CN106967044A - The method for preparing R lipoic acid cholinester halide - Google Patents
The method for preparing R lipoic acid cholinester halide Download PDFInfo
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- CN106967044A CN106967044A CN201710333536.9A CN201710333536A CN106967044A CN 106967044 A CN106967044 A CN 106967044A CN 201710333536 A CN201710333536 A CN 201710333536A CN 106967044 A CN106967044 A CN 106967044A
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- halide
- cholinester
- preparing
- esterification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
- C07D339/02—Five-membered rings
- C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
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- 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
Abstract
A kind of method for preparing R lipoic acid cholinester halide, belongs to pharmaceutical chemistry synthesis technical field.This method includes method A or method B：Described method A is that R lipoic acids and halogenation choline are carried out into esterification in the system that dehydrating agent, catalysts and solvents are constituted, and obtains R lipoic acid cholinester halide I；Described method B is that R sulphur caprylyl chloride and halogenation choline are carried out into esterification in the system of acid binding agent alkali and solvent, obtains R lipoic acid cholinester halide I.The impurity of each step reaction is less, and the operation such as post processing and purifying simplifies；Use safety, it is adaptable to industrial amplification production；Embody environmental protection effect.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, and in particular to a kind of LA cholinester halide of preparing
Method.
Background technology
Lipoic acid (α-Lipoic acid) is a kind of natural products with bioactivity, nineteen fifty-one by Reed first from
It is isolated in pork liver.Lipoic acid contains a chiral centre, and research shows, two enantiomters of lipoic acid, R- types pair
Reflecting body has bioactivity, and S- types enantiomer does not have activity substantially, also without toxicity.Lipoic acid has been widely used in America and Europe
Clinical medicine domain, such as hepatopathy, senile dementia, cataract, heart disease, diabetes, AIDS, psoriasis, eczema, op parkinson's
The diseases such as disease, rheumatism, heart disease, neurogenic disease, subacute necrosis encephalopathic, radiation damage disease, heavy metal poisoning are controlled
Treat, be described as " omnipotent antioxidant ".With the further investigation development of the pharmacology pharmacodynamic of lipoic acid, medical field researcher is to each
The derivative and its their salts for planting lipoic acid have carried out application and development, greatly enrich and extend lipoic acid series of products
Indication scope and therapeutic effect, to meet the medical clinical and market demand.
A kind of LA choline ester derivant has eye disclosed in patent WO2015134510A1 and US20150246903
Section's medical usage, including the ophthalmology diseases such as presbyopia, glaucoma and cataract are treated, and the preparation method about kind is provided.
Wherein, be esterified using LA with choline under conditions of dehydrating agent and catalyst, then by with iodomethane or a chlorine
Methane reaction, generation LA cholinester iodide or LA cholinester chloride, two step synthetic reaction formulas are as follows：
The iodomethane that this method is used is poisonous reagent, and environmental pollution is larger, is unfavorable for producers and environment
Protection.Monochloro methane is gas, it is necessary to be dissolved in methyl tertiary butyl ether(MTBE) to be added in reactant mixture, complex operation is cumbersome,
It is unfavorable for amplification production popularization and application.For the synthesis of LA cholinester bromide, patent US20150246903 it is also proposed that
The example of 1 one-step synthesis method route, it is as follows：
But the enlightenment in terms of preparation condition and operation is not provided.
The content of the invention
For the deficiencies in the prior art and defect, LA choline is prepared it is an object of the invention to provide one kind
The method of ester halide, it is high and to be satisfied R- sulphur pungent with total recovery that this method process route is reasonable, simple to operate, reagent is easy to get
The amplification production requirement of sour cholinester halide simultaneously can embody excellent environmental protection effect.
In order to realize foregoing invention purpose, the technical solution adopted by the present invention is：One kind prepares LA cholinester halogen
The method of compound, this method includes method A) or method B)：
Described method A) it is to enter LA in the system that dehydrating agent, catalysts and solvents are constituted with halogenation choline
Row esterification, obtains LA cholinester halide (I), and reaction equation is：
In formula, X is chlorine, bromine or iodine；
Described method B) it is to be esterified R- sulphur caprylyl chloride in the system of acid binding agent alkali and solvent with halogenation choline
Reaction, obtains LA cholinester halide (I), reaction equation is：
In formula, X is chlorine, bromine or iodine.
