CN110256402B - Lipoic acid hydroxylamine derivatives and preparation method and application thereof - Google Patents
Lipoic acid hydroxylamine derivatives and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of chemical pharmacy, and particularly relates to lipoic acid hydroxylamine derivatives and a preparation method and application thereof. The lipoic acid hydroxylamine derivative is R-benzaldehyde-derived lipoic acid hydroxylamine, and the structural formula of the lipoic acid hydroxylamine derivative is shown as the formula I:
wherein R is any one of hydrogen, 4-methyl, 4-phenyl, m-hydroxyl, 3-methoxy-4-hydroxyl, 3,4, 5-trimethoxy, 2-methoxy, 2, 3-dichloro, 2, 4-dichloro, 2, 5-dichloro, 2, 6-dichloro, 4-chloro, 4-bromo, m-methoxy, 4-isopropyl, 2-fluoro and 3-fluoro. The R-benzaldehyde-derived lipoic acid is subjected to reaction steps of ethyl esterification, hydroximic acid derivatization and the like to obtain R-benzaldehyde-derived lipoic acid hydroxylamine, and the prepared R-benzaldehyde-derived lipoic acid hydroxylamine has anti-tumor activity and is applied to preparation of medicines for treating lung cancer and ovarian cancer.
Description
Technical Field
The invention belongs to the technical field of chemical pharmacy, and particularly relates to lipoic acid hydroxylamine derivatives and a preparation method and application thereof.
Background
Lipoic Acid (LA) is a vitamin-like active functional molecule, is found in animal livers in 1950, has the effects of resisting oxidation and cholesterol, reducing damage of free radicals, stabilizing blood sugar, reducing blood sugar, balancing blood sugar concentration and the like, is concerned about the oxidation in early stage, is known as a universal antioxidant together with reduced dihydrolipoic acid (DHLA), and can also serve as a substitute when vitamin C and vitamin E in vivo are deficient. Recent studies have shown that lipoic acid also has anti-tumor efficacy.
Zhang, 2010, in Bioorganic & medical Chemistry Letters, 20 th 3078 and 3083, reported a Synthesis and anti-cancer evaluation of alpha-lipoic acid derivatives, which mainly introduced lipoic acid amide derivatives as anti-tumor molecule research, and indicated that the derivatives have high anti-tumor activity, and have significant effects on NCI-460, HO-8910, KB, BEL-7402 and PC-3 cell lines during in vitro tumor inhibition. An article entitled "synthesis of alpha-lipoic acid derivatives and anticancer activity research thereof" published by xu's prescription equal to 2014 in the journal of Chinese medicinal chemistry, volume 3, p196-200, indicates that active molecules with significant antitumor efficacy can be obtained by using lipoic acid as a precursor. The expression "synthetic and Biological Activity of lipid Acid Ester Derivatives" was published in 2018 in "advanced school chemistry" No. 10, vol.39, p2198-2205, and the expression of 23 Derivatives of Lipoic Acid was synthesized by structurally modifying the carboxyl group of Lipoic Acid, which was found to have good plasma stability.
In addition, in 2013, Hiratsuka et al published an article entitled DHL-TauZnNa, a newy synthesized alpha-lipoic acid derivative, indeces autophagy in human colorectal cancer cells at volume 6 of Oncology reports 29, and synthesized a new alpha-lipoic acid derivative named DHL-TauZnNa, which can induce autophagy of human colorectal cancer cells.
Hydroxylamines are very good synergistic groups, various physicochemical properties of the hydroxylammonium chloride are improved when the hydroxylammonium chloride is introduced into a medicament, hydroximic acid is a key active functional fragment in a structure of a hydroximic acid histone deacetylase inhibitor, and if the hydroximic acid does not participate in the functional group, the molecules cannot play the function of the histone deacetylase inhibitor and are the core structure of the hydroximic acid inhibitor. Wei Ye, equal to 2018, published on Anticancer Drugs, volume 29, stage 3, p262-270, antibiotic effects of histone deacetylase inhibitor hydrosamide in epidermal growth factor receptor-mutant non-small cell lung cancer cell line in vitro and in vivo (study of in vivo and in vitro anti-tumor effects of histone deacetylase inhibitor suberoylanilide hydroxamic acid on human epidermal growth factor receptor mutant non-small cell lung cancer cell lines) reported that histone inhibitor vorinostat, a hydroxylamine structure, had a significant therapeutic effect on EGFR mutant non-small cell lung cancer.
Disclosure of Invention
The invention aims to develop a histone deacetylase anti-tumor active molecule with a novel structure by using lipoic acid as a basic drug effect substance through benzaldehyde derivatization, esterification, hydroximic acid derivatization and other reaction steps. The invention not only obtains series hydroxylamine lipoic acid derivatives, but also verifies that the molecules have obvious antitumor activity through in vitro antitumor activity research.
In order to achieve the aim, the invention discloses lipoic acid hydroxylamine derivatives which are benzaldehyde-derived lipoic acid hydroxylamine and have a structural formula shown in a formula I:
wherein R is any one of hydrogen, 4-methyl, 4-phenyl, m-hydroxyl, 3-methoxy-4-hydroxyl, 3,4, 5-trimethoxy, 2-methoxy, 2, 3-dichloro, 2, 4-dichloro, 2, 5-dichloro, 2, 6-dichloro, 4-chloro, 4-bromo, m-methoxy, 4-isopropyl, 2-fluoro and 3-fluoro.
Preferably, R is any one of hydrogen, 4-methyl, 4-phenyl, m-hydroxy, 3-methoxy-4-hydroxy, 3,4, 5-trimethoxy and 2-methoxy.
Most preferably, R is any one of 2, 3-dichloro, 2, 4-dichloro, 2, 5-dichloro, 2, 6-dichloro, 4-chloro, 4-bromo, 3-methoxy, 4-isopropyl, 2-fluoro, 3-fluoro.
Most preferably, R is 2-methoxy.
A method for preparing the lipoic acid hydroxylamine derivatives of claims 1-3, comprising the steps of:
step one, preparing R-benzaldehyde derived lipoic acid ethyl ester:
weighing 3g R-benzaldehyde-derivatized thioctic acid, dissolving in 30mL of anhydrous ethanol, dropwise adding 1-2 drops of concentrated sulfuric acid into the system, heating and refluxing at 120 ℃, detecting the reaction end point by TLC, removing the ethanol by a rotary evaporation method after the reaction is completed, cooling, dissolving the reaction product in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product by 20mL of saturated sodium bicarbonate aqueous solution for 3 times, washing the dichloromethane solution of the reaction product to be neutral by 20mL of water, drying the dichloromethane solution of the washed reaction product by anhydrous magnesium sulfate, performing suction filtration, and spin-drying to remove dichloromethane, thus obtaining the R-benzaldehyde-derivatized thioctic acid ethyl ester.
