CN114380723A - Para hydroxybenzene sulfonate compound and preparation method and application thereof - Google Patents
Para hydroxybenzene sulfonate compound and preparation method and application thereof Download PDFInfo
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- CN114380723A CN114380723A CN202011119967.3A CN202011119967A CN114380723A CN 114380723 A CN114380723 A CN 114380723A CN 202011119967 A CN202011119967 A CN 202011119967A CN 114380723 A CN114380723 A CN 114380723A
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- -1 hydroxybenzene sulfonate compound Chemical class 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title description 11
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims abstract description 43
- 239000012535 impurity Substances 0.000 claims abstract description 36
- 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 claims abstract description 32
- 229960005438 calcium dobesilate Drugs 0.000 claims abstract description 30
- 229960003742 phenol Drugs 0.000 claims abstract description 25
- 229960004817 etamsylate Drugs 0.000 claims abstract description 20
- HBGOLJKPSFNJSD-UHFFFAOYSA-N Etamsylate Chemical compound CC[NH2+]CC.OC1=CC=C(O)C(S([O-])(=O)=O)=C1 HBGOLJKPSFNJSD-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 14
- 230000008569 process Effects 0.000 claims abstract description 8
- 239000000463 material Substances 0.000 claims abstract description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- 239000000047 product Substances 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- IULJSGIJJZZUMF-UHFFFAOYSA-N 2-hydroxybenzenesulfonic acid Chemical class OC1=CC=CC=C1S(O)(=O)=O IULJSGIJJZZUMF-UHFFFAOYSA-N 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 6
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 5
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 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
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000008186 active pharmaceutical agent Substances 0.000 claims 2
- 229940088679 drug related substance Drugs 0.000 claims 2
- 239000003814 drug Substances 0.000 abstract description 15
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 abstract description 14
- 229940079593 drug Drugs 0.000 abstract description 14
- 239000002994 raw material Substances 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 238000006277 sulfonation reaction Methods 0.000 abstract description 5
- 238000011160 research Methods 0.000 abstract description 3
- 238000001816 cooling Methods 0.000 description 15
- 239000012065 filter cake Substances 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- 239000012043 crude product Substances 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- JVEDXKIOAFPPPG-UHFFFAOYSA-L calcium;4-hydroxybenzenesulfonate Chemical compound [Ca+2].OC1=CC=C(S([O-])(=O)=O)C=C1.OC1=CC=C(S([O-])(=O)=O)C=C1 JVEDXKIOAFPPPG-UHFFFAOYSA-L 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- IKQCSJBQLWJEPU-UHFFFAOYSA-N 2,5-dihydroxybenzenesulfonic acid Chemical group OC1=CC=C(O)C(S(O)(=O)=O)=C1 IKQCSJBQLWJEPU-UHFFFAOYSA-N 0.000 description 5
- 208000032843 Hemorrhage Diseases 0.000 description 5
- 238000003908 quality control method Methods 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 238000002386 leaching Methods 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 230000002439 hemostatic effect Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
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- 206010067484 Adverse reaction Diseases 0.000 description 2
- 102000006395 Globulins Human genes 0.000 description 2
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- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 238000004566 IR spectroscopy Methods 0.000 description 2
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- 230000001737 promoting effect Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 1
- WMOTVIKCLHJGCF-UHFFFAOYSA-N 2-aminoethanesulfonic acid phenol Chemical compound S(=O)(=O)(O)CCN.C1(=CC=CC=C1)O WMOTVIKCLHJGCF-UHFFFAOYSA-N 0.000 description 1
- FEPBITJSIHRMRT-UHFFFAOYSA-N 4-hydroxybenzenesulfonic acid Chemical compound OC1=CC=C(S(O)(=O)=O)C=C1 FEPBITJSIHRMRT-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010007191 Capillary fragility Diseases 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 1
- 206010018276 Gingival bleeding Diseases 0.000 description 1
- 208000024283 Gingival haemorrhages Diseases 0.000 description 1
- 206010019617 Henoch-Schonlein purpura Diseases 0.000 description 1
- 208000031814 IgA Vasculitis Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 108010003541 Platelet Activating Factor Proteins 0.000 description 1
- 206010040860 Skin haemorrhages Diseases 0.000 description 1
- 206010043561 Thrombocytopenic purpura Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- TUUXRMVITABOSV-UHFFFAOYSA-L calcium;2-hydroxybenzenesulfonate Chemical compound [Ca+2].OC1=CC=CC=C1S([O-])(=O)=O.OC1=CC=CC=C1S([O-])(=O)=O TUUXRMVITABOSV-UHFFFAOYSA-L 0.000 description 1