The present invention a specific embodiment in, methods described A) described in dehydrating agent be N, N '-carbonyl two
Imidazoles, N, N '-dicyclohexyl phosphinylidyne diimine, N, N '-diisopropyl phosphinylidyne diimine, 1- ethyls-(3- dimethylaminos third
Base) phosphinylidyne diimmonium salt hydrochlorate, 1- hydroxy benzo triazoles, the carbon -7- alkene of 1,8- diazabicyclos [5.4.0] 11, N, N '-carbonyl
Base two (1,2,4- triazoles), O- BTAs-N, N, N ', N '-tetramethylurea hexafluorophosphate, O- BTA-N,
N, N ', N '-tetramethylurea tetrafluoro boric acid ester, 2- (7- azos BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester,
Hexafluorophosphoric acid BTA -1- bases-epoxide tripyrrole alkyl phosphorus, (dimethylamino) phosphorus of BTA -1- bases epoxide three
Hexafluorophosphate or PhosphorodichloridicAcid Acid Phenyl Ester；Described catalyst be triethylamine, diethylamine, N, N- diisopropylethylamine, pyridine,
Piperidines, tri-n-butylamine, trimethylamine, tri-isopropyl amine, diisopropylamine, aniline, N, accelerine, N, N- diethylanilines, 2,
6- lutidines, DMAP, TMG, 1-METHYLPYRROLIDONE, N-methylmorpholine or N-ethylmorpholine.
The present invention another specific embodiment in, described method A) described in LA, halogenation choline,
Mol ratio between dehydrating agent and catalyst is 1.0: 1.5~3.0: 1.1~1.3: 0.1~0.3.
In another specific embodiment of the present invention, methods described A) described in esterification temperature for 20~
50 DEG C, the time of esterification is 12~24h.
The present invention another specific embodiment in, methods described A) described in solvent be dichloromethane, 1,2-
Dichloroethanes, chloroform, chlorobenzene, acetonitrile, toluene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, 1,2- dimethoxy second
Alkane, methyl tertiary butyl ether(MTBE), tetrahydrofuran or acetone.
The present invention also have a specific embodiment in, methods described B) described in acid binding agent alkali be three second
Amine, diethylamine, N, N- diisopropylethylamine, pyridine, piperidines, tri-n-butylamine, trimethylamine, tri-isopropyl amine, diisopropylamine, aniline,
N, accelerine, N, N- diethylanilines, 2,6- lutidines, DMAP, TMG, N- methyl pyrroles
Pyrrolidone, N-methylmorpholine, N-ethylmorpholine or the carbon -7- alkene of 1,8- diazabicyclos [5.4.0] 11.
In a still more specific embodiment of the invention, methods described B) described in R- sulphur caprylyl chloride, halogenation courage
Mol ratio between alkali and acid binding agent alkali three is 1.0: 1.5~3.0: 2.0~4.0.
The present invention so that in a specific embodiment, methods described B) described in esterification temperature be 20
~50 DEG C, the time of esterification is 3~12h.
Methods described B in yet a further embodiment of the present invention) described in solvent be tetrahydrofuran,
Dichloromethane, 1,2- dichloroethanes, chloroform, chlorobenzene, acetonitrile, toluene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide,
Acetone, methyl tertiary butyl ether(MTBE) or 1,4- dioxane.
The technical scheme that the present invention is provided has following technique effect：First, the impurity of each step reaction is less, post processing and
The operation such as purifying simplifies；Second, initiation material and reagent used are easy to get, using safety, the technical scheme of synthetic reaction is reasonable,
Suitable for industrial amplification production；Third, due to pollutant will not be produced in preparation process, thus environmental protection can be embodied
Effect.
Embodiment
Technical scheme is further elaborated below in conjunction with specific embodiment, it is clear that protection of the invention
Scope is not limited to embodiment, and the other embodiment of the invention that those skilled in the art are done belongs to what the present invention was protected
Scope.
