CN117362269A - Alpha-lipoic acid intermediate compound and preparation method thereof - Google Patents

Alpha-lipoic acid intermediate compound and preparation method thereof Download PDF

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CN117362269A
CN117362269A CN202210782159.8A CN202210782159A CN117362269A CN 117362269 A CN117362269 A CN 117362269A CN 202210782159 A CN202210782159 A CN 202210782159A CN 117362269 A CN117362269 A CN 117362269A
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reaction
compound
alpha
lipoic acid
organic phase
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刘忠
朱国
时江华
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Shandong New Time Pharmaceutical Co Ltd
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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
    • C07D339/08—Six-membered rings
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention belongs to the field of pharmaceutical chemical industry, and particularly relates to an alpha-lipoic acid intermediate compound and a preparation method thereof. The invention takes 2, 2-dimethyl-1, 3-dithiane-1-oxide and 3-oxo-4-ethyl enoate as starting materials, and the new intermediate compound of alpha-lipoic acid, namely 5- (2, 2-dimethyl-3-oxide-1, 3-dithiane) -3-hydroxy-ethyl valerate, is obtained through reaction under the action of a catalyst, and the new intermediate is eliminated and hydrolyzed to obtain high-purity alpha-lipoic acid.

Description

Alpha-lipoic acid intermediate compound and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutical chemical industry, and particularly relates to an alpha-lipoic acid intermediate compound and a preparation method thereof.
Background
Alpha-lipoic acid (alpha-lipoic acid), the chemical name is 1, 2-dithiocyclopentanyl-3-pentanoic acid alpha-lipoic acid, which can eliminate pathogenic free radicals, belongs to vitamin medicines, and is the only universal antioxidant with both fat solubility and water solubility. Has therapeutic effects on liver disease, diabetes, AIDS, skin cancer, parkinson disease, rheumatism, etc., and has the following structural formula:
because of the important physiological roles of alpha-lipoic acid, chemical synthesis thereof has attracted extensive attention from researchers, and considerable reports have been made about total synthesis of alpha-lipoic acid. Among them, adipic acid and its derivatives, cyclohexanone and its derivatives are the main methods for synthesizing alpha-lipoic acid.
The method takes adipic acid as a starting material, and comprises seven steps of reaction of esterification, substitution, addition, reduction, re-substitution and vulcanization to obtain the alpha-lipoic acid, wherein the yield is 34.6%. However, the dosage of methanol is difficult to control during the esterification reaction, sodium sulfide is used in the method, a polymer is easy to form during the reaction, the polymer is difficult to separate, the purity of the product is low, and the reaction is as follows:
in 1961, the use of adipic acid derivatives has been improved by the scholars on the basis of this, mainly by the following two methods:
(1) Ethyl 4-chloroformyl valerate process: the method uses sodium benzoate to replace sodium sulfide, so that the purity of the prepared product is higher, but the product needs to react with sodium in liquid ammonia, the operation cost is high, the total yield is not more than 30 percent, and the reaction is as follows:
(2) Adipic acid monoethyl ester acyl chloride process: the adipic acid monoethyl ester acyl chloride is used as a starting material, and the plexyl octanoate ethyl ester-7-alkene-6-ketone is reduced, hydrobromic acid is brominated, and methyl esterification can obtain higher yield, but the disadvantage is that the price of phosphorus tribromide is higher. The reaction is as follows:
in 1999, wang Dun and the like, cyclohexanone is taken as a starting material, and alpha-lipoic acid is obtained through five reactions of enamine, addition, peroxidation, substitution and oxidation, and the total yield is 25%. The method has the characteristics of short reaction steps, simple operation and higher yield, and the synthesis route is as follows, in the synthesis of cyclohexanone and derivatives thereof, the key step is the synthesis of 6-hydroxy-8-acetoxy n-octanoic acid lactone, and the catalyst commonly used in the step is peroxy acid, such as: meta-chloroperbenzoic acid, trichloroperacetic acid, peracetic acid, and the like. However, most of these conventional catalysts are toxic and the resulting products are in the form of racemates:
the preparation process based on the alpha-lipoic acid in the route has more defects. Developing a new preparation process of alpha-lipoic acid, which is simple to operate, mild in reaction condition and beneficial to industrial production, is a problem which needs to be solved at present.
Disclosure of Invention
Based on the problems in the above route, the invention provides a novel alpha-lipoic acid intermediate compound and a method for preparing alpha-lipoic acid by using the novel intermediate compound, and the method has the advantages of simple operation, mild reaction conditions and contribution to industrial production.
In a first aspect, the present invention provides a novel alpha-lipoic acid intermediate compound having the structure of formula II:
the invention provides a preparation method of an alpha-lipoic acid intermediate compound II, which comprises the following specific steps: under the protection of inert gas, adding a compound SM-1 and an organic solvent A into a reaction bottle, and controlling the temperature T A Slowly adding alkali A, adding compound SM-2, reacting at constant temperature until the reaction is finished, adding saturated ammonium chloride aqueous solution for quenching, separating an organic phase, extracting an aqueous phase with ethyl acetate, washing the organic phase with water, washing with alkali, drying, concentrating, adding a reducing agent A and an organic solvent B into the concentrate, and reacting at room temperature until the reaction is finished to obtain a compound II, wherein the following steps are adopted:
preferably, the organic solvent A is selected from one or a combination of anhydrous tetrahydrofuran, acetonitrile, toluene and 1, 4-dioxane, and particularly preferably anhydrous tetrahydrofuran.
