Synthesis of high-purity 2,2'-[[(1S,2S)-1,2-(-)-1,2-(-)]-bis[6-(1,1- (-)]phenol

Abstract

The invention relates to the technical field of material synthesis, and discloses a method of using 3-aminopyridine as a starting material, undergoing amino protection, chlorination, deprotection, condensation and coupling reactions, and finally synthesizing a target product 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bis-iminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol. The method successfully converts the simple starting material 3-aminopyridine into a target product with a complex structure and a specific structure through a series of chemical reactions, including amino protection, chlorination, deprotection, condensation and coupling steps. Cheap ammonium bicarbonate is used as an ammonia source to react with benzaldehyde to in-situ prepare benzaldehyde imine. The method realizes the preparation of aryl-substituted chiral diamines under the catalysis of chiral pinacol borate esters derived from various alkyl-substituted chiral diols. The method has the characteristics of high efficiency, low price and green environmental protection.

Description

Technical Field

[0001] The present invention relates to the technical field of material synthesis, and specifically to the synthesis of 2,2'-[[(1S,2S)-1,2-diphenyl-1,2-ethylene-bis-iminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol (abbreviated as: 2,2'-[[(1S,2S)-1,2 - (-) -1,2 - (-)]-bis[6-(1,1 - (-)]phenol). Background Art

[0002] 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bis(iminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol is an organic compound with a unique structure and potential application value. In the field of materials science, its special molecular structure gives the material good optical, electrical and thermal properties, and can be used to prepare high-performance optical materials, electronic devices and thermally stable materials. In pharmaceutical chemistry, the specific structure of the compound may give it certain biological activities, such as antibacterial, antiviral, and antitumor, providing a potential lead compound for the development of new drugs.

[0003] The traditional method for synthesizing 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bis(iminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol relies on the chiral resolution of the racemate with stoichiometric chiral tartaric acid, which results in at least half of the non-target products being discarded as waste, resulting in huge waste.

[0004] With the rise of green chemistry and sustainable development concepts, as well as the continuous advancement of organic synthesis technology, the development of more efficient, environmentally friendly and economical synthesis methods has become an inevitable trend. The new technology aims to overcome the many shortcomings of traditional synthesis methods and achieve the green and efficient synthesis of 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bisiminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol through innovative reaction strategies, the application of new catalysts and optimized reaction conditions. Summary of the invention

[0005] In view of the deficiencies of the prior art, the present invention provides a method for synthesizing 2,2'-[[(1S,2S)-1,2-diphenyl-1,2-ethylene-bis(iminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol.

[0006] To achieve the above object, the present invention provides the following technical scheme: Synthesis of 2,2'-[[(1S,2S)-1,2-diphenyl-1,2-ethylene-bisiminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol, using 3-aminopyridine as a starting material, undergoing amino protection, chlorination, deprotection, condensation and coupling reactions, and finally synthesizing the target product 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bisiminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol; Specifically include: Step 1, amino protection of 3-aminopyridine: protecting the amino group by adding a protecting agent to obtain N-Boc-3-aminopyridine; Step 2, chlorination reaction of N-Boc-3-aminopyridine: Under the action of a suitable chlorination reagent, an electrophilic substitution reaction will occur at the ortho or para position of the 3-amino group on the pyridine ring to introduce a chlorine atom to obtain a crude N-Boc-2-chloro-3-aminopyridine; Step 3, deprotection reaction of N-Boc-2-chloro-3-aminopyridine: hydrochloric acid reacts with the Boc group in N-Boc-2-chloro-3-aminopyridine to remove it, generating 2-chloro-3-aminopyridine hydrochloride, and then alkalizing to obtain free 2-chloro-3-aminopyridine; Step 4: Condensation reaction of 2-chloro-3-aminopyridine and (1S,2S)-1,2-diphenyl-1,2-ethylenediamine: In the presence of a base, the lone pair of electrons on the amino nitrogen atom of (1S,2S)-1,2-diphenyl-1,2-ethylenediamine is nucleophilic and will attack the carbon atom connected to the chlorine atom in 2-chloro-3-aminopyridine, resulting in a nucleophilic substitution reaction. The chlorine atom leaves as a leaving group, thereby forming a carbon-nitrogen bond and achieving a condensation reaction; Step 5. Coupling reaction with 6-tert-butylphenol: In the presence of a base and a palladium catalyst, the chlorine atom on the pyridine ring in 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bisiminoethyl)]-bipyridine dichloride first undergoes an oxidative addition reaction with the palladium catalyst to form a palladium intermediate. Then, 6-tert-butylphenol forms a phenol oxide anion under the action of a base. The phenol oxide anion undergoes a metal transfer reaction with the palladium intermediate to generate a new intermediate. Finally, after a reduction elimination step, a carbon-oxygen bond is formed to obtain the target product 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bisiminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol.

