CN116041318A - Method for preparing lipoic acid - Google Patents
Method for preparing lipoic acid Download PDFInfo
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- CN116041318A CN116041318A CN202211705616.XA CN202211705616A CN116041318A CN 116041318 A CN116041318 A CN 116041318A CN 202211705616 A CN202211705616 A CN 202211705616A CN 116041318 A CN116041318 A CN 116041318A
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- lipoic acid
- acid
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- 235000019136 lipoic acid Nutrition 0.000 title claims abstract description 127
- 229960002663 thioctic acid Drugs 0.000 title claims abstract description 127
- AGBQKNBQESQNJD-UHFFFAOYSA-M lipoate Chemical compound [O-]C(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-M 0.000 title claims abstract description 118
- 238000000034 method Methods 0.000 title claims abstract description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 57
- 239000011593 sulfur Substances 0.000 claims abstract description 46
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 46
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 38
- 239000011734 sodium Substances 0.000 claims abstract description 38
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 38
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 29
- -1 sulfur ion Chemical class 0.000 claims abstract description 29
- 239000013522 chelant Substances 0.000 claims abstract description 12
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 12
- 230000020477 pH reduction Effects 0.000 claims abstract description 11
- 229910052751 metal Inorganic materials 0.000 claims abstract description 10
- 239000002184 metal Substances 0.000 claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- PHRUYNFFDRXZQY-UHFFFAOYSA-N [S].C(CCCCCCC)(=O)O Chemical compound [S].C(CCCCCCC)(=O)O PHRUYNFFDRXZQY-UHFFFAOYSA-N 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 238000010438 heat treatment Methods 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 229910052979 sodium sulfide Inorganic materials 0.000 claims description 12
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 3
- 239000010949 copper Substances 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 239000011701 zinc Substances 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 2
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 28
- 239000007787 solid Substances 0.000 abstract description 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000001816 cooling Methods 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- 238000000967 suction filtration Methods 0.000 description 20
- 239000012065 filter cake Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000007864 aqueous solution Substances 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- 238000001291 vacuum drying Methods 0.000 description 10
- 238000010992 reflux Methods 0.000 description 9
- 239000012043 crude product Substances 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000002351 wastewater Substances 0.000 description 5
- 230000008859 change Effects 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 238000007865 diluting Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 235000021395 porridge Nutrition 0.000 description 4
- 230000001376 precipitating effect Effects 0.000 description 4
- 238000004537 pulping Methods 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 238000001311 chemical methods and process Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 150000002736 metal compounds Chemical class 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 102000016912 Aldehyde Reductase Human genes 0.000 description 1
- 108010053754 Aldehyde reductase Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000011449 brick Substances 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000013505 freshwater Substances 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000000944 nerve tissue Anatomy 0.000 description 1
- YYZUSRORWSJGET-UHFFFAOYSA-N octanoic acid ethyl ester Natural products CCCCCCCC(=O)OCC YYZUSRORWSJGET-UHFFFAOYSA-N 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
- C07D339/02—Five-membered rings
- C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing lipoic acid, which belongs to the technical field of organic synthesis and comprises sulfur removal and acidification; in the sulfur removal step, adding acid and a compound containing metal ions into a sulfur ion-containing sodium lipoic acid system, reacting, and filtering to obtain a metal chelate of the sulfur octanoic acid; then, the metal chelate of the lipoic acid reacts with sodium hydroxide to obtain pure sodium lipoic acid; then acidifying the pure sodium lipoic acid to obtain lipoic acid. The method utilizes the characteristic that the lipoic acid is easy to chelate with metal ions to form solid, removes the sulfur ions while chelating the lipoic acid, greatly inhibits the generation of the impurity 1,2, 3-trithiocyclohexane-4-pentanoic acid, and has the advantages of low impurity content, high purity and high yield of the lipoic acid obtained by the method, and greatly improves the quality of the lipoic acid.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing lipoic acid.