Preferably, said T A Is at the temperature of-10 ℃ to 0 ℃.
Preferably, the base A is selected from one of n-butyllithium, tri-sec-butyllithium borohydride, lithium diisopropylamide and lithium borohydride, and among them, n-butyllithium is particularly preferred.
Preferably, the reducing agent A is selected from one of sodium borohydride and sodium cyanoborohydride, wherein sodium borohydride is particularly preferred.
Preferably, the feeding mole ratio of the compound SM-1, the alkali A, the compound SM-2 and the reducing agent A is as follows: 1.0:1.0 to 1.8:1.0 to 1.5:1.0 to 2.0:1.2 to 2.0, of which 1 is particularly preferred: 1.17:1.08:1.67.
preferably, the organic solvent B is selected from one or a combination of absolute methanol, ethanol, acetonitrile and tetrahydrofuran, and particularly preferably the absolute methanol
In a preferred scheme, after the reaction is finished, the post-treatment operation is needed, specifically, after the reaction is finished, the solvent is evaporated by concentrating under reduced pressure, ethyl acetate is added into the crude product, the organic phase is washed once by water and saturated saline solution respectively, the organic phase is separated, anhydrous sodium sulfate is added for drying, the drying agent is filtered and removed, the solvent is evaporated by concentrating under reduced pressure, and the crude product is recrystallized by n-hexane and ethyl acetate to obtain II.
The invention provides an application of a compound II in preparing alpha-lipoic acid, which comprises the following steps: eliminating the compound II to obtain a compound III; the compound III is hydrolyzed to obtain alpha-lipoic acid, and the synthetic route is as follows:
preferably, the above steps are described in further detail in the following section:
preparation of Compound III:
adding a compound II, a catalyst B, imidazole and an organic solvent C into a reaction bottle, slowly adding carbon disulfide, reacting at room temperature, cooling a reaction system to 0 ℃, slowly adding MeI, stirring at room temperature until the reaction is finished, slowly adding a saturated ammonium chloride aqueous solution at 0 ℃ for quenching reaction, separating an organic phase, extracting an aqueous phase with dichloromethane, washing the organic phase with water, washing with alkali, drying, concentrating under reduced pressure, evaporating the solvent, adding tributyltin hydride and the organic solvent D into the residual concentrate, heating the catalyst C, and refluxing until the reaction is finished, thus obtaining the compound III.
Preferably, the catalyst B is selected from any one of sodium hydride, sodium borohydride and calcium hydride, wherein sodium hydride is particularly preferred.
Preferably, the organic solvent C is selected from one or a combination of anhydrous tetrahydrofuran, acetonitrile, toluene, wherein anhydrous tetrahydrofuran is particularly preferred.
Preferably, the catalyst C is selected from one of azobisisobutyronitrile, azobisisoheptonitrile, dimethyl azobisisobutyrate, with azobisisobutyronitrile being particularly preferred.
Preferably, the organic solvent D is selected from one or a combination of anhydrous toluene, tetrahydrofuran, acetonitrile, wherein anhydrous toluene is particularly preferred
Preferably, the feeding mole ratio of the compound II to the catalyst B to the imidazole to the carbon disulfide to the MeI to the tributyl tin hydride to the catalyst C is 1:8.0-12.0:0.08-0.15:3.0-5.0:3.0-5.0:2.0-3.0:0.08-0.15, and particularly preferably 1:10:0.1:4.0:4.0:2.6:0.1.
In a preferred embodiment, after the reaction is completed, a post-treatment operation is performed, specifically: after the reaction was completed, the system was cooled slowly to room temperature, washed with water and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove the drying agent, concentrating under reduced pressure, and evaporating solvent to obtain the compound III.
Preparation of alpha-lipoic acid
Adding a compound III and methanol into a reaction bottle, stirring and dissolving, adding a sodium hydroxide aqueous solution for constant temperature reaction, pressing and distilling to remove the methanol after the reaction is finished, acidifying the aqueous phase with 2mol/L hydrochloric acid until the pH value is 3-4, separating out yellow oily matters, extracting with ethyl acetate (2X 100 mL), merging organic phases, washing the organic phases with saturated saline water, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain alpha-lipoic acid.
Compared with the prior art, the invention has the following effects
1. Provides a novel intermediate compound II of alpha-lipoic acid, and provides a novel method for simply and efficiently preparing the alpha-lipoic acid by using the compound, and the whole synthesis method has simple operation, high reaction yield and high purity of the obtained product;
2. the obtained new intermediate compound II has simple structure, no new impurity in the next elimination and hydrolysis reaction, high yield and high purity.
