CN113754630B - Synthetic method of alpha-lipoic acid - Google Patents
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Abstract
A method for synthesizing alpha-lipoic acid, belonging to the technical field of pharmaceutical chemistry synthesis. Firstly, N- (4-bromobutyl) phthalimide is taken as a raw material to prepare a zinc bromide intermediate, then the zinc bromide intermediate reacts with 3- { [2- (trimethylsilyl) ethoxy ] methoxy } propionyl chloride to generate an intermediate-1, and the intermediate-2 is obtained through a hydrazinolysis reaction; which is subjected to iodination reaction to obtain an intermediate-3; carrying out pressurized carbonyl insertion reaction on the intermediate-3 to obtain an intermediate-4; carrying out reduction reaction on the intermediate-4 to obtain an intermediate-5; carrying out deprotection reaction on the intermediate-5 under the action of tetrabutylammonium fluoride to obtain an intermediate-6; carrying out chlorination reaction on the intermediate-6 to obtain an intermediate-7; finally, alpha-lipoic acid is obtained through sulfhydrylation reaction and oxidation ring closing. The method has the advantages of mild process conditions, easily obtained raw materials, high purity of the intermediate and the final product, contribution to quality control and improvement of the raw material medicine of the final product, and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a synthesis method of alpha-lipoic acid.
Background
Alpha-lipoic acid is a compound which can eliminate free radicals which accelerate aging and cause diseases and is similar to vitamins, has the characteristics of water solubility and fat solubility, can assist coenzyme to carry out physiological metabolism which is beneficial to the immunity of an organism, and is a universal antioxidant medicine. Alpha-lipoic acid has certain effects on the treatment of liver diseases, diabetes, HIV virus, tumors, nervous system degeneration, radiation injury, heavy metal poisoning such as arsenic, mercury, cadmium and the like, and can be used for assisting in treating type II diabetes, improving islet function glucose metabolism, protecting nerve cells, preventing cataract, preventing muscle damage and the like.
The literature and patents have published a plurality of alpha-lipoic acid synthetic routes with various characteristics, but most of the routes have high cost, complex synthetic steps and harsh process conditions, easily generate polymer impurities and other process impurities, are difficult to separate and influence the product quality. The main prior art synthesis methods include the following:
1) adipic acid method: adipic acid is used as a starting material, and alpha-lipoic acid is prepared by six steps of methyl esterification, chlorination, ethylene addition, reduction, chlorination, cyclization and ester hydrolysis. The method has total yield of 34.6%, low yield and easy formation
(2) Cyclohexanone and vinyl ether process: cyclohexanone and vinyl ether are used as raw materials, and alpha-lipoic acid can be obtained by 4 steps of free radical addition, Baeyer-Villiger oxidation, lactone hydrolysis, nucleophilic substitution and air oxidation. The method has low cost of raw materials, but the yield is only 45%, the yield is lower, the condition requirement is relatively harsh, the reaction is complex, and a plurality of byproducts are generated, thereby being not beneficial to realizing industrialization.
(3) Ethyl 4-chloroformylvalerate: the method comprises the steps of taking 6, 8-dichloro ethyl caprylate as a raw material, reacting with sodium benzyl mercaptide, hydrolyzing with potassium hydroxide, reducing the ethyl caprylate into 6, 8-dimercaptocaprylate by using metal sodium in liquid ammonia, oxidizing to obtain the alpha-lipoic acid, wherein the yield of the three steps is 53 percent.
The methods for synthesizing alpha-lipoic acid in the prior art, including the three methods mentioned above, all have the disadvantages of high cost, low yield, large raw material consumption, incapability of meeting the requirements of industrial scale-up production, and non-compliance with the requirements of green and environment-friendly production due to high waste discharge.
In view of the above-mentioned prior art, it is necessary to search for a method for synthesizing alpha-lipoic acid that can remedy the above-mentioned deficiencies, and the technical solutions described below have been made in this context.
Disclosure of Invention
The invention aims to provide the alpha-lipoic acid synthesis method which has mild process conditions, is beneficial to reducing the preparation cost, improving the purity, yield and optical purity of the product and reflecting high efficiency, greenness and environmental protection so as to meet the requirement of industrial scale-up production.
