CN108276395B - Preparation method of doxazosin impurity - Google Patents
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- CN108276395B CN108276395B CN201810133890.1A CN201810133890A CN108276395B CN 108276395 B CN108276395 B CN 108276395B CN 201810133890 A CN201810133890 A CN 201810133890A CN 108276395 B CN108276395 B CN 108276395B
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- 239000012535 impurity Substances 0.000 title claims abstract description 70
- 229960001389 doxazosin Drugs 0.000 title claims abstract description 68
- RUZYUOTYCVRMRZ-UHFFFAOYSA-N doxazosin Chemical compound C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 RUZYUOTYCVRMRZ-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 239000002904 solvent Substances 0.000 claims abstract description 25
- 230000002378 acidificating effect Effects 0.000 claims abstract description 17
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 9
- 230000007935 neutral effect Effects 0.000 claims abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 239000000126 substance Substances 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 12
- 239000004094 surface-active agent Substances 0.000 claims description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- 229920001223 polyethylene glycol Polymers 0.000 claims description 5
- JTNCEQNHURODLX-UHFFFAOYSA-N 2-phenylethanimidamide Chemical compound NC(=N)CC1=CC=CC=C1 JTNCEQNHURODLX-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 229920000136 polysorbate Polymers 0.000 claims description 4
- 229910000343 potassium bisulfate Inorganic materials 0.000 claims description 4
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000342 sodium bisulfate Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000013558 reference substance Substances 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000005265 energy consumption Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 239000003814 drug Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- 229960000220 doxazosin mesylate Drugs 0.000 description 8
- VJECBOKJABCYMF-UHFFFAOYSA-N doxazosin mesylate Chemical compound [H+].CS([O-])(=O)=O.C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 VJECBOKJABCYMF-UHFFFAOYSA-N 0.000 description 8
- 239000012071 phase Substances 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 5
- 229920000053 polysorbate 80 Polymers 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000000605 extraction Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 3
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 3
- DBOAGRILJPETJN-UHFFFAOYSA-N 2-chloro-6,7-dimethoxy-1h-quinazolin-4-one Chemical compound N1=C(Cl)NC(=O)C2=C1C=C(OC)C(OC)=C2 DBOAGRILJPETJN-UHFFFAOYSA-N 0.000 description 2
- HWIIAAVGRHKSOJ-UHFFFAOYSA-N 2-chloro-6,7-dimethoxyquinazolin-4-amine Chemical compound ClC1=NC(N)=C2C=C(OC)C(OC)=CC2=N1 HWIIAAVGRHKSOJ-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical compound C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 description 1
- FLUPDJNTYCSBJZ-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxin-3-yl(piperazin-1-yl)methanone Chemical compound C1OC2=CC=CC=C2OC1C(=O)N1CCNCC1 FLUPDJNTYCSBJZ-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 206010013990 dysuria Diseases 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- ZKJKXGCLZUMGNT-UHFFFAOYSA-N methanesulfonic acid;piperazine Chemical compound CS(O)(=O)=O.C1CNCCN1 ZKJKXGCLZUMGNT-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- HRQDCDQDOPSGBR-UHFFFAOYSA-M sodium;octane-1-sulfonate Chemical compound [Na+].CCCCCCCCS([O-])(=O)=O HRQDCDQDOPSGBR-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D405/12—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 linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of doxazosin impurities, which comprises the following steps: the doxazosin is mixed with a solvent, and hydrolysis reaction is carried out under acidic condition or neutral condition to obtain the doxazosin impurity. The preparation method of doxazosin impurities provided by the invention has the advantages of short reaction route, low energy consumption, low synthesis cost, simple operation, suitability for mass preparation, good yield, and high purity of the doxazosin impurities obtained by preparation, and can be used as a reference substance.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method of doxazosin impurities.