Detailed Description
The invention is further illustrated by the following examples. It should be correctly understood that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
The structure of the novel compound obtained by the invention is confirmed:
high resolution mass spectrum of compound II: ESI-HRMS m/z=308.1118 [ M+H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ6.77(br,1H),4.13(m,1H),4.01(q,2H),2.61(d,1H),2.50(t,2H),2.41(m,3H),1.40(m,3H),1.3(m,8H),1.07(t,3H)； 13 C-NMR(100MHz,DMSO-d 6 )δ:173.1,67.5,61.3,42.0,41.0,40.0,37.2,37.1，21.3,21.2,21.0,14.0,9.0.
HPLC detection method of compound II
HPLC peak area normalization method:
chromatographic column YMC-Triart C 18 Columns (4.6 mm. Times.250 mm,5 μm);
mobile phase acetonitrile: water (90:10);
column temperature: 30 ℃;
detection wavelength: 210nm;
flow rate: 1.0ml/min;
sample injection amount: 10 μl;
retention time: 10.3min.
High resolution mass spectrum of compound III: ESI-HRMS m/z=293.4522 [ M+H ]] + ； 1 H-NMR(400MHz,DMSO-d6):4.01(q,2H),2.50(t,2H),2.40(dt,2H),2.32(t,2H),1.66(m,2H),1.40(m,1H),1.25(m,2H)，1.3(m,8H),1.07(t,3H)； 13 C-NMR(100MHz,DMSO-d 6 )δ:173.1,61.3,41.0,37.2,37.1，33.9,31.8,24.7，21.3,21.2,21.0,16.0,14.1.
HPLC peak area normalization method:
chromatographic column YMC-Triart C 18 Columns (4.6 mm. Times.250 mm,5 μm);
mobile phase acetonitrile: water (90:10);
column temperature: 30 ℃;
detection wavelength: 230nm;
flow rate: 1.0ml/min;
sample injection amount: 10 μl;
retention time: 16.8min.
High resolution mass spectrum of compound I: ESI-HRMS m/z=299.0330 [ M+Na ]] + ； 1 H-NMR(400MHz,CDCl 3 ):3.57(m,1H),3.15(m,2H),2.46(dt,1H),2.38(t,2H),1.91(dt,1H),1.68(m,4H),1.49(m,2H)； 13 C-NMR(100MHz,CDCl 3 )δ:179.21,56.30,40.24,38.52,34.61,33.72,28.69,24.41。
HPLC peak area normalization method:
chromatographic column YMC-Triart C 18 Columns (4.6 mm. Times.250 mm,5 μm);
mobile phase acetonitrile: water (20:80);
column temperature: 30 ℃;
detection wavelength: 230nm;
flow rate: 1.0ml/min;
sample injection amount: 10 μl;
retention time: 6.7min.
Preparation of Compound SM-1
Into a two-necked flask, 2-dimethyl-1, 3-dithiane (29.66 g,0.20 mol), naIO were added 4 (42.78 g,0.20 mol) with anhydrous methanol (250 mL), -5℃for 3 hours. After the reaction, the solvent was distilled off by concentration under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether (1:10, volume ratio)) to give SM-1 as a pale yellow oily compound in 98.5% yield and 99.95% HPLC purity [ HPLC peak area normalization method: chromatographic column YMC-Triart C 18 Columns (4.6 mm. Times.250 mm,5 μm); mobile phase acetonitrile: water (90:10); column temperature is 30 ℃; the detection wavelength is 230nm; the flow rate is 1.0ml/min; sample injection amount is 10 μl; retention time 18.6min]。 1 H-NMR(400MHz,DMSO-d 6 )δ:2.42(t,2H),1.70(m,2H),1.30(m,8H)； 13 C-NMR(100MHz,DMSO-d 6 )δ:43.2,41.0,37.1,37.0,30.6,25.0；ESI-HRMS(m/z):164.0333[M+H] + 。
Preparation of Compound II
Example 1
To a double-necked flask, compound SM-1 (20.00 g,0.12 mol) and dry tetrahydrofuran (50 mL) were added dropwise at 5℃under nitrogen protection, followed by reaction at constant temperature for 30 minutes by adding n-butyllithium (57.6 mL,0.14mol,2.5mol/L in n-hexane) and slowly adding compound SM-2 (17.9 g,0.13mol in 50mL of anhydrous tetrahydrofuran), followed by reaction at 5℃for 3 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (100 mL) was slowly added at 0 ℃ to quench, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (100 ml×3), the organic phases were combined, each of the organic phases was washed once with water and a saturated aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove desiccant, concentrating under reduced pressure to remove solvent, adding NaBH into the concentrate 4 (7.57 g,0.20 mol) and absolute methanol (150 mL) were dissolved with stirring, and reacted at 0℃for 1 hour and then at room temperature for 1 hour. After the completion of the reaction, the solvent was distilled off by concentration under reduced pressure, ethyl acetate (150 mL) was added to the crude product, and the organic phase was usedWashing water and saturated saline water once respectively, separating an organic phase, adding anhydrous sodium sulfate for drying, filtering to remove a drying agent, concentrating under reduced pressure, evaporating to remove a solvent, and recrystallizing a crude product by using n-hexane and ethyl acetate (200 ml, volume ratio is 1:1) to obtain a compound II, wherein the yield is 96.5%, and the HPLC purity is 99.85%.