- RBZMBUHZPQXOBZ-UHFFFAOYSA-L calcium;benzenesulfonate;hydrate Chemical compound O.[Ca+2].[O-]S(=O)(=O)C1=CC=CC=C1.[O-]S(=O)(=O)C1=CC=CC=C1 RBZMBUHZPQXOBZ-UHFFFAOYSA-L 0.000 description 1
- ZQNPDAVSHFGLIQ-UHFFFAOYSA-N calcium;hydrate Chemical group O.[Ca] ZQNPDAVSHFGLIQ-UHFFFAOYSA-N 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 208000001780 epistaxis Diseases 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
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- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 208000015446 immunoglobulin a vasculitis Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
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- 230000001926 lymphatic effect Effects 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
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- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/41—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton
- C07C309/42—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton having the sulfo groups bound to carbon atoms of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C211/03—Monoamines
- C07C211/05—Mono-, di- or tri-ethylamine
-
- 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
- C07C303/02—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
- C07C303/08—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 halogenosulfonic acids
-
- 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
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/42—Separation; Purification; Stabilisation; Use of additives
- C07C303/44—Separation; Purification
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- Chemical & Material Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a p-hydroxybenzene sulfonate compound and application thereof, wherein the p-hydroxybenzene sulfonate compound specifically comprises calcium dobesilate and phenalkamine impurities, the p-hydroxybenzene sulfonate compound is phenol which is an impurity brought in an initial raw material when hydroquinone is used as the initial material for synthesis, and is a process impurity generated in a sulfonation process, and the p-hydroxybenzene sulfonate compound has application in impurity comparison products of phenalkamine raw material medicines and calcium dobesilate raw material medicines. The invention has certain guiding significance for the quality research of the raw material medicines of the etamsylate and the calcium dobesilate.
Description
Technical Field
The invention relates to the field of synthesis of hydroxybenzene sulfonate compounds, in particular to a phenasulfoethylamine and calcium dobesilate impurity, and a preparation method and application thereof.
Background
The etamsylate (styptic) is an artificially synthesized hemostatic, has the effects of reducing capillary permeability, enhancing capillary resistance, shrinking blood vessels, shortening bleeding time, promoting the increase of platelet circulation, increasing platelet aggregation and adhesion, promoting the release of blood coagulation active substances from the platelets and accelerating the shrinkage of blood clots, and is a commonly used hemostatic in clinic. The etamsylate has a quick hemostatic effect, can maintain for 4-6 hours, and is suitable for preventing and treating hemorrhage caused by excessive surgical bleeding, thrombocytopenic purpura or anaphylactoid purpura and other reasons, such as cerebral hemorrhage, gastrointestinal hemorrhage, urinary tract hemorrhage, fundus hemorrhage, gingival hemorrhage, epistaxis, skin hemorrhage and the like. The structure is as follows:
the chemical name of the Calcium dobesilate is 2, 5-dihydroxy benzene sulfonate, also called dobes, the foreign product name is Doxium, the international non-patent medicine name is Calcium dobesilate, the Calcium dobesilate is a blood vessel nutrient for improving microcirculation, is mainly used for treating capillary vessel diseases caused by various reasons, and has good effect on acute myocardial infarction. And mainly refers to calcium benzenesulfonate monohydrate, the structural formula of which is:
the calcium 2, 5-dihydroxy benzene sulfonate can reduce capillary permeability increase and capillary fragility induced by active oxygen, enhance resistance, has antioxidant property, improves lymphatic fluid reflux, and reduces edema; inhibiting high permeability of capillary vessel active substances such as histamine, 5-hydroxytryptamine, hyaluronic acid, platelet activating factor, etc. to capillary vessel, reducing blood vessel intimal injury, improving biosynthesis of basement membrane collagen, and preventing thickening of capillary vessel basement membrane; reducing blood viscosity, reducing coagulation factor I and globulin levels, correcting albumin/globulin ratio, reducing platelet hyperaggregability, activating fibrinolytic activity, increasing fibrinolytic capacity, thereby preventing thrombosis and increasing red blood cell flexibility. After oral administration, it is absorbed through gastrointestinal tract, has a half-life of about 5h in plasma, and is excreted mainly in the prototype through feces and urine.