[0007] Preferably, the reaction formula of step 1 is: 3-aminopyridine + di-tert-butyl dicarbonate → triethylamine → N-Boc-3-aminopyridine; The specific steps are as follows: add 3-aminopyridine (10 g, 0.109 mol) and 100 mL of dichloromethane into a three-necked flask, turn on the stirrer, and completely dissolve 3-aminopyridine in dichloromethane. During this process, the solution is colorless and transparent; Under stirring conditions, slowly drop a dichloromethane solution (50 mL) of di-tert-butyl dicarbonate (24.7 g, 0.114 mol). During the dropwise addition process, the dropwise addition speed must be strictly controlled to ensure that the reaction temperature is maintained at 20-25°C. Because the reaction is an exothermic reaction, too fast a dropwise addition speed may cause a sharp rise in temperature and trigger side reactions; After the addition is complete, triethylamine (11.1 g, 0.109 mol) is added to the reaction system. Triethylamine, as a catalyst, can promote the reaction. After adding triethylamine, continue stirring the reaction for 4 hours. During the reaction, the color of the solution may gradually turn light yellow. After the reaction is completed, transfer the reaction solution to a separatory funnel. First, wash with 5% hydrochloric acid solution (2×50mL) to remove unreacted triethylamine and other alkaline impurities. At this time, stratification can be observed, with the lower layer being the organic phase and the upper layer being the aqueous phase. After separating the organic phase, wash with saturated sodium bicarbonate solution (2×50mL) to remove possible residual acidic impurities. Finally, wash with saturated brine (50mL) to reduce the moisture in the organic phase for subsequent drying. The washed organic phase was transferred to a dry conical flask and dried by adding anhydrous sodium sulfate. Anhydrous sodium sulfate can absorb the moisture in the organic phase. After standing for a period of time, the anhydrous sodium sulfate solid was removed by filtration. The filtrate was transferred to a rotary evaporator and the dichloromethane solvent was removed by vacuum distillation to obtain the crude N-Boc-3-aminopyridine. The crude product was a light yellow oily liquid; The crude product was purified by column chromatography, and a mixed solvent of petroleum ether: ethyl acetate = 3:1 was selected as the eluent. The crude product was loaded onto a silica gel column, and different components were separated in the silica gel column by the flow of the eluent. The eluate containing the target product was collected, and the eluent was removed by vacuum distillation to obtain white solid N-Boc-3-aminopyridine with a yield of 18.5 g and a yield of 85%.

[0008] Preferably, the reaction formula of step 2 is: N-Boc-3-aminopyridine + N-chlorosuccinimide → azobisisobutyronitrile, carbon tetrachloride → N-Boc-2-chloro-3-aminopyridine; The specific steps are as follows: in a dry reaction bottle, dissolve N-Boc-3-aminopyridine in an appropriate amount of solvent such as toluene or dichloromethane, then slowly drop phosphorus oxychloride, and after the dropwise addition is completed, stir and react at a certain temperature for several hours, and the reaction temperature is between 50-100°C; After the reaction is completed, the reaction solution is slowly poured into ice water for hydrolysis to decompose the excess phosphorus oxychloride, and then the product is extracted with an organic solvent such as ethyl acetate. The organic phase is washed with water, saturated sodium bicarbonate solution and saturated brine in sequence, dried and concentrated to obtain the chlorinated product N-Boc-2-chloro-3-aminopyridine.