Example 2
To a double-necked flask, compound SM-1 (20.00 g,0.12 mol) and dry acetonitrile (50 mL) were added dropwise at 10℃under nitrogen protection, followed by reaction at constant temperature for 30 minutes by adding n-butyllithium (48.0 mL,0.12mol,2.5mol/L in n-hexane) and slowly adding compound SM-2 (17.9 g,0.13mol in 50mL of anhydrous tetrahydrofuran), followed by reaction at 10℃for 3 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (100 mL) was slowly added at 0 ℃ to quench, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (100 ml×3), the organic phases were combined, each of the organic phases was washed once with water and a saturated aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove desiccant, concentrating under reduced pressure to remove solvent, adding NaBH into the concentrate 4 (7.57 g,0.20 mol) and absolute methanol (150 mL) were dissolved with stirring, and reacted at 0℃for 1 hour and then at room temperature for 1 hour. After the completion of the reaction, the solvent was distilled off by concentration under reduced pressure, ethyl acetate (150 mL) was added to the crude product, the organic phase was washed once with water and saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from n-hexane and ethyl acetate (200 mL, volume ratio 1:1) to give compound II in a yield of 92.2% and HPLC purity of 99.62%.
Example 3
To a double-necked flask, compound SM-1 (20.00 g,0.12 mol) and dry toluene (50 mL) were added dropwise at 0℃under nitrogen protection, and the mixture was reacted at constant temperature for 30 minutes by adding n-butyllithium (72.0 mL,0.18mol,2.5mol/L in n-hexane) and slowly adding compound SM-2 (17.9 g,0.13mol in 50mL of anhydrous tetrahydrofuran) and reacted at 0℃for 3 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (100 mL) was slowly added at 0 ℃ to quench, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (100 ml×3), the organic phases were combined, each of the organic phases was washed once with water and a saturated aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the solvent was distilled off by concentration under reduced pressure, sodium cyanoborohydride (12.57 g,0.20 mol) and absolute methanol (150 mL) were added to the above concentrate and dissolved with stirring, and the mixture was reacted at 0℃for 1 hour and then at room temperature for 1 hour. After the completion of the reaction, the solvent was distilled off by concentration under reduced pressure, ethyl acetate (150 mL) was added to the crude product, the organic phase was washed once with water and saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from n-hexane and ethyl acetate (200 mL, volume ratio 1:1) to give compound II in a yield of 93.6% and HPLC purity of 99.51%.
Example 4
To a double-necked flask, compound SM-1 (20.00 g,0.12 mol) and dried 1, 4-dioxane (50 mL) were added dropwise at 5℃under nitrogen protection, lithium tri-sec-butylborohydride (140.0 mL,0.14mol,1.0mol/L in tetrahydrofuran) was reacted at constant temperature for 30 minutes, compound SM-2 (17.04 g,0.12mol, dissolved in 50mL of anhydrous tetrahydrofuran) was slowly added, and the reaction was carried out at 5℃for 3 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (100 mL) was slowly added at 0 ℃ to quench, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (100 ml×3), the organic phases were combined, each of the organic phases was washed once with water and a saturated aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove desiccant, concentrating under reduced pressure to remove solvent, adding NaBH into the concentrate 4 (7.57 g,0.20 mol) and absolute methanol (150 mL) were dissolved with stirring, and reacted at 0℃for 1 hour and then at room temperature for 1 hour. After the completion of the reaction, the solvent was distilled off by concentration under reduced pressure, ethyl acetate (150 mL) was added to the crude product, the organic phase was washed once with water and saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from n-hexane and ethyl acetate (200 mL, volume ratio 1:1) to give compound II in a yield of 91.8% and an HPLC purity of 99.71%.
Example 5
Into a double-necked flask, under nitrogen protection, compound SM-1 (20.00 g,0.12 mol) and dry 1, 4-dioxane (50 mL) were added dropwise lithium diisopropylamide (70.0 mL,0.14mol,2.0 mol/L) at 5 ℃Tetrahydrofuran n-heptane mixed solution), for 30 minutes at constant temperature, compound SM-2 (34.08 g,0.24mol, dissolved in 50mL of anhydrous tetrahydrofuran) was slowly added and reacted at-5 ℃ for 3 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (100 mL) was slowly added at 0 ℃ to quench, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (100 ml×3), the organic phases were combined, each of the organic phases was washed once with water and a saturated aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove desiccant, concentrating under reduced pressure to remove solvent, adding NaBH into the concentrate 4 (7.57 g,0.20 mol) and absolute methanol (150 mL) were dissolved with stirring, and reacted at 0℃for 1 hour and then at room temperature for 1 hour. After the completion of the reaction, the solvent was distilled off by concentration under reduced pressure, ethyl acetate (150 mL) was added to the crude product, the organic phase was washed once with water and saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from n-hexane and ethyl acetate (200 mL, volume ratio 1:1) to give compound II in a yield of 93.2% and HPLC purity of 99.51%.