Background
Any substance that affects the purity of the drug is collectively referred to as an impurity. The research on impurities is an important content of drug development. It includes selecting proper analysis method, accurately distinguishing and measuring impurity content and integrating the results of pharmaceutical, toxicological and clinical research to determine reasonable limit of impurity. This study is throughout the entire process of drug development. The adverse reaction generated by the medicine in clinical use is not only related to the pharmacological activity of the medicine, but also has a great relationship with impurities in the medicine. For example, high molecular weight impurities such as polymers in antibiotics such as penicillin are a major cause of allergy. Therefore, the research on impurities is carried out in a standard way and controlled within a safe and reasonable limit range, which is directly related to the quality and safety of the marketed drugs [2005 edition of technical guidelines for research on impurities of chemical drugs ]. The medicine is indispensable to people, how to control the safety and reliability of the medicine becomes a vital problem in the society today, no matter a supervision department or an enterprise is responsible for improving the quality of the medicine, and with the higher and higher requirements on the quality of the medicine, the research on impurities in the medicine becomes more and more important. The organic impurities in the impurities mainly comprise impurities, degradation products and the like introduced in the process, and can be known or unknown, volatile or nonvolatile. Because the chemical structure of the impurities is generally similar to or has a source relationship with the active ingredients, the impurities can also be called related substances generally, and the control of the related substances is particularly important.
Doxazosin mesylate (doxazosin mesylate) is a new generation of quinazolinone alpha 1 receptor blocker developed and marketed by the American pfizer company, has long half-life, has obvious functions of reducing blood pressure and blood fat, and has 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 doxazosin mesylate raw material, wherein the synthesis of 2-chloro-4-amino-6, 7-dimethoxy quinazoline as a side chain raw material is to take 6, 7-dimethoxy quinazoline-2, 4-diketone as a raw material to chlorinate and ammoniate to obtain 2-chloro-4-amino-6, 7-dimethoxy quinazoline, the chloridization is incomplete in the process, the subsequent reaction is carried out to obtain 2-chloro-4-hydroxy-6, 7-dimethoxy quinazoline, and the 2-chloro-4-hydroxy-6, 7-dimethoxy quinazoline reacts with N- (1, 4-benzodioxane-2-carbonyl) piperazine to generate (I), and the generated impurity structural formula is shown as formula I:
the impurity I is not collected in the standards of European pharmacopoeia and United states pharmacopoeia doxazosin mesylate, but the doxazosin mesylate exists in the synthesis process, no reference substance is supplied at home and abroad, and no report of the impurity synthesis method exists in domestic and foreign documents and patents. The content of impurities in the doxazosin mesylate raw material and the preparation is strictly controlled, so that the synthesis method for obtaining the reference substance of the impurity I quickly, simply, conveniently and efficiently becomes urgent.
Disclosure of Invention
Based on the technical problems in the background art, the invention provides a preparation method of doxazosin impurities, which has the advantages of short reaction route, low energy consumption, low synthesis cost, simple operation, suitability for mass preparation, good yield and high purity of the prepared doxazosin impurities, and can be used as a reference substance.
The invention provides a preparation method of doxazosin impurities, which comprises the following steps: mixing doxazosin and a solvent, and carrying out hydrolysis reaction under an acidic condition or a neutral condition to obtain doxazosin impurities; wherein the structural formula of the doxazosin impurity is shown as a formula I:
preferably, the preparation method of the doxazosin impurity comprises the following steps: mixing doxazosin, a surfactant and a solvent to obtain a reaction solution, adjusting the reaction solution to be acidic or neutral, performing hydrolysis reaction under a reflux condition, and purifying to obtain doxazosin impurities.
Preferably, the solvent is water or a mixture of water and one or more of ethanol, methanol, acetonitrile, dimethylformamide, dimethyl sulfoxide and tetrahydrofuran.
Preferably, adding an acidic substance to adjust the reaction solution to be acidic or neutral; the acidic substance is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, sodium bisulfite, sodium bisulfate, potassium bisulfate, tartaric acid and citric acid.
Preferably, the surfactant is one or more of sodium dodecyl sulfate, polyethylene glycol and tween.
Preferably, the purification comprises cooling, pH adjustment, extraction, water washing, drying and solvent recovery.