Step two, synthesizing R-synthesized lipoic acid hydroxylamine derivatives:
weighing 5.92mmol (21.14 equivalent) of potassium hydroxide, adding the potassium hydroxide into 10mL of methanol solution, stirring until the potassium hydroxide is completely dissolved, adding 6.37mmol (22.75 equivalent) of hydroxylamine hydrochloride solid, and uniformly stirring until white precipitate is completely separated out; dissolving 0.28mmol of benzaldehyde-derivatized thioctic acid ethyl ester prepared in the first step in 10mL of tetrahydrofuran, adding the solution into the methanol system after the solution is completely dissolved, heating the solution at 50 ℃ for reaction, detecting the reaction end point by TLC, and spin-drying the solvent after the reaction is completely finished; dissolving the product obtained by the reaction in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium chloride aqueous solution for 3 times, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, filtering, and spin-drying to remove dichloromethane, thus obtaining the lipoic acid hydroxylamine derivative with the structure shown in the formula I, namely the R-benzaldehyde derivatization lipoic acid hydroxylamine.
The lipoic acid hydroxylamine derivative is applied to preparing the medicines for treating lung cancer and ovarian cancer.
Among these, of particular industrial pharmaceutical value are:
the invention has the beneficial effects that: the structural derivative of the formula I is a functional compound with a novel structure, which is obtained by esterification and hydroximic acidification on the basis of aldehyde-derived lipoic acid.
The benzaldehyde substituted lipoic acid used in the invention is a reserved product made by the laboratory. On the basis, a hydroximic acid structure is introduced into the structure, so that a brand-new histone deacetylase inhibitor molecule is developed and obtained. The introduction of the hydroximic acid in the molecule disclosed by the invention changes the solubility of the molecule to a great extent, and has important significance in the field of medicines.
Meanwhile, the antitumor activity of the invention shows that the lipoic acid hydroxylamine derivatives have obvious inhibitory activity on cancer cell strains OvCaR-3, A549 and NCI-H460, wherein the compound with optimal activity is 2-methoxybenzaldehyde lipoic acid amide derivatives and IC thereof50The values reached 0.29, 0.35 and 0.47. mu. mol, respectively, followed by 3,4, 5-trimethoxybenzaldehyde thioctic acid amide derivatives, their IC50Values of 0.34, 0.36 and 0.58. mu. mol were also achieved, respectively.
Drawings
FIG. 1 shows the results of the in vitro activity of lipoic acid hydroxylamine derivatives on OVCaR-3 tumor cells.
FIG. 2 shows the results of the in vitro activity of lipoic acid hydroxylamine derivatives on tumor cells A549.
FIG. 3 shows the results of the in vitro activity of lipoic acid hydroxylamine derivatives on tumor cells NCI-H460.
Detailed Description
The present invention is further explained by the following examples.
Example 1
A lipoic acid hydroxylamine derivative has a structural general formula shown in a formula I:
wherein:
in the formula I, R is hydrogen, and the lipoic acid hydroxylamine derivative is: benzaldehyde derivatizes lipoic acid hydroxylamine.
The synthetic route is as follows:
the preparation method comprises the following specific steps:
step one, preparing benzaldehyde-derivatized thioctic acid ethyl ester:
weighing 3g of benzaldehyde-derivatized thioctic acid, dissolving in 30mL of anhydrous ethanol, dropwise adding 1-2 drops of concentrated sulfuric acid into the system, heating and refluxing at 120 ℃, detecting the reaction end point by TLC, removing the ethanol by a rotary evaporation method after the reaction is completed, cooling, dissolving the reaction product in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product by 20mL of saturated sodium bicarbonate aqueous solution for 3 times, washing the dichloromethane solution of the reaction product to be neutral by 20mL of water, drying the dichloromethane solution of the washed reaction product by anhydrous magnesium sulfate, carrying out suction filtration, and removing the dichloromethane by rotary drying to obtain the benzaldehyde-derivatized thioctic acid ethyl ester.
Step two, synthesizing lipoic acid hydroxylamine derivatives:
weighing 5.92mmol (21.14 equivalent) of potassium hydroxide, adding the potassium hydroxide into 10mL of methanol solution, stirring until the potassium hydroxide is completely dissolved, adding 6.37mmol (22.75 equivalent) of hydroxylamine hydrochloride solid, and uniformly stirring until white precipitate is completely separated out; dissolving 0.28mmol of benzaldehyde-derivatized thioctic acid ethyl ester prepared in the first step in 10mL of tetrahydrofuran, adding the solution into the methanol system after the solution is completely dissolved, heating the solution at 50 ℃ for reaction, detecting the reaction end point by TLC, and removing the solvent after the reaction is completely finished by spin-drying; dissolving the product obtained by the reaction in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium chloride aqueous solution for 3 times, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, filtering, and spin-drying to remove dichloromethane, thus obtaining the lipoic acid hydroxylamine derivative with the structure shown in the formula I, namely benzaldehyde-derived lipoic acid hydroxylamine.
Example 2
A lipoic acid hydroxylamine derivative has a structural general formula shown in a formula I:
wherein:
in the formula I, R is 4-methyl, and the lipoic acid hydroxylamine derivative is as follows: 4-methyl-benzaldehyde-derivatized sulfur
A hydroxylamine octanoate.
The synthetic route is as follows:
the preparation method comprises the following specific steps:
step one, preparing 4-methyl-benzaldehyde-derived lipoic acid ethyl ester:
weighing 3g of 4-methylbenzaldehyde derived thioctic acid, dissolving in 30mL of anhydrous ethanol, dropwise adding 1-2 drops of concentrated sulfuric acid into the system, heating and refluxing at 120 ℃, detecting the reaction end point by using TLC, removing the ethanol by using a rotary evaporation method after the reaction is completed, cooling, dissolving the reaction product in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product by using 20mL of saturated sodium bicarbonate aqueous solution for 3 times, washing the dichloromethane solution of the reaction product to be neutral by using 20mL of water, drying the dichloromethane solution of the washed reaction product by using anhydrous magnesium sulfate, performing suction filtration, and spin-drying to remove dichloromethane, thus obtaining the 4-methyl-benzaldehyde derived thioctic acid ethyl ester.
Step two, synthesizing lipoic acid hydroxylamine derivatives:
weighing 5.92mmol (21.14 equivalent) of potassium hydroxide, adding the potassium hydroxide into 10mL of methanol solution, stirring until the potassium hydroxide is completely dissolved, adding 6.37mmol (22.75 equivalent) of hydroxylamine hydrochloride solid, and uniformly stirring until white precipitate is completely separated out; dissolving 0.28mmol of the 4-methylbenzaldehyde derived lipoic acid ethyl ester prepared in the step one in 10mL of tetrahydrofuran, adding the dissolved 4-methylbenzaldehyde derived lipoic acid ethyl ester into the methanol system after the dissolved 4-methylbenzaldehyde derived lipoic acid ethyl ester is completely dissolved, heating the mixture for reaction at 50 ℃, detecting the reaction end point by TLC (thin layer chromatography), and spin-drying the solvent after the reaction is completely finished; dissolving the product obtained by the reaction in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium chloride aqueous solution for 3 times, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, filtering, and spin-drying to remove dichloromethane, thus obtaining the lipoic acid hydroxylamine derivative with the structure shown in the formula I, namely 4-methyl-benzaldehyde-derived lipoic acid hydroxylamine.