Example 6
To a double-necked flask, compound SM-1 (20.00 g,0.12 mol) and dry tetrahydrofuran (50 mL) were added dropwise at 5℃under nitrogen protection, followed by reaction at constant temperature for 30 minutes by adding n-butyllithium (57.6 mL,0.14mol,2.5mol/L in n-hexane) and slowly adding compound SM-2 (17.9 g,0.13mol in 50mL of anhydrous tetrahydrofuran), followed by reaction at 5℃for 3 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (100 mL) was slowly added at 0 ℃ to quench, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (100 ml×3), the organic phases were combined, each of the organic phases was washed once with water and a saturated aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove desiccant, concentrating under reduced pressure to remove solvent, adding NaBH into the concentrate 4 (5.30 g,0.14 mol) and absolute ethanol (150 mL) were dissolved with stirring, and reacted at 0℃for 1 hour and then at room temperature for 1 hour. After the completion of the reaction, the solvent was distilled off by concentration under reduced pressure, ethyl acetate (150 mL) was added to the crude product, the organic phase was washed once with water and saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was purified by distillation with n-hexaneRecrystallisation from ethyl acetate (200 ml, 1:1 by volume) gave compound II in 93.0% yield and 99.74% HPLC purity.
Example 7
To a double-necked flask, compound SM-1 (20.00 g,0.12 mol) and dry tetrahydrofuran (50 mL) were added dropwise at 5℃under nitrogen protection, followed by reaction at constant temperature for 30 minutes by adding n-butyllithium (57.6 mL,0.14mol,2.5mol/L in n-hexane) and slowly adding compound SM-2 (17.9 g,0.13mol in 50mL of anhydrous tetrahydrofuran), followed by reaction at 5℃for 3 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (100 mL) was slowly added at 0 ℃ to quench, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (100 ml×3), the organic phases were combined, each of the organic phases was washed once with water and a saturated aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove desiccant, concentrating under reduced pressure to remove solvent, adding NaBH into the concentrate 4 (9.08 g,0.24 mol) and anhydrous acetonitrile (150 mL) were dissolved with stirring, and reacted at 0℃for 1 hour and then at room temperature for 1 hour. After the completion of the reaction, the solvent was distilled off by concentration under reduced pressure, ethyl acetate (150 mL) was added to the crude product, the organic phase was washed once with water and saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from n-hexane and ethyl acetate (200 mL, volume ratio 1:1) to give compound II in a yield of 92.3% and HPLC purity of 99.51%.
Example 8
To a double-necked flask, compound SM-1 (20.00 g,0.12 mol) and dry tetrahydrofuran (50 mL) were added dropwise at 15℃under nitrogen protection, followed by reaction at constant temperature for 30 minutes, compound SM-2 (17.9 g,0.13mol, dissolved in 50mL of anhydrous tetrahydrofuran) was slowly added, and reaction was carried out at 15℃for 3 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (100 mL) was slowly added at 0 ℃ to quench, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (100 ml×3), the organic phases were combined, each of the organic phases was washed once with water and a saturated aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove desiccant, concentrating under reduced pressure to remove solvent, adding NaBH into the concentrate 4 (4.54 g,0.12 mol) and anhydrousMethanol (150 mL) was dissolved by stirring, and the reaction was carried out at 0℃for 1 hour and then at room temperature for 1 hour. After the reaction was completed, the solvent was distilled off by concentration under reduced pressure, ethyl acetate (150 mL) was added to the crude product, the organic phase was washed once with water and saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from n-hexane and ethyl acetate (200 mL, volume ratio 1:1) to give compound II in a yield of 86.4% and an HPLC purity of 98.77%.
Example 9
To a double-necked flask, compound SM-1 (20.00 g,0.12 mol) and dry tetrahydrofuran (50 mL) were added dropwise at 5℃under nitrogen protection, and the mixture was reacted at constant temperature for 30 minutes, compound SM-2 (35.8 g,0.26mol, dissolved in 100mL of anhydrous tetrahydrofuran) was slowly added, and the reaction was carried out at 5℃for 3 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (100 mL) was slowly added at 0 ℃ to quench, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (100 ml×3), the organic phases were combined, each of the organic phases was washed once with water and a saturated aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove desiccant, concentrating under reduced pressure to remove solvent, adding NaBH into the concentrate 4 (10.0 g,0.26 mol) and absolute methanol (200 mL) were dissolved with stirring, and reacted at 0℃for 1 hour and then at room temperature for 1 hour. After the reaction was completed, the solvent was distilled off by concentration under reduced pressure, ethyl acetate (150 mL) was added to the crude product, the organic phase was washed once with water and saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was recrystallized from n-hexane and ethyl acetate (200 mL, volume ratio 1:1) to give compound II in a yield of 87.8% and an HPLC purity of 97.87%.