At present, the simplest synthetic method is to synthesize the etamsylate and the calcium p-hydroxybenzenesulfonate by taking hydroquinone as a raw material.
Chinese patent application CN01131818.X discloses a synthesis process of calcium hydroxybenzenesulfonate hydrate, which comprises the steps of sulfonating hydroquinone and concentrated sulfuric acid, adding ethanol for dissolving, adding calcium carbonate for neutralizing, adjusting pH value, filtering, decompressing and concentrating filtrate, cooling, crystallizing and filtering to obtain a crude product, cooling and crystallizing, and mixing anhydrous ethanol and water for washing to obtain high-purity calcium hydroxybenzenesulfonate.
Chinese patent application CN201910991493.2 discloses 1/20 water, a synthesis of etamsylate compound, which has high purity, good thermal stability and substantially no moisture absorption.
Chinese patent application CN201811481951.X discloses a preparation method of calcium dobesilate for reducing the impurity content of calcium dobesilate, which comprises sulfonation reaction, neutralization reaction, and cooling and crystallizing of crude products; and (3) performing sulfonation reaction, namely selecting 89-91% sulfuric acid, and mixing the sulfuric acid and hydroquinone in a molar ratio of 1: 1.38 to 1.43, keeping the temperature at 78 to 80 ℃ for reaction for 3 to 3.5 hours, and adding the water quantity which is two times that of hydroquinone; neutralization reaction, namely adding calcium carbonate into the substance subjected to the sulfonation reaction for neutralization reaction, and adjusting the pH value to be 4; filtering to remove solid products, and collecting filtrate; transferring the filtrate into a reduced pressure distillation device, heating to 58-60 deg.C, stopping heating when crystallization is separated out, cooling to 4 deg.C, and standing until primary crystal is separated out, wherein the heating process is not less than 2 hr, and the cooling process is not less than 7 hr; cooling and crystallizing after refining, mixing and dissolving the primary crystal with water, heating to 60 ℃, stopping heating, cooling to 4 ℃, placing until the fine crystal is separated out, drying to obtain calcium dobesilate, and measuring the content of calcium dobesilate in the calcium dobesilate to be less than 0.15 per mill and the purity of the calcium dobesilate to be 999.6 per mill.
Chinese patent application CN201811428838.5 discloses a method for producing high-purity etamsylate, which comprises the steps of carrying out sulfonation reaction on hydroquinone serving as a starting material, a sulfonating agent, a dispersing agent and an organic solvent to obtain 2, 5-dihydroxy benzene sulfonic acid, then cooling a reaction liquid to 45-70 ℃, adding a mixed solution of diethylamine and water to form a salt, and cooling and crystallizing to obtain the etamsylate, wherein a reaction system used in the method improves the fluidity of the system, and improves the efficiency of the three-pass-one reaction so as to improve the conversion rate of the material by 5-10%; after the reaction is finished, when the system is cooled to 45-70 ℃, the mixed solution of diethylamine and water is directly added into the system, so that the operation is simplified and the post-treatment time is shortened; the energy consumption is reduced due to the concentrated water, and the yield of the salified product reaches 80-85%; the product does not need recrystallization and an activated carbon color removal step, the purity directly reaches more than 99.5 percent, and all single impurities are lower than 0.05 percent; in addition, the use of a first class solvent and a reagent containing a genotoxicity warning structure is avoided, and a second class solvent and a third class solvent which are safe, low in toxicity and more friendly to human and environment are all used.