The task of the invention is accomplished by the following steps:
A) preparing an intermediate-1, mixing N- (4-bromobutyl) phthalimide with zinc powder, lithium chloride, trimethylchlorosilane, 1, 2-dibromoethane and tetrahydrofuran, reacting to generate a zinc bromide intermediate, controlling the reaction temperature and the reaction time of the reaction to generate the zinc bromide intermediate, and then carrying out substitution reaction on 3- { [2- (trimethylsilyl) ethoxy ] methoxy } propionyl chloride and the zinc bromide intermediate in a tetra (triphenylphosphine) palladium and tetrahydrofuran system to obtain an intermediate-1 (formula INT-1), wherein the reaction formula is as follows:
B) preparing an intermediate-2, and carrying out a hydrazinolysis reaction on the intermediate-1 obtained in the step A) and hydrazine hydrate in a water system to obtain an intermediate-2 (formula INT-2), wherein the reaction formula is as follows:
C) preparing an intermediate-3, mixing 2,4, 6-triphenylpyran boron tetrafluoride salt, potassium iodide, acetic acid and water, reacting to generate 2,4, 6-triphenylpyran iodide, controlling the reaction temperature and the reaction time of the reaction to generate 2,4, 6-triphenylpyran iodide, and carrying out iodination reaction on the intermediate-2 obtained in the step B) and the 2,4, 6-triphenylpyran iodide in a solvent system to obtain an intermediate-3 (formula INT-3), wherein the reaction formula is as follows:
D) preparing an intermediate-4, and carrying out pressurized carbonyl insertion reaction on the intermediate-3 obtained in the step C) and carbon monoxide in a palladium catalyst and solvent system to obtain an intermediate-4 (formula INT-4), wherein the reaction formula is as follows:
E) preparing an intermediate-5, and carrying out reduction reaction on the intermediate-4 obtained in the step D) and sodium borohydride to prepare an intermediate-5 (formula INT-5), wherein the reaction formula is as follows:
F) preparing an intermediate-6, and carrying out deprotection reaction on the intermediate-5 obtained in the step E) in a tetrabutylammonium fluoride and solvent system to obtain an intermediate-6 (formula INT-6), wherein the reaction formula is as follows:
G) preparing an intermediate-7, mixing the intermediate-6 obtained in the step F) with a chlorinating reagent, a catalyst and a solvent, and carrying out chlorination reaction to obtain an intermediate-7 (formula INT-7), wherein the reaction formula is as follows:
H) preparing an intermediate-8, adding the intermediate-7 obtained in the step G) into a system of thiourea and a solvent, and carrying out a sulfhydrylation reaction to obtain an intermediate-8 (formula INT-8), wherein the reaction formula is as follows:
I) preparing a finished product, namely performing oxidation ring closing reaction on the intermediate-8 obtained in the step H) and an oxidant system to obtain alpha-lipoic acid, wherein the reaction formula is as follows:
in a specific embodiment of the invention, the feeding molar ratio of the N- (4-bromobutyl) phthalimide, the 3- { [2- (trimethylsilyl) ethoxy ] methoxy } propionyl chloride, the zinc powder, the lithium chloride, the trimethylchlorosilane and the tetrakis (triphenylphosphine) palladium in the step A) is 1.0: 3.0-6.0: 1.5-2.5: 0.05-0.1; the reaction temperature and the reaction time for generating the zinc bromide intermediate by controlling the reaction are respectively controlled to be 40-60 ℃ and 1-3 h; the temperature of the substitution reaction is 20-35 ℃, and the reaction time is 2-6 h.
In another specific embodiment of the invention, the feeding molar ratio of the intermediate-1 and the hydrazine hydrate in the step B) is 1.0: 1.0-1.3; the temperature of the hydrazinolysis reaction is 80-100 ℃, and the reaction time is 1-3 h.
In another specific embodiment of the invention, the feeding molar ratio of the intermediate-2, 4, 6-triphenylpyran borotetrafluoride salt and potassium iodide in the step C) is 1.0: 1.1-1.3; the reaction temperature and the reaction time for generating the iodinated 2,4, 6-triphenylpyran by controlling the reaction temperature and the reaction time are respectively controlled to be 35-45 ℃ and 2-3 h.
In still another specific embodiment of the present invention, the solvent for the iodination reaction in step C) is toluene, xylene, N-dimethylformamide or N, N-dimethylacetamide; the temperature of the iodination reaction is 100-120 ℃, and the reaction time is 12-24 hours.
In yet another specific embodiment of the present invention, the palladium catalyst in step D) is palladium on carbon, palladium chloride, diallyldipalladium chloride, palladium acetate-triphenylphosphine complex, palladium trifluoroacetate, palladium hydroxide, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium or [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium; the solvent is tetrahydrofuran, ethanol, isopropanol or n-butanol; the feeding molar ratio of the intermediate-3 to the palladium catalyst is 1.0 to (0.05-0.10); the pressure of the carbonyl insertion reaction is 10-30 atmospheric pressure, the reaction temperature is 100-120 ℃, and the reaction time is 6-18 h.
In a more specific embodiment of the invention, the solvent in step F) is tetrahydrofuran, methyl tert-butyl ether or 1, 4-dioxane; the feeding molar ratio of the intermediate-5 to the tetrabutylammonium fluoride is 1.0: 2.0-4.5; the deprotection reaction temperature is 50-100 ℃, and the reaction time is 2-6 h.
In a further specific embodiment of the present invention, the chlorinating agent in step G) is thionyl chloride, phosphorus oxychloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, acetyl chloride or isobutyl chloroformate; the catalyst is triethylamine, N-diisopropylethylamine, diethylamine, ethylenediamine, pyridine, 4-dimethylaminopyridine, 2, 6-dimethylpyridine, tetramethylguanidine, N-methylpyrrolidone, N-methylmorpholine, N-ethylmorpholine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] -non-5-ene or 1, 4-diazabicyclo [2.2.2] octane; the solvent is dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, methyl tert-butyl ether, 1, 4-dioxane or acetonitrile; the feeding molar ratio of the intermediate-6 to the chlorinating agent to the catalyst is 1.0 to (3.5-6.0) to (0.5-1.5); the temperature of the chlorination reaction is 50-80 ℃, and the reaction time is 2-6 h.
In yet a more specific embodiment of the present invention, the solvent in step H) is methanol, ethanol, isopropanol or n-butanol; the feeding molar ratio of the intermediate-7 to the thiourea is 1.0 to (2.5-3.5); the temperature of the sulfhydrylation reaction is 50-90 ℃, and the reaction time is 2-6 h.
