CN109942426B - Treatment method for recycling S- (-) -lipoic acid - Google Patents
Treatment method for recycling S- (-) -lipoic acid Download PDFInfo
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- 229960002663 thioctic acid Drugs 0.000 title claims abstract description 47
- 238000004064 recycling Methods 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title claims abstract description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- 238000005273 aeration Methods 0.000 claims abstract description 12
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 6
- 238000005886 esterification reaction Methods 0.000 claims abstract description 6
- 230000020477 pH reduction Effects 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-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
- 239000002253 acid Substances 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 235000019136 lipoic acid Nutrition 0.000 abstract description 19
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 abstract description 14
- AGBQKNBQESQNJD-SSDOTTSWSA-N (R)-lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 abstract description 11
- RFYDWSNYTVVKBR-UHFFFAOYSA-N ethyl 6,8-dichlorooctanoate Chemical compound CCOC(=O)CCCCC(Cl)CCCl RFYDWSNYTVVKBR-UHFFFAOYSA-N 0.000 abstract description 10
- 230000002194 synthesizing effect Effects 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 7
- 239000003960 organic solvent Substances 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000002699 waste material Substances 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 9
- YYZUSRORWSJGET-UHFFFAOYSA-N octanoic acid ethyl ester Natural products CCCCCCCC(=O)OCC YYZUSRORWSJGET-UHFFFAOYSA-N 0.000 description 3
- 238000003672 processing method Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- HSKAEXWPLIDFGC-SSDOTTSWSA-N (6R)-6,8-dichlorooctanoic acid Chemical compound OC(=O)CCCC[C@@H](Cl)CCCl HSKAEXWPLIDFGC-SSDOTTSWSA-N 0.000 description 1
- HSKAEXWPLIDFGC-UHFFFAOYSA-N 6,8-dichlorooctanoic acid Chemical compound OC(=O)CCCCC(Cl)CCCl HSKAEXWPLIDFGC-UHFFFAOYSA-N 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001412 amines Chemical class 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
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a treatment method for recycling S- (-) -lipoic acid, which comprises the following steps: (1) dissolving S- (-) -thioctic acid in an organic solvent, and then adding alkali for alkalization treatment to obtain S- (-) -lipoic acid reaction solution; (2) carrying out aeration treatment on the S- (-) -lipoic acid reaction solution, and then carrying out acidification treatment to obtain a yellow paste; (3) and dissolving the yellow paste in an organic solvent, adding thionyl chloride for chlorination, adding ethanol for esterification reaction, and obtaining 6, 8-dichloro ethyl caprylate. The invention realizes the recycling of the S- (-) -lipoic acid, obtains the raw material 6, 8-dichloro ethyl caprylate for synthesizing the alpha-lipoic acid, solves the recycling problem of the S- (-) -lipoic acid, avoids material waste, greatly reduces the raw material cost for synthesizing the R-lipoic acid and provides a new way for industrial production of the R-lipoic acid.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a treatment method for recycling S- (-) -lipoic acid.
Background
Lipoic acid (alphalipoic acid) is a coenzyme present in mitochondria, like vitamins, and eliminates free radicals that cause accelerated aging and disease. The lipoic acid enters cells after being absorbed by intestinal tracts in vivo, has the characteristics of fat solubility and water solubility, can pass through the whole body without resistance and reach any cell part, provides comprehensive efficiency for a human body, and is a universal antioxidant with fat solubility and water solubility. Among them, it has been found that lipoic acid is the R-lipoic acid moiety that plays a major role. Therefore, the research on the synthesis of the R-lipoic acid has important significance for promoting the realization of the industrial production of the R-lipoic acid.
With the research on the synthesis method for synthesizing R-lipoic acid, various methods for synthesizing R-lipoic acid have been discovered from different starting raw materials. The main resolution methods at present are:
1. adipic acid is adopted as a starting material, and after multi-step synthesis, when 6-carbonyl-8-chloro ethyl caprylate is synthesized into 6-hydroxy-8-chloro ethyl caprylate, Ru substitute is used as a catalyst for asymmetric synthesis, so that the splitting process is omitted, and the process steps are simplified. But has the defects of low product purity, difficult repetition of industrial mass production and the like.
