A method for preparing a biotinylated amino acid derivative

Abstract

This invention belongs to the field of amino acid derivative preparation technology, and relates to a method for preparing biotinylated amino acid derivatives. The method involves adding amino acids and a base to biotin D-biotin, stirring, then adding a catalyst and a solvent, stirring the reaction, drying the solvent, extracting, and purifying to obtain the biotinylated amino acid derivative. The catalyst is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-hydroxybenzotriazole. This invention does not require metal catalysis or highly active acyl chlorides. Under the action of a base, the amino acidification of biotin D-biotin is achieved under mild conditions. This method is simple to operate, has mild reaction conditions, a wide range of applicable substrates, inexpensive and readily available raw materials, high product selectivity, and broad market prospects.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of amino acid derivative preparation, and relates to a preparation method of a biotinylated amino acid derivative. BACKGROUND

[0002] Biotin derivatives are an important class of organic functional molecules, which have wide applications in the fields of health medicine and biological materials. For example, the biotin derivatives NHS-biotin, Sulfo-NHS-biotin, NHS-LC-biotin and Sulfo-NHS-LC-Biotin are used to label the amino groups of proteins; the activated biotin Biotin-BMCC and Biotin-HPDP are used to label the sulfhydryl groups of proteins; and the Biotin-Hydrazide and Biotin-LC-Hydrazide and Biotin-LC-Hydrazide are used to label the carbonyl groups of proteins. Therefore, developing a method for preparing biotin derivatives has important significance and research value for developing new drugs and biological functional molecules. At present, many best-selling marker molecules on the market contain a biotin structural unit, and the combination of biotin and amino acids is an effective means of functionalizing amino acids. The functionalized amino acids not only retain the functions of amino acids but also have the new fluorescent tracking function of the biotin D-biotin structural unit, and the combination of the two will have important significance and practical value in the fields of health medicine and new drug development.

[0003]

[0004] At present, the most commonly used method for synthesizing amides is to react acyl chloride and amine to obtain amide. This method first needs to react carboxylic acid and thionyl chloride to obtain acyl chloride, for example, [Chem. Eur. J. 2008, 14, 9864-9867, [Org. Biomol. Chem., 2015, 13, 7803-7812] and the like. The reaction rate of acyl chloride and amine is fast, but the acyl chloride is too active, and the functional group compatibility is poor; the obtained secondary amide can continue to react with acyl chloride, the by-products are many, the yield is low, and the selectivity of the functional group is poor. The imine reaction catalyzed by transition metal can also be used to obtain amide, which needs to use expensive metal catalysts, for example, using dimeric rhodium acetate as a catalyst [Angew. Chem. Int. Ed. 2005, 44, 3096-3099]. The participation of metal increases the difficulty of subsequent separation and purification, especially in the medical production, the requirement for low metal content greatly reduces the practical value of the synthesis method.

[0005] Therefore, it is extremely urgent to provide a simple and efficient method for biotin D-biotin amino acidization without metal participation, which has important research significance and practical value in the field of health care and new drug development. SUMMARY

[0006] The present application aims to overcome the problems existing in the prior art, and provides a method for preparing functional amino acid derivatives by realizing the amidation reaction of D-biotin using biotin D-biotin and amino acids as raw materials and organic or inorganic bases as alkaline reagents, i.e. obtaining corresponding biotin derivatives using biotin D-biotin and amino acids as raw materials. The method is simple in operation, high in yield, wide in substrate application range, mild in reaction conditions and high in selectivity.

[0007] To achieve the above-mentioned purpose, the present application provides a method for preparing biotinylated amino acid derivatives, which uses biotin D-biotin and various amino acids as substrates, utilizes EDC and HOBt as catalysts in the presence of organic or inorganic bases, and performs directional amino acidization reaction of biotin D-biotin in organic solvents to obtain amino acidized biotin derivatives. The specific method is as follows: first, biotin D-biotin is added to a reaction tube, then amino acid and base are added under inert gas protection at-78℃, and stirred at room temperature for 0.5h; then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), 1-hydroxybenzotriazole (HOBt) and solvent are added under inert gas protection at-78℃, and stirred for 1-48h; the solvent is then extracted, washed with n-hexane, extracted with dichloromethane, and purified by chemical method to obtain the corresponding biotin derivatives.

