CN108276393B - Synthesis method of doxazosin impurity - Google Patents
Synthesis method of doxazosin impurity Download PDFInfo
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- CN108276393B CN108276393B CN201711469130.XA CN201711469130A CN108276393B CN 108276393 B CN108276393 B CN 108276393B CN 201711469130 A CN201711469130 A CN 201711469130A CN 108276393 B CN108276393 B CN 108276393B
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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Abstract
The invention discloses a method for synthesizing doxazosin impurities, which comprises the following steps: adding a solvent, 2-chloro-4-hydroxy-6, 7-dimethoxyquinazoline and N- (1, 4-benzodioxane-2-carbonyl) piperazine into a reactor, heating and stirring until the reaction is complete, cooling, filtering and drying to obtain doxazosin impurities. The high-purity doxazosin impurity prepared by the method can be used as a reference substance, and the method has the advantages of short reaction route, high yield, low energy consumption, low synthesis cost and simple operation, and is suitable for mass preparation.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a method for synthesizing doxazosin impurities.
Background
Hypertension is one of the major causes of death worldwide, and about 770 million deaths worldwide in 2010 can be attributed to hypertension. In China, 50% of patients with cardiovascular chronic nephropathy and diabetes die from hypertension. The awareness rate, control rate and treatment rate of hypertension are obviously improved in recent decades, which is due to the great efforts of China, but the prevalence rate of hypertension is still 28%, which is in a rising trend. In 2016, the JAMA son journal issues the research of the national hypertension queue, reveals the hypertension burden and basic condition in China, and reveals that the hypertension burden in China is eye-catching and surprise: of the 500,233 residents participating in the survey, the prevalence of hypertension was 32.5% (male 33.7%, female 31.9%); the prevalence of hypertension increases with age.
Doxazosin mesylate (doxazosin mesylate), a new generation of quinazolinone alpha developed and marketed by Pesper USA1The receptor blocking agent has long half-life period, obvious functions of lowering blood pressure and reducing blood fat, and good function on dysuria caused by simple prostatic hyperplasia. In 1988, doxazosin is marketed in Danish as a drug for treating hypertension, in 1995, FDA was approved in the United states for treating benign prostatic hyperplasia, and doxazosin controlled release tablets in 2002, 9 months, are marketed in China, and provide a new choice for domestic drug treatment of benign prostatic hyperplasia. At present, the traditional Chinese medicine becomes a first-line medicine for treating mild and moderate hypertension at home and abroad.
The chemical name of the doxazosin mesylate is 1- (4-amido-6, 7-dimethoxy-2-quinazolinyl) -4- (1, 4-benzodioxazole-2-formyl) piperazine mesylate, and the doxazosin mesylate has the following structure:
in the preparation process of a doxazosin mesylate raw material, a side chain raw material of the doxazosin mesylate is synthesized by taking 6, 7-dimethoxyquinazoline-2, 4-diketone as a raw material to chlorinate, ammoniating to obtain 2-chlorin-4-amino-6, 7-dimethoxyquinazoline, wherein the chlorin is incomplete in the process, the subsequent reaction is carried out to obtain 2-chlorin-4-hydroxy-6, 7-dimethoxyquinazoline, and the obtained 2-chlorin-4-hydroxy-6, 7-dimethoxyquinazoline reacts with N- (1, 4-benzodioxane-2-carbonyl) piperazine to generate doxazosin impurities, wherein the generated impurities have a structural formula shown in formula I.
The impurity I is not collected in the standards of European pharmacopoeia and United states pharmacopoeia doxazosin mesylate, domestic and foreign documents and patents do not report the method for synthesizing the impurity, no reference substance of the impurity I is supplied in the domestic and foreign doxazosin mesylate synthesis process, and a self-comparison method is adopted at present, but the accuracy of qualitative and quantitative determination is poor, and the risk of clinical medication is high. In order to improve the quality of the raw materials and the preparations in doxazosin mesylate and reduce the risk of clinical medication, the impurities in the raw materials and the preparations in the synthesis process of doxazosin mesylate need to be researched and monitored in more detail, so that the synthesis method for obtaining the reference substance of the impurity I, which can be used for quickly, simply, conveniently and efficiently, becomes a technical problem which needs to be solved at present urgently.