2. After 6, 8-dichloro octanoic acid ethyl ester is adopted for hydrolysis, the 6, 8-dichloro octanoic acid is subjected to S-phenylethylamine resolution to obtain R-6, 8-dichloro octanoic acid with higher purity, but the other half of the S-6, 8-dichloro octanoic acid cannot be recycled.
3. The alpha-lipoic acid is adopted as a raw material, methylbenzene and the like are adopted as solvents, chiral amine is selected for resolution, the yield and the purity are ideal, and after the resolution is finished, the recycling difficulty of the other half of S- (-) -lipoic acid remained in mother liquor is large. In the prior art, partial S- (-) -lipoic acid is racemized under the conditions of high temperature, high pressure and nitrogen protection, but the process conditions are harsh and lipoic acid polymerization is easily caused.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a treatment method for recycling S- (-) -lipoic acid, which comprises the steps of firstly carrying out alkalization treatment, then carrying out aeration, chlorination and esterification treatment to obtain an intermediate product 6, 8-dichloro ethyl caprylate for synthesizing and splitting raw material alpha-lipoic acid, and providing a new way for synthesizing R-lipoic acid while effectively solving the problem of recycling S- (-) -lipoic acid.
The purpose of the invention is realized by the following technical scheme:
the invention provides a processing method for recycling S- (-) -lipoic acid, which comprises the following steps:
(1) dissolving S- (-) -thioctic acid in an organic solvent, and then adding alkali for alkalization treatment to obtain S- (-) -lipoic acid reaction solution;
(2) carrying out aeration treatment on the S- (-) -lipoic acid reaction solution, and then carrying out acidification treatment to obtain a yellow paste;
(3) and dissolving the yellow paste in an organic solvent, adding thionyl chloride for chlorination, adding ethanol for esterification reaction, and obtaining 6, 8-dichloro ethyl caprylate.
Further, in the step (1), the concentration of the alkali is 20-40%, and the molar ratio of S- (-) -lipoic acid to alkali is 1: 1.2-2.0; the temperature of the alkalization treatment is 40-50 ℃, and the reaction time is 6-9 h.
Further, the aeration treatment time in the step (2) is 2-4 h; the acid concentration is 5-10%, and the acidification treatment is carried out at the temperature of 0-5 ℃ until the pH value of the solution is 2-4.
Further, in the step (3), the molar ratio of S- (-) -lipoic acid to thionyl chloride is 1: 1.0-1.5; the temperature of the chlorination reaction is 40-60 ℃, and the reaction time is 2-5 h; according to the molar ratio of S- (-) -lipoic acid to ethanol being 1: 2.0-3.5, the temperature of the esterification reaction is 0-20 ℃, and the reaction time is 3-6 h.
In the scheme, the organic solvent is toluene, ethyl acetate and tert-butyl methyl ether. The alkali is sodium hydroxide, potassium hydroxide or calcium hydroxide. The acid is hydrochloric acid, sulfuric acid, or acetic acid.
The invention has the following beneficial effects:
(1) the S- (-) -lipoic acid is subjected to alkalization, aeration, chlorination and esterification treatment, so that the recycling of the S- (-) -lipoic acid is realized, the raw material 6,8 dichloro ethyl caprylate for synthesizing the alpha-lipoic acid is obtained, and the problem of polymerization in racemization of the S- (-) -lipoic acid in the prior art is effectively solved.
(2) The method has the advantages of simple required equipment and reagents, simple and convenient operation, mild reaction conditions, low process operation cost, good recycling effect, high yield (the yield of the 6, 8-dichloro ethyl caprylate reaches more than 80%), no generation of pollutants such as wastewater, waste residue and the like, and accordance with the process requirements of industrial production of the R-lipoic acid.
(3) The invention not only solves the recycling problem of the S- (-) -lipoic acid, avoids the waste of materials, but also greatly reduces the cost of raw materials for synthesizing the R-lipoic acid and provides a new way for the industrial production of the R-lipoic acid.
The present invention will be described in further detail with reference to examples.