[0008] The method for preparing biotin derivatives of the present application has the following reaction formula:

[0009]

[0010] In the formula, R 1 is hydrogen, methyl, ethyl, tert-butyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, amino, substituted amino, vinyl, styryl, phenylacetylenyl, phenyl, amido, benzamido, hydroxyl, substituted hydroxyl, thiol, substituted thiol, pinacol boron, oxazolyl, pyrazolyl, pyridyl, thienyl, thiazolyl, furanyl, pyrrolyl, morpholino, piperidyl, fluorine, chlorine, bromine, iodine functional groups or cyclic groups; R 2hydrogen, (substituted) methyl, ethyl, tert-butyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, amino, substituted amino, vinyl, styryl, phenylethynyl, phenyl, amido, benzamido, hydroxyl, hydroxymethyl, thiol, thiomethyl, pinacol boron, oxazolyl, pyrazolyl, pyridyl, thienyl, thiazolyl, furanyl, pyrrolyl, morpholinyl, piperidinyl, fluorine, chlorine, bromine, iodine functional groups or cyclic groups.

[0011] The chemical structural formula of the EDC compound in the application is as follows:

[0012] The chemical structural formula of the HOBt compound in the application is as follows:

[0013] The chemical structural formula of the biotin D-biotin in the application is as follows:

[0014]

[0015] The amino acid in the application is at least one of glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine or pyrrolysine.

[0016] The solvent in the application is a polar solvent or a non-polar solvent, and is at least one of ethanol, methanol, ethyl acetate, diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, 1,2-dichloroethane, dichloromethane, acetonitrile, 1,4-dioxane, benzene, toluene, xylene, trifluorotoluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide.

[0017] The inert gas in the application is nitrogen or argon.

[0018] The reaction temperature in the application is between 0℃ and 100℃.

[0019] The reaction time in the application is 1-48 hours.

[0020] The molar ratio of biotin D-biotin, base, EDC, HOBt and amino acid in the application is 1:(1-10):(1-10):(1-10):(1-10).

[0021] The alkali described in this invention is an inorganic alkali or an organic alkali. The inorganic alkali is lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, calcium carbonate, sodium phosphate, disodium hydrogen phosphate, or sodium dihydrogen phosphate. The organic alkali is sodium methoxide, potassium ethoxide, potassium tert-butoxide, butyllithium, phenyllithium, diisopropylaminolithium (LDA), hexamethyldisilaminolithium (LiHMDS), triethylamine, or trimethylamine.

[0022] Compared with existing methods, the present invention has the following advantages: it does not require the participation of metal catalysts or highly active acyl chlorides, and achieves the amino acidification of biotin D-biotin under mild conditions in the presence of alkali. The method is simple to operate, has mild reaction conditions, a wide range of applicable substrates, inexpensive and readily available raw materials, high product selectivity, and broad market prospects. Attached image description:

[0023] Fig. 1 This is a product state diagram of Embodiment 2 of the present invention.

[0024] Fig. 2 The nuclear magnetic resonance spectrum of the product in Embodiment 2 of the present invention is shown.

[0025] Fig. 3 This is a high-resolution mass spectrum of the product of Embodiment 2 of the present invention. Detailed implementation method:

[0026] The present invention will be further described in detail below through embodiments.

[0027] Example 1:

[0028] This invention relates to a method for synthesizing and preparing a biotinylated amino acid derivative, wherein the selected amino acid is β-alanine, and the specific steps are as follows:

[0029]

[0030] In a reaction tube, 1 mmol of biotin D-biotin was added under nitrogen protection. At -78°C, 89 mg of β-alanine and 101 mg of triethylamine were added, and the mixture was stirred at room temperature for 0.5 h. Then, under nitrogen protection, at -78°C, 157 mg of EDC, 135 mg of HOBt, and 2 mL of LDCM (dichloromethane) were added, and the mixture was stirred at 35°C for 24 h. After the reaction was complete, the solvent was removed, the mixture was washed with n-hexane, extracted with dichloromethane, and the solvent was evaporated. The product was then subjected to silica gel column chromatography (eluent was a 1:1 volume mixture of petroleum ether and ethyl acetate) to give 252 mg of the product, with a yield of 80%.

