CN114181192A - Resin deamination method in R-lipoic acid synthesis process - Google Patents
Resin deamination method in R-lipoic acid synthesis process Download PDFInfo
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- CN114181192A CN114181192A CN202111381362.6A CN202111381362A CN114181192A CN 114181192 A CN114181192 A CN 114181192A CN 202111381362 A CN202111381362 A CN 202111381362A CN 114181192 A CN114181192 A CN 114181192A
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- lipoic acid
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- phenylethylamine
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- 235000019136 lipoic acid Nutrition 0.000 title claims abstract description 63
- 238000000034 method Methods 0.000 title claims abstract description 45
- AGBQKNBQESQNJD-SSDOTTSWSA-N (R)-lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 title claims abstract description 38
- 239000011347 resin Substances 0.000 title claims abstract description 36
- 229920005989 resin Polymers 0.000 title claims abstract description 36
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 22
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 20
- 230000009615 deamination Effects 0.000 title claims abstract description 7
- 238000006481 deamination reaction Methods 0.000 title claims abstract description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 46
- 229960002663 thioctic acid Drugs 0.000 claims abstract description 36
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 238000002425 crystallisation Methods 0.000 claims abstract description 12
- 230000008025 crystallization Effects 0.000 claims abstract description 12
- 239000003480 eluent Substances 0.000 claims abstract description 6
- 239000000243 solution Substances 0.000 claims description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000012153 distilled water Substances 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- 238000001179 sorption measurement Methods 0.000 claims description 8
- 238000000967 suction filtration Methods 0.000 claims description 8
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 7
- 239000003729 cation exchange resin Substances 0.000 claims description 7
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 6
- 239000012024 dehydrating agents Substances 0.000 claims description 6
- 238000001704 evaporation Methods 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000012670 alkaline solution Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 238000010828 elution Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 4
- 229940117803 phenethylamine Drugs 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 3
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000292 calcium oxide Substances 0.000 claims description 3
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 claims description 3
- 230000008020 evaporation Effects 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 5
- 230000020477 pH reduction Effects 0.000 abstract description 5
- 230000018044 dehydration Effects 0.000 abstract description 4
- 238000006297 dehydration reaction Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract description 3
- 230000006866 deterioration Effects 0.000 abstract description 3
- 239000003513 alkali Substances 0.000 abstract description 2
- 150000001768 cations Chemical class 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000005342 ion exchange Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 10
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 102000005751 Alcohol Oxidoreductases Human genes 0.000 description 1
- 108010031132 Alcohol Oxidoreductases Proteins 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- HJOGJYUYZQTDSW-UHFFFAOYSA-N C(=O)=C(CCCCC(=O)OCC)CCCl Chemical compound C(=O)=C(CCCCC(=O)OCC)CCCl HJOGJYUYZQTDSW-UHFFFAOYSA-N 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- YSFJHUHDLIFMPB-SECBINFHSA-N ethyl (6r)-8-chloro-6-hydroxyoctanoate Chemical compound CCOC(=O)CCCC[C@@H](O)CCCl YSFJHUHDLIFMPB-SECBINFHSA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- UUDFBRWLHZIIQX-UHFFFAOYSA-M sodium;5-(dithiolan-3-yl)pentanoate Chemical compound [Na+].[O-]C(=O)CCCCC1CCSS1 UUDFBRWLHZIIQX-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
- C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/84—Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a resin deamination method in the R-lipoic acid synthesis process, which comprises the steps of performing ion exchange on R-phenylethylamine in R-phenylethylamine lipoic acid double salt by using cation acid resin to obtain an R-thioctic acid solution, and separating after crystallization to obtain high-purity R-lipoic acid. The invention reduces the deterioration problem of acidification by hydrochloric acid and has high product purity and yield. The process method is simple and mild, the resin can be reused after being processed, and the eluent can be reused after alkali reaction and dehydration to obtain R-phenylethylamine, so that the production cost is reduced, the economic value is good, and a new way is provided for industrial production of R-lipoic acid.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a resin deamination method in the R-lipoic acid synthesis process.