[0009] Preferably, the reaction formula of step three is: N-Boc-2-chloro-3-aminopyridine+hydrochloric acid→dioxane→2-chloro-3-aminopyridine; The specific steps are: adding N-Boc-2-chloro-3-aminopyridine into a reaction bottle, then adding an appropriate amount of dioxane as a solvent, then passing dry hydrogen chloride gas or adding a dioxane solution of hydrochloric acid dropwise, and stirring the reaction at room temperature for several hours; After the reaction is completed, dioxane is first distilled off under reduced pressure, and then an appropriate amount of water is added to dissolve the product, and then the pH is adjusted to alkaline with alkali solution to free 2-chloro-3-aminopyridine, and finally extracted with an organic solvent, dried, and concentrated to obtain the target product 2-chloro-3-aminopyridine.

[0010] Preferably, the reaction formula of step 4 is: 2-chloro-3-aminopyridine+(1S,2S)-1,2-diphenyl-1,2-ethylenediamine→potassium carbonate, ethanol→2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bisiminoethyl)]-bipyridine dichloride; The specific steps are as follows: 2-chloro-3-aminopyridine (8.5 g, 0.061 mol), (1S,2S)-1,2-diphenyl-1,2-ethylenediamine (5.8 g, 0.029 mol), potassium carbonate (16.8 g, 0.122 mol) and 100 mL of ethanol were added to a 250 mL three-necked flask equipped with a stirrer, a thermometer and a reflux condenser, and heated to reflux for reaction for 12 h; After the reaction, the mixture was cooled to room temperature, insoluble matter was removed by filtration, ethanol was removed by distillation under reduced pressure from the filtrate, water (50 mL) was added to the residue, and the mixture was extracted with dichloromethane (3×50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain 12.5 g of a yellow solid with a yield of 78%.

[0011] Preferably, the reaction formula of step 5 is: 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bisiminoethyl)]-bipyridine dichloride + 6-tert-butylphenol → tetrakis(triphenylphosphine)palladium, potassium carbonate, toluene → 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bisiminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol; The specific steps are as follows: 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bis(iminoethyl)]-bipyridine dichloride (12.5 g, 0.023 mol), 6-tert-butylphenol (7.8 g, 0.046 mol), potassium carbonate (12.7 g, 0.092 mol), tetrakis(triphenylphosphine)palladium (0.8 g, 0.0007 mol) and 150 mL of toluene are added to a 250 mL three-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a nitrogen inlet tube, and heated under reflux for reaction for 24 h under nitrogen protection; After the reaction, the mixture was cooled to room temperature and the insoluble matter was removed by filtration. The filtrate was washed with dilute hydrochloric acid (2×50 mL) and then with water (2×50 mL). The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The mixture was purified by column chromatography to obtain 10.2 g of a white solid with a yield of 60%.

[0012] Preferably, in the column chromatography purification reaction in step 5, a silica gel column is selected as the stationary phase, and a mixed solvent of petroleum ether: ethyl acetate = 5:1 is selected as the eluent; The crude product was loaded onto a silica gel column, and the target product was separated from the impurities by the flow of the eluent. The eluent containing the target product was collected, and the eluent was removed by distillation under reduced pressure to obtain a white solid 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylidene-bisiminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol.

[0013] Compared with the prior art, the present invention provides a synthesis of 2,2'-[[(1S,2S)-1,2-diphenyl-1,2-ethylene-bisiminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol, which has the following beneficial effects: 1. The synthesis of 2,2'-[[(1S,2S)-1,2-diphenyl-1,2-ethylene-bis-iminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol is carried out by using 3-aminopyridine as a starting material, and undergoing amino protection, chlorination, deprotection, condensation and coupling reactions to finally synthesize the target product 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bis-iminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol. The impurity 2,6-dichloro-3-aminopyridine is less than 0.5%. Cheap ammonium bicarbonate is used as an ammonia source to react with benzaldehyde to in situ prepare benzaldehyde imine. The preparation of aromatic substituted chiral diamine is achieved under the catalysis of chiral pinacol borate esters derived from various alkyl substituted chiral diols. The method has the characteristics of high efficiency, low price and green environmental protection.