Example 3
A lipoic acid hydroxylamine derivative has a structural general formula shown in a formula I:
wherein:
in the formula I, R is 4-phenyl, and the lipoic acid hydroxylamine derivative is as follows: 4-phenyl-benzaldehyde derivatised lipoic acid hydroxylamine.
The synthetic route is as follows:
the preparation method comprises the following specific steps:
step one, preparing 4-phenyl-benzaldehyde-derived lipoic acid ethyl ester:
weighing 3g of 4-benzaldehyde-derivatized thioctic acid, dissolving in 30mL of anhydrous ethanol, dropwise adding 1-2 drops of concentrated sulfuric acid into the system, heating and refluxing at 120 ℃, detecting the reaction end point by TLC, removing the ethanol by a rotary evaporation method after the reaction is completed, cooling, dissolving the reaction product in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product by 20mL of saturated sodium bicarbonate aqueous solution for 3 times, washing the dichloromethane solution of the reaction product to be neutral by 20mL of water, drying the dichloromethane solution of the washed reaction product by anhydrous magnesium sulfate, performing suction filtration, and spin-drying to remove dichloromethane, thus obtaining the 4-phenyl-benzaldehyde-derivatized thioctic acid ethyl ester.
Step two, synthesizing lipoic acid hydroxylamine derivatives:
weighing 5.92mmol (21.14 equivalent) of potassium hydroxide, adding the potassium hydroxide into 10mL of methanol solution, stirring until the potassium hydroxide is completely dissolved, adding 6.37mmol (22.75 equivalent) of hydroxylamine hydrochloride solid, and uniformly stirring until white precipitate is completely separated out; dissolving 0.28mmol of the 4-benzaldehyde-derivatized lipoic acid ethyl ester prepared in the step one in 10mL of tetrahydrofuran, adding the dissolved 4-benzaldehyde-derivatized lipoic acid ethyl ester into the methanol system after the dissolved 4-benzaldehyde-derivatized lipoic acid ethyl ester is completely dissolved, heating the mixture to react at 50 ℃, detecting the reaction end point by TLC (thin layer chromatography), and spin-drying the solvent after the reaction is completely finished; dissolving the product obtained by the reaction in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium chloride aqueous solution for 3 times, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, filtering, and spin-drying to remove dichloromethane, thus obtaining the lipoic acid hydroxylamine derivative with the structure shown in the formula I, namely 4-phenyl-benzaldehyde-derived lipoic acid hydroxylamine.
Example 4
A lipoic acid hydroxylamine derivative has a structural general formula shown in a formula I:
wherein:
in the formula I, R is a m-hydroxyl group, and the lipoic acid hydroxylamine derivative is as follows: m-hydroxy-benzaldehyde derivatised lipoic acid hydroxylamine.
The synthetic route is as follows:
the preparation method comprises the following specific steps:
step one, preparing m-hydroxy-benzaldehyde-derived lipoic acid ethyl ester:
weighing 3g of m-hydroxybenzaldehyde derived thioctic acid, dissolving in 30mL of anhydrous ethanol, dropwise adding 1-2 drops of concentrated sulfuric acid into the system, heating and refluxing at 120 ℃, detecting the reaction end point by TLC, removing the ethanol by a rotary evaporation method after the reaction is completed, cooling, dissolving the reaction product in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product by 20mL of saturated sodium bicarbonate aqueous solution for 3 times, washing the dichloromethane solution of the reaction product to be neutral by 20mL of water, drying the dichloromethane solution of the washed reaction product by anhydrous magnesium sulfate, performing suction filtration, and spin-drying to remove dichloromethane, thus obtaining the m-hydroxy-benzaldehyde derived thioctic acid ethyl ester.
Step two, synthesizing lipoic acid hydroxylamine derivatives:
weighing 5.92mmol (21.14 equivalent) of potassium hydroxide, adding the potassium hydroxide into 10mL of methanol solution, stirring until the potassium hydroxide is completely dissolved, adding 6.37mmol (22.75 equivalent) of hydroxylamine hydrochloride solid, and uniformly stirring until white precipitate is completely separated out; dissolving 0.28mmol of m-hydroxy-benzaldehyde-derived lipoic acid ethyl ester prepared in the step one in 10mL of tetrahydrofuran, adding the dissolved m-hydroxy-benzaldehyde-derived lipoic acid ethyl ester into the methanol system after the m-hydroxy-benzaldehyde-derived lipoic acid ethyl ester is completely dissolved, heating the mixture to react at 50 ℃, detecting the reaction end point by TLC (thin layer chromatography), and spin-drying the solvent after the reaction is completely finished; dissolving the product obtained by the reaction in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium chloride aqueous solution for 3 times, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, filtering, and spin-drying to remove dichloromethane, thus obtaining the lipoic acid hydroxylamine derivative with the structure shown in the formula I, namely the m-hydroxy-benzaldehyde derivatization lipoic acid hydroxylamine.
Example 5
A lipoic acid hydroxylamine derivative has a structural general formula shown in a formula I:
wherein:
in the formula I, R is 2-methoxy-4 hydroxyl, and the lipoic acid hydroxylamine derivative is: 2-methoxy-4-hydroxy-benzaldehyde derivatised lipoic acid hydroxylamine.
The synthetic route is as follows:
the preparation method comprises the following specific steps:
step one, preparing 2-methoxy-4 hydroxy-benzaldehyde derivatization lipoic acid ethyl ester:
weighing 3g of 2-methoxy-4-hydroxybenzaldehyde-derivatized thioctic acid, dissolving in 30mL of absolute ethanol, dropwise adding 1-2 drops of concentrated sulfuric acid into the system, heating and refluxing at 120 ℃, detecting the reaction end point by TLC, removing ethanol by a rotary evaporation method after the reaction is completed, cooling, dissolving the reaction product in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product by 20mL of saturated sodium bicarbonate aqueous solution for 3 times, washing the dichloromethane solution of the reaction product to neutrality by 20mL of water, drying the dichloromethane solution of the washed reaction product by anhydrous magnesium sulfate, performing suction filtration, and spin-drying to remove dichloromethane, thereby obtaining 2-methoxy-4-hydroxy-benzaldehyde-derivatized thioctic acid ethyl ester.