The main molecular body of the etamsylate is consistent with that of calcium dobesilate, but the salt formed by the 2, 5-dihydroxy benzene sulfonic acid is different. The etamsylate is diethylamine salt of 2, 5-dihydroxybenzenesulfonic acid; the calcium dobesilate is calcium salt hydrate of 2, 5-dihydroxy benzene sulfonic acid. The two medicines have definite clinical curative effect and good safety, and the etamsylate and the calcium dobesilate have potential toxic and side effects so as to cause adverse reaction, and the generation of the adverse reaction has great relation with impurities in the medicines besides the pharmacological activity of the medicines. In the synthesis reaction, impurities of starting materials and impurities generated by side reactions are inevitably brought into finished products and become impurities which are difficult to remove, so that the impurities contained in the finished products of the etamsylate and the calcium dobesilate are found and confirmed to be structures and are prepared to be used as impurity reference substances for quality control of crude drugs and preparations of the etamsylate and the calcium dobesilate, and the method has important significance for quality and safety evaluation of the etamsylate and the calcium dobesilate. But the research work of impurities of the phenolsulfoethylamine and the calcium dobesilate is lagged at present.
Chinese patent application CN201911413121.8 discloses 4-type etamsylate and calcium dobesilate impurities and preparation methods thereof, wherein the impurities are respectively 2, 5-dihydroxy-1, 4-benzene disulfonic acid compound, 2, 4-dihydroxy-1, 5-benzene disulfonic acid compound, 2, 5-dihydroxy benzene sulfonate compound and 2, 3-dihydroxy benzene sulfonic acid compound, and the purity of the prepared compounds is more than 96 percent, so that the compounds can be applied to quality control of raw material medicines and preparations of etamsylate and calcium dobesilate.
In recent years, in order to enhance the quality and safety of medicines, the quality control of impurities of medicines by the national food and drug administration is more and more strict, and the research on impurities becomes a focus of attention of people.
Disclosure of Invention
The invention aims to provide a phenalkylamine impurity and a calcium dobesilate impurity, and a preparation method and application thereof, namely, the p-hydroxyphenylsulfonate compound can provide a reference substance for quality control of p-phenalkylamine and calcium dobesilate bulk drugs and preparations.
The structure of the p-hydroxybenzene sulfonate compound is as follows:
or
The invention also provides a preparation method of the p-hydroxybenzene sulfonate compound, which comprises the following steps:
(1) heating phenol and a sulfonating agent in a solvent to 25-95 ℃, stirring, preserving heat and reacting for 4-8h, and removing the solvent after the reaction is finished;
(2) and (2) adding water into the product obtained in the step (1) for dispersing, adding alkali into the product to form salt, filtering the salt while the salt is hot, stirring and crystallizing the filtrate at the temperature of between 0 and 5 ℃ for 6 to 8 hours, and washing the filtrate to obtain the product.
Preferably, the molar ratio of the phenol to the sulfonating agent is 1: 1.05-1.7.
Preferably, the sulfonating agent used in step (1) is chlorosulfonic acid or sulfuric acid.
More preferably, the sulfonating agent used is sulfuric acid, and the molar ratio of phenol to sulfuric acid in step (1) is 1:1.4 to 1.7.
Preferably, the solvent in the step (1) is one of n-heptane, n-hexane, chloroform and 1, 2-dichloroethane, and the dosage of the solvent is 3-5 times of the feeding volume of the phenol; the volume of the water added in the step (2) is 0.6-1.3 times of the mass of the phenol feeding material.
Preferably, the base added in the step (2) is diethylamine or calcium carbonate, and the molar ratio of the base to the phenol is 0.5-1.2: 1.
preferably, the method further comprises a step of recrystallizing after washing the product in the step (2), wherein the recrystallization solvent is water or a solution of water and isopropanol.
The invention also provides application of the p-hydroxybenzene sulfonate compound or the p-hydroxybenzene sulfonate compound prepared by any one of the methods as an impurity reference substance of a phenol sulfoethylamine raw material drug and a calcium dobesilate raw material drug.
