CN113234059B - Preparation method of lipoic acid impurity A - Google Patents
Preparation method of lipoic acid impurity A Download PDFInfo
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- CN113234059B CN113234059B CN202110578681.XA CN202110578681A CN113234059B CN 113234059 B CN113234059 B CN 113234059B CN 202110578681 A CN202110578681 A CN 202110578681A CN 113234059 B CN113234059 B CN 113234059B
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- C07D341/00—Heterocyclic compounds containing rings having three or more sulfur atoms as the only ring hetero atoms
Abstract
The invention relates to a preparation method of lipoic acid impurity A, belonging to the field of compound synthesis. The invention aims to overcome the defects of complex operation and harsh reaction conditions in the prior art, and provides a preparation method of lipoic acid impurity A with mild conditions and high product purity, which comprises the following steps: (1) Dissolving the thiooctanoic acid in a reaction solvent, adding an oxidant for reaction, and removing solids and the solvent after the reaction is completed to obtain a compound B; (2) Respectively adding the compound B, sodium thiosulfate and a catalyst into water, then adding hydrochloric acid, carrying out hydrolysis ring-opening reaction, and filtering after the reaction is finished to obtain a compound C; (3) And (3) respectively adding the compound C, sodium sulfide and formaldehyde into a reaction solvent for reaction, and extracting, drying and purifying after the reaction is finished to obtain the compound D lipoic acid impurity A. The method has mild conditions and the prepared lipoic acid impurity A has high purity.
Description
Technical Field
The invention belongs to the technical field of compound synthesis, and particularly relates to a preparation method of lipoic acid impurity A.
Background
Lipoic acid impurity a is also known as 1,2, 3-trithiocyclohexane-4-pentanoic acid, english name: 1,2,3-Trithiane-4-pentanoic Acid. The molecular formula: c (C) 8 H 14 O 2 S 3 Molecular weight: 238.39 the structural formula is
Lipoic acid is a substance capable of eliminating free radicals, similar to vitamins, which accelerate aging and cause diseases, and is an enzyme existing in mitochondria. Lipoic acid is absorbed by intestinal tracts in vivo and enters cells, and has the characteristics of both fat solubility and water solubility, so that lipoic acid can pass through the whole body without resistance, reaches any cell part, provides comprehensive efficacy for human body, and is the only universal oxygen activating agent with both fat solubility and water solubility.
Because lipoic acid has important pharmacological activity, the synthesis and preparation method of lipoic acid have attracted attention and research since Reed et al in 1951 successfully separated lipoic acid from pig liver for the first time. Many methods for producing lipoic acid have been reported so far, and chemical synthesis methods are mainly used, and they are classified into adipic acid method and cyclohexanone method according to the starting materials. Both of the above processes are accompanied by the production of impurity a during the preparation of lipoic acid.
The oxidation resistance of lipoic acid itself also determines its poor stability, and degradation impurities can occur both in bulk and as a formulation. Related impurity controls are needed during the quality study of lipoic acid drugs. Therefore, research on the preparation method of lipoic acid related impurities is of great significance in controlling the quality of lipoic acid bulk drugs and preparations.
CN107652264a discloses a method for preparing lipoic acid impurity a, which comprises the following steps of taking sulfur and sodium sulfide as raw materials to prepare sodium trisulfide, dropwise adding dichloro monoester while the sodium trisulfide is hot to carry out cyclization reaction, dropwise adding sodium hydroxide to carry out alkaline hydrolysis; then extracting with toluene after acidification with hydrochloric acid, collecting toluene liquid, separating the toluene liquid by silica gel chromatography to collect eluent containing impurity A, and finally refining the eluent to obtain lipoic acid impurity A. The method requires high-temperature reflux reaction and column chromatography, and has harsh reaction conditions and complicated operation.
Disclosure of Invention
Aiming at the problems of complex operation and harsh reaction conditions in the prior art, the invention provides a preparation method of lipoic acid impurity A, which has mild conditions and can prepare high-purity lipoic acid impurity A.
