high product purity, and provides a qualified impurity reference substance for the quality control of urapidil or urapidil hydrochloride.
2. Technical scheme
In order to solve the problems, the technical scheme adopted by the invention is as follows:
the invention provides an urapidil impurity compound, and the structural formula is shown in figure 1 (formula I).
In a preferred embodiment, the preparation method of the urapidil impurity compound comprises the following steps:
1) dissolving urapidil in a mixed solvent of an organic solvent and water, heating to completely dissolve the urapidil, and introducing carbon dioxide for pressure reaction;
2) and after the reaction is finished, decompressing, concentrating and drying the reaction solution, and purifying by column chromatography to obtain the urapidil hydrochloride impurity compound.
Preferably, the organic solvent is any one or combination of an alcohol solvent or a ketone solvent.
Preferably, the alcohol solvent is any one or combination of methanol, ethanol and isopropanol, and/or the ketone solvent is any one or combination of acetone and butanone.
According to the preferable scheme, the purity of the urapidil impurity compound obtained by the preparation is 92-100%.
Preferably, the pressure of the carbon dioxide in the step 1) is 15-60 psi, and/or the reaction temperature is 50-90 ℃.
In a preferable scheme, the urapidil impurity compound is used for quality control of urapidil or urapidil hydrochloride.
Preferably, the application comprises the following steps:
1) in the synthesis step of urapidil, the urapidil impurity compound is used for impurity control of an intermediate urapidil crude product: refining the obtained urapidil crude product through quality control to obtain urapidil;
2) and then using urapidil to carry out salification step to synthesize urapidil hydrochloride.
In a preferred embodiment, the purification comprises the following steps: the refining step comprises the following steps of purification: dissolving the urapidil crude product in absolute ethyl alcohol, heating for dissolving, cooling for crystallization, and filtering; and washing the filter cake with absolute ethyl alcohol and then drying to obtain urapidil.
In a preferable scheme, the content of the impurity compounds in the urapidil crude product is 1.4-3.4%.
In a preferable scheme, the content of the impurity compound in the intermediate urapidil crude product is 1.5%.
In a preferable scheme, the content of the impurity compounds contained in the urapidil is within 0.1%.
In a preferable scheme, the content of the impurity compounds contained in the urapidil hydrochloride is within 0.1%.
3. Advantageous effects
Compared with the prior art, the invention has the beneficial effects that:
(1) the urapidil impurity compound has higher purity, meets the requirement of an impurity reference substance in quality control, can be used for developing and verifying an urapidil or urapidil hydrochloride analysis method, and contributes to improving the quality standard of urapidil or urapidil hydrochloride, so that the product quality of urapidil or urapidil hydrochloride is better controlled.
(2) The urapidil impurity compound can be used for quality control in an urapidil synthesis process, can be used as an impurity reference substance for accurately and quantitatively detecting urapidil, is beneficial to developing a specific purification method aiming at the impurity compound, and can quickly obtain refined urapidil.
(3) The preparation method of the urapidil impurity compound is simple in process, the prepared impurity compound is 92-100% in purity, high in purity and capable of stably existing, and a qualified impurity reference substance can be provided for quality control of urapidil or urapidil hydrochloride.
(4) The purification method of urapidil of the invention comprises the steps of dissolving urapidil in absolute ethyl alcohol, heating for dissolving, cooling for crystallization, and filtering; the filter cake is washed by absolute ethyl alcohol and then dried, so that the purification purpose can be realized, not only the impurities of the compound shown in the formula I can be effectively removed, but also other unknown impurities can be simultaneously removed, the method is simple, and the specific impurity compounds of urapidil or urapidil hydrochloride can be reduced to be below 0.1% through one-time purification.
Drawings
FIG. 1 is a mass spectrum of an urapidil impurity compound obtained in example 1 of the present invention;
FIG. 2 is a nuclear magnetic hydrogen spectrum of urapidil impurity compound obtained in example 1 of the present invention;
FIG. 3 is a high performance liquid phase diagram of urapidil impurity compound obtained in example 1 of the present invention;
FIG. 4 is a preparation process route of urapidil hydrochloride;
FIG. 5 is a high performance liquid chromatography spectrum of urapidil obtained in example 4 of the present invention before purification;
fig. 6 is a high performance liquid chromatography of purified urapidil obtained in example 4 of the present invention.
Detailed Description
The invention is further described with reference to specific examples.
