CN106967044B - 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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- CN106967044B CN106967044B CN201710333536.9A CN201710333536A CN106967044B CN 106967044 B CN106967044 B CN 106967044B CN 201710333536 A CN201710333536 A CN 201710333536A CN 106967044 B CN106967044 B CN 106967044B
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- lipoic acid
- cholinester
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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
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Abstract
A method of r-lipoic acid cholinester halide is prepared, pharmaceutical chemistry synthesis technical field is belonged to.This method includes method A or method B: the method A is that r-lipoic acid and halogenation choline are carried out esterification in the system that dehydrating agent, catalysts and solvents form, and obtains r-lipoic acid cholinester halide I；The method B is that R- sulphur caprylyl chloride and halogenation choline are carried out 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 operations such as post-processing and purifying simplify；Using safe, it is suitable for industrial amplification production；Embody environmentally protective effect.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical fields, and in particular to a kind of r-lipoic acid cholinester halide of preparing
Method.
Background technique
Lipoic acid (α-Lipoic acid) is a kind of biologically active natural products, nineteen fifty-one by Reed for the first time from
It is isolated in pork liver.Lipoic acid contains a chiral centre, studies have shown that two enantiomters of lipoic acid, R- type pair
Body is reflected with bioactivity, and S- type 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 encephalopathy, radiation damage disease, heavy metal poisoning are controlled
It treats, is known 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 of kind lipoic acid have carried out application and development, greatly enrich and extend lipoic acid series of products
Indication range and therapeutic effect, to meet medicine clinic and the market demand.
A kind of r-lipoic acid choline ester derivant disclosed in patent WO2015134510A1 and US20150246903 has eye
The ophthalmology diseases such as section's medical usage, including treatment presbyopia, glaucoma and cataract, and the preparation method in relation to kind is provided.
Wherein, be esterified under conditions of dehydrating agent and catalyst using r-lipoic acid and choline, then by with iodomethane or a chlorine
Methane reaction generates r-lipoic acid cholinester iodide or r-lipoic acid cholinester chloride, two step synthetic reaction formulas is as follows:
The iodomethane that this method uses is poisonous reagent, and environmental pollution is larger, is unfavorable for producers and environment
Protection.Monochloro methane is gas, needs to be dissolved in methyl tertiary butyl ether(MTBE) to be added in reaction mixture, complicated for operation cumbersome,
It is unfavorable for amplification production to promote and apply.Synthesis for r-lipoic acid cholinester bromide, patent US20150246903 it is also proposed that
The example of 1 one-step synthesis method route, as follows:
But the enlightenment of preparation condition and operation etc. is not provided.
Summary of the invention
For the deficiencies in the prior art and defect, r-lipoic acid choline is prepared the object of the present invention is to provide a kind of
The method of ester halide, it is high with total recovery and to be satisfied R- sulphur pungent that this method process route is reasonable, easy to operate, reagent is easy to get
The amplification production requirement of sour cholinester halide simultaneously can embody excellent environmentally protective effect.
In order to achieve the above-mentioned object of the invention, the technical solution adopted by the present invention are as follows: a kind of to prepare r-lipoic acid cholinester halogen
The method of compound, this method include method A) or method B):
The method A) be by r-lipoic acid and halogenation choline in the system that dehydrating agent, catalysts and solvents form into
Row esterification obtains r-lipoic acid cholinester halide (I), reaction equation are as follows:
In formula, X is chlorine, bromine or iodine；
The 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 r-lipoic acid cholinester halide (I), reaction equation are as follows:
In formula, X is chlorine, bromine or iodine.
In a specific embodiment of the invention, the method A) described in dehydrating agent be N, N '-carbonyl two
Imidazoles, N, N '-dicyclohexylcarbodiimide, N, N '-diisopropyl phosphinylidyne diimine, 1- ethyl-(3- dimethylamino third
Base) phosphinylidyne diimmonium salt hydrochlorate, 1- hydroxy benzo triazole, 11 carbon -7- alkene of 1,8- diazabicyclo [5.4.0], N, N '-carbonyl
Base two (1,2,4- triazole), O- benzotriazole-N, N, N ', N '-tetramethylurea hexafluorophosphate, O- benzotriazole-N,
N, N ', N '-tetramethylurea tetrafluoro boric acid ester, 2- (7- azo benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester,
Hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus, three (dimethylamino) phosphorus of benzotriazole -1- base oxygroup
Hexafluorophosphate or PhosphorodichloridicAcid Acid Phenyl Ester；The catalyst be triethylamine, diethylamine, N, N- diisopropylethylamine, pyridine,
Piperidines, tri-n-butylamine, trimethylamine, tri-isopropyl amine, diisopropylamine, aniline, N, accelerine, N, N- diethylaniline, 2,
6- lutidines, 4-dimethylaminopyridine, tetramethylguanidine, N-Methyl pyrrolidone, N-methylmorpholine or N-ethylmorpholine.