The invention provides a preparation method of lipoic acid impurity A, which comprises the following steps:
(1) Dissolving the thiooctanoic acid in a reaction solvent, adding an oxidant for reaction, and removing solids and the solvent after the reaction is completed to obtain a compound B;
(2) Respectively adding the compound B, sodium thiosulfate and a catalyst into water, then adding hydrochloric acid, carrying out hydrolysis ring-opening reaction, and filtering after the reaction is finished to obtain a compound C;
(3) And (3) respectively adding the compound C, sodium sulfide and formaldehyde into a reaction solvent for reaction, and extracting, drying and purifying after the reaction is finished to obtain the compound D lipoic acid impurity A.
In the preparation method of the lipoic acid impurity A, in the step (1), the reaction solvent is selected from dichloromethane, chloroform or ethanol; preferably chloroform.
In the preparation method of the lipoic acid impurity A, in the step (1), the molar ratio of lipoic acid to oxidant is 1:1 to 2, preferably 1:1.3;
the oxidant is m-chloroperoxybenzoic acid.
Wherein, in the step (1), the reaction temperature is 0-40 ℃, preferably 0-10 ℃.
In the preparation method of the lipoic acid impurity A, in the step (2), the molar ratio of the compound B to the sodium thiosulfate is 1:2 to 2.5, preferably 1:2.2.
in the preparation method of the lipoic acid impurity A, in the step (2), the catalyst is selected from dodecyl trimethyl ammonium chloride, tetrabutylammonium bromide or tetrabutylammonium bisulfate, preferably tetrabutylammonium bromide; the catalyst is used in an amount of 4 to 6% by mass, preferably 4% by mass, based on the mass of the compound B.
Wherein, in the step (2), the reaction temperature is 25-45 ℃, preferably 40-45 ℃;
the reaction time is 1 to 5 hours, preferably 2 to 3 hours.
In the preparation method of the lipoic acid impurity A, in the step (3), the dosage ratio of the compound C to sodium sulfide to formaldehyde is 1:1 to 1.5:2 to 2.5, preferably 1:1.4:2.
in the preparation method of the lipoic acid impurity A, in the step (3), the reaction solvent is tetrahydrofuran, dioxane or isopropyl ether, preferably tetrahydrofuran; the reaction temperature is 0 to 50 ℃, preferably 10 to 20 ℃.
In the step (3), the purification refers to dissolving the dried substance in a mixed solvent, and crystallizing at the temperature of-10 to 10 ℃ to obtain the lipoic acid impurity A; preferably, the crystallization temperature is-5-0 ℃; the mixed solvent consists of tert-butyl acetate, ethyl acetate, isopropanol, petroleum ether and/or cyclohexane, preferably consists of mixed solvent of tert-butyl acetate, isopropanol and cyclohexane, and more preferably the volume ratio of isopropanol to tert-butyl acetate to cyclohexane is 1:2:10.
the invention has the beneficial effects that:
the lipoic acid impurity A is obtained through three steps of oxidation, hydrolysis and cyclization, the reaction condition is mild, and the purity of the prepared lipoic acid impurity A is high, so that the lipoic acid impurity A can be used for controlling the quality of lipoic acid bulk drugs and preparations.
Drawings
FIG. 1 is a chromatogram of lipoic acid impurity A prepared in example 1.
Detailed Description
The present invention will be described in more detail by way of examples, but the scope of the present invention is not limited thereto, and any changes or substitutions that would be apparent to one skilled in the art within the scope of the present invention should be construed as falling within the scope of the present invention.
The materials and instruments used in the detailed description of the invention are commercially available.
Example 1
(1) Preparation of Compound B
15g (72.7 mmol) of lipoic acid is dissolved in 100mL of chloroform, 16.31g (94.51 mmol) of m-chloroperoxybenzoic acid is slowly added in batches, after the addition, the reaction is kept at 0-10 ℃ for 2h, a large amount of solids are separated out after the reaction is completed, the filtration is carried out, and the filtrate is evaporated to dryness, so that a pale yellow solid compound B10.2g is obtained, and the yield is 63.11%.
(2) Preparation of Compound C
7.33g (32.97 mmol) of compound B, 13.79g (72.53 mmol) of sodium thiosulfate, 0.30g of tetrabutylammonium bromide and 70mL of purified water are respectively added into a 250mL three-necked flask, 10.03g (98.91 mmol) of hydrochloric acid solution is slowly added dropwise under the heating temperature of 40-45 ℃, the reaction is carried out for 3h after the dropwise addition, chloroform extraction is carried out after the reaction is finished, the water phase is discarded, the organic phase anhydrous magnesium sulfate is dried, the filtrate is evaporated to dryness after filtration, and the target product compound C3.52 g is obtained, and the yield is 51.24%.