Background
Lipoic acid (R- (+) -alpha lipoic acid) is coenzyme naturally produced by human body, is involved in aerobic metabolism to produce energy, is also a strong antioxidant, has the antioxidant capacity 200 times that of vitamin C, has the characteristics of fat solubility and water solubility, and is widely applied to preventing and treating heart disease, diabetes and senile dementia. Lipoic acid has the following effects:
(1) strong antioxidation, and has the capability of eliminating accelerated aging and pathogenic free radicals;
(2) stabilizing blood glucose level, and improving peripheral neuropathy symptoms related to diabetes;
(3) treating liver diseases such as chronic hepatitis.
(4) It has been found that by converting bioactive "R" form lipoic acid to sodium lipoate, a higher blood peak can be achieved than with pure R-lipoic acid.
With the research on the synthesis method of R-lipoic acid, various methods for synthesizing R-lipoic acid have been discovered from different starting raw materials. The main synthetic methods at present are:
1. adipic acid is adopted as an initial raw material, after multi-step synthesis, 6-carbonyl-8-chlorooctanoic acid ethyl ester is reduced into R-6-hydroxyl-8-chlorooctanoic acid ethyl ester by adopting an enzymatic reaction, then R-lipoic acid is continuously synthesized, and a carbonyl reductase catalyst is used, so that a biological synthesis method is hoped to replace the traditional chemical synthesis method, the yield is improved, and the discharge of three wastes is reduced. At present, the method is still in laboratory research, and industrial production is not yet developed.
2. The racemic lipoic acid is adopted, toluene is taken as a solvent, and R-phenylethylamine is selected for resolution, so that the yield and the purity are both ideal, and the method is an ideal method for synthesizing the R-lipoic acid at present. However, in the subsequent acidification process, hydrochloric acid is adopted for acidification, so that the product is deteriorated under the strong acid condition, and the yield is reduced.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a resin deamination method in the R-lipoic acid synthesis process, which adopts cation acid resin to exchange R-phenylethylamine in R-phenylethylamine lipoic acid double salt to obtain R-thioctic acid solution, and separates the R-thioctic acid solution after crystallization to obtain high-purity R-thioctic acid, so that the problem of deterioration of the R-phenylethylamine lipoic acid double salt and hydrochloric acid in the prior art when acidification is carried out is effectively solved, and a new way is provided for R-thioctic acid synthesis.
The purpose of the invention is realized by the following technical scheme:
the invention provides a resin deamination method in the R-lipoic acid synthesis process, which comprises the following steps:
(1) dissolving the racemic lipoic acid in a low-polarity organic solvent, adding R-phenylethylamine to perform low-temperature crystallization, and performing suction filtration to obtain R-phenylethylamine lipoic acid double salt; wherein, the weight ratio of the mixed lipoic acid to the low-polarity organic solvent to the R-phenethylamine is 1: 1-5: 0.3-0.6;
(2) dissolving the R-phenylethylamine lipoic acid double salt in a high-polarity organic solvent according to the mass ratio of the R-phenylethylamine lipoic acid double salt to the high-polarity organic solvent of 1: 3-5, adsorbing by using cation exchange resin, and filtering to obtain a filtrate, namely an R-lipoic acid solution;
(3) evaporating the R-lipoic acid solution to dryness, adding cyclohexane and ethyl acetate for low-temperature crystallization, and performing suction filtration to obtain R-lipoic acid; wherein the weight ratio of the mixed lipoic acid to the ethyl acetate to the cyclohexane is 1: 0.5-1: 4-10;
(4) adding a hydrochloric acid solution into the resin subjected to adsorption treatment in the step (2) for eluting until the resin is neutral, eluting by using distilled water until the pH value is more than 5, and repeating the next use;
(5) and (3) eluting hydrochloric acid eluent generated in the step (4) by using a hydrochloric acid solution, adding an alkaline solution to react, layering to obtain a crude product of R-phenylethylamine, adding a dehydrating agent to dehydrate to obtain a pure product of R-phenylethylamine, and repeating the next use.
