CN105622571A - Preparation method of R-lipoic acid tromethamine salt - Google Patents
Preparation method of R-lipoic acid tromethamine salt Download PDFInfo
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Abstract
The invention discloses a preparation method of R-lipoic acid tromethamine salt and belongs to the field of organic medicinal chemistry. The method includes the steps that (S)-6,8-dichloro ethyl caprylate and sulphur are put into a reaction vessel, the temperature is raised, a cyclization reaction is carried out, the temperature is preserved, extraction is carried out with a first organic solvent, concentration is carried out, and cyclization liquid is obtained; then, a hydrolysis reaction is carried out, cooling is carried out, and hydrolysis liquid is obtained; a second organic solvent is added into the hydrolysis liquid, the pH value is regulated, extraction is carried out, an obtained organic layer is washed with water to be neutral, the second organic solvent is removed at reduced pressure, and an initial product is obtained; mixed liquor is added into the initial product, the temperature is raised, a first filter aid is added, stirring adsorption is carried out, filtration is carried out, and light yellow liquid is obtained; cooling is carried out to separate out crystals, and R-lipoic acid is obtained; R-lipoic acid is dissolved, trihydroxymethyl aminomethane is added, the temperature is raised for solution, a second filter aid is added for filtration, and light yellow liquid is obtained; cooling is carried out to separate out crystals, centrifugal drying is carried out, and the finished product is obtained. According to the method, few steps are needed, efficiency is high, energy is saved, and waste discharge is reduced.
Description
Technical field
The invention belongs to organic medicinal chemistry field, it is specifically related to the preparation method of a kind of LA tromethane salt.
Background technology
LA tromethane salt (R (��) AlphalipoicAcidTromethaminesalt) is a kind of derivative of LA, and its molecular weight is 327.46, and its chemical structural formula is as follows:
Owing to LA tromethane salt has the activity (EP427247) of anti-inflammatory and Cell protection, is used for the treatment of diabetes and insulin resistance (DE4; 343; 593), for the metabolism disorder (DE4 of glucose of central nervous system (ZNS); 343; 592) with as appetite-inhibiting agent (DE19; 818,563), thus there is good medical usage and such as can be used for medical preparation (EP702953).
Research shows: LA tromethane salt is poisoning to therapic acid; Insulin-dependent and carbohydrate metabolism disturbance diabetes; Anti-inflammation; Food inhibitor (fat-reducing); The diseases such as cerebral protective agent have potential therapeutic value. Given this, synthesize LA tromethane salt and there is positive effect.
At present, the step of preparation of industrialization LA tromethane salt is: first prepare LA, then LA and Tutofusin tris are added nucleophilic compound in flux carries out salt-forming reaction, obtains LA tromethane salt. The preparation of current LA is mainly synthesized by chemical resolution method, specifically, first synthesize DL Thioctic Acid by chemical method, split as resolving agent with phenylethylamine again, obtain racemic thioctic acid phenylethylamine salt, and after through hydrochloric acid desalination, obtain (R)-Thioctic Acid crude product, finally by refining, obtain LA (Chinese Patent Application No. 02815066.X highlights to split by racemic modification alpha-lipoic acid and obtains LA). There is complex process in the preparation of aforementioned LA, it is necessary to repeatedly crystallization, cost height, and receipts rate is low, and not only causes the wasting of resources because (S)-Thioctic Acid can not effectively utilize, and produces to pollute to environment.
In view of above-mentioned prior art, it is necessary to exploring the preparation method of the LA tromethane salt being made up aforementioned deficiency, technical scheme described below produces under this background.
Summary of the invention
The task of the present invention is to provide the preparation method of a kind of LA tromethane salt, and the method contributes to remarkable Simplified flowsheet and uses and improve preparation efficiency and energy efficient, be conducive to effectively (S)-Thioctic Acid being converted into useful product in split process and use and avoid causing the wasting of resources and avoid damaging and environment, be of value to and improve receipts rate and use reduction preparation cost and meet industrial amplification production requirement.