[0031] Example 2:

[0032] This invention relates to a method for synthesizing biotinylated amino acid derivatives, using isoserine as the amino acid substrate. The specific steps are as follows:

[0033]

[0034] In a reaction tube, 1 mmol of biotin was added, and under nitrogen protection, 105 mg of isoserine and 101 mg of triethylamine were added at -78 °C. The mixture was stirred at room temperature for 0.5 h. Then, under nitrogen protection, 157 mg of EDC, 135 mg of HOBt, and 2 mL of DCM were added at -78 °C. The mixture was then stirred at 35 °C for 24 h. After the reaction was complete, the solvent was removed, the product was washed with n-hexane, extracted with dichloromethane, and the solvent was evaporated. The product was then subjected to silica gel column chromatography (eluent was a 1:1 mixture of petroleum ether and ethyl acetate) to give 248 mg of the product, with a yield of 75%. The product state, NMR, and high-resolution mass spectrometry characterization results are as follows: Figs. 1-3 As shown.

[0035] Example 3:

[0036] This invention relates to a method for synthesizing biotinylated amino acid derivatives, using glycine as the amino acid substrate. The specific steps are as follows:

[0037]

[0038] In a reaction tube, 1 mmol of biotin was added, and under nitrogen protection, 75 mg of glycine and 101 mg of triethylamine were added at -78 °C. The mixture was stirred at room temperature for 0.5 h. Under nitrogen protection, 157 mg of EDC, 135 mg of HOBt, and 2 mL of DCM were added, and the mixture was stirred at 35 °C for 24 h. After the reaction was complete, the solvent was dried under vacuum, the product was washed with n-hexane, extracted with dichloromethane, and the solvent was evaporated to dryness. The product was then subjected to silica gel column chromatography (eluent was a 1:1 mixture of petroleum ether and ethyl acetate) to give 210 mg of the product, with a yield of 70%.

[0039] Example 4:

[0040] This invention relates to a method for synthesizing biotinylated amino acid derivatives, using L-alanine as the amino acid substrate. The specific steps are as follows:

[0041]

[0042] In a reaction tube, 1 mmol of biotin was added, and under nitrogen protection, 89 mg of L-alanine and 101 mg of triethylamine were added at -78 °C. The mixture was stirred at room temperature for 0.5 h. Under nitrogen protection, 157 mg of EDC, 135 mg of HOBt, and 2 mL of DCM were added, and the mixture was stirred at 35 °C for 24 h. The solvent was removed by vacuum, and the product was washed with n-hexane, extracted with dichloromethane, and the solvent was evaporated to dryness. The product was then subjected to silica gel column chromatography (eluent was a 1:1 mixture of petroleum ether and ethyl acetate) to give 255 mg of the product, with a yield of 81%.

[0043] Example 5:

[0044] This invention relates to a method for synthesizing biotinylated amino acid derivatives, using serine as the amino acid substrate. The specific steps are as follows:

[0045]

[0046] In a reaction tube, 1 mmol of biotin was added, and under nitrogen protection, 105 mg of serine and 101 mg of triethylamine were added at -78 °C. The mixture was stirred at room temperature for 0.5 h. Under nitrogen protection, 157 mg of EDC, 135 mg of HOBt, and 2 mL of DCM were added at -78 °C. The mixture was then stirred at 35 °C for 24 h. After the reaction was complete, the solvent was dried under vacuum, the product was washed with n-hexane, extracted with dichloromethane, and the solvent was evaporated to dryness. The product was then subjected to silica gel column chromatography (eluent was a 1:1 volume mixture of petroleum ether and ethyl acetate) to give 166 mg of the product, with a yield of 50%.