The corresponding impurities of the etamsylate are p-hydroxy-benzene sulfonic acid diethylamine salt, and the structure is as follows:
the impurities corresponding to the calcium dobesilate are calcium parahydroxybenzenesulfonate salts, and the structure of the impurities is as follows:
the invention has the advantages that:
the invention discloses technological impurities of etamsylate and calcium dobesilate, and provides a reference substance for quality control of raw materials and preparations of etamsylate and calcium dobesilate. The impurity p-hydroxybenzene sulfonate synthesized by the invention is mainly generated by the impurity phenol contained in the initial raw material hydroquinone in the synthesis process of the etamsylate and the calcium dobesilate.
Drawings
FIG. 1 nuclear magnetic hydrogen spectrum of p-hydroxy-benzenesulfonic acid diethylamine salt impurity
FIG. 2-nuclear magnetic carbon spectrum of p-hydroxybenzene sulfonic acid diethylamine salt impurity
FIG. 3-Infrared Spectroscopy of p-hydroxyphenylsulfonic acid diethylamine salt impurity
FIG. 4 mass spectrum of p-hydroxy-benzenesulfonic acid diethylamine salt impurity
FIG. 5 nuclear magnetic hydrogen spectrum of p-hydroxy-benzene sulfonic acid calcium salt impurity
FIG. 6-nuclear magnetic carbon spectrum of p-hydroxy-benzenesulfonic acid calcium salt impurity
FIG. 7-Infrared Spectroscopy of calcium p-hydroxybenzenesulfonate impurity
FIG. 8 mass spectrum of p-hydroxy benzene sulfonic acid calcium salt impurity
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application, and it is obvious that the described embodiments are only a part of the embodiments of the present application, and not all the embodiments. The components of the embodiments of the present application, generally described and illustrated in the figures herein, can be arranged and designed in a wide variety of different configurations. Thus, the following detailed description of the embodiments of the present application, presented in the accompanying drawings, is not intended to limit the scope of the claimed application, but is merely representative of selected embodiments of the application. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present application without making any creative effort, shall fall within the protection scope of the present application.
In the description of the embodiments of the present application, it should be noted that the terms "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer", and the like indicate orientations or positional relationships based on the orientations or positional relationships shown in the drawings or orientations or positional relationships that the products of the present invention are usually placed in when used, and are only used for convenience of description and simplicity of description, but do not indicate or imply that the devices or elements that are referred to must have a specific orientation, be constructed and operated in a specific orientation, and thus, should not be construed as limiting the present application. Furthermore, the terms "first," "second," "third," and the like are used solely to distinguish one from another and are not to be construed as indicating or implying relative importance.
The experimental procedures in the following examples are conventional unless otherwise specified. The test materials used in the following examples were purchased from conventional suppliers unless otherwise specified.
EXAMPLE 1 Synthesis of diethylamine p-hydroxybenzenesulfonate salt
94.10g of phenol is taken, added with 282ml of n-heptane (3 times of the mass volume of the charged phenol) 142.10g of sulfuric acid (the dosage is 1.45 equivalent of the phenol), heated and stirred until the reflux is reached, and stirred and kept for reaction for 4 hours. After the reaction is finished, the solvent is removed, the temperature is reduced to room temperature, 56ml of water (the mass volume of the charged phenol is 0.6 times that of the charged phenol) is added for dispersion, and 87.68g of diethylamine (the dosage is 1.2 equivalents of the phenol) is added for salification at the temperature of 50-60 ℃. After salifying, cooling to 0-5 ℃, stirring, preserving heat, crystallizing for 6 hours, carrying out suction filtration, leaching a filter cake by using 150ml of isopropanol, and carrying out vacuum reduced pressure drying on the filter cake at 60 ℃ for 4 hours to obtain 209.02g of white powdery crude product with the molar yield of 84.52%.
200.04g of the crude product was removed, and 160ml of an aqueous isopropanol solution was added for recrystallization (isopropanol: water 8:2 by volume) and heated to reflux to dissolve the product. After dissolving and cleaning, naturally cooling to room temperature, cooling to the internal temperature of 0-5 ℃, stirring and crystallizing for 3h, carrying out suction filtration, leaching the filter cake with 150ml of isopropanol, collecting the filter cake, drying at 60 ℃ under reduced pressure for 4h to obtain 156.91g of pure target compound, wherein the refining yield is 78.45, the compound is white powdery crystal, and the purity of the liquid phase of the sample is 99.85%.