The task of the present invention completes like this, and the preparation method of a kind of LA tromethane salt, comprises the following steps:
A) LA is prepared: first drop into (S)-6 to being furnished with in the reaction vessel of whipping appts, 8-bis-chlorine ethyl octylate and sulphur, heat up, drip and add sodium sulfide solution and carry out ring-closure reaction, ring-closure reaction is incubated after terminating, then adopt the first organic solvent extraction and concentrate, obtain ring and close liquid, ring closes liquid again put into and be furnished with in the reaction vessel of whipping appts and add alkaline solution and be hydrolyzed reaction, after hydrolysis reaction terminates, cooling, obtain hydrolyzed solution, then the 2nd organic solvent is joined in hydrolyzed solution and use acid adjust pH, through extraction, the organic layer that extraction obtains is washed to neutrality, then the 2nd organic solvent is removed in decompression, obtain first product, finally mixed solution agent is joined in first product, rising temperature for dissolving, add the first flocculating aids, whip attachment, filter, obtain faint yellow liquid, through cooling crystallize out, obtain LA,
B) finished product is prepared, first to by steps A) LA that obtains adds stirring solvent dissolve, add Tutofusin tris again, heating up, stirring and dissolving, then adds the 2nd filter aid, obtain faint yellow liquid, cooling crystallize out, finally by centrifugal drying, obtains LA tromethane salt.
In a specific embodiment of the present invention, steps A) described in the first organic solvent be toluene, ethyl acetate, hexanaphthene, methylene dichloride or chloroform; The mol ratio of described (S)-6,8-two chlorine ethyl octylate, sulphur and sodium sulfide solution is 1: 1-2: 1-2.
In another specific embodiment of the present invention, steps A) described in intensification be that temperature is risen to 70-100 DEG C; Described add sodium sulfide solution drip that to add the time be 0.5-5h; The time of described insulation is 0.5-2h; The mass percent concentration of described sodium sulfide solution is 8-20%.
In another specific embodiment of the present invention, steps A) described in the ring mol ratio that closes liquid and alkaline solution be 1: 1-2, the sodium hydroxide solution of described alkaline solution to be mass percent concentration be 3-10%, potassium hydroxide solution, sodium carbonate solution or solution of potassium carbonate; The temperature of described hydrolysis reaction is 70-95 DEG C, and the time of hydrolysis reaction is 3-20h.
In another specific embodiment of the present invention, steps A) described in hydrolyzed solution and the volume ratio of described 2nd organic solvent be 1: 0.1-1; Described is that pH value is adjusted to pH=1 with acid for adjusting pH value; The extraction times of described extraction is twice; The 2nd described organic solvent is toluene, ethyl acetate, hexanaphthene, methylene dichloride or chloroform; The volumetric molar concentration of described acid is the hydrochloric acid of 0.5-2mol/L, sulfuric acid or phosphoric acid solution.
Also having in a specific embodiment in the present invention, steps A) described in the temperature of rising temperature for dissolving be 20-50 DEG C.
In more and in a specific embodiment of the present invention, steps A) described in mixed solvent be that ethyl acetate mixes the mixed solvent formed mutually with hexanaphthene, the weight ratio of described first product, ethyl acetate and hexanaphthene is 1:5-10:50-100; The first described flocculating aids is gac, silica gel or diatomite, and described crude product and the weight ratio of flocculating aids are 1:0.02-0.05.
The present invention's and then in a specific embodiment, described (S)-6,8-two chlorine ethyl octylate is prepared by biological enzyme.
In the present invention again more and in a specific embodiment, step B) described in solvent be ethyl acetate, acetone, THF, DMF, dehydrated alcohol, 95 ethanol or methyl alcohol; Described LA and the weight ratio of solvent are 1:1-1:10; Described LA and the mol ratio of Tutofusin tris are 1:1.0-1:1.1;
In again and then in a specific embodiment of the present invention, step B) described in the 2nd flocculating aids be gac, aluminum oxide, silica gel or diatomite, the temperature that the weight ratio of described LA and the 2nd flocculating aids is the intensification described in 1:0.02-0.05 is 40-70 DEG C, and the time is 1-4h; The cooling temperature of described cooling is-15-25 DEG C.
One of technique effect of technical scheme provided by the invention, owing to relative to prior art, processing step significantly reduces, thus has preparation efficiency height and saves the strong point of energy consumption; Two, owing to compensate for the drawback that in prior art, (S)-Thioctic Acid is difficult to be converted into useful products and cause waste, thus raw material consumption has not only been saved, and the fusing point making the LA tromethane salt obtained reaches 115-118 DEG C, specific rotation reaches 73-75 ��, ee value is more than 99.0%, content is more than 99.0%, and owing to preparation process significantly reducing waste discharge, thus it is possible not only to meet industrial amplification production requirement, and good environmental protection effect can be embodied.