Step two, synthesizing lipoic acid hydroxylamine derivatives:
weighing 5.92mmol (21.14 equivalent) of potassium hydroxide, adding the potassium hydroxide into 10mL of methanol solution, stirring until the potassium hydroxide is completely dissolved, adding 6.37mmol (22.75 equivalent) of hydroxylamine hydrochloride solid, and uniformly stirring until white precipitate is completely separated out; dissolving 0.28mmol of 2-methoxy-4-hydroxybenzaldehyde derived lipoic acid ethyl ester prepared in the step one in 10mL of tetrahydrofuran, adding the dissolved lipoic acid ethyl ester into the methanol system after complete dissolution, heating the mixture for reaction at 50 ℃, detecting the reaction end point by TLC (thin layer chromatography), and spin-drying the solvent after complete reaction; dissolving the product obtained by the reaction in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium chloride aqueous solution for 3 times, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, filtering, and spin-drying to remove dichloromethane, thus obtaining the lipoic acid hydroxylamine derivative with the structure shown in the formula I, namely 2-methoxy-4 hydroxy-benzaldehyde derivatization lipoic acid hydroxylamine.
Example 6
A lipoic acid hydroxylamine derivative has a structural general formula shown in a formula I:
wherein:
in the formula I, R is 3,4, 5-trimethoxy, and the lipoic acid hydroxylamine derivative is: 3,4, 5-trimethoxy-benzaldehyde derivatised lipoic acid hydroxylamine.
The synthetic route is as follows:
the preparation method comprises the following specific steps:
step one, preparing 3,4, 5-trimethoxybenzaldehyde-derivatized lipoic acid ethyl ester:
weighing 3g of 3,4, 5-trimethoxybenzaldehyde-derivatized thioctic acid, dissolving in 30mL of anhydrous ethanol, dropwise adding 1-2 drops of concentrated sulfuric acid into the system, heating and refluxing at 120 ℃, detecting the reaction end point by TLC, removing ethanol by a rotary evaporation method after the reaction is completed, cooling, dissolving the reaction product in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium bicarbonate aqueous solution for 3 times, washing the dichloromethane solution of the reaction product with 20mL of water to be neutral, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, performing suction filtration, and spin-drying to remove dichloromethane, thus obtaining the 3,4, 5-trimethoxybenzaldehyde-derivatized thioctic acid ethyl ester.
Step two, synthesizing lipoic acid hydroxylamine derivatives:
weighing 5.92mmol (21.14 equivalent) of potassium hydroxide, adding the potassium hydroxide into 10mL of methanol solution, stirring until the potassium hydroxide is completely dissolved, adding 6.37mmol (22.75 equivalent) of hydroxylamine hydrochloride solid, and uniformly stirring until white precipitate is completely separated out; dissolving 0.28mmol of 3,4, 5-trimethoxybenzaldehyde-derived lipoic acid ethyl ester prepared in the step one in 10mL of tetrahydrofuran, adding the dissolved lipoic acid ethyl ester into the methanol system after complete dissolution, heating the mixture for reaction at 50 ℃, detecting the reaction end point by TLC (thin layer chromatography), and spin-drying the solvent after complete reaction; dissolving the product obtained by the reaction in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium chloride aqueous solution for 3 times, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, filtering, and spin-drying to remove dichloromethane, thus obtaining the lipoic acid hydroxylamine derivative with the structure shown in the formula I, namely 3,4, 5-trimethoxy-benzaldehyde derivatization lipoic acid hydroxylamine.
Example 7
A lipoic acid hydroxylamine derivative has a structural general formula shown in a formula I:
wherein:
in the formula I, R is 2-methoxyl, and the lipoic acid hydroxylamine derivatives are: 2-methoxy-benzaldehyde derivatised lipoic acid hydroxylamine.
The synthetic route is as follows:
the preparation method comprises the following specific steps:
step one, preparing 2-methoxy benzaldehyde derived lipoic acid ethyl ester:
weighing 3g of 2-methoxybenzaldehyde-derivatized thioctic acid, dissolving in 30mL of anhydrous ethanol, dropwise adding 1-2 drops of concentrated sulfuric acid into the system, heating and refluxing at 120 ℃, detecting the reaction end point by TLC, removing the ethanol by a rotary evaporation method after the reaction is completed, cooling, dissolving the reaction product in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium bicarbonate aqueous solution for 3 times, washing the dichloromethane solution of the reaction product with 20mL of water to neutrality, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, performing suction filtration, and spin-drying to remove dichloromethane, thus obtaining the 2-methoxy-benzaldehyde-derivatized thioctic acid ethyl ester.
Step two, synthesizing lipoic acid hydroxylamine derivatives:
weighing 5.92mmol (21.14 equivalent) of potassium hydroxide, adding the potassium hydroxide into 10mL of methanol solution, stirring until the potassium hydroxide is completely dissolved, adding 6.37mmol (22.75 equivalent) of hydroxylamine hydrochloride solid, and uniformly stirring until white precipitate is completely separated out; dissolving 0.28mmol of 2-methoxybenzaldehyde derived lipoic acid ethyl ester prepared in the step one in 10mL of tetrahydrofuran, adding the dissolved lipoic acid ethyl ester into the methanol system after complete dissolution, heating the mixture for reaction at 50 ℃, detecting the reaction end point by TLC (thin layer chromatography), and spin-drying the solvent after complete reaction; dissolving the product obtained by the reaction in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium chloride aqueous solution for 3 times, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, filtering, and spin-drying to remove dichloromethane, thus obtaining the lipoic acid hydroxylamine derivative with the structure shown in the formula I, namely 2-methoxybenzaldehyde derived lipoic acid hydroxylamine.
Example 8
A lipoic acid hydroxylamine derivative has a structural general formula shown in a formula I:
wherein:
in the formula I, R is 2, 3-dichloro, and the lipoic acid hydroxylamine derivative is: 2, 3-dichloro-benzaldehyde derivatised lipoic acid hydroxylamine.
The synthetic route is as follows:
the preparation method comprises the following specific steps:
step one, preparing 2, 3-dichlorobenzaldehyde derived lipoic acid ethyl ester:
weighing 3g of 2, 3-dichlorobenzaldehyde derivatized thioctic acid, dissolving in 30mL of anhydrous ethanol, dropwise adding 1-2 drops of concentrated sulfuric acid into the system, heating and refluxing at 120 ℃, detecting the reaction end point by TLC, removing ethanol by a rotary evaporation method after the reaction is completed, cooling, dissolving the reaction product in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product by 20mL of saturated sodium bicarbonate aqueous solution for 3 times, washing the dichloromethane solution of the reaction product to be neutral by 20mL of water, drying the dichloromethane solution of the washed reaction product by anhydrous magnesium sulfate, performing suction filtration, and spin-drying to remove dichloromethane, thus obtaining the 2, 3-dichlorobenzaldehyde derivatized thioctic acid ethyl ester.
