CN114539101A - Method for preparing calcium dobesilate genotoxic impurities - Google Patents
Method for preparing calcium dobesilate genotoxic impurities Download PDFInfo
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- CN114539101A CN114539101A CN202011351513.9A CN202011351513A CN114539101A CN 114539101 A CN114539101 A CN 114539101A CN 202011351513 A CN202011351513 A CN 202011351513A CN 114539101 A CN114539101 A CN 114539101A
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- 239000012535 impurity Substances 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title claims abstract description 25
- 231100000024 genotoxic Toxicity 0.000 title claims abstract description 14
- 230000001738 genotoxic effect Effects 0.000 title claims abstract description 14
- QGNBTYAQAPLTMX-UHFFFAOYSA-L calcium dobesilate Chemical compound [Ca+2].OC1=CC=C(O)C(S([O-])(=O)=O)=C1.OC1=CC=C(O)C(S([O-])(=O)=O)=C1 QGNBTYAQAPLTMX-UHFFFAOYSA-L 0.000 title abstract description 12
- 229960005438 calcium dobesilate Drugs 0.000 title abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000002904 solvent Substances 0.000 claims abstract description 16
- 238000004108 freeze drying Methods 0.000 claims abstract description 9
- 239000005457 ice water Substances 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 239000007800 oxidant agent Substances 0.000 claims abstract description 9
- 239000000706 filtrate Substances 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- MVIOINXPSFUJEN-UHFFFAOYSA-N benzenesulfonic acid;hydrate Chemical compound O.OS(=O)(=O)C1=CC=CC=C1 MVIOINXPSFUJEN-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 6
- 230000001590 oxidative effect Effects 0.000 claims abstract description 6
- -1 2-sulfo-1, 4-benzoquinone manganese salt Chemical compound 0.000 claims abstract description 5
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 5
- 230000003647 oxidation Effects 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Inorganic materials O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 claims description 2
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 claims description 2
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 238000000354 decomposition reaction Methods 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 230000009467 reduction Effects 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract description 2
- IKQCSJBQLWJEPU-UHFFFAOYSA-N 2,5-dihydroxybenzenesulfonic acid Chemical compound OC1=CC=C(O)C(S(O)(=O)=O)=C1 IKQCSJBQLWJEPU-UHFFFAOYSA-N 0.000 abstract 1
- 239000000047 product Substances 0.000 description 12
- 229940005561 1,4-benzoquinone Drugs 0.000 description 8
- 229910052748 manganese Inorganic materials 0.000 description 8
- 239000011572 manganese Substances 0.000 description 8
- 238000009616 inductively coupled plasma Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 6
- 229910001437 manganese ion Inorganic materials 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000003795 desorption Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 238000000859 sublimation Methods 0.000 description 3
- 230000008022 sublimation Effects 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical group [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- GOPYZMJAIPBUGX-UHFFFAOYSA-N [O-2].[O-2].[Mn+4] Chemical group [O-2].[O-2].[Mn+4] GOPYZMJAIPBUGX-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000002696 manganese Chemical class 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 238000005096 rolling process Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 1
- QOIXLGYJPBDQSK-UHFFFAOYSA-N 3,6-dioxocyclohexa-1,4-diene-1-sulfonic acid Chemical compound OS(=O)(=O)C1=CC(=O)C=CC1=O QOIXLGYJPBDQSK-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- WAEMQWOKJMHJLA-UHFFFAOYSA-N Manganese(2+) Chemical compound [Mn+2] WAEMQWOKJMHJLA-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical group [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002354 inductively-coupled plasma atomic emission spectroscopy Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
- C07C303/04—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups
- C07C303/06—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups by reaction with sulfuric acid or sulfur trioxide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing calcium dobesilate genotoxic impurities, which comprises the steps of adding hydroquinone into an organic solvent, adding a sulfonating agent, heating for reaction, and obtaining dobesilate after the reaction is finished; adding the obtained hydroxybenzene sulfonic acid into a solvent, adding an oxidant for oxidation, adding ice water for filtration after the reaction is finished, and freeze-drying the obtained filtrate to obtain the genotoxic impurity 2-sulfo-1, 4-benzoquinone manganese salt shown in the formula I. The method of the invention can not only adopt the conventional synthesis method to prepare the impurity, but also meet the risk of difficult decomposition or impurity component reduction in the subsequent separation and purification process, obtain the impurity and meet the research requirement.