[0014] 2. The synthesis of 2,2'-[[(1S,2S)-1,2-diphenyl-1,2-ethylene-bis-iminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol successfully transforms the simple starting material 3-aminopyridine into a complex and specific target product through a series of carefully designed chemical reactions, including amino protection, chlorination, deprotection, condensation and coupling. This synthetic strategy provides an effective method for preparing organic compounds with specific structures and functions.

[0015] 3. The synthesis of 2,2'-[[(1S,2S)-1,2-diphenyl-1,2-ethylene-bis(iminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol introduces a tert-butyloxycarbonyl (Boc) protecting group to convert the active amino group into a relatively stable amide structure, thereby effectively avoiding the occurrence of these side reactions and improving the selectivity of the reaction and the purity of the product.

[0016] 4. In the synthesis of 2,2'-[[(1S,2S)-1,2-diphenyl-1,2-ethylene-bis(iminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol, the protected N-Boc-3-aminopyridine has better stability under different reaction conditions and can withstand the more severe conditions required for subsequent chlorination reactions, providing a reliable basis for subsequent synthesis steps.

[0017] 5. The synthesis of 2,2'-[[(1S,2S)-1,2-diphenyl-1,2-ethylene-bis(iminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol introduces a chlorine atom on the pyridine ring, providing an active site for subsequent nucleophilic substitution reactions. As a good leaving group, the chlorine atom can react with other nucleophilic reagents to construct a complex molecular structure of the target product.

[0018] 6. The synthesis of 2,2'-[[(1S,2S)-1,2-diphenyl-1,2-ethylene-bis(iminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol can achieve chlorination at a specific position of the pyridine ring by selecting a suitable chlorination reagent and reaction conditions to obtain a product substituted at the target position, which provides the possibility for the design of subsequent synthetic routes and the directional synthesis of products.

[0019] 7. The synthesis of 2,2'-[[(1S,2S)-1,2-diphenyl-1,2-ethylene-bis-iminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol removes the Boc protecting group to restore the activity of the amino group so that it can participate in the subsequent condensation reaction. The 2-chloro-3-aminopyridine obtained at this time has two active sites (amino group and chlorine atom), which provides the necessary conditions for building new chemical bonds. The product structure obtained after deprotection is relatively simple, which is easier to carry out subsequent reaction operations, and avoids the adverse effects of the protecting group on the subsequent reaction, such as steric hindrance. DETAILED DESCRIPTION

[0020] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0021] The synthesis of 2,2'-[[(1S,2S)-1,2-diphenyl-1,2-ethylene-bisiminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol is carried out by using 3-aminopyridine as a starting material, and undergoing amino protection, chlorination, deprotection, condensation and coupling reactions to finally synthesize the target product 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bisiminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol; Specifically include: Step 1, amino protection of 3-aminopyridine: protecting the amino group by adding a protecting agent to obtain N-Boc-3-aminopyridine; The reaction formula is: 3-aminopyridine + di-tert-butyl dicarbonate → triethylamine → N-Boc-3-aminopyridine; The specific steps are as follows: add 3-aminopyridine (10 g, 0.109 mol) and 100 mL of dichloromethane into a three-necked flask, turn on the stirrer, and completely dissolve 3-aminopyridine in dichloromethane. During this process, the solution is colorless and transparent; Under stirring conditions, slowly drop a dichloromethane solution (50 mL) of di-tert-butyl dicarbonate (24.7 g, 0.114 mol). During the dropwise addition process, the dropwise addition speed must be strictly controlled to ensure that the reaction temperature is maintained at 20-25°C. Because the reaction is an exothermic reaction, too fast a dropwise addition speed may cause a sharp rise in temperature and trigger side reactions; After the addition is complete, triethylamine (11.1 g, 0.109 mol) is added to the reaction system. Triethylamine, as a catalyst, can promote the reaction. After adding triethylamine, continue stirring the reaction for 4 hours. During the reaction, the color of the solution may gradually turn light yellow. After the reaction is completed, transfer the reaction solution to a separatory funnel. First, wash with 5% hydrochloric acid solution (2×50mL) to remove unreacted triethylamine and other alkaline impurities. At this time, stratification can be observed, with the lower layer being the organic phase and the upper layer being the aqueous phase. After separating the organic phase, wash with saturated sodium bicarbonate solution (2×50mL) to remove possible residual acidic impurities. Finally, wash with saturated brine (50mL) to reduce the moisture in the organic phase for subsequent drying. The washed organic phase was transferred to a dry conical flask and dried by adding anhydrous sodium sulfate. Anhydrous sodium sulfate can absorb the moisture in the organic phase. After standing for a period of time, the anhydrous sodium sulfate solid was removed by filtration. The filtrate was transferred to a rotary evaporator and the dichloromethane solvent was removed by vacuum distillation to obtain the crude N-Boc-3-aminopyridine. The crude product was a light yellow oily liquid; The crude product was purified by column chromatography, and a mixed solvent of petroleum ether: ethyl acetate = 3:1 was selected as the eluent. The crude product was loaded onto a silica gel column, and different components were separated in the silica gel column by the flow of the eluent. The eluate containing the target product was collected, and the eluent was removed by vacuum distillation to obtain white solid N-Boc-3-aminopyridine with a yield of 18.5 g and a yield of 85%.