Background
Lipoic acid is an antioxidant, a radical scavenger, by ion with iron, copper and other transition metal elements such as Mn 2+ 、Cd 2+ 、Zn 2+ Chelation, reduction of hydroxyl radical generation, further blocking lipid oxidation reaction of nerve tissue, preventing glycosylation of protein, inhibiting aldose reductase, and preventing conversion of glucose or galactose to sorbitol, thus preventing diabetes, controlling blood sugar, and preventing nerve mutation due to hyperglycemia, thus it is seen that lipoic acid is an important chemical drug.
The current industrial production route of lipoic acid with maturation and stability in industry is to use 6, 8-dichloro ethyl octanoate, sulfur and sodium sulfide as initial raw materials, and obtain lipoic acid through cyclization, hydrolysis, acidification and refining, the total yield is about 50%, and the production process flow chart is shown in figure 1. However, the process has the disadvantages that more sticky matters are easy to generate in the acidification process, the yield of the product is reduced, the purity is poor, and a large amount of impurity 1,2, 3-trithiocyclohexane-4-pentanoic acid is generated in the acidification process, and the content of the impurity is even 10-20%. Analysis of the acidification process found that: S-S bond formed in the cyclization process is easy to open in the acidification process, and the divalent sulfide ion in the system is inserted to form impurity 1,2, 3-trithiocyclohexane-4-pentanoic acid.
In practical production, in order to avoid excessive production of impurity 1,2, 3-trithiocyclohexane-4-pentanoic acid, usually, after the cyclization reaction, intermediate ethyl lipoic acid is separated from water, waste water containing a large amount of divalent sulfide ions is discarded, and then the ethyl lipoic acid is hydrolyzed and acidified. Pharmacopoeia prescribes that the content of impurity 1,2, 3-trithiocyclohexane-4-pentanoic acid should be below 0.2%, however, intermediate and water cannot be completely separated in production, which results in a small amount of sulfur-containing wastewater entering the subsequent hydrolysis and acidification steps, thereby increasing the content of impurity 1,2, 3-trithiocyclohexane-4-pentanoic acid and reducing the yield and purity of lipoic acid. Therefore, how to inhibit the generation of impurity 1,2, 3-trithiocyclohexane-4-pentanoic acid has a critical effect on improving the yield and purity of lipoic acid.
Disclosure of Invention
The invention aims to provide a method for preparing lipoic acid, which aims to solve the technical problems in the background technology.
To achieve the above object, the present invention discloses a method for preparing lipoic acid, comprising sulfur removal and acidification;
in the sulfur removal step, adding acid and a compound containing metal ions into a sulfur ion-containing sodium lipoic acid system, reacting, and filtering to obtain a metal chelate of the sulfur octanoic acid; then, the metal chelate of the lipoic acid reacts with sodium hydroxide to obtain pure sodium lipoic acid;
then acidifying the pure sodium lipoic acid to obtain lipoic acid.
Further, the preparation method of the sulfur ion-containing sodium lipoic acid system comprises the following steps: the method comprises the steps of taking sulfur, sodium sulfide and ethyl dichlorooctoate as raw materials, heating and reacting in an organic solvent to synthesize ethyl lipoic acid, and then adding sodium hydroxide to react to obtain a sulfur ion-containing sodium lipoic acid system.
Further, the metal ions include Fe 3+ 、Cu 2+ 、Mn 2+ 、Ca 2+ 、Cd 2+ And Zn 2+ One or more of them.
Further, the compound containing metal ions comprises one or more of ferric trichloride, zinc chloride, anhydrous copper sulfate and calcium chloride.
Further, the acid is an inorganic acid, including one or more of hydrochloric acid, sulfuric acid and nitric acid.
Further, the organic solvent comprises one or more of methanol, ethanol, isopropanol, n-propanol, acetone, benzene, toluene, pentane, diethyl ether, ethyl acetate and carbon tetrachloride.