Disclosure of Invention
Based on the technical problems in the background art, the invention provides a method for synthesizing doxazosin impurities, which has the advantages of simple and convenient synthesis process and low cost, and the prepared doxazosin impurities have high purity and can be used as a reference substance.
The invention provides a method for synthesizing doxazosin impurities, which comprises the following steps: adding solvent, 2-chloro-4-hydroxy-6, 7-dimethoxyquinazoline and N- (1, 4-benzodioxane-2-carbonyl) piperazine into a reactorHeating and stirring until the reaction is completed, cooling, filtering and drying to obtain doxazosin impurity (the chemical formula is C)23H24N4O6And) wherein the reaction equation for preparing the doxazosin impurity is as follows:
preferably, the solvent is one of isopropanol, DMF, DMSO, methanol, ethanol, n-butanol, preferably n-butanol.
Preferably, the mass ratio of the 2-chloro-4-hydroxy-6, 7-dimethoxyquinazoline to the N- (1, 4-benzodioxane-2-carbonyl) piperazine is 5.8-6.2: 6.8-7.2.
Preferably, the heating and stirring process further comprises a cooling reflux step.
Preferably, the reaction temperature is 70-120 ℃.
Preferably, the reaction time is from 1 to 8 hours, preferably from 3 to 6 hours.
Preferably, the drying temperature is 40-60 ℃.
The invention provides a method for synthesizing doxazosin impurities, which takes 2-chloro-4-hydroxy-6, 7-dimethoxy quinazoline and N- (1, 4-benzodioxane-2-carbonyl) piperazine as raw materials to prepare the high-purity doxazosin impurities which can be used as a reference substance. The method has the advantages of short reaction route, high yield, low energy consumption, low synthesis cost and simple operation, and is suitable for mass preparation.
Drawings
FIG. 1 is a schematic representation of the synthesis of doxazosin impurity of example 41H-NMR chart.
Figure 2 is an HPLC plot of the doxazosin impurity synthesized in example 4.
FIG. 3 is a MS diagram of the doxazosin impurity synthesized in example 4.
Detailed Description
The technical solution of the present invention will be described in detail below with reference to specific examples.
Example 1
A method for synthesizing doxazosin impurities comprises the following steps: adding 5ml of n-butanol, 0.24g of 2-chloro-4-hydroxy-6, 7-dimethoxyquinazoline and 0.28g N- (1, 4-benzodioxane-2-carbonyl) piperazine into a three-neck flask, heating to reflux, stirring for reaction for 1h, cooling, filtering and drying at 50 ℃ to obtain 0.42g of doxazosin impurity with the yield of 95%, wherein the reaction equation for preparing the doxazosin impurity is shown as follows:
example 2
A method for synthesizing doxazosin impurities comprises the following steps: adding 50ml of ethanol, 2.2g of 2-chloro-4-hydroxy-6, 7-dimethoxyquinazoline and 2.8g N- (1, 4-benzodioxane-2-carbonyl) piperazine into a three-neck flask, heating to 80 ℃, carrying out reflux stirring reaction for 5 hours, cooling, filtering and drying at the temperature of 40 ℃ to obtain 3.73g of doxazosin impurity with the yield of 90%, wherein the reaction equation for preparing the doxazosin impurity is shown as follows:
example 3