Embodiment
Embodiment 1:
A) LA is prepared: first drop into, to being furnished with in the reaction vessel of whipping appts, (S)-6 prepared by biological enzyme, 8-bis-chlorine ethyl octylate and sulphur, it is warmed up to 70 DEG C, drip add mass percent concentration be 8% sodium sulfide solution carry out ring-closure reaction, the 5 hours time of ring-closure reaction, (S)-6, 8-bis-chlorine ethyl octylate, the mol ratio of sulphur and sodium sulfide solution is 1:1.7:1, it is incubated 2h at 70 DEG C of temperature, ring-closure reaction terminates, the first organic solvent is adopted namely to adopt toluene to extract, concentrated, obtain ring and close liquid, again ring is closed liquid put into be furnished with in the reaction vessel of whipping appts and add mass percent concentration be 4% sodium hydroxide solution be hydrolyzed reaction, the mol ratio that ring conjunction liquid and mass percent concentration are the sodium hydroxide solution of 4% is 1:1.5, the temperature of hydrolysis reaction is 80 DEG C, the time of hydrolysis reaction is 10h, after hydrolysis reaction terminates, cooling, obtain hydrolyzed solution, then the 2nd organic solvent and toluene are joined in hydrolyzed solution and the salt acid for adjusting pH being 0.5mol/L by mol concentration is 1, extracting twice, the organic layer that extraction obtains is washed to neutrality, the 2nd organic solvent is removed in decompression again, namely toluene is removed, obtain LA mucus, namely first product is obtained, wherein: the volume ratio of described hydrolyzed solution and described toluene is 1:0.5, finally join in first product by the mixed solvent of ethyl acetate and hexanaphthene, first product, the weight ratio of ethyl acetate and hexanaphthene is 1:8:60, rising temperature for dissolving, the temperature of rising temperature for dissolving is 20 DEG C, add the gac whip attachment as the first flocculating aids, the weight ratio of crude product and gac is 1:0.03, filter, the faint yellow liquid obtained, cooling crystallize out, this crystal is LA, specific rotation is 117.9 ��, ee value is 99.4%, content is 99.5%,
B) finished product is prepared: first to by steps A) LA that obtains adds acetic acid ethyl dissolution, the weight ratio of LA and ethyl acetate is 1: 10 stirring and dissolving, add Tutofusin tris, the mol ratio of LA and Tutofusin tris is be warmed up to 60 DEG C stirring and dissolving at 1: 1, insulation 2h, add the gac as the 2nd flocculating aids, the weight ratio of LA and gac is 1: 0.02, filter, obtain faint yellow liquid, cooling crystallize out, after 0 DEG C, centrifugal drying obtains LA tromethane salt. The fusing point of LA tromethane salt is 115.2-118 DEG C, and specific rotation is 74.6 ��, and ee value is 99.32%, and content is 99.52%.
Embodiment 2:
A) LA is prepared: first drop into, to being furnished with in the reaction vessel of whipping appts, (S)-6 prepared by biological enzyme, 8-bis-chlorine ethyl octylate and sulphur, it is warmed up to 80 DEG C, drip add mass percent concentration be 20% sodium sulfide solution carry out ring-closure reaction, the 0.5 hour time of ring-closure reaction, (S)-6, 8-bis-chlorine ethyl octylate, the mol ratio of sulphur and sodium sulfide solution is 1:1.5:1, it is incubated 1.5h at 80 DEG C of temperature, ring-closure reaction terminates, the first organic solvent is adopted namely to adopt extraction into ethyl acetate, concentrated, obtain ring and close liquid, again ring is closed liquid put into be furnished with in the reaction vessel of whipping appts and add mass percent concentration be 3% potassium hydroxide solution be hydrolyzed reaction, the mol ratio that ring conjunction liquid and mass percent concentration are the potassium hydroxide solution of 3% is 1:1.1, the temperature of hydrolysis reaction is 80 DEG C, the time of hydrolysis reaction is 8h, after hydrolysis reaction terminates, cooling, obtain hydrolyzed solution, then the 2nd organic solvent and ethyl acetate are joined in hydrolyzed solution and the salt acid for adjusting pH being 0.7mol/L by mol concentration is 1, extracting twice, the organic layer that extraction obtains is washed to neutrality, the 2nd organic solvent is removed in decompression again, namely ethyl acetate is removed, obtain LA mucus, namely first product is obtained, wherein: the volume ratio of described hydrolyzed solution and described ethyl acetate is 1:0.1, finally join in first product by the mixed solvent of ethyl acetate and hexanaphthene, first product, the weight ratio of ethyl acetate and hexanaphthene is 1:5:50, rising temperature for dissolving, the temperature of rising temperature for dissolving is 30 DEG C, add the gac whip attachment as the first flocculating aids, the weight ratio of crude product and gac is 1:0.02, filter, the faint yellow liquid obtained, cooling crystallize out, this crystal is LA, specific rotation is 117.7 ��, ee value is 99.2%, content is 99.8%,
B) finished product is prepared: first to by steps A) LA that obtains adds acetone solution, the weight ratio of LA and acetone is 1: 8 stirring and dissolving, add Tutofusin tris, the mol ratio of LA and Tutofusin tris is be warmed up to 40 DEG C stirring and dissolving at 1: 1.01, insulation 4h, add the silica gel as the 2nd flocculating aids, LA and the weight ratio with silica gel are 1: 0.03, filter, obtain faint yellow liquid, cooling crystallize out, after 25 DEG C, centrifugal drying obtains LA tromethane salt. The fusing point of LA tromethane salt is 115.8-117.8 DEG C, and specific rotation is 73.2 ��, and ee value is 99.43%, and content is 99.64%.