Preferably, the preparation method of the doxazosin impurity comprises the following steps: mixing 0.4-0.6g of doxazosin and 80-120ml of Tween 80 aqueous solution with the mass fraction of 0.3-0.8 wt%, adjusting the pH value to 4-7 by using hydrochloric acid with the mass fraction of 0.08-0.12 wt%, and carrying out reflux reaction until the volume ratio of dichloromethane to methanol in the system is 8-12: 1, cooling to room temperature, adjusting the pH value to 7-8 by using sodium bicarbonate, extracting by using dichloromethane, washing an organic phase by water, drying by using anhydrous sodium sulfate, and recovering a solvent by reducing pressure to obtain the doxazosin impurity.
Preferably, the preparation method of the doxazosin impurity comprises the following steps: mixing 0.5g of doxazosin with 100ml of 0.5 wt% Tween 80 aqueous solution, adjusting the pH value to 4 by using 0.1 wt% hydrochloric acid, and carrying out reflux reaction until the volume ratio of dichloromethane to methanol in the system is 10: 1, cooling to room temperature, adjusting the pH value to 8 by using sodium bicarbonate, extracting by using dichloromethane, washing an organic phase by water, drying by using anhydrous sodium sulfate, and recovering a solvent by reducing pressure to obtain the doxazosin impurity.
Preferably, during the reflux reaction, the contents of dichloromethane and methanol in the system are detected by TLC method or HPLC method.
The reaction formula of the preparation method of the doxazosin impurity is as follows:
the doxazosin impurity preparation method provided by the invention takes doxazosin as a raw material, and the doxazosin impurity obtained by controlling the reaction conditions has high purity and can be used as a reference substance.
Drawings
FIG. 1 is a mass spectrum of doxazosin impurity prepared in example 8 of the present invention;
FIG. 2 is a NMR spectrum of doxazosin impurity prepared in example 8 of the present invention;
FIG. 3 is an HPLC chromatogram of doxazosin impurity prepared in example 8 of the present invention.
Detailed Description
The technical solution of the present invention will be described in detail below with reference to specific examples.
Example 1
The invention provides a preparation method of doxazosin impurities, which comprises the following steps: and mixing the doxazosin with a solvent, and carrying out hydrolysis reaction under an acidic condition to obtain the doxazosin impurity.
Example 2
The invention provides a preparation method of doxazosin impurities, which comprises the following steps: mixing doxazosin, a surfactant and a solvent to obtain a reaction solution, adjusting the reaction solution to be neutral, performing hydrolysis reaction under a reflux condition, and purifying to obtain doxazosin impurities.
Example 3
The invention provides a preparation method of doxazosin impurities, which comprises the following steps: mixing doxazosin, a surfactant and a solvent to obtain a reaction solution, adding an acidic substance to adjust the reaction solution to be neutral, performing hydrolysis reaction under a reflux condition, and purifying to obtain doxazosin impurities;
wherein the solvent is a mixture of water and ethanol, and the volume ratio of the water to the ethanol is 3: 1;
the acidic substance is sodium bisulfite;
the surfactant is sodium dodecyl sulfate;
the purification comprises cooling, pH value adjustment, extraction, water washing, drying and solvent recovery.
Example 4
The invention provides a preparation method of doxazosin impurities, which comprises the following steps: mixing doxazosin, a surfactant and a solvent to obtain a reaction solution, adding an acidic substance to adjust the reaction solution to be acidic, carrying out hydrolysis reaction under a reflux condition, and purifying to obtain doxazosin impurities;
wherein the solvent is a mixture of acetonitrile and water, and the volume ratio of the acetonitrile to the water is 1: 5;
the acidic substance is tartaric acid;
the surfactant is polyethylene glycol;
the purification comprises cooling, pH value adjustment, extraction, water washing, drying and solvent recovery.