[0047] Example 6:

[0048] This invention relates to a method for synthesizing biotinylated amino acid derivatives, using tertiary leucine as the amino acid substrate. The specific steps are as follows:

[0049]

[0050] In a reaction tube, 1 mmol of biotin was added, and under nitrogen protection, 131 mg of tert-leucine and 101 mg of triethylamine were added at -78 °C. The mixture was stirred at room temperature for 0.5 h. Under nitrogen protection, 157 mg of EDC, 135 mg of HOBt, and 2 mL of DCM were added at -78 °C. The mixture was then stirred at 35 °C for 24 h. After the reaction was complete, the solvent was dried under vacuum, the product was washed with n-hexane, extracted with dichloromethane, and the solvent was evaporated to dryness. The product was then subjected to silica gel column chromatography (eluent was a 1:1 volume mixture of petroleum ether and ethyl acetate) to give 242 mg of the product, with a yield of 68%.

[0051] Example 7:

[0052] This invention relates to a method for synthesizing biotinylated amino acid derivatives, using threonine as the amino acid substrate. The specific steps are as follows:

[0053]

[0054] In a reaction tube, 1 mmol of biotin was added, and under nitrogen protection, 119 mg of threonine and 101 mg of triethylamine were added at -78 °C. The mixture was stirred at room temperature for 0.5 h. Under nitrogen protection, 157 mg of EDC, 135 mg of HOBt, and 2 mL of DCM were added at -78 °C. The mixture was then stirred at 35 °C for 24 h. After the reaction was complete, the solvent was dried under vacuum, the product was washed with n-hexane, extracted with dichloromethane, and the solvent was evaporated to dryness. The product was then subjected to silica gel column chromatography (eluent was a 1:1 volume mixture of petroleum ether and ethyl acetate) to give 207 mg of the product, with a yield of 60%.

[0055] Example 8:

[0056] This invention relates to a method for synthesizing biotinylated amino acid derivatives, using β-hydroxyvaline as the amino acid substrate. The specific steps are as follows:

[0057]

[0058] In a reaction tube, 1 mmol of biotin was added, and under nitrogen protection, 133 mg of β-hydroxyvaline and 101 mg of triethylamine were added at -78 °C. The mixture was stirred at room temperature for 0.5 h. Under nitrogen protection, 157 mg of EDC, 135 mg of HOBt, and 2 mL of DCM were added at -78 °C. The mixture was then stirred at 35 °C for 24 h. After the reaction was complete, the solvent was dried under vacuum, the product was washed with n-hexane, extracted with dichloromethane, and the solvent was evaporated to dryness. The product was then subjected to silica gel column chromatography (eluent was a 1:1 volume mixture of petroleum ether and ethyl acetate) to give 219 mg of the product, with a yield of 61%.

[0059] Example 9:

[0060] This invention relates to a method for synthesizing biotinylated amino acid derivatives, using methionine as the amino acid substrate. The specific reaction equations and steps are as follows:

[0061]

[0062] In a reaction tube, 1 mmol of biotin was added, and under nitrogen protection, 146 mg of methionine and 101 mg of triethylamine were added at -78 °C. The mixture was stirred at room temperature for 0.5 h. Under nitrogen protection, 157 mg of EDC, 135 mg of HOBt, and 2 mL of DCM were added at -78 °C. The mixture was then stirred at 35 °C for 24 h. After the reaction was complete, the solvent was dried under vacuum, the product was washed with n-hexane, extracted with dichloromethane, and the solvent was evaporated to dryness. The product was then subjected to silica gel column chromatography (eluent was a 1:1 volume mixture of petroleum ether and ethyl acetate) to give 270 mg of the product, with a yield of 72%.

[0063] Example 10:

[0064] This invention relates to a method for synthesizing biotinylated amino acid derivatives, using cysteine ​​as the selected amino acid substrate. The specific reaction equations and steps are as follows:

[0065]

[0066] In a reaction tube, 1 mmol of biotin was added, and under nitrogen protection, 121 mg of cysteine ​​and 101 mg of triethylamine were added at -78 °C. The mixture was stirred at room temperature for 0.5 h. Under nitrogen protection, 157 mg of EDC, 135 mg of HOBt, and 2 mL of DCM were added at -78 °C. The mixture was then stirred at 35 °C for 24 h. After the reaction was complete, the solvent was dried under vacuum, the product was washed with n-hexane, extracted with dichloromethane, and the solvent was evaporated to dryness. The product was then subjected to silica gel column chromatography (eluent was a 1:1 volume mixture of petroleum ether and ethyl acetate) to give 191 mg of the product, with a yield of 55%.