Further, the lipoic acid obtained after acidification is subjected to post-treatment, wherein the post-treatment comprises dissolution and crystallization by adopting cyclohexane.
Compared with the prior art, the method for preparing the lipoic acid has the following beneficial effects:
(1) According to the method, the characteristic that lipoic acid is easy to chelate with metal ions to form solid is utilized, a compound containing metal ions is added into a lipoic acid sodium system containing a large amount of sulfur-containing wastewater to form solid lipoic acid metal chelate, meanwhile, the sulfur ions and the metal ions form precipitate, then alkaline hydrolysis is used for the precipitate, the lipoic acid metal chelate reforms sodium lipoic acid into fresh water again, and the sulfur ions are separated and removed in a precipitation form, so that the generation of impurity 1,2, 3-trithiocyclohexane-4-pentanoic acid is greatly inhibited.
(2) The preparation method is an improvement on the basis of the existing production process, does not need to modify production equipment, and has low equipment investment.
(3) The lipoic acid obtained by the preparation method has low impurity content, high purity and high yield, and the quality of the lipoic acid is greatly improved.
Drawings
Fig. 1: the current industrial production process flow diagram of lipoic acid in the industry.
Fig. 2: partial chemical process flow diagram for the preparation of lipoic acid according to the invention.
Detailed Description
Embodiments of the present invention will now be described in detail with reference to the following examples, which are provided for illustration only and are not to be construed as limiting the scope of the invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer.
A method for preparing lipoic acid, based on a sodium lipoic acid system containing sulfur ions, comprises the steps of removing sulfur and acidizing to obtain high-purity lipoic acid, and specifically comprises the following steps:
first, sodium lipoic acid is synthesized. The method comprises the steps of adopting the prior art, sequentially adding sulfur and ethyl dichlorooctoate into an organic solvent in a reaction container, heating to 60-70 ℃ (reflux), then adding sodium sulfide at the temperature, and reacting to obtain the ethyl lipoic acid; cooling to 55-60 ℃, adding sodium hydroxide, and removing the organic solvent after the reaction is finished to obtain a sodium lipoic acid system, wherein a large amount of sulfur ions remain in the reaction system, so that the sodium lipoic acid system containing sulfur ions is obtained;
in this step, the organic solvent includes one or more of methanol, ethanol, isopropanol, n-propanol, acetone, benzene, toluene, pentane, diethyl ether, ethyl acetate and carbon tetrachloride, preferably methanol.
Then, sulfur removal is performed. The sulfur removal process is divided into two steps: (1) Adding acid into a sulfur ion-containing sodium lipoic acid system, adjusting the pH value of the system to be 6-7, then adding a metal ion-containing compound, gradually generating a large amount of solids in the system, stirring, and carrying out suction filtration to obtain a filter cake; the filtrate after suction filtration contains raw materials and other impurities which are not completely reacted to form wastewater, and the wastewater is discarded, and the filter cake contains metal chelate of lipoic acid and metal compound of sulfur; (2) And (3) reacting the filter cake with sodium hydroxide, wherein metal chelate of the lipoic acid is dissociated in the presence of alkali to form sodium lipoic acid, filtering to remove filter residues (the filter residues are metal compounds of sulfur), and reserving filtrate, wherein the filtrate is sodium lipoic acid solution after sulfur ions are removed, namely pure sodium lipoic acid, so that the sulfur removal process is completed. Almost no sulfur ions exist in the filtrate after sulfur removal, the generation of impurity 1,2, 3-trithiocyclohexane-4-pentanoic acid is inhibited, and the impurity content in the final product is greatly reduced.
In this step, the acid is an inorganic acid including one or more of hydrochloric acid, sulfuric acid and nitric acid, preferably hydrochloric acid.
Then acidizing is carried out. And adding acid into the sodium lipoic acid solution after the sulfur ions are removed, and acidifying the sodium lipoic acid to generate a crude lipoic acid product.