In yet another embodiment of the present invention, the oxidant system in step I) is O2/FeCl3/NaOH/H2O or I2KI/ethanol/H2O; the temperature of the oxidation reaction is 35-55 ℃, and the reaction time is 6-12 h.
The technical scheme provided by the invention has the following technical effects: firstly, the process conditions are mild, the optical purity of the intermediate and the final product bulk drug is high, and the quality control and improvement of the final product bulk drug are facilitated; secondly, the reagent raw materials used in the process route of the invention are easy to obtain, the technical scheme is reasonable and environment-friendly, and the method can be used for mass production to meet the use requirements and is suitable for industrial production.
Detailed Description
The technical solutions of the present invention will be further described with reference to specific examples, and it is obvious that the protection scope of the present invention is not limited to the examples, and other examples of the present invention made by those skilled in the art belong to the protection scope of the present invention. The starting material, 3- { [2- (trimethylsilyl) ethoxy ] methoxy } propionyl chloride, can be prepared by ether synthesis, hydrolysis and acid chlorination from methyl 3-hydroxypropionate with 2- (trimethylsilyl) ethoxymethyl chloride, see an invention patent application No. 202110532923.1 which the applicant has already proposed.
In the examples which follow, reference is made to intermediate-1 simultaneously represented by the formula INT-1, intermediate-2 simultaneously represented by the formula INT-2, intermediate-3 simultaneously represented by the formula INT-3, intermediate-4 simultaneously represented by the formula INT-4, intermediate-5 simultaneously represented by the formula INT-5, intermediate-6 simultaneously represented by the formula INT-6, intermediate-7 simultaneously represented by the formula INT-7 and intermediate-8 simultaneously represented by the formula INT-8.
Example 1:
A) preparation of intermediate-1:
adding anhydrous tetrahydrofuran (200 mL) into a 2L reaction bottle, adding anhydrous lithium chloride (11.5 g,0.27 mol) and zinc powder (35.0 g,0.54 mol) under the protection of nitrogen and stirring at normal temperature, stirring for 10min, adding a mixed solvent of 1, 2-dibromoethane (10 mL) and anhydrous tetrahydrofuran (100 mL), adding trimethylchlorosilane (1.0 g,9.2 mmol), heating to 40 ℃, stirring for 30min, cooling to normal temperature, adding N- (4-bromobutyl) phthalimide (50.0 g,0.18 mol), heating the reaction mixture to 40 ℃, reacting for 3h, cooling to normal temperature, filtering to remove insoluble substances, collecting filtrate, adding tetrakis (triphenylphosphine) palladium (10.5 g,9.1 mmol), stirring at normal temperature for 30min, adding an anhydrous tetrahydrofuran solution (200 mL) of 3- { [2- (trimethylsilyl) ethoxy ] methoxy } propionyl chloride (42.5 g,0.18 mol), after the reaction is finished, dropwise adding a 10% ammonium chloride aqueous solution in stirring, adding dichloromethane for extraction, carrying out layering, collecting an organic phase, washing with salt water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, and purifying a crude product by a chromatographic column to obtain an intermediate-1 (65.2 g) with a yield of 91%, wherein the reaction formula of the embodiment (namely the step) is as follows:
B) preparation of intermediate-2:
mixing the intermediate-1 (65.0 g,0.16 mol) with 80% hydrazine hydrate (10.0 g,0.16 mol), adding water (100 mL), heating to 80 ℃ for reaction for 3h, cooling to room temperature after the reaction is finished, dropwise adding a dilute acetic acid solution to acidify to pH = 6-7, cooling to 10 ℃, filtering to remove insoluble substances, collecting filtrate, adding ammonia water to adjust pH =10, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, and performing reduced pressure rotary evaporation to dryness to obtain an intermediate-2 (41.5 g), wherein the yield is 94%, and the reaction formula of the embodiment is as follows:
C) preparation of intermediate-3:
mixing 2,4, 6-triphenylpyran boron tetrafluoride salt (63.5 g,0.16 mol) with water (300 mL) to obtain a suspension mixed solution, adding acetic acid (0.5 mL) and potassium iodide (26.5 g,0.16 mol), stirring at 35 ℃ for 3h, cooling to-10 ℃ to crystallize for 1h, performing suction filtration and drying to obtain red solid 2,4, 6-triphenylpyran iodide, dissolving the red solid 2,4, 6-triphenylpyran iodide and intermediate-2 (40 g,0.15 mol) in toluene (500 mL), heating to 100 ℃ to react for 24h, performing reduced pressure concentration to remove an organic solvent, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, performing reduced pressure rotary evaporation to dryness, recrystallizing a crude product with ethanol, performing vacuum drying to obtain intermediate-3 (50.7 g), and obtaining yield of 90%, wherein the reaction formula in the embodiment is as follows:
D) preparation of intermediate-4:
dissolving intermediate-3 (386.35 g,0.13 mol) in tetrahydrofuran (800 mL), adding sodium acetate (17.5 g,0.13 mol) and palladium chloride (1.2 g,6.8 mmol), placing the reaction mixture in a sealed stainless steel, introducing carbon monoxide into the reaction system, adjusting the temperature in the reaction kettle to be 100 ℃ and the pressure in the reaction kettle to be 30 atm, stirring for reaction for 18h, after the reaction is finished, cooling to 40 ℃ and releasing the system pressure, filtering the mixed solution, cooling the filtrate to 10 ℃ for crystallization for 3h, filtering, and recrystallizing with isopropanol to obtain intermediate-4 (33.4 g), wherein the yield is 85%, and the reaction formula of the embodiment is as follows:
E) preparation of intermediate-5:
dissolving intermediate-4 (33.0 g,0.11 mol) in methanol (500 mL), cooling to 10 ℃, adding sodium borohydride (6.0 g,0.16 mol), reacting for 2h under heat preservation, filtering to remove insoluble substances, concentrating the filtrate under reduced pressure to remove organic solvents, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, recrystallizing the crude product with ethanol, and carrying out vacuum drying to obtain intermediate-5 (30.8 g) with a yield of 93%, wherein the reaction formula in the embodiment is as follows:
F) preparation of intermediate-6:
adding intermediate-5 (30.0 g,97.9 mmol) and tetrahydrofuran (200 mL) into a 1L reaction bottle, stirring for dissolving, adding tetrabutylammonium fluoride (51.5 g,0.20 mol), heating to 50 ℃ for reacting for 6h, cooling to room temperature after the reaction is finished, filtering with diatomite, collecting filtrate, concentrating under reduced pressure to remove organic solvent, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, performing reduced pressure rotary evaporation to dryness, purifying the crude product by a chromatographic column to obtain intermediate-6 (16.0 g), wherein the yield is 93%, and the reaction formula of the embodiment is as follows:
G) preparation of intermediate-7:
dissolving intermediate-6 (16.0 g,90.8 mmol) and triethylamine (4.6 g,45.5 mmol) in dichloromethane (300 mL), cooling to 10 ℃, dropwise adding a solution of thionyl chloride (38.0 g,0.32 mol) in anhydrous dichloromethane (100 mL), heating to 50 ℃ to react for 6h, after the reaction is finished, dropwise adding water to quench the reaction solution, concentrating under reduced pressure to remove the organic solvent, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, performing reduced pressure rotary evaporation to dryness, recrystallizing the crude product with an ethyl acetate-n-hexane mixed solvent, and performing vacuum drying to obtain intermediate-7 (16.8 g) with yield of 87%, wherein the reaction formula in the embodiment is as follows:
H) preparation of intermediate-8:
intermediate-7 (16.0 g,75.1 mmol) and thiourea (14.5 g,0.19 mol) were dissolved in methanol (500 mL), heated to 50 ℃ for reaction for 6h, cooled to 30 ℃, left to layer, the oil layer was extracted with toluene, purified and dried to give intermediate-8 (15.0 g) with a yield of 96%, the reaction formula in this example is as follows:
I) preparing a finished product, namely preparing alpha-lipoic acid:
in a 2L reaction flask, intermediate-8 (15.0 g,72.0 mmol), FeCl were added3(6.0 g,37.0 mmol), NaOH (3.5 g,87.5 mmol) and water (600 mL), introducing oxygen while stirring, keeping the temperature at 35 ℃ for reaction for 12h, cooling to room temperature, carrying out reduced pressure rotary evaporation at 50 ℃ to remove the organic solvent, cooling to 10 ℃ in an ice bath, dropwise adding concentrated hydrochloric acid to reach pH =1, carrying out suction filtration and vacuum drying to obtain alpha-lipoic acid (14.0 g), wherein the yield is 94%, and the reaction formula of the embodiment is as follows:
example 2:
A) preparation of intermediate-1:
adding anhydrous tetrahydrofuran (80 mL) into a 2L reaction bottle, adding anhydrous lithium chloride (6.0 g,0.14 mol) and zinc powder (20.0 g,0.31 mol) under the protection of nitrogen and stirring at normal temperature, stirring for 10min, adding a mixed solvent of 1, 2-dibromoethane (10 mL) and anhydrous tetrahydrofuran (80 mL), adding trimethylchlorosilane (0.5 g,4.6 mmol), heating to 50 ℃, stirring for 30min, cooling to normal temperature, adding N- (4-bromobutyl) phthalimide (20.0 g,70.9 mmol), heating the reaction mixture to 50 ℃, reacting for 2h, cooling to normal temperature, filtering to remove insoluble substances, collecting filtrate, adding tetrakis (triphenylphosphine) palladium (6.0 g,5.2 mmol), stirring at normal temperature for 30min, adding an anhydrous tetrahydrofuran solution (50 mL) of 3- { [2- (trimethylsilyl) ethoxy ] methoxy } propionyl chloride (17.0 g,71.2 mmol), keeping the temperature at 30 ℃ for reaction for 4h, after the reaction is finished, dropwise adding a stirred 10% ammonium chloride aqueous solution, adding dichloromethane for extraction, layering, collecting an organic phase, washing with salt water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, and purifying a crude product by using a chromatographic column to obtain an intermediate-1 (27.0 g), wherein the yield is 94%, and the reaction formula is the same as that of example 1;
B) preparation of intermediate-2:
mixing the intermediate-1 (27.0 g,66.5 mmol) with 80% hydrazine hydrate (5.0 g,79.9 mmol), adding water (50 mL), heating to 90 ℃ for reacting for 2h, cooling to room temperature after the reaction is finished, dropwise adding a dilute acetic acid solution to acidify to pH = 6-7, cooling to 10 ℃, filtering to remove insoluble substances, collecting filtrate, adding ammonia water to adjust the pH =10, adding dichloromethane for extraction, washing with brine, drying with anhydrous sodium sulfate, and carrying out reduced pressure rotary evaporation to dryness to obtain an intermediate-2 (17.0 g), wherein the yield is 93%, and the reaction formula is the same as that in example 1;
C) preparation of intermediate-3:
mixing 2,4, 6-triphenylpyran boron tetrafluoride salt (30.0 g,75.7 mmol) with water (400 mL) to obtain a suspension mixed solution, adding acetic acid (0.5 mL) and potassium iodide (12.0 g,72.3 mmol), stirring at 40 ℃ for 2.5h, reducing the temperature to-10 ℃ for crystallization for 1h, carrying out suction filtration and drying to obtain red solid 2,4, 6-triphenylpyran iodide, dissolving intermediate-2 (17.0 g,61.7 mmol) in xylene (400 mL), heating to 110 ℃ for reaction for 18h, carrying out reduced pressure concentration to remove an organic solvent, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, carrying out rotary evaporation to dryness, recrystallizing a crude product with ethanol, carrying out vacuum drying to obtain intermediate-3 (21.0 g), wherein the yield is 88%, and the reaction formula is the same as in example 1;
D) preparation of intermediate-4:
dissolving the intermediate-3 (20.0 g,51.8 mmol) in ethanol (400 mL), adding sodium acetate (3.5 g,25.7 mmol) and palladium hydroxide (0.5 g,3.6 mmol), placing the reaction mixture in a sealed stainless steel, introducing carbon monoxide into the reaction system, adjusting the temperature in the reaction kettle to be 110 ℃ and 20 atm, stirring for reaction for 12 hours, after the reaction is finished, cooling to 40 ℃ and releasing the system pressure, filtering the mixed solution, cooling the filtrate to 10 ℃ for crystallization for 3 hours, filtering, and recrystallizing in isopropanol to obtain the intermediate-4 (14.0 g), wherein the yield is 89%, and the reaction formula is the same as that in example 1;
E) preparation of intermediate-5:
dissolving intermediate-4 (13.5 g,44.3 mmol) in ethanol (300 mL), cooling to 10 ℃, adding sodium borohydride (2.7 g,71.4 mmol), reacting for 2h under heat preservation, filtering to remove insoluble substances, concentrating the filtrate under reduced pressure to remove organic solvent, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, performing reduced pressure rotary evaporation to dryness, recrystallizing the crude product with ethanol, and performing vacuum drying to obtain intermediate-5 (13.0 g), wherein the yield is 96%, the reaction formula is the same as that in example 1;
F) preparation of intermediate-6:
adding intermediate-5 (12.0 g,39.2 mmol) and methyl tert-butyl ether (150 mL) into a 1L reaction bottle, stirring for dissolving, adding tetrabutylammonium fluoride (30.0 g,0.12 mol), heating to 80 ℃ for reaction for 4h, cooling to room temperature after the reaction is finished, filtering with diatomite, collecting filtrate, concentrating under reduced pressure to remove organic solvent, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, performing reduced pressure rotary evaporation to dryness, purifying the crude product with a chromatographic column to obtain intermediate-6 (6.0 g), wherein the yield is 87%, and the reaction formula is the same as in example 1;
G) preparation of intermediate-7:
dissolving the intermediate-6 (6.0 g,34.1 mmol) and N, N-diisopropylethylamine (4.5 g,34.8 mol) in tetrahydrofuran (200 mL), cooling to 10 ℃, dropwise adding an anhydrous tetrahydrofuran (80 mL) solution of phosphorus oxychloride (25.0 g,0.16 mol), heating to 60 ℃ for reaction for 4 hours, dropwise adding water to quench the reaction solution after the reaction is finished, concentrating under reduced pressure to remove the organic solvent, adding dichloromethane for extraction, washing with brine, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, recrystallizing the crude product with an ethyl acetate-N-hexane mixed solvent, and carrying out vacuum drying to obtain an intermediate-7 (6.5 g), wherein the yield is 90%, and the reaction formula is the same as in example 1;
H) preparation of intermediate-8:
dissolving intermediate-7 (6.5 g,30.5 mmol) and thiourea (7.0 g,92.0 mmol) in ethanol (200 mL), heating to 70 ℃ for reaction for 4h, cooling to 30 ℃, standing for layering, extracting an oil layer with toluene, refining and drying to obtain intermediate-8 (6.0 g), wherein the yield is 94%, and the reaction formula is the same as that in example 1;
I) preparing a finished product, namely preparing alpha-lipoic acid:
in a 1L reaction flask, intermediate-8 (6.0 g,28.8 mmol), I2(8.8 g,34.7 mmol), KI (7.0 g,42.2 mmol), ethanol (100 mL) and water (30 mL), stirring the solvent, heating to 45 ℃ for reaction for 9h, cooling to room temperature, carrying out rotary evaporation at 50 ℃ under reduced pressure to remove the organic solvent, cooling to 10 ℃ in an ice bath, dropwise adding concentrated hydrochloric acid until the pH is =1, carrying out suction filtration, and carrying out vacuum drying to obtain alpha-lipoic acid (5.0 g), wherein the yield is 84%, and the reaction formula is the same as that in example 1.