Detailed Description
The first embodiment is as follows:
the present embodiment relates to a processing method for recycling S- (-) -lipoic acid, which comprises the following steps:
(1) dissolving 20.6g S- (-) -lipoic acid in 100mL of ethyl acetate, adding 6.7g of KOH aqueous solution with the concentration of 30%, and stirring and reacting at the temperature of 45 ℃ for 8 hours to obtain S- (-) -lipoic acid reaction solution;
(2) introducing the S- (-) -lipoic acid reaction solution into an aeration device (aeration can be air and low-concentration oxygen), and carrying out aeration treatment for 4 hours; then cooling to 0 ℃, and dropwise adding 5% sulfuric acid until the pH value of the solution is 4 to obtain yellow paste;
(3) dissolving the yellow paste in toluene, dropwise adding 7.8g of thionyl chloride, and reacting at the temperature of 60 ℃ for 4 hours; then cooled to 10 ℃, and 12mL of ethanol is added dropwise to continue the reaction for 3 hours, thereby obtaining 20.0g of 6, 8-dichloro ethyl caprylate.
The yield of ethyl 6, 8-dichlorooctanoate in this example was 83%.
Example two:
the present embodiment relates to a processing method for recycling S- (-) -lipoic acid, which comprises the following steps:
(1) dissolving 20.6g S- (-) -lipoic acid in 100mL of toluene, adding 8g of 20% NaOH aqueous solution, and stirring and reacting at the temperature of 50 ℃ for 6 hours to obtain an S- (-) -lipoic acid reaction solution;
(2) introducing the S- (-) -lipoic acid reaction solution into an aeration device (aeration can be air and low-concentration oxygen), and carrying out aeration treatment for 2 h; then cooling to 5 ℃, and dropwise adding hydrochloric acid with the concentration of 10% until the pH value of the solution is 2 to obtain yellow paste;
(3) dissolving the yellow paste in toluene, dropwise adding 11.7g of thionyl chloride, and reacting at the temperature of 60 ℃ for 3 hours; then cooled to 5 ℃, and 20mL of ethanol is added dropwise to continue the reaction for 6 hours, so that 21.5g of 6, 8-dichloro ethyl octanoate is obtained.
The yield of ethyl 6, 8-dichlorooctanoate in this example was 89%.
Claims (2)
1. A treatment method for recycling S- (-) -lipoic acid is characterized by comprising the following steps:
(1) dissolving S- (-) -lipoic acid in toluene, ethyl acetate or tert-butyl methyl ether, adding 20-40% alkali, and performing alkalization treatment at the temperature of 40-50 ℃ for 6-9 hours to obtain S- (-) -lipoic acid reaction solution; wherein, the molar ratio of S- (-) -lipoic acid to alkali is 1: 1.2-2.0, and the alkali is sodium hydroxide or potassium hydroxide;
(2) carrying out aeration treatment on the S- (-) -lipoic acid reaction solution for 2-4 h, and then adding 5-10% acid at the temperature of 0-5 ℃ for acidification treatment until the pH value of the solution is 2-4 to obtain a yellow paste;
(3) dissolving the yellow paste into toluene, ethyl acetate or tert-butyl methyl ether, adding thionyl chloride according to a molar ratio of S- (-) -lipoic acid to thionyl chloride of 1: 1.0-1.5, carrying out chlorination reaction at the temperature of 40-60 ℃ for 2-5 h, adding ethanol according to a molar ratio of S- (-) -lipoic acid to ethanol of 1: 2.0-3.5, and continuing esterification reaction at the temperature of 0-20 ℃ for 3-6 h to obtain 6, 8-ethyl dichlorooctoate.
2. The method for recycling S- (-) -lipoic acid as set forth in claim 1, characterized in that: the acid is hydrochloric acid, sulfuric acid, or acetic acid.
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| WO2002030919A1 (en) * | 2000-10-10 | 2002-04-18 | Laboratorio Chimico Internazionale S.P.A. | SYNTHESIS OF R(+)α-LIPOIC ACID |
| WO2010144529A1 (en) * | 2009-06-12 | 2010-12-16 | Ampac Fine Chemicals Llc | Preparation of polymer-free r-(+)-alpha-lipoic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20070055070A1 (en) * | 2005-09-07 | 2007-03-08 | Lawrence Lowell J | Novel esters of lipoic acid |
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