Description
Technical Field
The invention relates to the field of chemical medicine, in particular to a method for preparing genotoxic impurities in calcium dobesilate.
Background
Calcium Dobesilate (Calcium Dobesilate) is a drug which acts on the endothelial cell layer and the basal layer of a capillary vessel, regulates and improves the permeability and flexibility of the capillary vessel, increases the resistance of the capillary vessel wall, reduces the permeability of the capillary vessel, has an activation effect on a lymph circulatory system, reduces the viscosity of blood and plasma, corrects the albumin/globulin ratio, reduces the high aggregation of platelets, reduces the viscosity of the plasma and prevents thrombosis. The structural formula is as follows:
the molecular formula is as follows: 2C6H5O5S.ca, molecular weight: 418.41
Calcium dobesilate has a high electron cloud density of the benzene ring, so that hydroxyl is easily oxidized in the presence of an oxidant. The product is phenylsulfonate, ethanol is adopted in the recrystallization process of raw materials, benzene sulfonic acid impurities (warning structures containing genotoxic impurities) can be generated, the impurities are close to calcium dobesilate in polarity, good in water solubility and unstable in structure, the product is prepared by a synthesis method, and stable target compounds are difficult to separate through conventional post-treatment (column chromatography, extraction and the like) and are easy to decompose or reduce in components. In order to better control the quality of the final product of the calcium dobesilate, the method for providing the high-purity 2-sulfo-1, 4-benzoquinone impurity as an impurity reference substance during the detection of the bulk drug or the preparation thereof is very urgent.
Disclosure of Invention
The invention aims to solve the technical problem of providing a method for preparing 2-sulfo-1, 4-benzoquinone manganese salt serving as a genotoxic impurity in calcium dobesilate as shown in a formula I. The method can not only adopt the conventional synthesis method to prepare the impurity, but also meet the risk of difficult decomposition or reduction of impurity components in the subsequent separation and purification process, obtain the impurity and meet the research requirement.
The molecular formula is as follows: 2C6H3O5S.mn, molecular weight: 429.23.
the preparation method of the invention comprises the following steps:
(1) adding hydroquinone into an organic solvent, adding a sulfonating agent, heating for reaction, and obtaining hydroxybenzene sulfonic acid after the reaction is finished;
(2) adding the hydroxybenzene sulfonic acid obtained in the step (1) into a solvent, adding an oxidant for oxidation, adding ice water for filtration after the reaction is finished, and freeze-drying the obtained filtrate to obtain the genotoxic impurity 2-sulfo-1, 4-benzoquinone manganese salt shown in the formula I.
In some embodiments, the organic solvent in step (1) of the present invention is an alkane solvent, and in a specific embodiment, the organic solvent is cyclohexane or isooctane.
In some embodiments, the amount of the organic solvent used in step (1) of the present invention is 3 to 10 times, preferably 3 to 7 times, the mass of hydroquinone.
In some embodiments, the sulfonating agent in step (1) of the present invention is selected from chlorosulfonic acid, concentrated sulfuric acid, fuming sulfuric acid, etc., and is preferably concentrated sulfuric acid which is low in raw material purchase cost and easy to store from the viewpoint of safety and economy, and the inventors have found that the product purity can be further improved by using concentrated sulfuric acid. The concentrated sulfuric acid is a sulfuric acid aqueous solution with the mass fraction of more than or equal to 70%.
In some embodiments, the sulfonating agent used in step (1) of the present invention is 1 to 2 times, preferably 1.5 to 1.65 times the molar amount of hydroquinone.
In some embodiments, the temperature of the temperature raising reaction in step (1) of the present invention is 70 to 80 ℃.
In some embodiments, after the step (1) of the present invention is completed, the mixture is cooled to room temperature and filtered to obtain the hydroxybenzenesulfonic acid.
In some embodiments, the solvent in step (2) is water, methanol, ethanol, tetrahydrofuran, acetonitrile, or the like, preferably acetonitrile, and since the inorganic manganese salt is easily dissolved in water, the use of acetonitrile as the reaction solvent can avoid the use of water as the solvent or the residue of the inorganic manganese salt in the product during the water post-treatment process, which can further improve the purity of the product.
In some embodiments, the solvent used in step (2) of the present invention is 5 to 20ml/g hydroquinone.