Embodiment 1：
Method A)：LA (10.0g, 48.5mmol) and toluene (200mL) are added in reaction bulb, stirring and dissolving, plus
Enter N, N '-dicyclohexyl phosphinylidyne diimine (12.0g, 58.2mmol) and DMAP (1.2g, 9.7mmol), ice bath
Cooling, adds Choline Chloride (15.2g, 109.1mmol), and reactant mixture reacts 18h at 35 DEG C.Post processing and purifying, crude product
Recrystallized with isopropanol, obtain LA cholinester chloride, light yellow solid (14.8g), yield 93%, reaction equation
For：
Embodiment 2：
Method B)：R- sulphur caprylyl chloride (10.0g, 44.5mmol) and chloroform (200mL) are added in reaction bulb, stirring and dissolving,
N is added, N- diethylanilines (26.6g, 178.0mmol), ice bath cooling adds Choline Chloride (18.6g, 133.5mmol), instead
Mixture is answered to react 12h at 20 DEG C.Post processing and purifying, crude product are recrystallized with isopropanol, obtain LA cholinester chlorine
Compound, light yellow solid (12.7g), yield 87%, reaction equation is：
Embodiment 3：
Method A)：LA (10.0g, 48.5mmol) and 1,2- dichloroethanes (200mL) are added in reaction bulb, stirring
Dissolving, adds N, N '-carbonyl dimidazoles (8.6g, 53.3mmol) and 2,6- lutidines (0.5g, 4.8mmol), ice bath is cold
But, choline bromide (26.8g, 145.4mmol) is added, reactant mixture reacts 24h at 20 DEG C.Post processing and purifying, crude product are used
Isopropanol is recrystallized, and obtains LA cholinester bromide, light yellow solid (17.1g), yield 95%, and reaction equation is：
Embodiment 4：
Method B)：R- sulphur caprylyl chloride (10.0g, 44.5mmol) and toluene (200mL) are added in reaction bulb, stirring and dissolving,
DIPEA (11.5g, 89.0mmol) is added, ice bath cooling adds choline bromide (12.3g, 66.7mmol), instead
Mixture is answered to react 8h at 35 DEG C.Post processing and purifying, crude product are recrystallized with isopropanol, obtain LA cholinester bromination
Thing, light yellow solid (14.2g), yield 86%, reaction equation is：
Embodiment 5：
Method A)：LA (10.0g, 48.5mmol) and 1,2- dimethoxy-ethane (200mL) are added in reaction bulb,
Stirring and dissolving, adds N, N '-diisopropyl phosphinylidyne diimine (8.0g, 63.0mmol) and pyridine (1.2g, 14.5mmol), ice bath
Cooling, adds choline iodide (16.8g, 72.7mmol), and reactant mixture reacts 12h at 50 DEG C.Post processing and purifying, crude product are used
Isopropanol is recrystallized, and obtains LA cholinester iodide, light yellow solid (18.3g), yield 90%, and reaction equation is：
Embodiment 6：
Method B)：R- sulphur caprylyl chloride (10.0g, 44.5mmol) and tetrahydrofuran (200mL) are added in reaction bulb, are stirred molten
Solution, adds N, and N- dimethylanilines (16.2g, 133.5mmol), ice bath cooling adds choline iodide (23.6g, 102.3mmol),
Reactant mixture reacts 3h at 50 DEG C.Post processing and purifying, crude product are recrystallized with isopropanol, obtain LA cholinester iodine
Compound, light yellow solid (16.8g), yield 90%, reaction equation is：
Claims (9)
1. a kind of method for preparing LA cholinester halide, it is characterised in that this method includes method A) or method B)：
Described method A) it is that LA and halogenation choline are subjected to ester in the system that dehydrating agent, catalysts and solvents are constituted
Change reaction, obtain LA cholinester halide (I), reaction equation is：
In formula, X is chlorine, bromine or iodine；
Described method B) it is that R- sulphur caprylyl chloride and halogenation choline are subjected to esterification in the system of acid binding agent alkali and solvent,
LA cholinester halide (I) is obtained, reaction equation is：
In formula, X is chlorine, bromine or iodine.
2. the method according to claim 1 for preparing LA cholinester halide, it is characterised in that methods described A)
Described in dehydrating agent be N, N '-carbonyl dimidazoles, N, N '-dicyclohexyl phosphinylidyne diimine, N, N '-diisopropyl phosphinylidyne two are sub-
Amine, 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate, 1- hydroxy benzo triazoles, 1,8- diazabicyclos
[5.4.0] 11 carbon -7- alkene, N, N '-carbonyl two (1,2,4- triazoles), O- BTAs-N, N, N ', N '-tetramethylurea
Hexafluorophosphate, O- BTAs-N, N, N ', N '-tetramethylurea tetrafluoro boric acid ester, 2- (7- azos BTA)-N,
N, N ', N '-tetramethylurea hexafluorophosphoric acid ester, hexafluorophosphoric acid BTA -1- bases-epoxide tripyrrole alkyl phosphorus, BTA -
(dimethylamino) the phosphorus hexafluorophosphate of 1- bases epoxide three or PhosphorodichloridicAcid Acid Phenyl Ester；Described catalyst is triethylamine, two
Ethamine, N, N- diisopropylethylamine, pyridine, piperidines, tri-n-butylamine, trimethylamine, tri-isopropyl amine, diisopropylamine, aniline, N, N- bis-
Methylaniline, N, N- diethylanilines, 2,6- lutidines, DMAP, TMG, N- crassitudes
Ketone, N-methylmorpholine or N-ethylmorpholine.