Embodiment 3:
A) LA is prepared: first drop into, to being furnished with in the reaction vessel of whipping appts, (S)-6 prepared by biological enzyme, 8-bis-chlorine ethyl octylate and sulphur, it is warmed up to 90 DEG C, drip add mass percent concentration be 12% sodium sulfide solution carry out ring-closure reaction, the 3 hours time of ring-closure reaction, (S)-6, 8-bis-chlorine ethyl octylate, the mol ratio of sulphur and sodium sulfide solution is 1:2:1.5, it is incubated 1h at 90 DEG C of temperature, ring-closure reaction terminates, the first organic solvent is adopted namely to adopt hexanaphthene to extract, concentrated, obtain ring and close liquid, again ring is closed liquid put into be furnished with in the reaction vessel of whipping appts and add mass percent concentration be 8% sodium carbonate solution be hydrolyzed reaction, the mol ratio that ring conjunction liquid and mass percent concentration are the sodium carbonate solution of 8% is 1:2, the temperature of hydrolysis reaction is 75 DEG C, the time of hydrolysis reaction is 20h, after hydrolysis reaction terminates, cooling, obtain hydrolyzed solution, then organic solvent and hexanaphthene are joined in hydrolyzed solution and the phosphorus acid for adjusting pH being 1mol/L by mol concentration is 1, extracting twice, the organic layer that extraction obtains is washed to neutrality, the 2nd organic solvent is removed in decompression again, namely hexanaphthene is removed, obtain LA mucus, namely first product is obtained, wherein: the volume ratio of described hydrolyzed solution and described hexanaphthene is 1:1, finally join in first product by the mixed solvent of ethyl acetate and hexanaphthene, first product, the weight ratio of ethyl acetate and hexanaphthene is 1:10:80, rising temperature for dissolving, the temperature of rising temperature for dissolving is 40 DEG C, add the silicon bath soil whip attachment as the first flocculating aids, the weight ratio of crude product and silicon bath soil is 1:0.04, filter, the faint yellow liquid obtained, cooling crystallize out, this crystal is LA, specific rotation is 118 ��, ee value is 99.4%, content is 99.2%,
B) finished product is prepared: first to by steps A) LA that obtains adds THF dissolve, the weight ratio of LA and THF is 1: 1 stirring and dissolving, add Tutofusin tris, the mol ratio of LA and Tutofusin tris is 1: .05 be warmed up to 50 DEG C of stirring and dissolving, insulation 1h, add the diatomite as the 2nd flocculating aids, the weight ratio of LA and diatomite is 1: 0.04, filter, obtain faint yellow liquid, cooling crystallize out, after-15 DEG C, centrifugal drying obtains LA tromethane salt. The fusing point of LA tromethane salt is 115-117 DEG C, and specific rotation is 73.9 ��, and ee value is 99.32%, and content is 99.61%.