And then post-treatment is performed. Firstly, carrying out vacuum drying on the crude lipoic acid, dissolving the dried crude lipoic acid with cyclohexane, crystallizing, and carrying out suction filtration and vacuum drying on the precipitated crystals to obtain the pure lipoic acid.
The partial chemical process flow for preparing the lipoic acid is shown in fig. 2, and the step is omitted because the preparation of the sodium lipoic acid system containing the sulfur ions is a conventional technology.
The content of the impurity 1,2, 3-trithiocyclohexane-4-pentanoic acid in the lipoic acid prepared by the method is greatly reduced, the requirement of pharmacopoeia is met, and in the preparation process, the product yield and the purity of the final product are greatly improved through multiple suction filtration and cleaning steps. Through detection, the yield of the final product lipoic acid is larger than or equal to 70%, the content of the impurity 1,2, 3-trithiocyclohexane-4-pentanoic acid is smaller than or equal to 0.15%, and the content of other impurities is smaller than 0.1%.
Example 1
(1) Synthesizing sodium lipoic acid: sequentially adding 50.0mL of methanol, 1.74g of sulfur and 10.88g of ethyl 6, 8-dichloro octoate into a 250mL four-neck flask, heating to 65 ℃ (reflux), slowly dropwise adding a sodium sulfide aqueous solution (5.62 g of sodium sulfide is dissolved in 20.0mL of water) at the temperature, and after dropwise adding, keeping the temperature for reaction for 3 hours, wherein the content of the ethyl 6, 8-dichloro octoate is reduced to below 0.5%, and stopping the reaction;
cooling to 55-60 ℃, adding sodium hydroxide aqueous solution (3.6 g of sodium hydroxide is dissolved in 33mL of water) into the four-neck flask, and reacting for 4 hours while keeping the temperature, wherein the content of the ethyl lipoic acid is reduced to below 0.5%, and stopping the reaction. Removing methanol by decompression and desolventizing to obtain the sodium lipoic acid. The sodium lipoic acid in the water layer is calibrated, the calibration yield is 90%, and the purity is 91%.
(2) Sulfur removal: then cooling to 15-20 ℃, dropwise adding 6M HCl solution into the four-necked flask until the pH value of the system is=6-7, stirring for 0.5h, and re-measuring the pH value without change;
then cooling to 0-5 ℃, adding 3.7g of zinc chloride into the four-neck flask, gradually generating a large amount of white solid in the system, stirring for 0.5h, and performing suction filtration to obtain a filter cake 1;
adding 20mL of ice water into the filter cake 1 for pulping, and carrying out suction filtration again after 0.5h to obtain a filter cake 2; then adding 10mL of water into the filter cake 2, stirring to porridge, heating to 15-20 ℃, then dropwise adding 10% sodium hydroxide aqueous solution until the pH value of the system is=10-11, gradually diluting the system, stirring for 0.5h, and carrying out suction filtration to obtain pale yellow filtrate.
(3) Acidifying: slowly dripping 2M HCl solution into the filtrate until the pH=1-2, precipitating a large amount of solid in the system, stirring for 0.5h at the temperature, and suction-filtering after retesting the pH to obtain the lipoic acid crude product.
(4) Post-treatment: vacuum drying is carried out on the crude lipoic acid to obtain 7.65g of dried crude lipoic acid, the yield is 82.17 percent, and the purity is 98.5 percent;
suspending the dried lipoic acid crude product in 75mL of cyclohexane, heating to reflux, preserving the heat for 0.5h after dissolving, and then stopping heating and slowly cooling. Slowly cooling to 15-20 ℃ after crystallization, preserving heat for 0.5h, and performing suction filtration to obtain a lipoic acid pure product;
vacuum drying is carried out on the pure lipoic acid product to obtain 7.0g lipoic acid, the yield is 75.18 percent, the purity is 99.3 percent, and the impurity 1,2, 3-trithiocyclohexane-4-pentanoic acid content is: 0.05 percent and the rest impurities are less than 0.1 percent.