Step two, synthesizing lipoic acid hydroxylamine derivatives:
weighing 5.92mmol (21.14 equivalent) of potassium hydroxide, adding the potassium hydroxide into 10mL of methanol solution, stirring until the potassium hydroxide is completely dissolved, adding 6.37mmol (22.75 equivalent) of hydroxylamine hydrochloride solid, and uniformly stirring until white precipitate is completely separated out; dissolving 0.28mmol of 2, 3-dichloro-benzaldehyde derivatization lipoic acid ethyl ester prepared in the step one in 10mL of tetrahydrofuran, adding the dissolved lipoic acid ethyl ester into the methanol system after complete dissolution, heating the mixture for reaction at 50 ℃, detecting the reaction end point by TLC (thin layer chromatography), and spin-drying the solvent after complete reaction; dissolving the product obtained by the reaction in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium chloride aqueous solution for 3 times, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, filtering, and spin-drying to remove dichloromethane, thus obtaining the lipoic acid hydroxylamine derivative with the structure shown in the formula I, namely 2, 3-dichloro-benzaldehyde derivatization lipoic acid hydroxylamine.
Example 9
A lipoic acid hydroxylamine derivative has a structural general formula shown in a formula I:
wherein:
in the formula I, R is 2, 4-dichloro, and the lipoic acid hydroxylamine derivative is: 2, 4-dichloro-benzaldehyde derivatised lipoic acid hydroxylamine.
The synthetic route is as follows:
the preparation method comprises the following specific steps:
step one, preparing 2, 4-dichlorobenzaldehyde derived lipoic acid ethyl ester:
weighing 3g of 2, 4-dichlorobenzaldehyde derivatized thioctic acid, dissolving in 30mL of absolute ethanol, dropwise adding 1-2 drops of concentrated sulfuric acid into the system, heating and refluxing at 120 ℃, detecting the reaction end point by TLC, removing ethanol by a rotary evaporation method after the reaction is completed, cooling, dissolving the reaction product in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product by 20mL of saturated sodium bicarbonate aqueous solution for 3 times, washing the dichloromethane solution of the reaction product to be neutral by 20mL of water, drying the dichloromethane solution of the washed reaction product by anhydrous magnesium sulfate, filtering, and spin-drying the solvent to obtain the 2, 4-dichlorobenzaldehyde derivatized thioctic acid ethyl ester.
Step two, synthesizing lipoic acid hydroxylamine derivatives:
weighing 5.92mmol (21.14 equivalent) of potassium hydroxide, adding the potassium hydroxide into 10mL of methanol solution, stirring until the potassium hydroxide is completely dissolved, adding 6.37mmol (22.75 equivalent) of hydroxylamine hydrochloride solid, and uniformly stirring until white precipitate is completely separated out; dissolving 0.28mmol of 2, 4-dichlorobenzaldehyde derived lipoic acid ethyl ester prepared in the step one in 10mL of tetrahydrofuran, adding the dissolved lipoic acid ethyl ester into the methanol system after the lipoic acid ethyl ester is completely dissolved, heating the mixture for reaction at 50 ℃, detecting the reaction end point by TLC (thin layer chromatography), and spin-drying the solvent after the reaction is completely finished; dissolving the product obtained by the reaction in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium chloride aqueous solution for 3 times, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, filtering, and spin-drying to remove dichloromethane, thus obtaining the lipoic acid hydroxylamine derivative with the structure shown in the formula I, namely 2, 4-dichlorobenzaldehyde derivatized lipoic acid hydroxylamine.
Example 10
A lipoic acid hydroxylamine derivative has a structural general formula shown in a formula I:
wherein:
in the formula I, R is 2, 5-dichloro, and the lipoic acid hydroxylamine derivative is: 2, 5-Dichlorobenzaldehyde derivatizes lipoic acid hydroxylamine.
The synthetic route is as follows:
the preparation method comprises the following specific steps:
step one, preparing 2, 5-dichlorobenzaldehyde derived lipoic acid ethyl ester:
weighing 3g of 2, 5-dichlorobenzaldehyde derivatized thioctic acid, dissolving in 30mL of absolute ethanol, dropwise adding 1-2 drops of concentrated sulfuric acid into the system, heating and refluxing at 120 ℃, detecting the reaction end point by TLC, removing ethanol by a rotary evaporation method after the reaction is completed, cooling, dissolving the reaction product in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product by 20mL of saturated sodium bicarbonate aqueous solution for 3 times, washing the dichloromethane solution of the reaction product to be neutral by 20mL of water, drying the dichloromethane solution of the washed reaction product by anhydrous magnesium sulfate, performing suction filtration, and spin-drying to remove dichloromethane, thus obtaining the 2, 5-dichlorobenzaldehyde derivatized thioctic acid ethyl ester.
Step two, synthesizing lipoic acid hydroxylamine derivatives:
weighing 5.92mmol (21.14 equivalent) of potassium hydroxide, adding the potassium hydroxide into 10mL of methanol solution, stirring until the potassium hydroxide is completely dissolved, adding 6.37mmol (22.75 equivalent) of hydroxylamine hydrochloride solid, and uniformly stirring until white precipitate is completely separated out; dissolving 0.28mmol of 2, 5-dichlorobenzaldehyde derived lipoic acid ethyl ester prepared in the step one in 10mL of tetrahydrofuran, adding the dissolved lipoic acid ethyl ester into the methanol system after the lipoic acid ethyl ester is completely dissolved, heating the mixture for reaction at 50 ℃, detecting the reaction end point by TLC (thin layer chromatography), and spin-drying the solvent after the reaction is completely finished; dissolving the product obtained by the reaction in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium chloride aqueous solution for 3 times, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, filtering, and spin-drying to remove dichloromethane, thus obtaining the lipoic acid hydroxylamine derivative with the structure shown in the formula I, namely 2, 5-dichloro-benzaldehyde derivatization lipoic acid hydroxylamine.
Example 11
A lipoic acid hydroxylamine derivative has a structural general formula shown in a formula I:
wherein:
in the formula I, R is 2, 6-dichloro, and the lipoic acid hydroxylamine derivative is: 2, 6-dichlorobenzaldehyde derivatised lipoic acid hydroxylamine.
The synthetic route is as follows:
the preparation method comprises the following specific steps:
step one, preparing 2, 6-dichlorobenzaldehyde derived lipoic acid ethyl ester:
weighing 3g of 2, 6-dichlorobenzaldehyde derivatized thioctic acid, dissolving in 30mL of absolute ethanol, dropwise adding 1-2 drops of concentrated sulfuric acid into the system, heating and refluxing at 120 ℃, detecting the reaction end point by TLC, removing ethanol by a rotary evaporation method after the reaction is completed, cooling, dissolving the reaction product in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product by 20mL of saturated sodium bicarbonate aqueous solution for 3 times, washing the dichloromethane solution of the reaction product to be neutral by 20mL of water, drying the dichloromethane solution of the washed reaction product by anhydrous magnesium sulfate, performing suction filtration, and spin-drying to remove dichloromethane, thus obtaining the 2, 6-dichlorobenzaldehyde derivatized thioctic acid ethyl ester.