Further, the low-temperature crystallization temperature in the step (1) is 0-10 ℃, and the crystallization time is 2-5 h. And (3) the resin elution speed in the adsorption treatment in the step (2) is 2-3 times of column volume/h. In the step (3), the evaporation temperature is 50-70 ℃, and the crystallization temperature is 0-10 ℃. The concentration of the hydrochloric acid solution in the step (4) is 1mol/L, the flow rate of the hydrochloric acid and the distilled water is 1-1.5 times of column volume/h, and the using amount of the hydrochloric acid and the distilled water is 2-3 times of the column volume. And (5) the alkaline solution in the step (5) is a sodium hydroxide or potassium hydroxide aqueous solution with the concentration of 20-30 wt%.
In the scheme, the purity of the R lipoic acid obtained in the step (3) is more than or equal to 98%, and the yield is more than or equal to 40%. The low-polarity organic solvent in the step (1) is toluene or tert-butyl methyl ether. The high-polarity organic solvent in the step (2) is methanol, ethanol or isopropanol. The dehydrating agent in the step (5) is calcium chloride and calcium oxide, and the dosage of the dehydrating agent is 0.5-5 wt% of the R-phenylethylamine in the step (1).
The invention has the following beneficial effects:
(1) the invention adopts R-phenylethylamine to split and obtain R-phenylethylamine lipoic acid double salt, and adds cation exchange resin to exchange R-phenylethylamine, thereby reducing the deterioration problem caused by acidification with hydrochloric acid and improving the yield of R-lipoic acid by 5%. Meanwhile, the method is simple and mild, and the resin can be repeatedly used after being processed, thereby providing a new way for industrial production of the R-lipoic acid.
(2) The hydrochloric acid eluent generated after the treatment of the invention is R-phenylethylamine hydrochloride, the R-phenylethylamine is obtained after the addition of alkali for reaction and dehydration, the purity of the product is 99 percent, the recovery rate is 80 percent, and the product can be repeatedly used, thereby reducing the production cost and having good economic value.
(3) The method has the advantages of simple required equipment and reagents, simple and convenient operation, mild reaction conditions, high product purity and yield, low process operation cost and good synthesis effect, and meets the process requirements of industrial production of the R-lipoic acid.
The present invention will be described in further detail with reference to examples.
Detailed Description
The first embodiment is as follows:
this embodiment is a method for de-aminating resin in the synthesis of R-lipoic acid, comprising the following steps:
(1) dissolving 100g of racemic lipoic acid in 200g of toluene, adding 30g R-phenylethylamine, stirring and crystallizing at the temperature of 3 ℃ for 2 hours, and performing suction filtration to obtain 72g R-phenylethylamine lipoic acid double salt;
(2) dissolving the R-phenethylamine lipoic acid double salt in 230g of methanol, and stirring and dissolving for 0.5h to obtain a methanol solution containing the double salt; loading 1000g of cation exchange resin into a chromatographic column, adding distilled water for eluting until the pH value is more than 5, then passing the methanol solution containing the double salt through the column for cation exchange resin adsorption, controlling the flow rate at 2 times of the column volume/h, then adding 50ml of methanol for eluting again, and filtering the solution to obtain 400ml of R-thioctic acid solution;
(3) evaporating the R-thioctic acid solution to dryness at 55 ℃, adding 60g of ethyl acetate and 480g of cyclohexane, stirring, crystallizing at 5 ℃, and performing suction filtration to obtain 42g R-thioctic acid (the content is 98.5%, and the alpha is 119 ℃);
(4) adding a hydrochloric acid solution with the concentration of 1mol/L into the resin subjected to adsorption and elution in the step (2), eluting the resin at the flow rate of 1 time of column volume/h until the resin is neutral, eluting the resin at the flow rate of 1 time of column volume/h until the pH value is more than 5, and repeating the next use;
(5) and (3) eluting hydrochloric acid eluent generated in the step (4) by using a hydrochloric acid solution, adding a 20% sodium hydroxide aqueous solution, stirring for reaction, layering to obtain a crude product of the R-phenylethylamine, adding 0.5g of calcium chloride, stirring for dehydration to obtain 28g of a pure product of the R-phenylethylamine with the purity of 99%, and repeatedly using the pure product for the next time.