Embodiment 4:
A) LA is prepared: first drop into, to being furnished with in the reaction vessel of whipping appts, (S)-6 prepared by biological enzyme, 8-bis-chlorine ethyl octylate and sulphur, it is warmed up to 100 DEG C, drip add mass percent concentration be 15% sodium sulfide solution carry out ring-closure reaction, the 2 hours time of ring-closure reaction, (S)-6, 8-bis-chlorine ethyl octylate, the mol ratio of sulphur and sodium sulfide solution is 1:2:1.2, it is incubated 0.5h at 100 DEG C of temperature, ring-closure reaction terminates, the first organic solvent is adopted namely to adopt dichloromethane extraction, concentrated, obtain ring and close liquid, again ring is closed liquid put into be furnished with in the reaction vessel of whipping appts and add mass percent concentration be 10% solution of potassium carbonate be hydrolyzed reaction, the mol ratio that ring conjunction liquid and mass percent concentration are the solution of potassium carbonate of 10% is 1:1, the temperature of hydrolysis reaction is 70 DEG C, the time of hydrolysis reaction is 16h, after hydrolysis reaction terminates, cooling, obtain hydrolyzed solution, then the 2nd organic solvent and methylene dichloride are joined in hydrolyzed solution and the salt acid for adjusting pH being 2mol/L by mol concentration is 1, extracting twice, the organic layer that extraction obtains is washed to neutrality, the 2nd organic solvent is removed in decompression again, namely methylene dichloride is removed, obtain LA mucus, namely first product is obtained, wherein: the volume ratio of described hydrolyzed solution and described methylene dichloride is 1:0.2, finally join in first product by the mixed solvent of ethyl acetate and hexanaphthene, first product, the weight ratio of ethyl acetate and hexanaphthene is 1:8:100, rising temperature for dissolving, the temperature of rising temperature for dissolving is 25 DEG C, add the silicon bath soil whip attachment as the first flocculating aids, the weight ratio of crude product and silicon bath soil is 1:0.025, filter, the faint yellow liquid obtained, cooling crystallize out, this crystal is LA, specific rotation is 119.9 ��, ee value is 99.2%, content is 99.2%,
B) finished product is prepared: first to by steps A) LA that obtains adds DMF dissolve, the weight ratio of LA and DMF is 1: 2 stirring and dissolving, add Tutofusin tris, the mol ratio of LA and Tutofusin tris is be warmed up to 55 DEG C stirring and dissolving at 1: 1.02, insulation 2h, add the diatomite as the 2nd flocculating aids, the weight ratio of LA and diatomite is 1: 0.05, filter, obtain faint yellow liquid, cooling crystallize out, after-10 DEG C, centrifugal drying obtains LA tromethane salt. The fusing point of LA tromethane salt is 115.1-117.4 DEG C, and specific rotation is 74.3 ��, and ee value is 99.45%, and content is 99.67%.
Embodiment 5:
A) LA is prepared: first drop into, to being furnished with in the reaction vessel of whipping appts, (S)-6 prepared by biological enzyme, 8-bis-chlorine ethyl octylate and sulphur, it is warmed up to 75 DEG C, drip add mass percent concentration be 18% sodium sulfide solution carry out ring-closure reaction, the 1 hour time of ring-closure reaction, (S)-6, 8-bis-chlorine ethyl octylate, the mol ratio of sulphur and sodium sulfide solution is 1:1:1.8, it is incubated 1.2h at 75 DEG C of temperature, ring-closure reaction terminates, the first organic solvent is adopted namely to adopt chloroform extraction, concentrated, obtain ring and close liquid, again ring is closed liquid put into be furnished with in the reaction vessel of whipping appts and add mass percent concentration be 5% sodium hydroxide solution be hydrolyzed reaction, the mol ratio that ring conjunction liquid and mass percent concentration are the sodium hydroxide solution of 5% is 1:1.8, the temperature of hydrolysis reaction is 90 DEG C, the time of hydrolysis reaction is 5h, after hydrolysis reaction terminates, cooling, obtain hydrolyzed solution, then the 2nd organic solvent and chloroform are joined in hydrolyzed solution and the salt acid for adjusting pH being 1.2mol/L by mol concentration is 1, extracting twice, the organic layer that extraction obtains is washed to neutrality, the 2nd organic solvent is removed in decompression again, namely chloroform is removed, obtain LA mucus, namely first product is obtained, wherein: the volume ratio of described hydrolyzed solution and described chloroform is 1:0.8, finally join in first product by the mixed solvent of ethyl acetate and hexanaphthene, first product, the weight ratio of ethyl acetate and hexanaphthene is 1:10:90, rising temperature for dissolving, the temperature of rising temperature for dissolving is 30 DEG C, add the silica gel whip attachment as the first flocculating aids, the weight ratio of crude product and silica gel is 1:0.05, filter, the faint yellow liquid obtained, cooling crystallize out, this crystal is LA, specific rotation is 117.1 ��, ee value is 99.4%, content is 99.6%,
B) finished product is prepared: first to by steps A) LA that obtains adds anhydrous alcohol solution, the weight ratio of LA and dehydrated alcohol is 1: 3 stirring and dissolving, add Tutofusin tris, the mol ratio of LA and Tutofusin tris is be warmed up to 55 DEG C stirring and dissolving at 1: 1.05, insulation 2.5h, add the gac as the 2nd flocculating aids, the weight ratio of LA and gac is 1: 0.03, filter, obtain faint yellow liquid, cooling crystallize out, after 0 DEG C, centrifugal drying obtains LA tromethane salt. The fusing point of LA tromethane salt is 115.4-117.5 DEG C, and specific rotation is 74.6 ��, and ee value is 99.32%, and content is 99.51%.