Example 3:
A) preparation of intermediate-1:
adding anhydrous tetrahydrofuran (60 mL) into a 2L reaction bottle, adding anhydrous lithium chloride (13.5 g,0.32 mol) and zinc powder (50.0 g,0.77 mol) under the protection of nitrogen and stirring at normal temperature, stirring for 10min, adding a mixed solvent of 1, 2-dibromoethane (10 mL) and anhydrous tetrahydrofuran (80 mL), adding trimethylchlorosilane (1.3 g,12.0 mmol), heating to 60 ℃, stirring for 30min, cooling to normal temperature, adding N- (4-bromobutyl) phthalimide (36.0 g,0.13 mol), heating the reaction mixture to 60 ℃, reacting for 1h, cooling to normal temperature, filtering to remove insoluble substances, collecting filtrate, adding tetrakis (triphenylphosphine) palladium (14.5 g,12.6 mmol), stirring at normal temperature for 30min, adding an anhydrous tetrahydrofuran solution (70 mL) of 3- { [2- (trimethylsilyl) ethoxy ] methoxy } propionyl chloride (30.5 g,0.13 mol), keeping the temperature at 35 ℃ for 2h, after the reaction is finished, dropwise adding a stirred 10% ammonium chloride aqueous solution, adding dichloromethane for extraction, carrying out layering, collecting an organic phase, washing with salt water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, and purifying a crude product by using a chromatographic column to obtain an intermediate-1 (48.0 g), wherein the yield is 93%, and the reaction formula is the same as that of example 1;
B) preparation of intermediate-2:
mixing the intermediate-1 (48.0 g,0.12 mol) with 80% hydrazine hydrate (9.5 g,0.15 mol), adding water (80 mL), heating to 100 ℃ for reaction for 1h, cooling to room temperature after the reaction is finished, dropwise adding a dilute acetic acid solution for acidification to pH = 6-7, cooling to 10 ℃, filtering to remove insoluble substances, collecting filtrate, adding ammonia water for adjusting pH =10, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, and carrying out reduced pressure rotary evaporation to dryness to obtain an intermediate-2 (30.0 g), wherein the yield is 92%, and the reaction formula is the same as that in example 1;
C) preparation of intermediate-3:
mixing 2,4, 6-triphenylpyran boron tetrafluoride salt (56.0 g,0.14 mol) with water (700 mL) to obtain a suspension mixed solution, adding acetic acid (0.5 mL) and potassium iodide (23.0 g,0.14 mol), stirring for 2h at 45 ℃, reducing to-10 ℃ to crystallize for 1h, carrying out suction filtration and drying to obtain red solid 2,4, 6-triphenylpyran iodide, dissolving intermediate-2 (30.0 g,0.11 mol) in N, N-dimethylformamide (600 mL), heating to 120 ℃ to react for 12h, carrying out reduced pressure concentration to remove an organic solvent, adding dichloromethane for extraction, washing with brine, drying anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, recrystallizing the crude product with ethanol, carrying out vacuum drying to obtain intermediate-3 (39.5 g), obtaining the yield of 94%, and carrying out the same reaction formula as in example 1;
D) preparation of intermediate-4:
dissolving the intermediate-3 (39.5 g,0.10 mol) in isopropanol (500 mL), adding sodium acetate (14.0 g,0.10 mol) and bis (dibenzylideneacetone) palladium (5.8 g,10.1 mmol), placing the reaction mixture in a sealed stainless steel, introducing carbon monoxide into the reaction system, adjusting the temperature in the reaction kettle to 120 ℃ and 10 atm, stirring and reacting for 6h, after the reaction is finished, cooling to 40 ℃ and releasing the system pressure, filtering the mixed solution, cooling the filtrate to 10 ℃ and crystallizing for 3h, filtering, recrystallizing the isopropanol to obtain an intermediate-4 (28.7 g), wherein the yield is 92%, and the reaction formula is the same as that in example 1;
E) preparation of intermediate-5:
dissolving intermediate-4 (28.0 g,92.0 mmol) in isopropanol (400 mL), cooling to 10 ℃, adding sodium borohydride (6.0 g,0.16 mol), reacting for 2.5h under heat preservation, filtering to remove insoluble substances, concentrating the filtrate under reduced pressure to remove an organic solvent, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, recrystallizing the crude product with ethanol, and carrying out vacuum drying to obtain intermediate-5 (25.2 g), wherein the yield is 89%, and the reaction formula is the same as that in example 1;
F) preparation of intermediate-6:
adding intermediate-5 (25.0 g,81.6 mmol) and 1, 4-dioxane (200 mL) into a 2L reaction bottle, stirring for dissolving, adding tetrabutylammonium fluoride (95.0 g,0.36 mol), heating to 100 ℃ for reaction for 2h, cooling to room temperature, filtering with diatomite, collecting filtrate, concentrating under reduced pressure to remove organic solvent, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, performing reduced pressure rotary evaporation to dryness, and purifying the crude product by a chromatographic column to obtain intermediate-6 (13.1 g), wherein the yield is 91%, and the reaction formula is the same as in example 1;
G) preparation of intermediate-7:
dissolving intermediate-6 (13.0 g,73.8 mmol) diethylamine (8.0 g,0.11 mol) in acetonitrile (300 mL), cooling to 10 ℃, dropping sulfuryl chloride (59.0 g,0.44 mmol) in anhydrous acetonitrile (100 mL), heating to 80 ℃ for reaction for 2h, after the reaction is finished, dropping water quenching reaction liquid, decompressing and concentrating to remove organic solvent, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, decompressing and rotary evaporating to dryness, recrystallizing the crude product with ethyl acetate-n-hexane mixed solvent, and drying in vacuum to obtain intermediate-7 (14.4 g), the yield is 92%, the reaction formula is the same as that in example 1;
H) preparation of intermediate-8:
dissolving intermediate-7 (14.0 g,65.7 mmol) and thiourea (17.0 g,0.22 mol) in isopropanol (500 mL), heating to 90 ℃ for reaction for 2h, cooling to 30 ℃, standing for layering, extracting an oil layer with toluene, refining and drying to obtain intermediate-8 (12.3 g), wherein the yield is 90%, and the reaction formula is the same as that in example 1;
I) preparing a finished product, namely preparing alpha-lipoic acid:
in a 1L reaction flask, intermediate-8 (12.0 g,57.6 mmol), FeCl were added3(7.0 g,43.2 mmol), NaOH (2.8 g,70.0 mmol) and water (200 mL), introducing oxygen while stirring, keeping the temperature at 55 ℃ for reaction for 6h, cooling to room temperature, carrying out reduced pressure rotary evaporation at 50 ℃ to remove the organic solvent, cooling to 10 ℃ in an ice bath, dropwise adding concentrated hydrochloric acid to reach the pH =1, carrying out suction filtration and vacuum drying to obtain alpha-lipoic acid (10.3 g), wherein the yield is 87%The reaction formula is the same as that of example 1.
Although the preferred embodiments of the present invention have been described in detail, the present invention is not limited to the details of the embodiments, and various equivalent modifications can be made within the technical spirit of the present invention, and the scope of the present invention is also within the scope of the present invention.
Claims (9)
1. The method for synthesizing alpha-lipoic acid is characterized by comprising the following steps of:
A) preparing an intermediate-1, mixing N- (4-bromobutyl) phthalimide with zinc powder, lithium chloride, trimethylchlorosilane, 1, 2-dibromoethane and tetrahydrofuran, reacting to generate a zinc bromide intermediate, controlling the reaction temperature and the reaction time of the reaction to generate the zinc bromide intermediate, and then carrying out substitution reaction on 3- { [2- (trimethylsilyl) ethoxy ] methoxy } propionyl chloride and the zinc bromide intermediate in a tetrakis (triphenylphosphine) palladium and tetrahydrofuran system to obtain an intermediate-1, wherein the structural formula of the intermediate-1 is shown as the formula (INT-1);
B) preparing an intermediate-2, and carrying out a hydrazinolysis reaction on the intermediate-1 obtained in the step A) and hydrazine hydrate in a water system to obtain an intermediate-2, wherein the structural formula of the intermediate-2 is shown as the formula (INT-2);
C) preparing an intermediate-3, mixing 2,4, 6-triphenylpyran boron tetrafluoride salt, potassium iodide, acetic acid and water, reacting to generate 2,4, 6-triphenylpyran iodide, controlling the reaction temperature and the reaction time of the reaction to generate the 2,4, 6-triphenylpyran iodide, and carrying out iodination reaction on the intermediate-2 obtained in the step B) and the 2,4, 6-triphenylpyran iodide in a solvent system to obtain an intermediate-3, wherein the structural formula of the intermediate-3 is shown as the formula (INT-3);
D) preparing an intermediate-4, and carrying out pressurized carbonyl insertion reaction on the intermediate-3 obtained in the step C) and carbon monoxide in a palladium catalyst and solvent system to obtain an intermediate-4, wherein the structural formula of the intermediate-4 is shown as the formula (INT-4);
the palladium catalyst is palladium carbon, palladium chloride, diallyl palladium chloride, palladium acetate, a palladium acetate-triphenylphosphine compound, palladium trifluoroacetate, palladium hydroxide, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium or [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride; the solvent is tetrahydrofuran, ethanol, isopropanol or n-butanol; the feeding molar ratio of the intermediate-3 to the palladium catalyst is 1.0 to (0.05-0.10); the pressure of the carbonyl insertion reaction is 10-30 atmospheric pressure, the reaction temperature is 100-120 ℃, and the reaction time is 6-18 h;
E) preparing an intermediate-5, and carrying out reduction reaction on the intermediate-4 obtained in the step D) and sodium borohydride to prepare an intermediate-5, wherein the structural formula of the intermediate-5 is shown as the formula (INT-5);
F) preparing an intermediate-6, and carrying out deprotection reaction on the intermediate-5 obtained in the step E) in a tetrabutylammonium fluoride and solvent system to obtain an intermediate-6, wherein the structural formula of the intermediate-6 is shown as the formula (INT-6);
G) preparing an intermediate-7, mixing the intermediate-6 obtained in the step F) with a chlorination reagent, a catalyst and a solvent, and carrying out chlorination reaction to obtain an intermediate-7, wherein the structural formula of the intermediate-7 is shown as the formula (INT-7);
H) preparing an intermediate-8, adding the intermediate-7 obtained in the step G) into a system of thiourea and a solvent, and carrying out sulfhydrylation reaction to obtain an intermediate-8, wherein the structural formula of the intermediate-8 is shown as the formula (INT-8);
I) preparing a finished product, namely performing oxidation ring closing reaction on the intermediate-8 obtained in the step H) and an oxidant system to obtain alpha-lipoic acid;
2. the method for synthesizing alpha-lipoic acid as claimed in claim 1, wherein in step A), the molar ratio of N- (4-bromobutyl) phthalimide to 3- { [2- (trimethylsilyl) ethoxy ] methoxy } propionyl chloride to zinc powder to lithium chloride to trimethylchlorosilane to tetrakis (triphenylphosphine) palladium is 1.0: 3.0-6.0: 1.5-2.5: 0.05-0.1;
the reaction temperature and the reaction time for generating the zinc bromide intermediate by controlling the reaction are respectively controlled to be 40-60 ℃ and 1-3 h;
the temperature of the substitution reaction is 20-35 ℃, and the reaction time is 2-6 h.