Example two:
this embodiment is a method for de-aminating resin in the synthesis of R-lipoic acid, comprising the following steps:
(1) dissolving 100g of racemic lipoic acid in 200g of tert-butyl methyl ether, adding 40g R-phenylethylamine, stirring and crystallizing at the temperature of 3 ℃ for 2 hours, and performing suction filtration to obtain 76g R-phenylethylamine lipoic acid double salt;
(2) dissolving the R-phenethylamine lipoic acid double salt in 300g of ethanol, and stirring and dissolving for 0.5h to obtain an ethanol solution containing the double salt; loading 1000g of cation exchange resin into a chromatographic column, adding distilled water for eluting until the pH value is more than 5, passing the ethanol solution containing the double salt through the column for cation exchange resin adsorption, controlling the flow rate at 2 times of the column volume/h, then adding 50ml of ethanol for eluting again, and filtering the solution to obtain 450ml of R-thioctic acid solution;
(3) evaporating the R-thioctic acid solution to dryness at 55 ℃, adding 70g of ethyl acetate and 500g of cyclohexane, stirring, crystallizing at 5 ℃, and performing suction filtration to obtain 45g R-lipoic acid (the content is 98.7%, and the alpha value is 118 degrees);
(4) adding a hydrochloric acid solution with the concentration of 1mol/L into the resin subjected to adsorption and elution in the step (2), eluting the resin at the flow rate of 1.5 times of the column volume/h until the resin is neutral, eluting the resin with distilled water at the flow rate of 1.5 times of the column volume/h until the pH value is more than 5, and repeating the next use;
(5) and (3) eluting hydrochloric acid eluent generated in the step (4) by using a hydrochloric acid solution, adding a 25% potassium hydroxide aqueous solution, stirring for reaction, layering to obtain a crude product of the R-phenylethylamine, adding 1g of calcium oxide, stirring for dehydration to obtain 35g of a pure product of the R-phenylethylamine with the purity of 99%, and repeating the next use.
Claims (10)
1. A resin deamination method in the synthesis process of R-lipoic acid is characterized by comprising the following steps:
(1) dissolving the racemic lipoic acid in a low-polarity organic solvent, adding R-phenylethylamine to perform low-temperature crystallization, and performing suction filtration to obtain R-phenylethylamine lipoic acid double salt; wherein, the weight ratio of the mixed lipoic acid to the low-polarity organic solvent to the R-phenethylamine is 1: 1-5: 0.3-0.6;
(2) dissolving the R-phenylethylamine lipoic acid double salt in a high-polarity organic solvent according to the mass ratio of the R-phenylethylamine lipoic acid double salt to the high-polarity organic solvent of 1: 3-5, adsorbing by using cation exchange resin, and filtering to obtain a filtrate, namely an R-lipoic acid solution;
(3) evaporating the R-lipoic acid solution to dryness, adding cyclohexane and ethyl acetate for low-temperature crystallization, and performing suction filtration to obtain R-lipoic acid; wherein the weight ratio of the mixed lipoic acid to the ethyl acetate to the cyclohexane is 1: 0.5-1: 4-10;
(4) adding a hydrochloric acid solution into the resin subjected to adsorption treatment in the step (2) for eluting until the resin is neutral, eluting by using distilled water until the pH value is more than 5, and repeating the next use;
(5) and (3) eluting hydrochloric acid eluent generated in the step (4) by using a hydrochloric acid solution, adding an alkaline solution to react, layering to obtain a crude product of R-phenylethylamine, adding a dehydrating agent to dehydrate to obtain a pure product of R-phenylethylamine, and repeating the next use.
2. The method for de-aming resin in the synthesis process of R-lipoic acid according to claim 1, characterised in that: the low-temperature crystallization temperature in the step (1) is 0-10 ℃, and the crystallization time is 2-5 h.
3. The method for de-aming resin in the synthesis process of R-lipoic acid according to claim 1, characterised in that: and (3) the resin elution speed in the adsorption treatment in the step (2) is 2-3 times of column volume/h.
4. The method for de-aming resin in the synthesis process of R-lipoic acid according to claim 1, characterised in that: in the step (3), the evaporation temperature is 50-70 ℃, and the crystallization temperature is 0-10 ℃.