In some embodiments, the oxidizing agent of step (2) of the present invention is MnO2DDQ or hydrogen peroxide of 25-33%, and the like, wherein MnO is preferably selected for more stably obtaining a target product2. In some embodiments of the invention, MnO is elected2When the temperature is lower than 30 ℃, the adding temperature is controlled.
In some embodiments, the amount of the oxidant used in step (2) of the present invention is 3 to 7 times, preferably 4.5 to 5.5 times the molar amount of hydroquinone.
In some embodiments, the oxidation reaction in step (2) of the present invention is stirred at room temperature for 10 to 15 hours.
In some embodiments, the amount of ice water added in step (2) of the present invention is 3 to 10 times, preferably 4 to 6 times, the mass of the solvent.
In some embodiments, after the reaction in step (2) of the present invention is completed, the reaction solution is poured into ice anhydrous ethanol, and ice water is added after filtration for filtration. In some embodiments, the amount of the ice absolute ethyl alcohol added is 1 to 5 times, preferably 1 to 3 times, the mass of the solvent.
The lyophilization of the filtrate in step (2) of the present invention may be performed by a method and parameters conventional in the art, such as the lyophilization operation with the pre-freezing coolant temperature set at-45 ℃ and the time to reach the set temperature: 30min, and keeping for 300 min. And carrying out sublimation drying and desorption drying by vacuumizing and starting a heating mode.
The invention has the beneficial effects that:
the invention provides a method for preparing 2-sulfonic acid-1, 4-benzoquinone manganese salt serving as a genotoxic impurity in calcium dobesilate, which is simple and convenient to operate, suitable for industrial production and high in yield. The obtained product can be used in the quality control of the calcium dobesilate bulk drug or the preparation thereof and used as an impurity reference substance.
Drawings
FIG. 1 shows the preparation of genotoxic impurity 2-sulfonic acid-1, 4-benzoquinone manganese saltNuclear magnetic resonance hydrogen spectrum (1H-NMR) chart.
FIG. 2 is a High Resolution Mass Spectrum (HRMS) diagram of 2-sulfonic acid-1, 4-benzoquinone manganese salt as a genotoxic impurity.
FIG. 3 is a diagram of inductively coupled plasma direct-reading (ICP) spectrum of 2-sulfonic acid-1, 4-benzoquinone manganese salt as a genotoxic impurity.
Detailed Description
The invention is illustrated below with reference to specific examples. It will be understood by those skilled in the art that the following examples are intended to illustrate preferred embodiments of the present invention and are not intended to limit the scope of the present invention.
The raw materials and reagents in the examples of the present invention are commercially available products.
The preparation method of the embodiment of the invention comprises the following steps:
if the embodiment of the invention is not particularly described, the related detection of the product is as follows:
the chemical structure of the product is determined by combining the synthesis process route of the 2-sulfonic acid-1, 4-benzoquinone manganese salt reference substance and measuring the product by nuclear magnetic resonance hydrogen spectrum, high resolution mass spectrum and inductively coupled plasma spectrum.
1) Nuclear magnetic resonance spectrum (1H-NMR)
The instrument comprises the following steps: BRUKER AV-300 type nuclear magnetic resonance spectrometer
Solvent: DMSO-d6
Internal standard: TMS
2) High Resolution Mass Spectrum (HRMS)
The instrument comprises the following steps: agilent 6200Q-TOF mass spectrometer
Solvent: methanol
An ionization mode: ESI (-)
3) Analysis and determination of metal ion element (ICP)
The instrument comprises the following steps: PE5300DV type inductively coupled plasma direct-reading spectrometer
The detection method comprises the following steps: JY/T015-1996 inductively coupled plasma atomic emission spectrometry
Example 1
Slowly dropping concentrated sulfuric acid (14.7g, 0.15mol) into a cyclohexane (50g) solution of hydroquinone (10g, 0.09mol) at room temperature (20-25 ℃) under the protection of nitrogen and mechanical stirring, heating to 70-80 ℃ for reaction for 0.5 hour after dropping, cooling to room temperature, adding water (50mL) to dissolve solids, separating liquid after dissolving, separating a lower water layer, placing the lower water layer into a three-neck flask of 250mL, adding purified water (50mL), adding manganese dioxide (40g, 0.46mol) at the temperature of less than 30 ℃, and stirring for reaction for 12 hours at room temperature. After the reaction, the reaction solution was poured into ice water (400mL, 4v/v, based on the volume of the reaction solution), filtered to remove manganese dioxide residue, the obtained filtrate was filtered with a 0.45 μm filter membrane, and the obtained filtrate was lyophilized to obtain 5g of 2-sulfonic acid-1, 4-benzoquinone manganese salt, HPLC: 98.78 percent. The lyophilization operation was as follows:
controlling the temperature of the heat-conducting oil to reach-10 ℃, and starting to enter the tank.