The structure is confirmed by nuclear magnetic hydrogen spectrum, nuclear magnetic carbon spectrum, infrared spectrum and mass spectrum, and is shown in figures 1-4.
EXAMPLE 2 calcium p-hydroxybenzenesulfonate Synthesis
94.23g of phenol is added into 424ml of normal hexane (the dosage is 4.5 times of the mass volume of the charged phenol) and 147.51g of sulfuric acid (the dosage is 1.5 equivalent of the charged phenol), the mixture is heated and stirred to reflux, and the mixture is stirred and kept for reaction for 8 hours. After the reaction, the temperature was reduced to room temperature, the solvent was removed, 122.5ml of water (1.3 times the mass volume of the charged phenol) was added for dispersion, and 114.13g of calcium carbonate (1.14 equivalents of the charged phenol) was added in portions to adjust the pH to 5 to form a salt. After the salt formation, insoluble substances are filtered, the filtrate is concentrated under vacuum at 50 ℃ until the system is slightly turbid, and the concentration is stopped. And cooling the concentrated residual liquid to 0-5 ℃, stirring and crystallizing for 8 hours, carrying out suction filtration, and leaching a filter cake with 120ml of isopropanol. The filter cake was collected and dried under vacuum at 60 ℃ for 4h to give 124.75g of crude product in 64.57% molar yield as an off-white powder.
Adding 115.41g of crude product into 126ml (the water consumption is 1.1 times of the feeding volume of the crude product), heating until the mixture is refluxed and dissolved to be clear, then carrying out reduced pressure concentration at 50 ℃ until the system is slightly turbid, stopping concentration, cooling to room temperature, cooling to the internal temperature of 0-5 ℃, stirring and crystallizing for 7 hours, filtering, leaching a filter cake with 100ml of isopropanol, collecting the filter cake, carrying out vacuum reduced pressure drying for 5 hours at 60 ℃ to obtain 59.78g of target compound sample, wherein the sample is white-like powder, the refining yield is 51.45%, and the purity of the compound liquid phase is 99.35%.
The structure is confirmed by nuclear magnetic hydrogen spectrum, nuclear magnetic carbon spectrum, infrared spectrum and mass spectrum, and is shown in figures 5-8.
The above-mentioned embodiments only express the specific embodiments of the present application, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present application. It should be noted that, for those skilled in the art, without departing from the technical idea of the present application, several changes and modifications can be made, which are all within the protection scope of the present application.
Claims (9)
1. A p-hydroxybenzene sulfonate compound having the structure:
or
2. The process for preparing p-hydroxybenzenesulfonate compound according to claim 1, comprising the steps of:
(1) heating phenol and a sulfonating agent in a solvent to 25-95 ℃, stirring, preserving heat and reacting for 4-8h, and removing the solvent after the reaction is finished;
(2) and (2) adding water into the product obtained in the step (1) for dispersing, adding alkali into the product to form salt, filtering the salt while the salt is hot, stirring and crystallizing the filtrate at the temperature of between 0 and 5 ℃ for 6 to 8 hours, and washing the filtrate to obtain the product.
3. The process for preparing a high purity hydroxybenzenesulfonate salt according to claim 2, wherein the molar ratio of phenol to sulfonating agent is 1: 1.05-1.7.
4. The method for preparing a high-purity hydroxybenzenesulfonate as claimed in claim 2 or 3, wherein the sulfonating agent used in the step (1) is chlorosulfonic acid or sulfuric acid.
5. The process for producing a high-purity hydroxybenzenesulfonate salt according to any one of claims 2 to 4, wherein the sulfonating agent used is sulfuric acid, and the molar ratio of phenol to sulfuric acid in step (1) is 1:1.4 to 1.7.