5. The method for de-aming resin in the synthesis process of R-lipoic acid according to claim 1, characterised in that: the concentration of the hydrochloric acid solution in the step (4) is 1mol/L, the flow rate of the hydrochloric acid and the distilled water is 1-1.5 times of column volume/h, and the using amount of the hydrochloric acid and the distilled water is 2-3 times of the column volume.
6. The method for de-aming resin in the synthesis process of R-lipoic acid according to claim 1, characterised in that: and (5) the alkaline solution in the step (5) is a sodium hydroxide or potassium hydroxide aqueous solution with the concentration of 20-30 wt%.
7. The method for de-aming resin in the synthesis process of R-lipoic acid according to claim 1, characterised in that: the purity of the R lipoic acid obtained in the step (3) is more than or equal to 98 percent, and the yield is more than or equal to 40 percent.
8. The method for de-aming resin in the synthesis process of R-lipoic acid according to claim 1, characterised in that: the low-polarity organic solvent in the step (1) is toluene or tert-butyl methyl ether.
9. The method for de-aming resin in the synthesis process of R-lipoic acid according to claim 1, characterised in that: the high-polarity organic solvent in the step (2) is methanol, ethanol or isopropanol.
10. The method for de-aming resin in the synthesis process of R-lipoic acid according to claim 1, characterised in that: the dehydrating agent in the step (5) is calcium chloride and calcium oxide, and the dosage of the dehydrating agent is 0.5-5 wt% of the R-phenylethylamine in the step (1).
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101024641A (en) * | 2006-02-20 | 2007-08-29 | 南京莱尔生物化工有限公司 | R(1) lipoic acid and its salt preparation |
| CN102442994A (en) * | 2011-10-31 | 2012-05-09 | 江苏同禾药业有限公司 | Racemization method of S-lipoic acid and preparing method of R-lipoic acid |
| CN105524040A (en) * | 2016-02-19 | 2016-04-27 | 苏州富士莱医药股份有限公司 | Preparation method of (R)-(+)-lipoic acid |
| CN107573248A (en) * | 2017-09-25 | 2018-01-12 | 苏州华诺医药有限公司 | The recovery method of resolving agent R phenyl ethylamines in prepared by R-DHLA |
| CN108003134A (en) * | 2018-01-19 | 2018-05-08 | 华东师范大学 | A kind of R-（+）The preparation method of-lipoic acid |
| CN111500651A (en) * | 2020-04-10 | 2020-08-07 | 宁波酶赛生物工程有限公司 | Preparation method of phenylethylamine |
| CN113087630A (en) * | 2021-04-06 | 2021-07-09 | 宣城美诺华药业有限公司 | Method for recycling and applying perindopril intermediate resolving agent (R) - (+) -alpha-phenylethylamine |
-
2021
- 2021-11-21 CN CN202111381362.6A patent/CN114181192A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101024641A (en) * | 2006-02-20 | 2007-08-29 | 南京莱尔生物化工有限公司 | R(1) lipoic acid and its salt preparation |
| CN102442994A (en) * | 2011-10-31 | 2012-05-09 | 江苏同禾药业有限公司 | Racemization method of S-lipoic acid and preparing method of R-lipoic acid |
| CN105524040A (en) * | 2016-02-19 | 2016-04-27 | 苏州富士莱医药股份有限公司 | Preparation method of (R)-(+)-lipoic acid |
| CN107573248A (en) * | 2017-09-25 | 2018-01-12 | 苏州华诺医药有限公司 | The recovery method of resolving agent R phenyl ethylamines in prepared by R-DHLA |
| CN108003134A (en) * | 2018-01-19 | 2018-05-08 | 华东师范大学 | A kind of R-（+）The preparation method of-lipoic acid |
| CN111500651A (en) * | 2020-04-10 | 2020-08-07 | 宁波酶赛生物工程有限公司 | Preparation method of phenylethylamine |
| CN113087630A (en) * | 2021-04-06 | 2021-07-09 | 宣城美诺华药业有限公司 | Method for recycling and applying perindopril intermediate resolving agent (R) - (+) -alpha-phenylethylamine |
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