3. The method for synthesizing alpha-lipoic acid as claimed in claim 1, wherein the molar ratio of the intermediate-1 and hydrazine hydrate in step B) is 1.0: 1.0-1.3;
the temperature of the hydrazinolysis reaction is 80-100 ℃, and the reaction time is 1-3 h.
4. The method for synthesizing alpha-lipoic acid as claimed in claim 1, wherein the feeding molar ratio of the intermediate 2,4, 6-triphenylpyran boron tetrafluoride salt and potassium iodide in step C) is 1.0: 1.1-1.3;
the reaction temperature and the reaction time for generating the iodinated 2,4, 6-triphenylpyran by controlling the reaction temperature and the reaction time are respectively controlled to be 35-45 ℃ and 2-3 h.
5. The method for synthesizing alpha-lipoic acid according to claim 1, characterized by that in the step C) the solvent for iodination reaction is toluene, xylene, N-dimethylformamide or N, N-dimethylacetamide;
the temperature of the iodination reaction is 100-120 ℃, and the reaction time is 12-24 hours.
6. The method for synthesizing alpha-lipoic acid according to the claim 1, characterized by that in step F) the solvent is tetrahydrofuran, methyl tert-butyl ether or 1, 4-dioxane;
the feeding molar ratio of the intermediate-5 to the tetrabutylammonium fluoride is 1.0: 2.0-4.5;
the deprotection reaction temperature is 50-100 ℃, and the reaction time is 2-6 h.
7. The method for synthesizing alpha-lipoic acid according to claim 1, characterized by that in step G) the described chlorinating agent is thionyl chloride, phosphorus oxychloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, acetyl chloride or isobutyl chloroformate;
the catalyst is triethylamine, N-diisopropylethylamine, diethylamine, ethylenediamine, pyridine, 4-dimethylaminopyridine, 2, 6-dimethylpyridine, tetramethylguanidine, N-methylpyrrolidone, N-methylmorpholine, N-ethylmorpholine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] -non-5-ene or 1, 4-diazabicyclo [2.2.2] octane;
the solvent is dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, methyl tert-butyl ether, 1, 4-dioxane or acetonitrile;
the feeding molar ratio of the intermediate-6 to the chlorinating agent to the catalyst is 1.0 to (3.5-6.0) to (0.5-1.5);
the temperature of the chlorination reaction is 50-80 ℃, and the reaction time is 2-6 h.
8. The method for synthesizing alpha-lipoic acid as claimed in claim 1, wherein said solvent in step H) is methanol, ethanol, isopropanol or n-butanol;
the feeding molar ratio of the intermediate-7 to the thiourea is 1.0 to (2.5-3.5);
the temperature of the sulfhydrylation reaction is 50-90 ℃, and the reaction time is 2-6 h.
9. The method of synthesizing alpha-lipoic acid according to claim 1, characterized by that in step I) said oxidant system is O2/FeCl3/NaOH/H2O or I2KI/ethanol/H2O；
The temperature of the oxidation reaction is 35-55 ℃, and the reaction time is 6-12 h.
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| CN101195568A (en) * | 2006-12-06 | 2008-06-11 | 上海医药工业研究院 | (S) or (R)-6-hydroxyl-8-alkoxide octylic acid, its ester, salt, amide, preparation method and application thereof |
| CN106083811A (en) * | 2016-06-14 | 2016-11-09 | 苏州富士莱医药股份有限公司 | (R) preparation method of alpha lipoic acid |
| CN113185494A (en) * | 2021-05-17 | 2021-07-30 | 苏州富士莱医药股份有限公司 | Preparation method of R-lipoic acid |
| CN113429386A (en) * | 2021-07-09 | 2021-09-24 | 苏州富士莱医药股份有限公司 | Synthetic method of R-lipoic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101195568A (en) * | 2006-12-06 | 2008-06-11 | 上海医药工业研究院 | (S) or (R)-6-hydroxyl-8-alkoxide octylic acid, its ester, salt, amide, preparation method and application thereof |
| CN106083811A (en) * | 2016-06-14 | 2016-11-09 | 苏州富士莱医药股份有限公司 | (R) preparation method of alpha lipoic acid |
| CN113185494A (en) * | 2021-05-17 | 2021-07-30 | 苏州富士莱医药股份有限公司 | Preparation method of R-lipoic acid |
| CN113429386A (en) * | 2021-07-09 | 2021-09-24 | 苏州富士莱医药股份有限公司 | Synthetic method of R-lipoic acid |
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