[0067] Example 11:

[0068] This invention relates to a method for synthesizing biotinylated amino acid derivatives, using histidine as the amino acid substrate. The specific reaction equations and steps are as follows:

[0069]

[0070] In a reaction tube, 1 mmol of biotin was added, and under nitrogen protection, 155 mg of histidine and 101 mg of triethylamine were added at -78 °C. The mixture was stirred at room temperature for 0.5 h. Under nitrogen protection, 157 mg of EDC, 135 mg of HOBt, and 2 mL of DCM were added at -78 °C. The mixture was then stirred at 35 °C for 24 h. After the reaction was complete, the solvent was dried under vacuum, the product was washed with n-hexane, extracted with dichloromethane, and the solvent was evaporated to dryness. The product was then subjected to silica gel column chromatography (eluent was a 1:1 volume mixture of petroleum ether and ethyl acetate) to give 186 mg of the product, with a yield of 49%.

[0071] Example 12:

[0072] Compared with Example 1, this embodiment replaces triethylamine with potassium carbonate. The specific steps are as follows:

[0073]

[0074] In a reaction tube, 1 mmol of biotin was added, and under nitrogen protection, 146 mg of β-alanine and 138 mg of potassium carbonate were added at -78 °C. The mixture was stirred at room temperature for 0.5 h. Under nitrogen protection, 157 mg of EDC, 135 mg of HOBt, and 2 mL of DCM were added, and the mixture was stirred at 35 °C for 24 h. The solvent was removed by vacuum, and the product was washed with n-hexane, extracted with dichloromethane, and the solvent was evaporated to dryness. The product was then subjected to silica gel column chromatography (eluent was a 1:1 mixture of petroleum ether and ethyl acetate) to give 258 mg of the product, with a yield of 82%. This indicates that the reaction can also be achieved by replacing triethylamine with potassium carbonate.

[0075] Comparative Example 1:

[0076] Compared with Example 1, this comparative example replaces the solvent DCM with THF. The specific steps are as follows:

[0077]

[0078] In a reaction tube, 1 mmol of biotin was added, and under nitrogen protection, 146 mg of β-alanine and 101 mg of triethylamine were added at -78 °C. The mixture was stirred at room temperature for 0.5 h. Under nitrogen protection, 157 mg of EDC, 135 mg of HOBt, and 2 mL of THF (tetrahydrofuran) were added, and the mixture was stirred at 35 °C for 24 h. The solvent was removed by vacuum, and the mixture was washed with n-hexane, extracted with dichloromethane, and the solvent was evaporated to dryness. The product was then subjected to silica gel column chromatography (eluent was a 1:1 mixture of petroleum ether and ethyl acetate) to give 236 mg of the product, with a yield of 75%.

[0079] Comparative Example 2:

[0080] Compared with Example 1, the reaction temperature in this comparative example was set to 100°C, and the specific steps are as follows:

[0081]

[0082] In a reaction tube, 1 mmol of biotin was added, and under nitrogen protection, 146 mg of β-alanine and 101 mg of triethylamine were added at -78 °C. The mixture was stirred at room temperature for 0.5 h. Under nitrogen protection, 157 mg of EDC, 135 mg of HOBt, and 2 mL of DCM were added. The mixture was then stirred at 100 °C for 24 h. The solvent was removed by vacuum, and the mixture was washed with n-hexane, extracted with dichloromethane, and the solvent was evaporated. The product was then subjected to silica gel column chromatography (eluent was a 1:1 volume mixture of petroleum ether and ethyl acetate) to give 252 mg of the product, with a yield of 80%.

[0083] Comparative Example 3:

[0084] Compared with Example 1, this comparative example did not include triethylamine in the reaction raw materials. The specific steps are as follows:

[0085]

[0086] In a reaction tube, 1 mmol of biotin was added under nitrogen protection. Then, 146 mg of β-alanine was added at -78°C, and the mixture was stirred at room temperature for 0.5 h. Under nitrogen protection, 157 mg of EDC, 135 mg of HOBt, and 2 mL of DCM were added, and the mixture was stirred at 35°C for 24 h. The solvent was removed by vacuum, and the mixture was washed with n-hexane, extracted with dichloromethane, and the solvent was evaporated. The solution was then subjected to silica gel column chromatography (eluent was a 1:1 mixture of petroleum ether and ethyl acetate) to give 0 mg of product, with a yield of 0%. This indicates that without the presence of a base, biotin and amino acids cannot react, and amino acid derivatives cannot be obtained.