It should be noted that the terms "upper", "lower", "left", "right" and "middle" used in the present specification are for the sake of clarity, and are not intended to limit the scope of the present invention, and changes or adjustments of the relative relationship thereof may be made without substantial technical changes.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs; as used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
As used herein, the term "about" is used to provide the flexibility and inaccuracy associated with a given term, measure or value. The degree of flexibility for a particular variable can be readily determined by one skilled in the art.
As used herein, at least one of the terms "is intended to be synonymous with one or more of. For example, "at least one of A, B and C" explicitly includes a only, B only, C only, and combinations thereof, respectively.
Concentrations, amounts, and other numerical data may be presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a numerical range of about 1 to about 4.5 should be interpreted to include not only the explicitly recited limit values of 1 to about 4.5, but also include individual numbers (such as 2,3, 4) and sub-ranges (such as 1 to 3, 2 to 4, etc.). The same principle applies to ranges reciting only one numerical value, such as "less than about 4.5," which should be construed to include all of the aforementioned values and ranges. Moreover, such an interpretation should apply regardless of the breadth of the range or feature being described.
Any steps recited in any method or process claims may be executed in any order and are not limited to the order presented in the claims.
The invention is further described with reference to specific examples.
Example 1
The embodiment prepares an urapidil impurity compound, and the preparation method of the urapidil impurity compound comprises the following steps:
adding 10 g of urapidil, 20 mL of 95% ethanol and 20 mL of water into a pressure reaction container, removing air in the reaction container by using carbon dioxide gas, introducing the carbon dioxide gas to the set pressure of 60 psi, and keeping the temperature at about 60 ℃ for reaction for 12 hours. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure. And (3) performing column chromatography purification to obtain 2.1 g of urapidil impurity compound (yield is 18.9%, purity is 94.0%).
Product characterization of urapidil impurity compound:
(1) mass spectrometry (ESI-MS) was performed on the urapidil impurity compound prepared in example 1: m/z =432.2[ M + H ] +, mass spectrum of urapidil impurity compound is shown in figure 1.
(2) Nuclear magnetic analysis was performed on urapidil impurity compound prepared in example 1:1H-NMR（500MHz，d6-DMSO）6.97~6.86（4H，m），6.74（1H，s），4.71 (1H, s), 4.11 (2H, t), 3.79 (3H, s), 3.51 (4H, m), 3.28 (3H, s), 3.17 (2H, q), 3.10 (3H, s), 2.92 (4H, m), 1.89 (2H, m). FIG. 2 is a nuclear magnetic hydrogen spectrum diagram of urapidil impurity compound.
The high performance liquid phase diagram of the urapidil impurity compound obtained in example 1 is shown in fig. 3, and the urapidil impurity compound is defined as impurity O, and the purity of the urapidil impurity compound is found to satisfy 94%.
Example 2
The preparation method of the urapidil impurity compound comprises the following steps:
adding 10 g of urapidil, 20 mL of methanol and 20 mL of water into a pressure reaction container, removing air in the reaction container by using carbon dioxide gas, introducing the carbon dioxide gas to the set pressure of 40psi, and keeping the temperature at about 50 ℃ for reacting for 16 hours. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure. And (3) performing column chromatography purification to obtain 1.8 g of urapidil impurity compound (yield is 16.2%, and purity is 93.3%).
Example 3
The preparation method of the urapidil impurity compound comprises the following steps:
adding 10 g of urapidil, 10 mL of acetone and 20 mL of water into a pressure reaction container, removing air in the reaction container by using carbon dioxide gas, introducing the carbon dioxide gas to set pressure of 50psi, and keeping the temperature at about 50 ℃ for reacting for 16 hours. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure. And (4) purifying by column chromatography to obtain 1.7 g of urapidil impurity compound (yield 15.3%, purity 92.1%).
The urapidil impurity compounds prepared in examples 2 and 3 are characterized, and the results are consistent with the impurity characterization conclusion of example 1.
Example 4
The embodiment provides the application of urapidil impurity compounds to the reference substance in the quality control of the preparation process of urapidil or urapidil hydrochloride.
The preparation process route of urapidil hydrochloride is shown in figure 4, and HPLC detection is carried out on urapidil crude products prepared by the process route under the following detection conditions: octadecylsilane chemically bonded silica is used as a filling agent; taking sodium acetate solution (taking 8.2g of anhydrous sodium acetate and 40ml of glacial acetic acid, adding water for dissolving and diluting to 600 ml) -methanol (70: 30) as a mobile phase; the detection wavelength was 268 nm.