Embodiment 6:
A) LA is prepared: first drop into, to being furnished with in the reaction vessel of whipping appts, (S)-6 prepared by biological enzyme, 8-bis-chlorine ethyl octylate and sulphur, it is warmed up to 85 DEG C, drip add mass percent concentration be 10% sodium sulfide solution carry out ring-closure reaction, the 4 hours time of ring-closure reaction, (S)-6, 8-bis-chlorine ethyl octylate, the mol ratio of sulphur and sodium sulfide solution is 1:1.2:1.6, it is incubated 1.6h at 85 DEG C of temperature, ring-closure reaction terminates, the first organic solvent is adopted namely to adopt chloroform extraction, concentrated, obtain ring and close liquid, again ring is closed liquid put into be furnished with in the reaction vessel of whipping appts and add mass percent concentration be 6% sodium hydroxide solution be hydrolyzed reaction, the mol ratio that ring conjunction liquid and mass percent concentration are the sodium hydroxide solution of 6% is 1:1.2, the temperature of hydrolysis reaction is 95 DEG C, the time of hydrolysis reaction is 3h, after hydrolysis reaction terminates, cooling, obtain hydrolyzed solution, then the 2nd organic solvent and methylene dichloride are joined in hydrolyzed solution and the salt acid for adjusting pH being 2mol/L by mol concentration is 1, extracting twice, the organic layer that extraction obtains is washed to neutrality, the 2nd organic solvent is removed in decompression again, namely methylene dichloride is removed, obtain LA mucus, namely first product is obtained, wherein: the volume ratio of described hydrolyzed solution and described methylene dichloride is 1:0.3, finally join in first product by the mixed solvent of ethyl acetate and hexanaphthene, first product, the weight ratio of ethyl acetate and hexanaphthene is 1:9:70, rising temperature for dissolving, the temperature of rising temperature for dissolving is 50 DEG C, add the silica gel whip attachment as the first flocculating aids, the weight ratio of crude product and silica gel is 1:0.035, filter, the faint yellow liquid obtained, cooling crystallize out, this crystal is LA, specific rotation is 117.7 ��, ee value is 99.3%, content is 99.2%,
B) finished product is prepared: first to by steps A) LA that obtains adds the dissolve with ethanol that mass percent concentration is 95%, LA and mass percent concentration are the weight ratio of the ethanol of 95% is 1: 4 stirring and dissolving, add Tutofusin tris, the mol ratio of LA and Tutofusin tris is be warmed up to 55 DEG C stirring and dissolving at 1: 1.05, insulation 3h, add the gac as the 2nd flocculating aids, the weight ratio of LA and gac is 1: 0.03, filter, obtain faint yellow liquid, cooling crystallize out, after 10 DEG C, centrifugal drying obtains LA tromethane salt. the fusing point of LA tromethane salt is 115.1-116.9 DEG C, and specific rotation is 73.2 ��, and ee value is 99.21%, and content is 99.32%.
Embodiment 7:
A) LA is prepared: first drop into, to being furnished with in the reaction vessel of whipping appts, (S)-6 prepared by biological enzyme, 8-bis-chlorine ethyl octylate and sulphur, it is warmed up to 82 DEG C, drip add mass percent concentration be 9% sodium sulfide solution carry out ring-closure reaction, the 3.5 hours time of ring-closure reaction, (S)-6, 8-bis-chlorine ethyl octylate, the mol ratio of sulphur and sodium sulfide solution is 1:1.8:1.7, it is incubated 1h at 82 DEG C of temperature, ring-closure reaction terminates, the first organic solvent is adopted namely to adopt toluene to extract, concentrated, obtain ring and close liquid, again ring is closed liquid put into be furnished with in the reaction vessel of whipping appts and add mass percent concentration be 6.5% sodium hydroxide solution be hydrolyzed reaction, the mol ratio that ring conjunction liquid and mass percent concentration are the sodium hydroxide solution of 6.5% is 1:1.2, the temperature of hydrolysis reaction is 92 DEG C, the time of hydrolysis reaction is 8h, after hydrolysis reaction terminates, cooling, obtain hydrolyzed solution, then the 2nd organic solvent and toluene are joined in hydrolyzed solution and the salt acid for adjusting pH being 1.4mol/L by mol concentration is 1, extracting twice, the organic layer that extraction obtains is washed to neutrality, the 2nd organic solvent is removed in decompression again, namely toluene is removed, obtain LA mucus, namely first product is obtained, wherein: the volume ratio of described hydrolyzed solution and described toluene is 1:0.25, finally join in first product by the mixed solvent of ethyl acetate and hexanaphthene, first product, the weight ratio of ethyl acetate and hexanaphthene is 1:7:95, rising temperature for dissolving, the temperature of rising temperature for dissolving is 20 DEG C, add the silica gel whip attachment as the first flocculating aids, the weight ratio of crude product and silica gel is 1:0.02, filter, the faint yellow liquid obtained, cooling crystallize out, this crystal is LA, specific rotation is 117.4 ��, ee value is 99.7%, content is 99.5%,
B) finished product is prepared: first to by steps A) LA that obtains adds dissolve with methanol, the weight ratio of LA and methyl alcohol is 1: 10 stirring and dissolving, add Tutofusin tris, the mol ratio of LA and Tutofusin tris is be warmed up to 68 DEG C stirring and dissolving at 1: 1.7, insulation 2h, add the gac as the 2nd flocculating aids, the weight ratio of LA and gac is 1: 0.04, filter, obtain faint yellow liquid, cooling crystallize out, after 20 DEG C, centrifugal drying obtains LA tromethane salt. The fusing point of LA tromethane salt is 115.7-117.7 DEG C, and specific rotation is 73.4 ��, and ee value is 99.36%, and content is 99.33%.