Example 5
The invention provides a preparation method of doxazosin impurities, which comprises the following steps: mixing doxazosin, a surfactant and a solvent to obtain a reaction solution, adding an acidic substance to adjust the reaction solution to be neutral, performing hydrolysis reaction under a reflux condition, and purifying to obtain doxazosin impurities;
wherein the solvent is a mixture of water, ethanol and dimethylformamide, and the volume ratio of the water, the ethanol and the dimethylformamide is 3:4: 2;
the acid substance is a mixture of phosphoric acid, potassium bisulfate and citric acid, and the weight ratio of the phosphoric acid to the potassium bisulfate to the citric acid is 4:3: 2;
the surfactant is a mixture of sodium dodecyl sulfate, polyethylene glycol and tween, and the weight ratio of the sodium dodecyl sulfate to the polyethylene glycol to the tween is 4:3: 2;
the purification comprises cooling, pH value adjustment, extraction, water washing, drying and solvent recovery.
Example 6
The invention provides a preparation method of doxazosin impurities, which comprises the following steps: mixing 0.6g of doxazosin and 80ml of Tween 80 aqueous solution with the mass fraction of 0.8 wt%, adjusting the pH value to 7 by using hydrochloric acid with the mass fraction of 0.08 wt%, and carrying out reflux reaction until the volume ratio of dichloromethane to methanol in the system is 8: 1, cooling to room temperature, adjusting the pH value to 8 by using sodium bicarbonate, extracting by using dichloromethane, washing an organic phase by water, drying by using anhydrous sodium sulfate, and recovering a solvent by reducing pressure to obtain the doxazosin impurity.
Example 7
The invention provides a preparation method of doxazosin impurities, which comprises the following steps: mixing 0.4g of doxazosin with 120ml of Tween 80 aqueous solution with the mass fraction of 0.3 wt%, adjusting the pH value to 4 by using hydrochloric acid with the mass fraction of 0.12 wt%, and carrying out reflux reaction until the volume ratio of dichloromethane to methanol in the system is 12: 1, cooling to room temperature, adjusting the pH value to 7 by using sodium bicarbonate, extracting by using dichloromethane, washing an organic phase by water, drying by using anhydrous sodium sulfate, and recovering a solvent by reducing pressure to obtain the doxazosin impurity.
Example 8
The invention provides a preparation method of doxazosin impurities, which comprises the following steps: mixing 0.5g of doxazosin and 100ml of Tween 80 aqueous solution with the mass fraction of 0.5 wt%, adjusting the pH value to 4 by using hydrochloric acid with the mass fraction of 0.1 wt%, carrying out reflux reaction, detecting the content of dichloromethane and methanol in a system by using a TLC method, and when the volume ratio of dichloromethane to methanol in the system is 10: stopping the reaction at 1 hour, cooling to room temperature, adjusting the pH value to 8 by using sodium bicarbonate, extracting by using dichloromethane, washing an organic phase by water, drying by using anhydrous sodium sulfate, and recovering the solvent by reducing pressure to obtain the doxazosin impurity.