(3) Preparation of Compound D
To a 100mL three-necked flask, 2.23g (10.7 mmol) of Compound C, 1.90g (21.41 mmol) of a 35% aqueous formaldehyde solution and 20mL of tetrahydrofuran were added, and an aqueous sodium sulfide solution composed of 3.61g (14.99 mmol) of sodium sulfide nonahydrate and 30mL of purified water was added at a temperature of 10℃or lower, followed by 1-hour dropping. After the dripping, the temperature is raised to 20 ℃ and the reaction is carried out for 2 hours. After the reaction is finished, chloroform is added for extraction, a water phase is discarded, an organic phase is dried and evaporated to dryness to obtain crude lipoic acid impurity A, the crude lipoic acid impurity A is dissolved in a mixed solvent of 2mL of tertiary butyl acetate and 1mL of isopropanol at the temperature of 40 ℃, 20mL of cyclohexane is added after the crude lipoic acid impurity A is dissolved, the mixture is stirred for 10 minutes, the temperature is slowly reduced to below 0 ℃ and is stirred for 10 hours, the mixture is filtered to obtain a compound D (lipoic acid impurity A) of 0.818g, the purity of the lipoic acid impurity A detected by HPLC is 99.788%, and the yield is 32.06%.
Claims (21)
1. The preparation method of the lipoic acid impurity A is characterized by comprising the following steps:
(1) Dissolving the thiooctanoic acid in a reaction solvent, adding an oxidant for reaction, and removing solids and the solvent after the reaction is completed to obtain a compound B;
(2) Respectively adding the compound B, sodium thiosulfate and tetrabutylammonium bromide serving as a catalyst into water, then adding hydrochloric acid, carrying out hydrolysis ring-opening reaction, and filtering after the reaction is finished to obtain a compound C;
(3) And (3) respectively adding the compound C, sodium sulfide and formaldehyde into a reaction solvent for reaction, and extracting, drying and purifying after the reaction is finished to obtain the compound D lipoic acid impurity A.
2. The method for preparing lipoic acid impurity a according to claim 1, characterized in that: in the step (1), the reaction solvent is selected from dichloromethane, chloroform or ethanol.
3. The method for preparing lipoic acid impurity a according to claim 2, characterized in that: in the step (1), the reaction solvent is chloroform.
4. The method for preparing lipoic acid impurity a according to claim 2, characterized in that: in the step (1), the molar ratio of lipoic acid to oxidant is 1: 1-2, wherein the oxidant is m-chloroperoxybenzoic acid.
5. The method for producing lipoic acid impurity a according to claim 4, characterized in that: in the step (1), the molar ratio of lipoic acid to oxidant is 1:1.3.
6. the method for producing lipoic acid impurity a according to claim 4, characterized in that: in the step (1), the reaction temperature is 0-40 ℃.
7. The method for producing lipoic acid impurity a according to claim 6, characterized in that: in the step (1), the reaction temperature is 0-10 ℃.
8. The method for preparing lipoic acid impurity a according to claim 1, characterized in that: in the step (2), the molar ratio of the compound B to the sodium thiosulfate is 1:2 to 2.5.
9. The method for preparing lipoic acid impurity a according to claim 8, characterized in that: in the step (2), the molar ratio of the compound B to the sodium thiosulfate is 1:2.2.
10. the method for preparing lipoic acid impurity a according to claim 8, characterized in that: in the step (2), the catalyst is used in an amount of 4-6% of the mass of the compound B.
11. The method for preparing lipoic acid impurity a according to claim 10, characterized in that: in the step (2), the catalyst is used in an amount of 4% by mass of the compound B.
12. The method for producing lipoic acid impurity a according to claim 6, characterized in that: in the step (2), the reaction temperature is 25-45 ℃ and the reaction time is 1-5 hours.
13. The method for preparing lipoic acid impurity a according to claim 12, characterized in that: in the step (2), the reaction temperature is 40-45 ℃; the reaction time is 2-3 hours.