Example 2
(1) Synthesizing sodium lipoic acid: sequentially adding 50.0mL of methanol, 1.74g of sulfur and 10.88g of ethyl 6, 8-dichloro octoate into a 250mL four-neck flask, heating to 65 ℃ (reflux), slowly dropwise adding a sodium sulfide aqueous solution (5.62 g of sodium sulfide is dissolved in 20.0mL of water) at the temperature, and after dropwise adding, keeping the temperature for reaction for 3 hours, wherein the content of the ethyl 6, 8-dichloro octoate is reduced to below 0.5%, and stopping the reaction;
cooling to 55-60 ℃, adding sodium hydroxide aqueous solution (3.6 g of sodium hydroxide is dissolved in 33mL of water) into the four-neck flask, and reacting for 4 hours while keeping the temperature, wherein the content of the ethyl lipoic acid is reduced to below 0.5%, and stopping the reaction. Removing methanol by decompression and desolventizing to obtain the sodium lipoic acid. The sodium lipoic acid in the water layer is calibrated, the calibration yield is 88.5%, and the purity is 92.5%.
(2) Sulfur removal: then cooling to 15-20 ℃, dropwise adding 6M HCl solution into the four-necked flask until the pH value of the system is=6-7, stirring for 0.5h, and re-measuring the pH value without change;
then cooling to 0-5 ℃, adding 2.93g of ferric trichloride into the four-neck flask, gradually generating a large amount of brick red solids in the system, stirring for 0.5h, and performing suction filtration to obtain a filter cake 1;
adding 20mL of ice water into the filter cake 1 for pulping, and carrying out suction filtration again after 0.5h to obtain a filter cake 2; then adding 10mL of water into the filter cake 2, stirring to porridge, heating to 15-20 ℃, then dropwise adding 10% sodium hydroxide aqueous solution until the pH value of the system is=10-11, gradually diluting the system, stirring for 0.5h, and carrying out suction filtration to obtain pale yellow filtrate.
(3) Acidifying: slowly dripping 2M HCl solution into the filtrate until the pH=1-2, precipitating a large amount of solid in the system, stirring for 0.5h at the temperature, and suction-filtering after retesting the pH to obtain the lipoic acid crude product.
(4) Post-treatment: vacuum drying is carried out on the crude lipoic acid to obtain 7.9g of dried crude lipoic acid, the yield is 84.85%, and the purity is 97.5%;
suspending the dried lipoic acid crude product in 75mL of cyclohexane, heating to reflux, preserving the heat for 0.5h after dissolving, and then stopping heating and slowly cooling. Slowly cooling to 15-20 ℃ after crystallization, preserving heat for 0.5h, and performing suction filtration to obtain a lipoic acid pure product;
vacuum drying is carried out on the pure lipoic acid product to obtain 7.15g lipoic acid, the yield is 76.8 percent, the purity is 99.1 percent, and the impurity 1,2, 3-trithiocyclohexane-4-pentanoic acid content is: 0.08 percent, and the rest impurities are less than 0.1 percent.
Example 3
(1) Synthesizing sodium lipoic acid: sequentially adding 50.0mL of methanol, 1.74g of sulfur and 10.88g of ethyl 6, 8-dichloro octoate into a 250mL four-neck flask, heating to 65 ℃ (reflux), slowly dropwise adding a sodium sulfide aqueous solution (5.62 g of sodium sulfide is dissolved in 20.0mL of water) at the temperature, and after dropwise adding, keeping the temperature for reaction for 3 hours, wherein the content of the ethyl 6, 8-dichloro octoate is reduced to below 0.5%, and stopping the reaction;
cooling to 55-60 ℃, adding sodium hydroxide aqueous solution (3.6 g of sodium hydroxide is dissolved in 33mL of water) into the four-neck flask, and reacting for 4 hours while keeping the temperature, wherein the content of the ethyl lipoic acid is reduced to below 0.5%, and stopping the reaction. Removing methanol by decompression and desolventizing to obtain the sodium lipoic acid. The sodium lipoic acid in the water layer is calibrated, the calibration yield is 87%, and the purity is 92%.