A method for synthesizing doxazosin impurities comprises the following steps: adding 50ml of methanol, 2.4g of 2-chloro-4-hydroxy-6, 7-dimethoxyquinazoline and 2.6g N- (1, 4-benzodioxane-2-carbonyl) piperazine into a three-neck flask, heating to 70 ℃, stirring for reacting for 8 hours, cooling, filtering and drying at 60 ℃ to obtain 3.57g of doxazosin impurity, wherein the yield is 85%, and the reaction equation for preparing the doxazosin impurity is shown as follows:
example 4
A method for synthesizing doxazosin impurities comprises the following steps: adding 50ml of n-butyl alcohol, 2.6g of 2-chloro-4-hydroxy-6, 7-dimethoxyquinazoline and 3.0g of 3.0g N- (1, 4-benzodioxane-2-carbonyl) piperazine into a three-neck flask, heating to reflux, stirring under reflux for reaction for 1h, cooling, filtering and drying at 50 ℃ to obtain 4.37g of doxazosin impurity with the yield of 95%, wherein the reaction equation for preparing the doxazosin impurity is shown as follows:
the doxazosin impurity synthesized in example 4 is subjected to1H-NMR, HPLC and MS (ESI) tests:1H-NMR (400MHz, CDCl3) delta: 11.16(1H, s, -OH), 7.40(1H, s, Ar-H), 7.05 to 67.9(5H, m, Ar-H), 4.92(1H, dd, J ═ 7.9, 2.5Hz, -CH), 4.56(1H, dd, J ═ 11.9, 2.5Hz, -CH2), 4.40(1H, dd, J ═ 11.9, 7.9Hz, -CH2), 4.05(7H, m, -OCH3, -NCH2 x 2), 39.4(3H, s, -OCH3), 3.89 to 3.65(4H, m, -NCH2 x 2), as shown in fig. 1; purity by HPLC was: 97.9%, as in FIG. 2 below; ESI-MS (m/z): 453.3[ M + H]+As shown in the following figure 3, the test shows that the product synthesized by the invention is the target product doxazosin impurity C23H24N4O6。
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (8)
1. A method for synthesizing doxazosin impurities is characterized by comprising the following steps: adding a solvent, 2-chloro-4-hydroxy-6, 7-dimethoxyquinazoline and N- (1, 4-benzodioxane-2-carbonyl) piperazine into a reactor, heating and stirring until the reaction is complete, cooling, filtering and drying to obtain doxazosin impurities, wherein the reaction equation for preparing the doxazosin impurities is as follows:
2. the method for synthesizing doxazosin impurity as claimed in claim 1, wherein the solvent is one of isopropanol, DMF, DMSO, methanol, ethanol, and n-butanol.
3. The method for synthesizing doxazosin impurity according to claim 1, wherein the solvent is n-butanol.
4. The method for synthesizing doxazosin impurity according to claim 1 or 2, wherein the mass ratio of 2-chloro-4-hydroxy-6, 7-dimethoxyquinazoline to N- (1, 4-benzodioxane-2-carbonyl) piperazine is 5.8-6.2: 6.8-7.2.
5. The method for synthesizing doxazosin impurity according to claim 1 or 2, wherein the heating and stirring process further comprises a cooling reflux step.
6. The method for synthesizing doxazosin impurity according to claim 1 or 2, wherein the reaction temperature is 70-120 ℃ and the reaction time is 1-8 hours.
7. The method for synthesizing doxazosin impurity according to claim 1 or 2, wherein the reaction temperature is 70-120 ℃ and the reaction time is 3-6 hours.
8. The method for synthesizing doxazosin impurity according to claim 1 or 2, wherein the drying temperature is 40-60 ℃ and the drying time is 2-8 h.
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| US4188390A (en) * | 1977-11-05 | 1980-02-12 | Pfizer Inc. | Antihypertensive 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl) piperazin-1-yl or homopiperazin-1-yl]quinazolines |
| AU2009249106A1 (en) * | 2008-05-21 | 2009-11-26 | Genentech, Inc. | Arylsulfonamide compounds, compositions and methods of use |
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