Step two, synthesizing lipoic acid hydroxylamine derivatives:
weighing 5.92mmol (21.14 equivalent) of potassium hydroxide, adding the potassium hydroxide into 10mL of methanol solution, stirring until the potassium hydroxide is completely dissolved, adding 6.37mmol (22.75 equivalent) of hydroxylamine hydrochloride solid, and uniformly stirring until white precipitate is completely separated out; dissolving 0.28mmol of 2, 6-dichlorobenzaldehyde derived lipoic acid ethyl ester prepared in the step one in 10mL of tetrahydrofuran, adding the dissolved lipoic acid ethyl ester into the methanol system after the lipoic acid ethyl ester is completely dissolved, heating the mixture for reaction at 50 ℃, detecting the reaction end point by TLC (thin layer chromatography), and spin-drying the solvent after the reaction is completely finished; dissolving the product obtained by the reaction in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium chloride aqueous solution for 3 times, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, filtering, and spin-drying to remove dichloromethane, thus obtaining the lipoic acid hydroxylamine derivative with the structure shown in the formula I, namely 2, 6-dichlorobenzaldehyde derivatized lipoic acid hydroxylamine.
Example 12
A lipoic acid hydroxylamine derivative has a structural general formula shown in a formula I:
wherein:
in the formula I, R is 4-chlorine, and the lipoic acid hydroxylamine derivative is as follows: 4-chlorobenzaldehyde derivatizing lipoic acid hydroxylamine.
The synthetic route is as follows:
the preparation method comprises the following specific steps:
step one, preparing 4-chlorobenzaldehyde derived lipoic acid ethyl ester:
weighing 3g of 4-chlorobenzaldehyde-derivatized thioctic acid, dissolving in 30mL of anhydrous ethanol, dropwise adding 1-2 drops of concentrated sulfuric acid into the system, heating and refluxing at 120 ℃, detecting the reaction end point by TLC, removing the ethanol by a rotary evaporation method after the reaction is completed, cooling, dissolving the reaction product in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product by 20mL of saturated sodium bicarbonate aqueous solution for 3 times, washing the dichloromethane solution of the reaction product to be neutral by 20mL of water, drying the dichloromethane solution of the washed reaction product by anhydrous magnesium sulfate, performing suction filtration, and spin-drying to remove dichloromethane, thus obtaining the 4-chlorobenzaldehyde-derivatized thioctic acid ethyl ester.
Step two, synthesizing lipoic acid hydroxylamine derivatives:
weighing 5.92mmol (21.14 equivalent) of potassium hydroxide, adding the potassium hydroxide into 10mL of methanol solution, stirring until the potassium hydroxide is completely dissolved, adding 6.37mmol (22.75 equivalent) of hydroxylamine hydrochloride solid, and uniformly stirring until white precipitate is completely separated out; dissolving 0.28mmol of the 4-chlorobenzaldehyde derived lipoic acid ethyl ester prepared in the step one in 10mL of tetrahydrofuran, adding the dissolved 4-chlorobenzaldehyde derived lipoic acid ethyl ester into the methanol system after the dissolved 4-chlorobenzaldehyde derived lipoic acid ethyl ester is completely dissolved, heating the mixture for reaction at the temperature of 50 ℃, detecting the reaction end point by TLC, and spin-drying the solvent after the reaction is completely finished; dissolving the product obtained by the reaction in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium chloride aqueous solution for 3 times, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, filtering, and spin-drying to remove dichloromethane, thus obtaining the lipoic acid hydroxylamine derivative with the structure shown in the formula I, namely 4-chlorobenzaldehyde derived lipoic acid hydroxylamine.
Example 13
A lipoic acid hydroxylamine derivative has a structural general formula shown in a formula I:
wherein:
in the formula I, R is 4-bromine, and the lipoic acid hydroxylamine derivative is as follows: 4-bromobenzaldehyde-derivatized lipoic acid hydroxylamine.
The synthetic route is as follows:
the preparation method comprises the following specific steps:
step one, preparing 4-bromobenzaldehyde derived lipoic acid ethyl ester:
weighing 3g of 4-bromobenzaldehyde-derivatized thioctic acid, dissolving in 30mL of anhydrous ethanol, dropwise adding 1-2 drops of concentrated sulfuric acid into the system, heating and refluxing at 120 ℃, detecting the reaction end point by TLC, removing the ethanol by a rotary evaporation method after the reaction is completed, cooling, dissolving the reaction product in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium bicarbonate aqueous solution for 3 times, washing the dichloromethane solution of the reaction product with 20mL of water to be neutral, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, performing suction filtration, and spin-drying to remove dichloromethane, thereby obtaining the 4-bromobenzaldehyde-derivatized thioctic acid ethyl ester.
Step two, synthesizing lipoic acid hydroxylamine derivatives:
weighing 5.92mmol (21.14 equivalent) of potassium hydroxide, adding the potassium hydroxide into 10mL of methanol solution, stirring until the potassium hydroxide is completely dissolved, adding 6.37mmol (22.75 equivalent) of hydroxylamine hydrochloride solid, and uniformly stirring until white precipitate is completely separated out; dissolving 0.28mmol of the 4-bromo-benzaldehyde-derived lipoic acid ethyl ester prepared in the step one in 10mL of tetrahydrofuran, adding the dissolved lipoic acid ethyl ester into the methanol system after complete dissolution, heating the mixture for reaction at 50 ℃, detecting the reaction end point by TLC (thin layer chromatography), and spin-drying the solvent after complete reaction; dissolving the product obtained by the reaction in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium chloride aqueous solution for 3 times, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, filtering, and spin-drying to remove dichloromethane, thus obtaining the lipoic acid hydroxylamine derivative with the structure shown in the formula I, namely 4-bromobenzaldehyde derived lipoic acid hydroxylamine.
Example 14
A lipoic acid hydroxylamine derivative has a structural general formula shown in a formula I:
wherein:
in the formula I, R is 3-methoxyl, and the lipoic acid hydroxylamine derivatives are: 3-methoxybenzaldehyde-derivatized lipoic acid hydroxylamine.