In another specific embodiment of the invention, the method A) described in r-lipoic acid, halogenation choline,
Molar 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 invention, the method A) described in esterification temperature be 20~
50 DEG C, time of esterification is 12~for 24 hours.
In another specific embodiment of the invention, the method A) described in solvent be methylene chloride, 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.
Of the invention there are one in specific embodiment, the method 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- diethylaniline, 2,6- lutidines, 4-dimethylaminopyridine, tetramethylguanidine, N- methyl pyrrole
Pyrrolidone, 11 carbon -7- alkene of N-methylmorpholine, N-ethylmorpholine or 1,8- diazabicyclo [5.4.0].
In a still more specific embodiment of the invention, the method B) described in R- sulphur caprylyl chloride, halogenation gallbladder
Molar ratio between alkali and acid binding agent alkali three is 1.0: 1.5~3.0: 2.0~4.0.
In an of the invention and then specific embodiment, the method B) described in the temperature of esterification be 20
~50 DEG C, the time of esterification is 3~12h.
The method B in yet a further embodiment of the present invention) described in solvent be tetrahydrofuran,
Methylene chloride, 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.
Technical solution provided by the invention has following technical effect that first, the impurity of each step reaction is less, post-processing and
The operations such as purifying simplify；Second, starting material and reagent used are easy to get, use is safe, and the technical solution of synthetic reaction is reasonable,
Suitable for industrial amplification production；Third, since pollutant will not be generated during the preparation process, thus can embody environmentally protective
Effect.
Specific embodiment
Technical solution of the present invention is further elaborated below in conjunction with specific embodiment, it is clear that protection of the invention
Range is not limited to embodiment, and the other embodiment of the present invention that those skilled in the art are done belongs to what the present invention protected
Range.
Embodiment 1:
Method A): r-lipoic acid (10.0g, 48.5mmol) and toluene (200mL) are added in reaction flask, and stirring and dissolving adds
Enter N, N '-dicyclohexylcarbodiimide (12.0g, 58.2mmol) and 4-dimethylaminopyridine (1.2g, 9.7mmol), ice bath
It is cooling, it is added choline chloride (15.2g, 109.1mmol), reaction mixture is in 35 DEG C of reaction 18h.Post-processing and purifying, crude product
It is recrystallized with isopropanol, obtains r-lipoic acid cholinester chloride, light yellow solid (14.8g), yield 93%, reaction equation
Are as follows:
Embodiment 2:
Method B): R- sulphur caprylyl chloride (10.0g, 44.5mmol) and chloroform (200mL) are added in reaction flask, stirring and dissolving,
N is added, N- diethylaniline (26.6g, 178.0mmol), ice bath is cooling, is added choline chloride (18.6g, 133.5mmol), instead
Answer mixture in 20 DEG C of reaction 12h.Post-processing and purifying, crude product are recrystallized with isopropanol, obtain r-lipoic acid cholinester chlorine
Compound, light yellow solid (12.7g), yield 87%, reaction equation are as follows:
Embodiment 3:
Method A): r-lipoic acid (10.0g, 48.5mmol) and 1,2- dichloroethanes (200mL) are added in reaction flask, stirring
N is added in dissolution, and 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, reaction mixture reacts for 24 hours at 20 DEG C.Post-processing and purifying, crude product are used
Isopropanol is recrystallized, and r-lipoic acid cholinester bromide, light yellow solid (17.1g), yield 95%, reaction equation are obtained are as follows:
Embodiment 4:
Method B): R- sulphur caprylyl chloride (10.0g, 44.5mmol) and toluene (200mL) are added in reaction flask, stirring and dissolving,
It is added n,N-diisopropylethylamine (11.5g, 89.0mmol), ice bath is cooling, is added choline bromide (12.3g, 66.7mmol), instead
Answer mixture in 35 DEG C of reaction 8h.Post-processing and purifying, crude product are recrystallized with isopropanol, obtain r-lipoic acid cholinester bromination
Object, light yellow solid (14.2g), yield 86%, reaction equation are as follows:
Embodiment 5:
Method A): r-lipoic acid (10.0g, 48.5mmol) and 1,2- dimethoxy-ethane (200mL) are added in reaction flask,
N, N '-diisopropyl phosphinylidyne diimine (8.0g, 63.0mmol) and pyridine (1.2g, 14.5mmol), ice bath is added in stirring and dissolving