(2) Sulfur removal: then cooling to 15-20 ℃, dropwise adding 6M HCl solution into the four-necked flask until the pH value of the system is=6-7, stirring for 0.5h, and re-measuring the pH value without change;
then cooling to 0-5 ℃, adding 6.76g of copper sulfate pentahydrate into the four-neck flask, gradually generating a large amount of blue solids in the system, stirring for 0.5h, and performing suction filtration to obtain a filter cake 1;
adding 20mL of ice water into the filter cake 1 for pulping, and carrying out suction filtration again after 0.5h to obtain a filter cake 2; then adding 10mL of water into the filter cake 2, stirring to porridge, heating to 15-20 ℃, then dropwise adding 10% sodium hydroxide aqueous solution until the pH value of the system is=10-11, gradually diluting the system, stirring for 0.5h, and carrying out suction filtration to obtain pale yellow filtrate.
(3) Acidifying: slowly dripping 2M HCl solution into the filtrate until the pH=1-2, precipitating a large amount of solid in the system, stirring for 0.5h at the temperature, and suction-filtering after retesting the pH to obtain the lipoic acid crude product.
(4) Post-treatment: vacuum drying is carried out on the crude lipoic acid to obtain 7.5g of dried crude lipoic acid, the yield is 80.55 percent, and the purity is 98.8 percent;
suspending the dried lipoic acid crude product in 75mL of cyclohexane, heating to reflux, preserving the heat for 0.5h after dissolving, and then stopping heating and slowly cooling. Slowly cooling to 15-20 ℃ after crystallization, preserving heat for 0.5h, and performing suction filtration to obtain a lipoic acid pure product;
vacuum drying is carried out on the pure lipoic acid product to obtain 6.84g lipoic acid, the yield is 73.5%, the purity is 99.5%, and the impurity 1,2, 3-trithiocyclohexane-4-pentanoic acid content is: 0.01% and the rest impurities are less than 0.1%.
Example 4
(1) Synthesizing sodium lipoic acid: sequentially adding 50.0mL of methanol, 1.74g of sulfur and 10.88g of ethyl 6, 8-dichloro octoate into a 250mL four-neck flask, heating to 65 ℃ (reflux), slowly dropwise adding a sodium sulfide aqueous solution (5.62 g of sodium sulfide is dissolved in 20.0mL of water) at the temperature, and after dropwise adding, keeping the temperature for reaction for 3 hours, wherein the content of the ethyl 6, 8-dichloro octoate is reduced to below 0.5%, and stopping the reaction;
cooling to 55-60 ℃, adding sodium hydroxide aqueous solution (3.6 g of sodium hydroxide is dissolved in 33mL of water) into the four-neck flask, and reacting for 4 hours while keeping the temperature, wherein the content of the ethyl lipoic acid is reduced to below 0.5%, and stopping the reaction. Removing methanol by decompression and desolventizing to obtain the sodium lipoic acid. The sodium lipoic acid in the water layer is calibrated, the calibration yield is 86.5%, and the purity is 93.5%.
(2) Sulfur removal: then cooling to 15-20 ℃, dropwise adding 6M HCl solution into the four-necked flask until the pH value of the system is=6-7, stirring for 0.5h, and re-measuring the pH value without change;
then cooling to 0-5 ℃, adding 3.0g of calcium chloride into the four-neck flask, gradually generating a large amount of white solid in the system, stirring for 0.5h, and performing suction filtration to obtain a filter cake 1;
adding 20mL of ice water into the filter cake 1 for pulping, and carrying out suction filtration again after 0.5h to obtain a filter cake 2; then adding 10mL of water into the filter cake 2, stirring to porridge, heating to 15-20 ℃, then dropwise adding 10% sodium hydroxide aqueous solution until the pH value of the system is=10-11, gradually diluting the system, stirring for 0.5h, and carrying out suction filtration to obtain pale yellow filtrate.