3. the method according to claim 1 for preparing LA cholinester halide, it is characterised in that described method
A the mol ratio between LA, halogenation choline, dehydrating agent and catalyst described in) is 1.0: 1.5~3.0: 1.1
~1.3: 0.1~0.3.
4. the method according to claim 1 for preparing LA cholinester halide, it is characterised in that methods described A)
Described in the temperature of esterification be 20~50 DEG C, time of esterification is 12~24h.
5. the method according to claim 1 for preparing LA cholinester halide, it is characterised in that methods described A)
Described in solvent be dichloromethane, 1,2- dichloroethanes, chloroform, chlorobenzene, acetonitrile, toluene, N,N-dimethylformamide, N, N-
Dimethyl acetamide, 1,2- dimethoxy-ethanes, methyl tertiary butyl ether(MTBE), tetrahydrofuran or acetone.
6. the method according to claim 1 for preparing LA cholinester halide, it is characterised in that methods described B)
Described in acid binding agent alkali be triethylamine, diethylamine, N, N- diisopropylethylamine, pyridine, piperidines, tri-n-butylamine, trimethylamine,
Tri-isopropyl amine, diisopropylamine, aniline, N, accelerine, N, N- diethylanilines, 2,6- lutidines, 4- diformazan ammonia
Yl pyridines, TMG, 1-METHYLPYRROLIDONE, N-methylmorpholine, N-ethylmorpholine or 1,8- diazabicyclos [5.4.0] ten
One carbon -7- alkene.
7. the method according to claim 1 for preparing LA cholinester halide, it is characterised in that methods described B)
Described in R- sulphur caprylyl chloride, halogenation choline and acid binding agent alkali three between mol ratio be 1.0: 1.5~3.0: 2.0~4.0.
8. the method according to claim 1 for preparing LA cholinester halide, it is characterised in that methods described B)
Described in the temperature of esterification be 20~50 DEG C, time of esterification is 3~12h.
9. the method according to claim 1 for preparing LA cholinester halide, it is characterised in that methods described B)
Described in solvent be tetrahydrofuran, dichloromethane, 1,2- dichloroethanes, chloroform, chlorobenzene, acetonitrile, toluene, N, N- dimethyl methyls
Acid amides, DMAC N,N' dimethyl acetamide, acetone, methyl tertiary butyl ether(MTBE) or 1,4- dioxane.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108822077A (en) * | 2018-08-07 | 2018-11-16 | 苏州富士莱医药股份有限公司 | A kind of refining methd of r-lipoic acid cholinester halide |
| US11135239B1 (en) | 2020-03-13 | 2021-10-05 | Novartis Ag | Pharmaceutical compositions of lipoic acid choline ester salts and methods of treatment using same |
| KR20220139825A (en) * | 2022-09-27 | 2022-10-17 | 하나제약 주식회사 | Methods for the synthesis of choline alfoscerate ester derivatives and use thereof |
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| WO2010147962A1 (en) * | 2009-06-15 | 2010-12-23 | Encore Health, Llc | Choline esters |
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| WO2010147962A1 (en) * | 2009-06-15 | 2010-12-23 | Encore Health, Llc | Choline esters |
| CN106455563A (en) * | 2014-03-03 | 2017-02-22 | 安可视觉公司 | Lipoic acid choline ester compositions and methods of use |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108822077A (en) * | 2018-08-07 | 2018-11-16 | 苏州富士莱医药股份有限公司 | A kind of refining methd of r-lipoic acid cholinester halide |
| US11135239B1 (en) | 2020-03-13 | 2021-10-05 | Novartis Ag | Pharmaceutical compositions of lipoic acid choline ester salts and methods of treatment using same |
| CN115279745A (en) * | 2020-03-13 | 2022-11-01 | 诺华股份有限公司 | Pharmaceutical compositions of lipoic acid choline ester salts and methods of treatment using the same |
| US11590158B2 (en) | 2020-03-13 | 2023-02-28 | Novartis Ag | Pharmaceutical compositions of lipoic acid choline ester salts and methods of treatment using same |
| KR20220139825A (en) * | 2022-09-27 | 2022-10-17 | 하나제약 주식회사 | Methods for the synthesis of choline alfoscerate ester derivatives and use thereof |
| KR102595126B1 (en) * | 2022-09-27 | 2023-10-30 | 하나제약 주식회사 | Methods for the synthesis of choline alfoscerate ester derivatives and use thereof |
| WO2024071959A1 (en) * | 2022-09-27 | 2024-04-04 | 하나제약 주식회사 | Method for preparing choline alposcerate ester derivative and use thereof |
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