6. The process for preparing a high-purity hydroxybenzenesulfonate according to any one of claims 2 to 5, wherein the solvent in the step (1) is one of n-heptane, n-hexane, chloroform and 1, 2-dichloroethane, and the amount of the solvent is 3 to 5 times the charge volume of phenol; the volume of the water added in the step (2) is 0.6-1.3 times of the mass of the phenol feeding material.
7. The process for producing a high-purity hydroxybenzenesulfonate salt according to any one of claims 2 to 6, wherein: the alkali added in the step (2) is diethylamine or calcium carbonate, and the molar ratio of the alkali to the phenol is 0.5-1.2: 1.
8. the process for producing a high-purity hydroxybenzenesulfonate salt according to any one of claims 2 to 7, wherein: and (3) a step of recrystallizing after washing the product in the step (2), wherein the recrystallization solvent is water or a solution of water and isopropanol.
9. Use of a p-hydroxybenzenesulfonate compound as defined in claim 1 or as prepared by the method of any one of claims 2 to 8 as an impurity control for a etamsylate drug substance and a calcium dobesilate drug substance.
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|---|---|---|---|---|
| CN115403489A (en) * | 2022-07-29 | 2022-11-29 | 湖北广辰药业有限公司 | Crystallization method for controlling particle size of calcium dobesilate |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH596156A5 (en) * | 1976-02-04 | 1978-02-28 | Om Lab Sa | Calcium (2,5)-dihydroxy-benzene sulphonate prepn. |
| JPH04290862A (en) * | 1991-03-20 | 1992-10-15 | Kao Corp | Production of anhydrous phenolsulfonic acid salt |
| US20110144337A1 (en) * | 2008-01-03 | 2011-06-16 | Action Medicines S.L. | Processes for the preparation of 2,5-dihydroxybenzenesulfonic acid salts |
| CN102942509A (en) * | 2012-10-17 | 2013-02-27 | 山东方明药业集团股份有限公司 | Synthetic method of etamsylate |
| CN109467522A (en) * | 2018-11-27 | 2019-03-15 | 成都平和安康医药科技有限公司 | A method of producing high-purity etamsylate |
| CN110092736A (en) * | 2018-12-05 | 2019-08-06 | 湖北广辰药业有限公司 | A kind of Calcium Dobesilate preparation method reducing oxybenzene disulfonic acid calcium impurities content |
| 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
- 2020-10-19 CN CN202011119967.3A patent/CN114380723A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH596156A5 (en) * | 1976-02-04 | 1978-02-28 | Om Lab Sa | Calcium (2,5)-dihydroxy-benzene sulphonate prepn. |
| JPH04290862A (en) * | 1991-03-20 | 1992-10-15 | Kao Corp | Production of anhydrous phenolsulfonic acid salt |
| US20110144337A1 (en) * | 2008-01-03 | 2011-06-16 | Action Medicines S.L. | Processes for the preparation of 2,5-dihydroxybenzenesulfonic acid salts |
| CN102942509A (en) * | 2012-10-17 | 2013-02-27 | 山东方明药业集团股份有限公司 | Synthetic method of etamsylate |
| CN109467522A (en) * | 2018-11-27 | 2019-03-15 | 成都平和安康医药科技有限公司 | A method of producing high-purity etamsylate |
| CN110092736A (en) * | 2018-12-05 | 2019-08-06 | 湖北广辰药业有限公司 | A kind of Calcium Dobesilate preparation method reducing oxybenzene disulfonic acid calcium impurities content |
| 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 (5)
| Title |
|---|
| 中华人民共和国卫生部药典委员会编: "《中华人民共和国药典 1990年版 二部 药典注释》", 28 February 1993, 化学工业出版社 * |
| 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》 * |
| 国家药典委员会编: "《中华人民共和国药典 2015年版 二部》", 30 June 2015, 中国医药科技出版社 * |
| 王绯等: "羟苯磺酸钙有关物质方法的建立", 《广东药学院学报》 * |
| 靳广毅，曾荣华: "酚磺乙胺合成工艺改进", 《中国现代应用药学》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115403489A (en) * | 2022-07-29 | 2022-11-29 | 湖北广辰药业有限公司 | Crystallization method for controlling particle size of calcium dobesilate |
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