The detection process comprises the following steps: taking a proper amount of urapidil reference substance and a proper amount of 1, 3-dimethyl-4- (gamma-chloropropylamino) uracil (impurity I) reference substance respectively, adding mobile phase for dissolving and diluting to prepare a mixed solution containing 0.1mg of urapidil and 0.01mg of impurity I in each 1ml, injecting 20 mu l of the mixed solution into a liquid chromatograph, recording a chromatogram, wherein the separation degree of the urapidil peak and the impurity I peak is in accordance with the requirement, and the theoretical plate number is not less than 2000 calculated according to urapidil.
The chromatogram obtained by the HPLC detection is shown in FIG. 5, and as can be seen from FIG. 5, the impurities in the crude urapidil product are as follows: 96.3 percent of main component, 1.5 percent of maximum single impurity and 3.7 percent of total impurity.
Specific purification steps are carried out on impurity compounds of the urapidil crude product, and the purification method comprises the following steps: dissolving the crude urapidil product in absolute ethyl alcohol, heating to dissolve, cooling to crystallize, filtering, washing a filter cake with absolute ethyl alcohol, and drying to obtain a refined urapidil product, wherein the content of impurity compounds is 0.063%.
After purification, HPLC detection is carried out, and the obtained spectrogram is shown in figure 6, so that the specific purification method disclosed by the invention has an effective reduction effect on other impurities. For purification of urapidil, the present example provides only one purification method for the scheme of the present invention, and is not limited to other purification methods.
After the urapidil is purified for one time, a salifying step is carried out, the urapidil hydrochloride is prepared, and the final product, namely the urapidil hydrochloride, is obtained, wherein the content of impurity compounds in the urapidil hydrochloride is below 0.1%, and the content of total impurities is reduced to a lower level.
Claims (10)
1. An urapidil impurity compound, which is characterized in that: the structural formula is shown as formula I:
2. a method for preparing urapidil impurity compounds according to claim 1, characterized in that: the method comprises the following steps:
1) dissolving urapidil in a mixed solvent of an organic solvent and water, heating to completely dissolve the urapidil, and introducing carbon dioxide for pressure reaction;
2) and after the reaction is finished, decompressing, concentrating and drying the reaction solution, and purifying by column chromatography to obtain the urapidil hydrochloride impurity compound.
3. The method for preparing urapidil impurity compound according to claim 2, characterized in that: the organic solvent comprises any one or combination of alcohol or ketone solvents.
4. The method for preparing urapidil impurity compound according to claim 3, characterized in that: the alcohol solvent comprises any one or combination of methanol, ethanol or isopropanol, and/or the ketone solvent comprises any one or combination of acetone or butanone.
5. The method for preparing urapidil impurity compound according to claim 4, characterized in that: the purity of the prepared impurity compound is 92-100%.
6. The method for preparing urapidil impurity compound according to claim 4, characterized in that: in the step 1), the pressurization pressure of the carbon dioxide is 15-60 psi, and/or the reaction temperature is 50-90 ℃.
7. The use of urapidil impurity compounds according to claim 1, characterized in that: the urapidil impurity compound is used as an impurity reference substance and is applied to the quality control of urapidil or urapidil hydrochloride.
8. Use according to claim 7, characterized in that: the method comprises the following steps:
1) in the synthesis step of urapidil hydrochloride, the urapidil impurity compound is used for impurity control of an intermediate urapidil: refining the obtained urapidil crude product through quality control to obtain urapidil;
2) and then using urapidil to carry out salification step to synthesize urapidil hydrochloride.
9. Use according to claim 8, characterized in that: the purification comprises the following steps: the refining step comprises the following steps of purification: dissolving the urapidil crude product in absolute ethyl alcohol, heating for dissolving, cooling for crystallization, and filtering; and washing the filter cake with absolute ethyl alcohol and then drying to obtain urapidil.
10. Use according to claim 9, characterized in that: the urapidil or the urapidil hydrochloride contains no impurity compound of urapidil within 0.1%.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114652675A (en) * | 2020-12-23 | 2022-06-24 | 燃点(南京)生物医药科技有限公司 | Preparation method of urapidil hydrochloride injection |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114652675A (en) * | 2020-12-23 | 2022-06-24 | 燃点(南京)生物医药科技有限公司 | Preparation method of urapidil hydrochloride injection |
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