Preparation of Compound III
Example 10
Into a single vial was added Compound II (18.45 g,0.06 mol), naH (14.40 g,0.60 mol), imidazole (0.41 g,6.0 mmol) and anhydrous tetrahydrofuran (600 mL), and CS was slowly added 2 (18.27 g,0.24 mol) was reacted at room temperature for 1 hour. The reaction system was again cooled to 0deg.C, meI (34.07 g,0.24 mol) was slowly added and reacted at room temperature for 3 hoursWhen (1). After the reaction was completed, a saturated aqueous ammonium chloride solution (600 mL) was slowly added at 0 ℃ to quench, the organic phase was separated, the aqueous phase was extracted with methylene chloride (450 ml×3), the organic phases were combined, each of the organic phases was washed once with water and a saturated aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove desiccant, concentrating under reduced pressure, and evaporating solvent; to the concentrate were added tributyltin hydride (46.57 g,0.16 mol) and anhydrous toluene (200 mL), azodiisobutyronitrile (0.99 g,6.0 mmol), and the mixture was refluxed at an elevated temperature for 2 hours. After the reaction was completed, the system was cooled slowly to room temperature, washed with water (250 mL. Times.3) and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is distilled off by vacuum concentration, and the crude product is concentrated under vacuum to obtain the compound IV with the yield of 98.3 percent and the HPLC purity of 99.80 percent.
Example 11
Into a single vial was added Compound II (18.45 g,0.06 mol), naH (11.52 g,0.48 mol), imidazole (0.41 g,6.0 mmol) and anhydrous acetonitrile (600 mL), followed by slow addition of CS 2 (18.27 g,0.24 mol) was reacted at room temperature for 1 hour. The reaction was again cooled to 0℃and MeI (34.07 g,0.24 mol) was slowly added and reacted at room temperature for 3 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (600 mL) was slowly added at 0 ℃ to quench, the organic phase was separated, the aqueous phase was extracted with methylene chloride (450 ml×3), the organic phases were combined, each of the organic phases was washed once with water and a saturated aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove desiccant, concentrating under reduced pressure, and evaporating solvent; to the concentrate were added tributyltin hydride (46.57 g,0.16 mol) and anhydrous toluene (200 mL), azodiisoheptonitrile (1.49 g,6.0 mmol) and refluxed for 2 hours at a temperature. After the reaction was completed, the system was cooled slowly to room temperature, washed with water (250 mL. Times.3) and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was concentrated under reduced pressure to give compound IV in 93.3% yield with a purity of 99.72% by HPLC.
Example 12
Into a single vial was added Compound II (18.45 g,0.06 mol), naH (17.28 g,0.72 mol), imidazole (0.41 g,6.0 mmol) and anhydrous toluene (600 mL) and CS was slowly added 2 (18.27 g,0.24 mol), 1 hour at room temperatureWhen (1). The reaction was again cooled to 0℃and MeI (34.07 g,0.24 mol) was slowly added and reacted at room temperature for 3 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (600 mL) was slowly added at 0 ℃ to quench, the organic phase was separated, the aqueous phase was extracted with methylene chloride (450 ml×3), the organic phases were combined, each of the organic phases was washed once with water and a saturated aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove desiccant, concentrating under reduced pressure, and evaporating solvent; to the concentrate were added tributyltin hydride (46.57 g,0.16 mol) and anhydrous toluene (200 mL), dimethyl azodiisobutyrate (1.38 g,6.0 mmol) was added, and the mixture was refluxed at an elevated temperature for 2 hours. After the reaction was completed, the system was cooled slowly to room temperature, washed with water (250 mL. Times.3) and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is distilled off by vacuum concentration, and the crude product is concentrated under vacuum to obtain the compound IV with the yield of 94.0 percent and the HPLC purity of 99.55 percent.
Example 13
In a single vial was added Compound II (18.45 g,0.06 mol), naH (14.40 g,0.60 mol), imidazole (0.33 g,4.8 mmol) and anhydrous tetrahydrofuran (600 mL), and CS was slowly added 2 (13.71 g,0.18 mol) was reacted at room temperature for 1 hour. The reaction was again cooled to 0℃and MeI (25.55 g,0.18 mol) was slowly added and reacted at room temperature for 3 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (600 mL) was slowly added at 0 ℃ to quench, the organic phase was separated, the aqueous phase was extracted with methylene chloride (450 ml×3), the organic phases were combined, each of the organic phases was washed once with water and a saturated aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove desiccant, concentrating under reduced pressure, and evaporating solvent; to the concentrate were added tributyltin hydride (46.57 g,0.16 mol) and anhydrous toluene (200 mL), azodiisobutyronitrile (0.99 g,6.0 mmol), and the mixture was refluxed at an elevated temperature for 2 hours. After the reaction was completed, the system was cooled slowly to room temperature, washed with water (250 mL. Times.3) and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is distilled off by vacuum concentration, and the crude product is concentrated under vacuum to obtain the compound IV with the yield of 93.2% and the HPLC purity of 99.70%.