Embodiment 8:
A) LA is prepared: obtain LA by the preparation method of embodiment 1 or 2;
B) finished product is prepared: first to by steps A) LA that obtains adds methyl alcohol, the weight ratio of LA and methyl alcohol is 1: 10 stirring and dissolving, add Tutofusin tris, the mol ratio of LA and Tutofusin tris is be warmed up to 68 DEG C stirring and dissolving at 1: 1.07, insulation 2h, add the gac as the 2nd flocculating aids, the weight ratio of LA and gac is 1: 0.04, filter, obtain faint yellow liquid, cooling crystallize out, after 20 DEG C, centrifugal drying obtains LA tromethane salt. The fusing point of LA tromethane salt is 115.7-117.7 DEG C, and specific rotation is 73.4 ��, and ee value is 99.36%, and content is 99.33%.
Embodiment 9:
A) LA is prepared: obtain LA by the preparation method of embodiment 3 or 4;
B) finished product is prepared: first to by steps A) LA that obtains adds dehydrated alcohol, the weight ratio of LA and dehydrated alcohol is 1: 6 stirring and dissolving, add Tutofusin tris, the mol ratio of LA and Tutofusin tris is be warmed up to 52 DEG C stirring and dissolving at 1: 1, insulation 3.5h, add the gac as the 2nd flocculating aids, the weight ratio of LA and gac is 1: 0.03, filter, obtain faint yellow liquid, cooling crystallize out, after 25 DEG C, centrifugal drying obtains LA tromethane salt. The fusing point of LA tromethane salt is 116-118 DEG C, and specific rotation is 74.8 ��, and ee value is 99.32%, and content is 99.49%.
Embodiment 10:
A) LA is prepared: obtain LA by the preparation method of embodiment 5 or 6;
B) finished product is prepared: first to by steps A) LA that obtains adds acetone, the weight ratio of LA and acetone is 1: 10 stirring and dissolving, add Tutofusin tris, the mol ratio of LA and Tutofusin tris is be warmed up to 40 DEG C stirring and dissolving at 1: 01, insulation 4h, add the gac as the 2nd flocculating aids, the weight ratio of LA and gac is 1: 0.03, filter, obtain faint yellow liquid, cooling crystallize out, after 25 DEG C, centrifugal drying obtains LA tromethane salt. The fusing point of LA tromethane salt is 115.4-117.4 DEG C, and specific rotation is 73.9 ��, and ee value is 99.31%, and content is 99.14%.
Embodiment 11:
A) LA is prepared: obtain LA by the preparation method of embodiment 7;
B) finished product is prepared: first to by steps A) LA that obtains adds the dissolve with ethanol that mass percent concentration is 95%, LA and mass percent concentration are the weight ratio of the ethanol of 95% is 1: 2 stirring and dissolving, add Tutofusin tris, the mol ratio of LA and Tutofusin tris is be warmed up to 70 DEG C stirring and dissolving at 1: 1.01, insulation 1h, add the gac as the 2nd flocculating aids, the weight ratio of LA and gac is 1: 0.02, filter, obtain faint yellow liquid, cooling crystallize out, after 15 DEG C, centrifugal drying obtains LA tromethane salt. the fusing point of LA tromethane salt is 115.1-117.2 DEG C, and specific rotation is 74.1 ��, and ee value is 99.52%, and content is 99.36%.