It is cooling, it is added choline iodide (16.8g, 72.7mmol), reaction mixture is in 50 DEG C of reaction 12h.Post-processing and purifying, crude product are used
Isopropanol is recrystallized, and r-lipoic acid cholinester iodide, light yellow solid (18.3g), yield 90%, reaction equation are obtained are as follows:
Embodiment 6:
Method B): R- sulphur caprylyl chloride (10.0g, 44.5mmol) and tetrahydrofuran (200mL) are added in reaction flask, stir molten
N is added in solution, and N- dimethylaniline (16.2g, 133.5mmol), ice bath is cooling, is added choline iodide (23.6g, 102.3mmol),
Reaction mixture is in 50 DEG C of reaction 3h.Post-processing and purifying, crude product are recrystallized with isopropanol, obtain r-lipoic acid cholinester iodine
Compound, light yellow solid (16.8g), yield 90%, reaction equation are as follows:
Claims (8)
1. a kind of method for preparing r-lipoic acid cholinester halide, it is characterised in that this method includes method A) or method B):
The method A) it is that r-lipoic acid and halogenation choline are subjected to ester in the system that dehydrating agent, catalysts and solvents form
Change reaction, obtain r-lipoic acid cholinester halide (I), reaction equation are as follows:
In formula, X is chlorine, bromine or iodine；
The dehydrating agent is N, N '-carbonyl dimidazoles, N, N '-dicyclohexylcarbodiimide or N, N '-diisopropyl phosphinylidyne
Diimine；The catalyst is pyridine, 2,6- lutidines or 4-dimethylaminopyridine；
The 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,
Obtain r-lipoic acid cholinester halide (I), reaction equation are as follows:
In formula, X is chlorine, bromine or iodine.
2. the method for preparation r-lipoic acid cholinester halide according to claim 1, it is characterised in that the method
A r-lipoic acid, halogenation choline, dehydrating agent described in) and the molar ratio between catalyst are 1.0: 1.5~3.0: 1.1
~1.3: 0.1~0.3.
3. the method for preparation r-lipoic acid cholinester halide according to claim 1, it is characterised in that the method A)
Described in the temperature of esterification be 20~50 DEG C, time of esterification is 12~for 24 hours.
4. the method for preparation r-lipoic acid cholinester halide according to claim 1, it is characterised in that the method A)
Described in solvent be methylene chloride, 1,2- dichloroethanes, chloroform, chlorobenzene, acetonitrile, toluene, N,N-dimethylformamide, N, N-
Dimethyl acetamide, 1,2- dimethoxy-ethane, methyl tertiary butyl ether(MTBE), tetrahydrofuran or acetone.
5. the method for preparation r-lipoic acid cholinester halide according to claim 1, it is characterised in that the method 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- diethylaniline, 2,6- lutidines, 4- diformazan ammonia
Yl pyridines, tetramethylguanidine, N-Methyl pyrrolidone, N-methylmorpholine, N-ethylmorpholine or 1,8- diazabicyclo [5.4.0] ten
One carbon -7- alkene.
6. the method for preparation r-lipoic acid cholinester halide according to claim 1, it is characterised in that the method B)
Described in R- sulphur caprylyl chloride, the molar ratio between halogenation choline and acid binding agent alkali three be 1.0: 1.5~3.0: 2.0~4.0.
7. the method for preparation r-lipoic acid cholinester halide according to claim 1, it is characterised in that the method B)
Described in the temperature of esterification be 20~50 DEG C, time of esterification is 3~12h.
8. the method for preparation r-lipoic acid cholinester halide according to claim 1, it is characterised in that the method B)
Described in solvent be tetrahydrofuran, methylene chloride, 1,2- dichloroethanes, chloroform, chlorobenzene, acetonitrile, toluene, N, N- dimethyl methyl
Amide, DMAC N,N' dimethyl acetamide, acetone, methyl tertiary butyl ether(MTBE) or 1,4- dioxane.
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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 |
| CN113387923A (en) | 2020-03-13 | 2021-09-14 | 诺华股份有限公司 | Pharmaceutical compositions of lipoic acid choline ester salts and methods of treatment using the same |
| KR102595126B1 (en) * | 2022-09-27 | 2023-10-30 | 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 |
| WO2015134510A1 (en) * | 2014-03-03 | 2015-09-11 | Encore Vision Inc. | Lipoic acid choline ester compositions and methods of use |
| CA3022351A1 (en) * | 2015-04-29 | 2016-11-03 | Kardiatonos, Inc. | Methods and compositions for reversing disruption of the glycocalyx, inflammation, and oxidative damage |
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