Example 14
Into a single vial was added Compound II (18.45 g,0.06 mol), naH (14.40 g,0.60 mol), imidazole(0.61 g,9.0 mmol) and anhydrous tetrahydrofuran (600 mL) were slowly added to CS 2 (22.84 g,0.3 mol) was reacted at room temperature for 1 hour. The reaction was again cooled to 0℃and MeI (42.58 g,0.3 mol) was slowly added and reacted at room temperature for 3 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (600 mL) was slowly added at 0 ℃ to quench, the organic phase was separated, the aqueous phase was extracted with methylene chloride (450 ml×3), the organic phases were combined, each of the organic phases was washed once with water and a saturated aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove desiccant, concentrating under reduced pressure, and evaporating solvent; to the concentrate were added tributyltin hydride (46.57 g,0.16 mol) and anhydrous toluene (200 mL), azodiisobutyronitrile (0.99 g,6.0 mmol), and the mixture was refluxed at an elevated temperature for 2 hours. After the reaction was completed, the system was cooled slowly to room temperature, washed with water (250 mL. Times.3) and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is distilled off by vacuum concentration, and the crude product is concentrated under vacuum to obtain the compound IV with the yield of 95.0 percent and the HPLC purity of 99.49 percent.
Example 15
In a single vial was added Compound II (18.45 g,0.06 mol), naH (14.40 g,0.60 mol), imidazole (0.41 g,6.0 mmol) and anhydrous tetrahydrofuran (600 mL), and CS was slowly added 2 (18.27 g,0.24 mol) was reacted at room temperature for 1 hour. The reaction was again cooled to 0℃and MeI (34.07 g,0.24 mol) was slowly added and reacted at room temperature for 3 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (600 mL) was slowly added at 0 ℃ to quench, the organic phase was separated, the aqueous phase was extracted with methylene chloride (450 ml×3), the organic phases were combined, each of the organic phases was washed once with water and a saturated aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove desiccant, concentrating under reduced pressure, and evaporating solvent; to the concentrate were added tributyltin hydride (34.93 g,0.12 mol) and anhydrous tetrahydrofuran (200 mL), azodiisobutyronitrile (0.79 g,4.8 mmol) and the mixture was refluxed at an elevated temperature for 2 hours. After the reaction was completed, the system was cooled slowly to room temperature, washed with water (250 mL. Times.3) and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is distilled off by vacuum concentration, and the crude product is concentrated under vacuum to obtain the compound IV with the yield of 93.1% and the HPLC purity of 99.71%.
Example 16
Into a single vial was added Compound II (18.45 g,0.06 mol), naH (14.40 g,0.60 mol), imidazole (0.41 g,6.0 mmol) and anhydrous tetrahydrofuran (600 mL), and CS was slowly added 2 (18.27 g,0.24 mol) was reacted at room temperature for 1 hour. The reaction was again cooled to 0℃and MeI (34.07 g,0.24 mol) was slowly added and reacted at room temperature for 3 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (600 mL) was slowly added at 0 ℃ to quench, the organic phase was separated, the aqueous phase was extracted with methylene chloride (450 ml×3), the organic phases were combined, each of the organic phases was washed once with water and a saturated aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove desiccant, concentrating under reduced pressure, and evaporating solvent; to the concentrate were added tributyltin hydride (52.39 g,0.18 mol) and anhydrous acetonitrile (200 mL), azodiisobutyronitrile (1.48 g,9.0 mmol), and the mixture was refluxed at an elevated temperature for 2 hours. After the reaction was completed, the system was cooled slowly to room temperature, washed with water (250 mL. Times.3) and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent is distilled off by vacuum concentration, and the crude product is concentrated under vacuum to obtain the compound IV with the yield of 96.5 percent and the HPLC purity of 99.45 percent.
Example 17
Into a single vial was added Compound II (18.45 g,0.06 mol), naH (10.08 g,0.42 mol), imidazole (0.29 g,4.2 mmol) and anhydrous tetrahydrofuran (600 mL), and CS was slowly added 2 (12.18 g,0.16 mol) was reacted at room temperature for 1 hour. The reaction was again cooled to 0℃and MeI (22.71 g,0.16 mol) was slowly added thereto and reacted at room temperature for 3 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (600 mL) was slowly added at 0 ℃ to quench, the organic phase was separated, the aqueous phase was extracted with methylene chloride (450 ml×3), the organic phases were combined, each of the organic phases was washed once with water and a saturated aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove desiccant, concentrating under reduced pressure, and evaporating solvent; to the concentrate were added tributyltin hydride (29.10 g,0.1 mol) and anhydrous toluene (200 mL), azodiisobutyronitrile (0.69 g,4.2 mmol), and the mixture was refluxed for 2 hours at a temperature. After the reaction was completed, the system was cooled slowly to room temperature, washed with water (250 mL. Times.3) and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove desiccant, concentrating under reduced pressure to remove solvent, concentrating crude product under reduced pressure to obtain the final productCompound IV, 86.1% yield, HPLC purity 98.60%.