[0087] Comparative Example 4:

[0088] Compared with Example 1, this comparative example did not include EDC in the reaction raw materials. The specific steps are as follows:

[0089]

[0090] In a reaction tube, 1 mmol of biotin was added under nitrogen protection. Then, 146 mg of β-alanine and 101 mg of triethylamine were added at -78 °C, and the mixture was stirred at room temperature for 0.5 h. Under nitrogen protection, 135 mg of HOBt and 2 mL of DCM were added, and the mixture was stirred at 35 °C for 24 h. The solvent was removed by vacuum, the mixture was washed with n-hexane, extracted with dichloromethane, and the solvent was evaporated. The solution was then subjected to silica gel column chromatography (eluent was a 1:1 mixture of petroleum ether and ethyl acetate) to obtain 0 mg of product, with a yield of 0%. This indicates that without the participation of EDC, biotin and amino acids cannot react, and amino acid derivatives cannot be obtained.

[0091] Comparative Example 5:

[0092] Compared with Example 1, no HOBt was added to the reaction raw materials in this comparative example. The specific steps are as follows:

[0093]

[0094] In a reaction tube, 1 mmol of biotin was added under nitrogen protection. Then, 146 mg of β-alanine and 101 mg of triethylamine were added at -78 °C, and the mixture was stirred at room temperature for 0.5 h. Under nitrogen protection, 157 mg of EDC and 2 mL of DCM were added at -78 °C, and the mixture was stirred at 35 °C for 24 h. The solvent was removed by vacuum, the mixture was washed with n-hexane, extracted with dichloromethane, and the solvent was evaporated. The solution was then subjected to silica gel column chromatography (eluent was a 1:1 mixture of petroleum ether and ethyl acetate) to obtain 0 mg of product, with a yield of 0%. This indicates that without the participation of HOBt, biotin and amino acids cannot react, and amino acid derivatives cannot be obtained.

Claims

1. A method for preparing a biotinylated amino acid derivative, characterized by, The biotin D-biotin is first added into a reaction tube, then the amino acid and the base are added under inert gas protection at -78℃, and stirred at room temperature for 0.5h; then the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), 1-hydroxybenzotriazole (HOBt) and the solvent are added under inert gas protection at -78℃, the reaction is stirred, the solvent is extracted and dried, and the biotinylated amino acid derivative is obtained after purification; The amino acid is at least one of glycine, alanine, valine, leucine, isoleucine, methionine, serine, tyrosine, cysteine, phenylalanine, threonine, histidine and selenocysteine.

2. The method for preparing a biotinylated amino acid derivative according to claim 1, characterized by, The stirring reaction time is 1-48h, and the temperature is 0℃-100℃.

3. The method for preparing biotinylated amino acid derivatives according to claim 1, characterized in that, The molar ratio of the biotin D-biotin, the base, the EDC, the HOBt and the amino acid is 1:(1-10):(1-10):(1-10):(1-10).

4. The method for preparing biotinylated amino acid derivatives according to claim 1, characterized in that, The solvent is at least one of ethanol, methanol, ethyl acetate, diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, 1,2-dichloroethane, dichloromethane, acetonitrile, 1,4-dioxane, benzene, toluene, xylene, trifluorotoluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide.

5. The method for preparing biotinylated amino acid derivatives according to claim 1, characterized in that, The base is an inorganic base or an organic base, the inorganic base is lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, calcium carbonate, sodium phosphate, disodium hydrogen phosphate or sodium dihydrogen phosphate, and the organic base is sodium methoxide, potassium ethoxide, potassium tert-butoxide, butyllithium, phenyllithium, lithium diisopropylamide, lithium hexamethyldisilazide, triethylamine or trimethylamine.

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