(3) Acidifying: slowly dripping 2M HCl solution into the filtrate until the pH=1-2, precipitating a large amount of solid in the system, stirring for 0.5h at the temperature, and suction-filtering after retesting the pH to obtain the lipoic acid crude product.
(4) Post-treatment: vacuum drying is carried out on the crude lipoic acid to obtain 7.58g of dried crude lipoic acid, the yield is 81.5%, and the purity is 97%;
suspending the dried lipoic acid crude product in 75mL of cyclohexane, heating to reflux, preserving the heat for 0.5h after dissolving, and then stopping heating and slowly cooling. Slowly cooling to 15-20 ℃ after crystallization, preserving heat for 0.5h, and performing suction filtration to obtain a lipoic acid pure product;
vacuum drying is carried out on the pure lipoic acid product to obtain 6.7g lipoic acid, the yield is 72 percent, the purity is 99.1 percent, and the impurity 1,2, 3-trithiocyclohexane-4-pentanoic acid content is as follows: 0.15 percent and the rest impurities are less than 0.1 percent.
Therefore, the lipoic acid obtained by the preparation method has high yield, low impurity content and high purity, and the content of the impurity 1,2, 3-trithiocyclohexane-4-pentanoic acid accords with pharmacopoeia regulations, so that the technical problems of low lipoic acid yield and high impurity content obtained by the existing production process are solved.
The above description is only of the preferred embodiments of the present invention, and is not intended to limit the invention, but any modifications, equivalent substitutions, improvements, etc. within the design concept of the present invention should be included in the scope of the present invention.
Claims (7)
1. A method of preparing lipoic acid, characterized by: including sulfur removal and acidification;
in the sulfur removal step, adding acid and a compound containing metal ions into a sulfur ion-containing sodium lipoic acid system, reacting, and filtering to obtain a metal chelate of the sulfur octanoic acid; then, the metal chelate of the lipoic acid reacts with sodium hydroxide to obtain pure sodium lipoic acid;
then acidifying the pure sodium lipoic acid to obtain lipoic acid.
2. A method of preparing lipoic acid according to claim 1, characterized in that: the preparation method of the sulfur ion-containing sodium lipoic acid system comprises the following steps: the method comprises the steps of taking sulfur, sodium sulfide and ethyl dichlorooctoate as raw materials, heating and reacting in an organic solvent to synthesize ethyl lipoic acid, and then adding sodium hydroxide to react to obtain a sulfur ion-containing sodium lipoic acid system.
3. A method of preparing lipoic acid according to claim 2, characterized in that: the organic solvent comprises one or more of methanol, ethanol, isopropanol, n-propanol, acetone, benzene, toluene, pentane, diethyl ether, ethyl acetate and carbon tetrachloride.
4. A method of preparing lipoic acid according to claim 1, characterized in that: the metal ion includes Fe 3+ 、Cu 2+ 、Mn 2+ 、Ca 2+ 、Cd 2+ And Zn 2+ One or more of them.
5. The method for preparing lipoic acid according to claim 4, wherein: the compound containing metal ions comprises one or more of ferric trichloride, zinc chloride, anhydrous copper sulfate and calcium chloride.
6. A method of preparing lipoic acid according to claim 1, characterized in that: in the sulfur removal step, the added acid is inorganic acid and comprises one or more of hydrochloric acid, sulfuric acid and nitric acid.
7. The method of preparing lipoic acid according to any one of claims 1-6, characterized in that: and (3) carrying out post-treatment on the lipoic acid obtained after acidification, wherein the post-treatment comprises dissolving with cyclohexane and then crystallizing.
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