Example 18
Into a single vial was added Compound II (18.45 g,0.06 mol), naH (18.0 g,0.75 mol), imidazole (0.68 g,10 mmol) and anhydrous tetrahydrofuran (600 mL), and CS was slowly added 2 (25.13 g,0.33 mol) was reacted at room temperature for 1 hour. The reaction was again cooled to 0deg.C, meI (46.84 g,0.33 mol) was slowly added and reacted at room temperature for 3 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (600 mL) was slowly added at 0 ℃ to quench, the organic phase was separated, the aqueous phase was extracted with methylene chloride (450 ml×3), the organic phases were combined, each of the organic phases was washed once with water and a saturated aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate. Filtering to remove desiccant, concentrating under reduced pressure, and evaporating solvent; to the concentrate were added tributyltin hydride (61.13 g,0.21 mol) and anhydrous toluene (200 mL), azobisisobutyronitrile (1.67 g,10 mmol), and the mixture was refluxed for 2 hours. After the reaction was completed, the system was cooled slowly to room temperature, washed with water (250 mL. Times.3) and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the solvent was distilled off by concentration under reduced pressure, and the crude product was concentrated under reduced pressure to give compound IV in 87.7% yield and 97.60% purity by HPLC.
Preparation of alpha-lipoic acid
Example 19
To a single flask, compound III (5.85 g,0.02 mol) was added and dissolved with methanol (45 mL) under stirring, and an aqueous sodium hydroxide solution (ω=20%, 17.80 mL) was added at room temperature to react at constant temperature for 6 hours. After the reaction, methanol was distilled off under reduced pressure, the aqueous phase was acidified with 2mol/L hydrochloric acid to a pH of 3 to 4, a yellow oily substance was precipitated, extracted with ethyl acetate (2X 100 mL), the organic phases were combined, washed with saturated brine (2X 50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give Compound I in a yield of 96.3% and an HPLC purity of 99.92%.

Claims (10)

1. An alpha-lipoic acid intermediate compound is characterized in that the structure of the alpha-lipoic acid intermediate compound is shown as a formula II:
2. a process for the preparation of the alpha-lipoic acid intermediate compound II according to claim 1, characterized in that the process comprises the steps of: under the protection of inert gas, adding a compound SM-1 and an organic solvent A into a reaction bottle, and controlling the temperature T A Slowly adding alkali A, adding compound SM-2, reacting at constant temperature until the reaction is finished, adding saturated ammonium chloride aqueous solution for quenching, separating an organic phase, extracting an aqueous phase with ethyl acetate, washing the organic phase with water, washing with alkali, drying, concentrating, adding a reducing agent A and an organic solvent B into the concentrate, and reacting at room temperature until the reaction is finished to obtain a compound II, wherein the following steps are adopted:
3. the preparation method according to claim 2, wherein the base A is one selected from n-butyllithium, tri-sec-butyllithium borohydride, lithium diisopropylamide and lithium borohydride.
4. The preparation method according to claim 2, wherein the reducing agent A is one selected from sodium borohydride and sodium cyanoborohydride.
5. The preparation method according to claim 2, wherein the organic solvent a is selected from one or a combination of anhydrous tetrahydrofuran, acetonitrile, toluene, 1, 4-dioxane; the reaction temperature T A Is at the temperature of-10 ℃ to 0 ℃.
6. The preparation method according to claim 2, wherein the compound SM-1, the alkali A, the compound SM-2 and the reducing agent A are fed in the following molar ratio: 1.0:1.0 to 1.8:1.0 to 1.5:1.0 to 2.0:1.2 to 2.0.
7. Use of compound II according to claim 1 for the preparation of alpha-lipoic acid.
8. Use of an alpha-lipoic acid intermediate compound II according to claim 1 for the preparation of alpha-lipoic acid, characterized in that the preparation method comprises the following steps:
step (1): adding a compound II, a catalyst B, imidazole and an organic solvent C into a reaction bottle, slowly adding carbon disulfide, reacting at room temperature, cooling a reaction system to 0 ℃, slowly adding MeI, stirring at room temperature until the reaction is finished, slowly adding a saturated ammonium chloride aqueous solution at 0 ℃ for quenching reaction, separating an organic phase, extracting an aqueous phase with dichloromethane, washing the organic phase with water, washing with alkali, drying, concentrating under reduced pressure, evaporating to remove the solvent, adding tributyltin hydride and an organic solvent D into the residual concentrate, heating and refluxing the catalyst C until the reaction is finished, and obtaining a compound III;
step (2): adding a compound III and methanol into a reaction bottle, stirring and dissolving, adding a sodium hydroxide aqueous solution for constant-temperature reaction, and after the reaction is detected, acidifying the reaction solution to obtain alpha-lipoic acid, wherein the synthetic route is as follows:
9. the use according to claim 8, wherein the catalyst B of step (1) is selected from any one of sodium hydride, sodium borohydride, calcium hydride; the organic solvent C is selected from one or a combination of anhydrous tetrahydrofuran, acetonitrile and toluene; the catalyst C is selected from one of azodiisobutyronitrile, azodiisoheptonitrile and dimethyl azodiisobutyrate; the organic solvent D is selected from one or a combination of anhydrous toluene, tetrahydrofuran and acetonitrile.
10. The use according to claim 8, wherein the molar ratio of the compound II, the catalyst B, the imidazole, the carbon disulfide, the MeI, the tributyltin hydride and the catalyst C in the step (1) is 1.0:8.0-12.0:0.08-0.15:3.0-5.0:3.0-5.0:2.0-3.0:0.08-0.15.
CN202210782159.8A 2022-07-01 2022-07-01 Alpha-lipoic acid intermediate compound and preparation method thereof Pending CN117362269A (en)

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