Pre-freezing: setting the temperature of the heat-conducting oil to be-45 ℃, and the time for reaching the set temperature: 30min, and keeping for 300 min.
Sublimation drying and desorption drying: vacuum was pulled and heat turned on.
Temperature rising procedure:
and (5) plugging after freeze-drying, taking out of the box and rolling a cover.
Example 2:
slowly dropping concentrated sulfuric acid (29.4g, 0.30mol) into a cyclohexane (100g) solution of hydroquinone (20g, 0.18mol) at room temperature (20-25 ℃) under the protection of nitrogen and mechanical stirring, heating to 70-80 ℃ for reaction for 0.5 hour after dropping, cooling to room temperature, separating cyclohexane, adding acetonitrile (200mL) to dissolve solids, adding manganese dioxide (80g, 0.92mol) after dissolving clearly, controlling the internal temperature to be less than 30 ℃, and stirring for reaction for 12 hours at room temperature. After the reaction, the reaction solution was poured into ice anhydrous ethanol (400mL, 2v/v), manganese dioxide residue was removed by filtration, the obtained filtrate was added to ice water (800mL, 4v/v, in terms of the volume of the reaction solution), and then filtered with a 0.45 μm filter, and the obtained filtrate was lyophilized to obtain 14g of 2-sulfonic acid-1, 4-benzoquinone manganese salt, HPLC: 99.6 percent. The lyophilization operation was as follows:
controlling the temperature of the heat-conducting oil to reach-10 ℃, and starting to enter the tank.
Pre-freezing: setting the temperature of the heat-conducting oil to be-45 ℃, and the time for reaching the set temperature: 30min, and keeping for 300 min.
Sublimation drying and desorption drying: vacuum was pulled and heat turned on.
Temperature rising procedure:
and (5) plugging after freeze-drying, taking out of the box and rolling a cover.
Referring to fig. 1, the sample of this example has a hydrogen nuclear magnetic resonance spectrum, and because the sample is a divalent manganese salt structure, the metal manganese ion interferes with the proton peak, resulting in a small response.
In this example, the High Resolution Mass Spectrometry (HRMS) of the sample refers to fig. 2, and the elemental composition measured under the condition of ESI (-) of the sample is obtained from the high resolution analysis report: c6H4O5S, the error between the measured value and the theoretical calculated value is less than 0.0030, and the molecular formula C of the 2-sulfonic acid-1, 4-benzoquinone6H4O5And S is consistent.
In the sample inductively coupled plasma direct-reading (ICP) of this example, referring to fig. 3, 2-sulfonic acid-1, 4-benzoquinone manganese salt impurity samples, because manganese ions are in a positive divalent state, two parent nuclei with sulfonic acid groups can be combined to form a salt, the molecular weight of manganese ions is 187.15 according to the molecular weight of the parent nuclei, the molecular weight of manganese ions is 54.94 according to the molecular weight, the content of manganese ions is 12.8% according to the molecular weight conversion, the content of manganese ions is 10.2% according to the content conversion of 78.7% after the sample is hydrated according to 21.3%, the result is basically consistent with the measurement result of an instrument, the molecular composition of a sample to be tested and a target can be preliminarily determined to be consistent, and thus the product structure is determined to be a manganese salt structure.
Claims (10)
1. A method for preparing 2-sulfo-1, 4-benzoquinone manganese salt serving as a genotoxic impurity shown as a formula I is characterized by comprising the following steps:
(1) adding hydroquinone into an organic solvent, adding a sulfonating agent, heating for reaction, and obtaining hydroxybenzene sulfonic acid after the reaction is finished;
(2) adding the hydroxybenzene sulfonic acid obtained in the step (1) into a solvent, adding an oxidant for oxidation, adding ice water for filtration after the reaction is finished, and freeze-drying the obtained filtrate to obtain the genotoxic impurity 2-sulfo-1, 4-benzoquinone manganese salt shown in the formula I.