The synthetic route is as follows:
the preparation method comprises the following specific steps:
step one, preparing 3-methoxy benzaldehyde derived lipoic acid ethyl ester:
weighing 3g of 3-methoxybenzaldehyde-derivatized thioctic acid, dissolving in 30mL of anhydrous ethanol, dropwise adding 1-2 drops of concentrated sulfuric acid into the system, heating and refluxing at 120 ℃, detecting the reaction end point by TLC, removing the ethanol by a rotary evaporation method after the reaction is completed, cooling, dissolving the reaction product in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium bicarbonate aqueous solution for 3 times, washing the dichloromethane solution of the reaction product with 20mL of water to be neutral, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, performing suction filtration, and spin-drying to remove dichloromethane, thus obtaining the 3-methoxybenzaldehyde-derivatized thioctic acid ethyl ester.
Step two, synthesizing lipoic acid hydroxylamine derivatives:
weighing 5.92mmol (21.14 equivalent) of potassium hydroxide, adding the potassium hydroxide into 10mL of methanol solution, stirring until the potassium hydroxide is completely dissolved, adding 6.37mmol (22.75 equivalent) of hydroxylamine hydrochloride solid, and uniformly stirring until white precipitate is completely separated out; dissolving 0.28mmol of 3-methoxybenzaldehyde derived lipoic acid ethyl ester prepared in the step one in 10mL of tetrahydrofuran, adding the dissolved lipoic acid ethyl ester into the methanol system after complete dissolution, heating the mixture for reaction at 50 ℃, detecting the reaction end point by TLC (thin layer chromatography), and spin-drying the solvent after complete reaction; dissolving the product obtained by the reaction in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium chloride aqueous solution for 3 times, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, filtering, and spin-drying to remove dichloromethane, thus obtaining the lipoic acid hydroxylamine derivative with the structure shown in the formula I, namely 3-methoxybenzaldehyde derived lipoic acid hydroxylamine.
Example 15
A lipoic acid hydroxylamine derivative has a structural general formula shown in a formula I:
wherein:
in the formula I, R is 4-isopropyl, and the lipoic acid hydroxylamine derivative is: 4-isopropyl-benzaldehyde derivatised lipoic acid hydroxylamine.
The synthetic route is as follows:
the preparation method comprises the following specific steps:
step one, preparing 4-isopropyl benzaldehyde-derivatized lipoic acid ethyl ester:
weighing 3g of 4-isopropylbenzaldehyde derivatized thioctic acid, dissolving in 30mL of anhydrous ethanol, dropwise adding 1-2 drops of concentrated sulfuric acid into the system, heating and refluxing at 120 ℃, detecting a reaction end point by TLC, removing the ethanol by a rotary evaporation method after the reaction is completed, cooling, dissolving the reaction product in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product by 20mL of saturated sodium bicarbonate aqueous solution for 3 times, washing the dichloromethane solution of the reaction product to be neutral by 20mL of water, drying the dichloromethane solution of the washed reaction product by anhydrous magnesium sulfate, performing suction filtration, and spin-drying to remove dichloromethane, thus obtaining the 4-isopropylbenzaldehyde derivatized thioctic acid ethyl ester.
Step two, synthesizing lipoic acid hydroxylamine derivatives:
weighing 5.92mmol (21.14 equivalent) of potassium hydroxide, adding the potassium hydroxide into 10mL of methanol solution, stirring until the potassium hydroxide is completely dissolved, adding 6.37mmol (22.75 equivalent) of hydroxylamine hydrochloride solid, and uniformly stirring until white precipitate is completely separated out; dissolving 0.28mmol of the 4-isopropylbenzaldehyde-derivatized lipoic acid ethyl ester prepared in the first step in 10mL of tetrahydrofuran, adding the dissolved 4-isopropylbenzaldehyde-derivatized lipoic acid ethyl ester into the methanol system after the dissolved lipoic acid ethyl ester is completely dissolved, heating the mixture for reaction at 50 ℃, detecting the reaction end point by TLC (thin layer chromatography), and spin-drying the solvent after the reaction is completely finished; dissolving the product obtained by the reaction in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium chloride aqueous solution for 3 times, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, filtering, and spin-drying to remove dichloromethane, thus obtaining the lipoic acid hydroxylamine derivative with the structure shown in the formula I, namely 4-isopropylbenzaldehyde derivatization lipoic acid hydroxylamine.
Example 16
A lipoic acid hydroxylamine derivative has a structural general formula shown in a formula I:
wherein:
in the formula I, R is 2-fluorine, and the lipoic acid hydroxylamine derivative is as follows: 2-fluoro-benzaldehyde derivatised lipoic acid hydroxylamine.
The synthetic route is as follows:
the preparation method comprises the following specific steps:
step one, preparing 2-fluorobenzaldehyde derived lipoic acid ethyl ester:
weighing 3g of 2-fluorobenzaldehyde derived thioctic acid, dissolving in 30mL of anhydrous ethanol, dropwise adding 1-2 drops of concentrated sulfuric acid into the system, heating and refluxing at 120 ℃, detecting the reaction end point by TLC, removing the ethanol by a rotary evaporation method after the reaction is completed, cooling, dissolving the reaction product in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium bicarbonate aqueous solution for 3 times, washing the dichloromethane solution of the reaction product with 20mL of water to be neutral, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, performing suction filtration, and spin-drying to remove dichloromethane, thus obtaining the 2-fluorobenzaldehyde derived thioctic acid ethyl ester.
Step two, synthesizing lipoic acid hydroxylamine derivatives:
weighing 5.92mmol (21.14 equivalent) of potassium hydroxide, adding the potassium hydroxide into 10mL of methanol solution, stirring until the potassium hydroxide is completely dissolved, adding 6.37mmol (22.75 equivalent) of hydroxylamine hydrochloride solid, and uniformly stirring until white precipitate is completely separated out; dissolving 0.28mmol of 2-fluorobenzaldehyde derived lipoic acid ethyl ester prepared in the step one in 10mL of tetrahydrofuran, adding the dissolved lipoic acid ethyl ester into the methanol system after complete dissolution, heating the mixture for reaction at 50 ℃, detecting the reaction end point by TLC (thin layer chromatography), and spin-drying the solvent after complete reaction; dissolving the product obtained by the reaction in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium chloride aqueous solution for 3 times, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, filtering, and spin-drying to remove dichloromethane, thus obtaining the lipoic acid hydroxylamine derivative with the structure shown in the formula I, namely 2-fluorobenzaldehyde derived lipoic acid hydroxylamine.
Example 17
The structural general formula of the lipoic acid hydroxylamine derivatives is shown as formula I:
wherein:
in the formula I, R is 3-fluorine, and the lipoic acid hydroxylamine derivative is as follows: 3-fluoro-benzaldehyde derivatised lipoic acid hydroxylamine.