14. The method for preparing lipoic acid impurity a according to claim 1, characterized in that: in the step (3), the molar ratio of the compound C to sodium sulfide to formaldehyde is 1:1 to 1.5:2 to 2.5.
15. The method for preparing lipoic acid impurity a according to claim 14, characterized in that: in the step (3), the molar ratio of the compound C to sodium sulfide to formaldehyde is 1:1.4:2.
16. the method for preparing lipoic acid impurity a according to claim 14, characterized in that: in the step (3), tetrahydrofuran, dioxane or isopropyl ether is selected as the reaction solvent; the reaction temperature is 0-50 ℃.
17. The method for preparing lipoic acid impurity a according to claim 16, characterized in that: in the step (3), the reaction solvent is tetrahydrofuran; the reaction temperature is 10-20 ℃.
18. The method for preparing lipoic acid impurity a according to claim 16, characterized in that: in the step (3), the purification refers to dissolving the dried substance in a mixed solvent, and crystallizing at the temperature of-10 to 10 ℃ to obtain the lipoic acid impurity A.
19. The method for preparing lipoic acid impurity a according to claim 18, characterized in that: in the step (3), the crystallization temperature is-5-0 ℃; the mixed solvent consists of tert-butyl acetate, ethyl acetate, isopropanol, petroleum ether and/or cyclohexane.
20. The method for preparing lipoic acid impurity a according to claim 19, characterized in that: in the step (3), the mixed solvent is a mixed solvent of tert-butyl acetate, isopropanol and cyclohexane.
21. The method for preparing lipoic acid impurity a according to claim 20, characterized in that: in the step (3), the volume ratio of the isopropanol to the tert-butyl acetate to the cyclohexane is 1:2:10.
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| CN113717150A (en) * | 2021-10-28 | 2021-11-30 | 苏州富士莱医药股份有限公司 | Preparation method of lipoic acid impurity A |
| CN115716817B (en) * | 2022-11-22 | 2024-04-19 | 国药集团威奇达药业有限公司 | Preparation method of 6, 8-cyclotristhioctic acid |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4614821A (en) * | 1983-10-28 | 1986-09-30 | Takeda Chemical Industries, Ltd. | Method of producing 1,2,3-trithiane compounds |
| CN1355167A (en) * | 2000-11-30 | 2002-06-26 | 贵州华庆化工有限责任公司 | Process for preparing trithiocyclohexane hydrochloride |
| CN105175432A (en) * | 2015-09-09 | 2015-12-23 | 山东罗欣药业集团股份有限公司 | Preparation method of cefditore |
| CN107652264A (en) * | 2017-09-25 | 2018-02-02 | 苏州华诺医药有限公司 | The preparation method of lipoic acid impurity A |
| CN110407805A (en) * | 2019-07-09 | 2019-11-05 | 江苏第二师范学院（江苏省教育科学研究院） | Lipoic acid aldehyde derivative and preparation method thereof, application |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| ITMI20050466A1 (en) * | 2005-03-22 | 2006-09-23 | Laboratorio Chimico Int Spa | PURIFICATION PROCESS IN WATER OF TIOTIC ACID |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4614821A (en) * | 1983-10-28 | 1986-09-30 | Takeda Chemical Industries, Ltd. | Method of producing 1,2,3-trithiane compounds |
| CN1355167A (en) * | 2000-11-30 | 2002-06-26 | 贵州华庆化工有限责任公司 | Process for preparing trithiocyclohexane hydrochloride |
| CN105175432A (en) * | 2015-09-09 | 2015-12-23 | 山东罗欣药业集团股份有限公司 | Preparation method of cefditore |
| CN107652264A (en) * | 2017-09-25 | 2018-02-02 | 苏州华诺医药有限公司 | The preparation method of lipoic acid impurity A |
| CN110407805A (en) * | 2019-07-09 | 2019-11-05 | 江苏第二师范学院（江苏省教育科学研究院） | Lipoic acid aldehyde derivative and preparation method thereof, application |
Non-Patent Citations (1)
| Title |
|---|
| α -硫辛酸合成方法及其衍生物的研究进展;温全武 等;《应用化学》;第42卷(第1期);第144-151页 * |
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