Claims (10)
1. the preparation method of a LA tromethane salt, it is characterised in that comprise the following steps:
A) LA is prepared: first drop into (S)-6 to being furnished with in the reaction vessel of whipping appts, 8-bis-chlorine ethyl octylate and sulphur, heat up, drip and add sodium sulfide solution and carry out ring-closure reaction, ring-closure reaction is incubated after terminating, then adopt the first organic solvent extraction and concentrate, obtain ring and close liquid, ring closes liquid again put into and be furnished with in the reaction vessel of whipping appts and add alkaline solution and be hydrolyzed reaction, after hydrolysis reaction terminates, cooling, obtain hydrolyzed solution, then the 2nd organic solvent is joined in hydrolyzed solution and use acid adjust pH, through extraction, the organic layer that extraction obtains is washed to neutrality, then the 2nd organic solvent is removed in decompression, obtain first product, finally mixed solution agent is joined in first product, rising temperature for dissolving, add the first flocculating aids, whip attachment, filter, obtain faint yellow liquid, through cooling crystallize out, obtain LA,
B) finished product is prepared, first to by steps A) LA that obtains adds stirring solvent dissolve, add Tutofusin tris again, heating up, stirring and dissolving, then adds the 2nd filter aid, obtain faint yellow liquid, cooling crystallize out, finally by centrifugal drying, obtains LA tromethane salt.
2. the preparation method of a kind of LA tromethane salt according to claim 1, it is characterised in that steps A) described in the first organic solvent be toluene, ethyl acetate, hexanaphthene, methylene dichloride or chloroform; The mol ratio of described (S)-6,8-two chlorine ethyl octylate, sulphur and sodium sulfide solution is 1: 1-2: 1-2.
3. the preparation method of a kind of LA tromethane salt according to claim 1, it is characterised in that steps A) described in intensification be that temperature is risen to 70-100 DEG C; Described add sodium sulfide solution drip that to add the time be 0.5-5h; The time of described insulation is 0.5-2h; The mass percent concentration of described sodium sulfide solution is 8-20%.
4. the preparation method of a kind of LA tromethane salt according to claim 1, it is characterized in that steps A) described in the ring mol ratio that closes liquid and alkaline solution be 1: 1-2, the sodium hydroxide solution of described alkaline solution to be mass percent concentration be 3-10%, potassium hydroxide solution, sodium carbonate solution or solution of potassium carbonate; The temperature of described hydrolysis reaction is 70-95 DEG C, and the time of hydrolysis reaction is 3-20h.
5. the preparation method of a kind of LA tromethane salt according to claim 1, it is characterised in that steps A) described in hydrolyzed solution and the volume ratio of described 2nd organic solvent be 1: 0.1-1; Described is that pH value is adjusted to pH=1 with acid for adjusting pH value; The extraction times of described extraction is twice; The 2nd described organic solvent is toluene, ethyl acetate, hexanaphthene, methylene dichloride or chloroform; The volumetric molar concentration of described acid is the hydrochloric acid of 0.5-2mol/L, sulfuric acid or phosphoric acid solution.
6. the preparation method of a kind of LA tromethane salt according to claim 1, it is characterised in that steps A) described in the temperature of rising temperature for dissolving be 20-50 DEG C.
7. the preparation method of a kind of LA tromethane salt according to claim 1, it is characterized in that steps A) described in mixed solvent be that ethyl acetate mixes the mixed solvent formed mutually with hexanaphthene, the weight ratio of described first product, ethyl acetate and hexanaphthene is 1:5-10:50-100; The first described flocculating aids is gac, silica gel or diatomite, and described crude product and the weight ratio of flocculating aids are 1:0.02-0.05.
8. the preparation method of a kind of LA tromethane salt according to claim 1 and 2, it is characterised in that described (S)-6,8-two chlorine ethyl octylate is prepared by biological enzyme.
9. the preparation method of a kind of LA tromethane salt according to claim 1, it is characterised in that step B) described in solvent be ethyl acetate, acetone, THF, DMF, dehydrated alcohol, 95 ethanol or methyl alcohol; Described LA and the weight ratio of solvent are 1:1-1:10; Described LA and the mol ratio of Tutofusin tris are 1:1.0-1:1.1.
10. the preparation method of a kind of LA tromethane salt according to claim 1, it is characterized in that step B) described in the 2nd flocculating aids be gac, aluminum oxide, silica gel or diatomite, the temperature that the weight ratio of described LA and the 2nd flocculating aids is the intensification described in 1:0.02-0.05 is 40-70 DEG C, and the time is 1-4h; The cooling temperature of described cooling is-15-25 DEG C.
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| CN112778270A (en) * | 2021-01-25 | 2021-05-11 | 苏州富士莱医药股份有限公司 | Preparation method of R-lipoic acid tromethamine salt |
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| CN113292533A (en) * | 2021-05-25 | 2021-08-24 | 四川智强医药科技开发有限公司 | Method for purifying polymer impurities in lipoic acid |
| CN113292533B (en) * | 2021-05-25 | 2024-04-16 | 四川智强医药科技开发有限公司 | Method for purifying polymer impurities in 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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