The synthetic route is as follows:
the preparation method comprises the following specific steps:
step one, preparing 3-fluorobenzaldehyde derived lipoic acid ethyl ester:
weighing 3g of 3-fluorobenzaldehyde derived thioctic acid, dissolving in 30mL of anhydrous ethanol, dropwise adding 1-2 drops of concentrated sulfuric acid into the system, heating and refluxing at 120 ℃, detecting the reaction end point by TLC, removing the ethanol by a rotary evaporation method after the reaction is completed, cooling, dissolving the reaction product in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium bicarbonate aqueous solution for 3 times, washing the dichloromethane solution of the reaction product with 20mL of water to be neutral, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, performing suction filtration, and spin-drying to remove dichloromethane, thus obtaining the 3-fluorobenzaldehyde derived thioctic acid ethyl ester.
Step two, synthesizing lipoic acid hydroxylamine derivatives:
weighing 5.92mmol (21.14 equivalent) of potassium hydroxide, adding the potassium hydroxide into 10mL of methanol solution, stirring until the potassium hydroxide is completely dissolved, adding 6.37mmol (22.75 equivalent) of hydroxylamine hydrochloride solid, and uniformly stirring until white precipitate is completely separated out; dissolving 0.28mmol of 3-fluorobenzaldehyde derived lipoic acid ethyl ester prepared in the step one in 10mL of tetrahydrofuran, adding the dissolved lipoic acid ethyl ester into the methanol system after complete dissolution, heating the mixture for reaction at 50 ℃, detecting the reaction end point by TLC (thin layer chromatography), and spin-drying the solvent after complete reaction; dissolving the product obtained by the reaction in 50mL of dichloromethane solution, washing for 3 times by using 20mL of saturated sodium chloride aqueous solution, drying the dichloromethane solution of the washed reaction product by using anhydrous magnesium sulfate, carrying out suction filtration, and carrying out spin drying to remove dichloromethane, thus obtaining the lipoic acid hydroxylamine derivative with the structure shown in the formula I, namely 3-fluorobenzaldehyde derived lipoic acid hydroxylamine.
Antitumor activity studies were carried out on lipoic acid hydroxylamine derivatives of formula i prepared in examples 1 to 17:
tumor cells OvCaR-3, A549 and NCI-H460 are selected as detection cells, an MTT method is adopted, an enzyme-labeling instrument is used for measuring the absorbance under the condition of 570nm, and the OD value is calculated.
IC50The value calculation method is shown as the formula:
cell inhibition (%) - (control OD-Experimental OD)/control OD × 100%
The result shows that the lipoic acid hydroxylamine derivatives have obvious inhibitory activity on cancer cell strains OvCaR-3, A549 and NCI-H460, and the experimental results are shown in the figure 1-figure 3, wherein the compound with the optimal activity is the hydroxylamine compound 7, and then the compound 6 and the compound 3.
The technical means disclosed by the scheme of the invention are not limited to the technical means disclosed by the technical means, and also comprise the technical scheme formed by equivalent replacement of the technical features. The present invention is not limited to the details given herein, but is within the ordinary knowledge of those skilled in the art.
Claims (7)
1. Lipoic acid hydroxylamine derivatives are characterized in that the structural formula is shown as a formula I:
formula (II)
Wherein R is any one of hydrogen, 4-methyl, 4-phenyl, 3-hydroxy, 2-methoxy-4-hydroxy, 3,4, 5-trimethoxy, 2-methoxy, 2, 3-dichloro, 2, 4-dichloro, 2, 5-dichloro, 2, 6-dichloro, 4-chloro, 4-bromo, 3-methoxy, 4-isopropyl, 2-fluoro and 3-fluoro.
2. The lipoic acid hydroxylamine derivative of claim 1, wherein R is any one of hydrogen, 4-methyl, 4-phenyl, 3-hydroxy, 2-methoxy-4-hydroxy, 3,4, 5-trimethoxy, and 2-methoxy.
3. The lipoic acid hydroxylamine derivative of claim 1, wherein R is any one of 2, 3-dichloro, 2, 4-dichloro, 2, 5-dichloro, 2, 6-dichloro, 4-chloro, 4-bromo, 3-methoxy, 4-isopropyl, 2-fluoro, and 3-fluoro.
4. The lipoic acid hydroxylamine derivative of claim 1, wherein R is any one of 2-methoxy, 3,4, 5-trimethoxy and 4-phenyl.
5. The lipoic acid hydroxylamine derivative of claim 1, wherein R is 2-methoxy.
6. A method for preparing lipoic acid hydroxylamine derivatives of any one of claims 1-5, characterized by the following specific synthetic route:
the preparation method comprises the following steps:
step one, preparing a compound shown as a formula II:
formula II
Weighing 3g of a compound III, dissolving the compound III in 30mL of absolute ethanol, dropwise adding 1-2 drops of concentrated sulfuric acid into the system, heating and refluxing at 120 ℃, detecting a reaction end point by TLC (thin layer chromatography), removing ethanol by using a rotary evaporation method after the reaction is completed, cooling, dissolving a reaction product in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product by using 20mL of saturated sodium bicarbonate aqueous solution for 3 times, washing the dichloromethane solution of the reaction product to neutrality by using 20mL of water, drying the dichloromethane solution of the washed reaction product by using anhydrous magnesium sulfate, removing the magnesium sulfate by suction filtration, and removing dichloromethane by rotary drying to obtain a compound shown in a formula II;
step two, synthesizing lipoic acid hydroxylamine derivatives I:
formula I
Weighing 5.92mmol (21.14 equivalent) of potassium hydroxide, adding the potassium hydroxide into 10mL of methanol solution, stirring until the potassium hydroxide is completely dissolved, adding 6.37mmol (22.75 equivalent) of hydroxylamine hydrochloride solid, and uniformly stirring until white precipitate is completely separated out; dissolving 0.28mmol of the compound II prepared in the step one in 10mL of tetrahydrofuran, adding the compound II into the methanol system after complete dissolution, heating and reacting at 50 ℃, detecting the reaction end point by TLC, and spin-drying the solvent after complete reaction; dissolving the product obtained by the reaction in 50mL of dichloromethane solution, washing the dichloromethane solution of the reaction product with 20mL of saturated sodium chloride aqueous solution for 3 times, drying the dichloromethane solution of the washed reaction product with anhydrous magnesium sulfate, performing suction filtration, and spin-drying to remove dichloromethane, thereby obtaining the lipoic acid hydroxylamine derivative with the structure shown in the formula I;
wherein R is any one of hydrogen, 4-methyl, 4-phenyl, 3-hydroxy, 2-methoxy-4-hydroxy, 3,4, 5-trimethoxy, 2-methoxy, 2, 3-dichloro, 2, 4-dichloro, 2, 5-dichloro, 2, 6-dichloro, 4-chloro, 4-bromo, 3-methoxy, 4-isopropyl, 2-fluoro and 3-fluoro.
7. The use of lipoic acid hydroxylamine derivatives as claimed in any one of claims 1 to 5, characterised in that said lipoic acid hydroxylamine derivatives are used for the preparation of a medicament for the treatment of lung cancer and ovarian cancer.
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