2. The method according to claim 1, wherein the organic solvent of step (1) is an alkane solvent; preferably, the organic solvent is cyclohexane or isooctane; preferably, the amount of the organic solvent used in the step (1) is 3-10 times of the mass of hydroquinone, and more preferably 3-7 times.
3. The process of claim 1, wherein the sulfonating agent of step (1) is selected from chlorosulfonic acid, concentrated sulfuric acid, or fuming sulfuric acid; concentrated sulfuric acid is preferred; preferably, the dosage of the sulfonating agent in the step (1) is 1-2 times of the molar weight of hydroquinone, and more preferably 1.5-1.65 times.
4. The method according to claim 1, wherein the temperature of the temperature-raising reaction in the step (1) is 70 to 80 ℃.
5. The method according to claim 1, wherein the solvent of step (2) is water, methanol, ethanol, tetrahydrofuran or acetonitrile; preferably acetonitrile; preferably, the dosage of the solvent is 5-20 ml/g of hydroquinone.
6. The method of claim 1, wherein the oxidizing agent of step (2) is MnO2DDQ or hydrogen peroxide of 25-33 percent; preferably MnO2。
7. The method of claim 6, wherein MnO is selected as the oxidizing agent2When the temperature is lower than 30 ℃, the adding temperature is controlled.
8. The method according to claim 1, wherein the amount of the oxidant used in the step (2) is 3 to 7 times, preferably 4.5 to 5.5 times, the molar amount of the hydroquinone; preferably, the oxidation reaction in the step (2) is performed by stirring at room temperature for 10-15 hours.
9. The method according to claim 1, wherein the amount of ice water added in step (2) is 3 to 10 times, preferably 4 to 6 times, the mass of the solvent.
10. The method as claimed in claim 1, wherein after the reaction in step (2) is completed, the reaction solution is poured into ice absolute ethyl alcohol, and after filtration, ice water is added for filtration; preferably, the adding amount of the ice anhydrous ethanol is 1-5 times of the mass of the solvent, and more preferably 1-3 times.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1418338A (en) * | 1972-05-17 | 1975-12-17 | Esteve Labor Dr | Sulphone salts deriving from 2,5-dihydroxy benzene monosulphonic and 2,5-dihydroxy genzene disulphonic acids |
| CN102219715A (en) * | 2011-04-26 | 2011-10-19 | 北京振东光明药物研究院有限公司 | Method for preparing medicinal high-purity calcium dobesilate |
| CN109678764A (en) * | 2018-12-05 | 2019-04-26 | 湖北广辰药业有限公司 | A kind of oxybenzene disulfonic acid and its calcium salt and preparation method |
| CN111018749A (en) * | 2019-12-31 | 2020-04-17 | 成都平和安康医药科技有限公司 | Phenolsulam and calcium dobesilate impurities as well as preparation method and application thereof |
-
2020
- 2020-11-26 CN CN202011351513.9A patent/CN114539101A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1418338A (en) * | 1972-05-17 | 1975-12-17 | Esteve Labor Dr | Sulphone salts deriving from 2,5-dihydroxy benzene monosulphonic and 2,5-dihydroxy genzene disulphonic acids |
| CN102219715A (en) * | 2011-04-26 | 2011-10-19 | 北京振东光明药物研究院有限公司 | Method for preparing medicinal high-purity calcium dobesilate |
| CN109678764A (en) * | 2018-12-05 | 2019-04-26 | 湖北广辰药业有限公司 | A kind of oxybenzene disulfonic acid and its calcium salt and preparation method |
| CN111018749A (en) * | 2019-12-31 | 2020-04-17 | 成都平和安康医药科技有限公司 | Phenolsulam and calcium dobesilate impurities as well as preparation method and application thereof |
Non-Patent Citations (4)
| Title |
|---|
| 于梦等: "RP-HPLC测定羟苯磺酸钙含量及有关物质", 《中国实验方剂学杂志》 * |
| 安宁等: "RP-HPLC法测定羟苯磺酸钙的有关物质", 《中国药品标准》 * |
| 王绯等: "羟苯磺酸钙有关物质方法的建立", 《广东药学院学报》 * |
| 祝清芬等: "左羟丙哌嗪和羟苯磺酸钙中2个1类杂质的遗传毒性(Q)SAR评价及质控限度评估", 《药物分析杂志》 * |
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