Detecting the doxazosin impurity obtained in the example 8, wherein a figure 1 is a mass spectrogram of the doxazosin impurity prepared in the example 8 of the invention; as can be seen from FIG. 1, the MS data are ESI-MS M/z 453.3[ M + H ]]+.calcd for C23H24N4O6[M+H]+453.3, found 453.3; FIG. 2 is a schematic representation of the practice of the present inventionNuclear magnetic resonance hydrogen spectra of doxazosin impurity prepared in example 8; as can be seen from FIG. 2, the NMR data are: 1H-NMR (400MHz, CDCl)3)δ11.13(1H,s,-OH),7.37(1H,s,Ar-H),6.86-6.93(5H,m,Ar-H),4.88-4.90(1H,dd,J＝7.9,2.5Hz,-CH),4.51-4.55(1H,dd,J＝11.9,2.5Hz,-CH2),4.35-4.40(1H,dd,J＝11.9,7.9Hz,-CH2),3.78-3.91(7H,m,-OCH3,-NCH2×2),3.71(3H,s,-OCH3),3.71-3.68(4H,m,-NCH2×2)。
The doxazosin impurity prepared in example 8 is subjected to HPLC detection, and specific parameters are as follows:
a chromatographic column: octadecylsilane chemically bonded silica gel column, Agilent TC-C18(2), 250mm × 4.6mm, 5 μm;
mobile phase A: 1.2g of sodium octane sulfonate is dissolved in 1000ml of water, and the pH value is adjusted to 3.4 by using a phosphoric acid solution with the volume fraction of 10 percent; mobile phase B: acetonitrile; the volume fractions of mobile phase a and mobile phase B are shown in the following table:
| time/min | Mobile phase A/%) | Mobile phase B/%) |
| 0-7 | 70 | 30 |
| 7-30 | 65 | 35 |
| 30-55 | 55 | 45 |
| 55-70 | 70 | 30 |
Detection wavelength: 248 nm;
sample concentration: 0.1mg/ml (solvent as mobile phase);
flow rate: 1.0 ml/min;
column temperature: 40 ℃;
sample introduction amount: 10 mu l of the mixture;
FIG. 3 is an HPLC chromatogram of doxazosin impurity prepared in example 8 of the present invention; the analysis of FIG. 3 resulted in the following table:
as shown in FIG. 3, the doxazosin impurity obtained in example 8 is more than 96 wt% by HPLC.
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 (4)
1. The preparation method of doxazosin impurities is characterized by comprising the following steps:
mixing doxazosin, a surfactant and a solvent to obtain a reaction solution, adjusting the reaction solution to be acidic or neutral, performing hydrolysis reaction under a reflux condition, and purifying to obtain doxazosin impurities; wherein the surfactant is one or a mixture of sodium dodecyl sulfate, polyethylene glycol and tween; wherein the structural formula of the doxazosin impurity is shown as a formula I:
2. the method for preparing doxazosin impurity according to claim 1, wherein the solvent is water or a mixture of water and one or more of ethanol, methanol, acetonitrile, dimethylformamide, dimethyl sulfoxide and tetrahydrofuran.
3. The preparation method of doxazosin impurity as claimed in claim 1, wherein acidic substance is added to adjust the reaction solution to be acidic or neutral; the acidic substance is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, sodium bisulfite, sodium bisulfate, potassium bisulfate, tartaric acid and citric acid.
4. The process of claim 1, wherein the purifying comprises cooling, adjusting pH, extracting, washing with water, drying, and recovering the solvent.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101535280A (en) * | 2006-11-15 | 2009-09-16 | 健泰科生物技术公司 | Arylsulfonamide compounds |
| WO2009143246A2 (en) * | 2008-05-21 | 2009-11-26 | Genentech, Inc. | Arylsulfonamide compounds, compositions and methods of use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101535280A (en) * | 2006-11-15 | 2009-09-16 | 健泰科生物技术公司 | Arylsulfonamide compounds |
| WO2009143246A2 (en) * | 2008-05-21 | 2009-11-26 | Genentech, Inc. | Arylsulfonamide compounds, compositions and methods of use |
Non-Patent Citations (3)
| Title |
|---|
| Pyridopyrimidine based cannabinoid-1 receptor inverse agonists: Synthesis and biological evaluation;John S. Debenham，et al.;《Bioorganic & Medicinal Chemistry Letters》;20090309;第19卷;第2591-2594页 * |
| Quinazoline Sulfonamides as Dual Binders of the Proteins B-Cell Lymphoma 2 and B-Cell Lymphoma Extra Long with Potent Proapoptotic Cell-Based Activity;Brad E. Sleebs,et al.;《J. Med. Chem.》;20110302;第54卷;第1914-1926页 * |
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Denomination of invention: A preparation method for impurities in doxazosin Effective date of registration: 20231228 Granted publication date: 20210226 Pledgee: China Construction Bank Corporation Hefei Shushan sub branch Pledgor: HEFEI HUAFANG PHARMACEUTICAL SCIENCES & TECHNOLOGY Co.,Ltd. Registration number: Y2023980075424 |
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