[0022] Step 2, chlorination reaction of N-Boc-3-aminopyridine: Under the action of a suitable chlorination reagent, an electrophilic substitution reaction will occur at the ortho or para position of the 3-amino group on the pyridine ring to introduce a chlorine atom to obtain a crude N-Boc-2-chloro-3-aminopyridine; The reaction formula is: N-Boc-3-aminopyridine + N-chlorosuccinimide → azobisisobutyronitrile, carbon tetrachloride → N-Boc-2-chloro-3-aminopyridine; The specific steps are as follows: in a dry reaction bottle, dissolve N-Boc-3-aminopyridine in an appropriate amount of solvent such as toluene or dichloromethane, then slowly drop phosphorus oxychloride, and after the dropwise addition is completed, stir and react at a certain temperature for several hours, and the reaction temperature is between 50-100°C; After the reaction is completed, the reaction solution is slowly poured into ice water for hydrolysis to decompose the excess phosphorus oxychloride, and then the product is extracted with an organic solvent such as ethyl acetate. The organic phase is washed with water, saturated sodium bicarbonate solution and saturated brine in sequence, dried and concentrated to obtain the chlorinated product N-Boc-2-chloro-3-aminopyridine.

[0023] Step 3, deprotection reaction of N-Boc-2-chloro-3-aminopyridine: hydrochloric acid reacts with the Boc group in N-Boc-2-chloro-3-aminopyridine to remove it, generating 2-chloro-3-aminopyridine hydrochloride, and then alkalizing to obtain free 2-chloro-3-aminopyridine; The reaction formula is: N-Boc-2-chloro-3-aminopyridine + hydrochloric acid → dioxane → 2-chloro-3-aminopyridine; The specific steps are: adding N-Boc-2-chloro-3-aminopyridine into a reaction bottle, then adding an appropriate amount of dioxane as a solvent, then passing dry hydrogen chloride gas or adding a dioxane solution of hydrochloric acid dropwise, and stirring the reaction at room temperature for several hours; After the reaction is completed, dioxane is first distilled off under reduced pressure, and then an appropriate amount of water is added to dissolve the product, and then the pH is adjusted to alkaline with alkali solution to free 2-chloro-3-aminopyridine, and finally extracted with an organic solvent, dried, and concentrated to obtain the target product 2-chloro-3-aminopyridine.

[0024] Step 4: Condensation reaction of 2-chloro-3-aminopyridine and (1S,2S)-1,2-diphenyl-1,2-ethylenediamine: In the presence of a base, the lone pair of electrons on the amino nitrogen atom of (1S,2S)-1,2-diphenyl-1,2-ethylenediamine is nucleophilic and will attack the carbon atom connected to the chlorine atom in 2-chloro-3-aminopyridine, resulting in a nucleophilic substitution reaction. The chlorine atom leaves as a leaving group, thereby forming a carbon-nitrogen bond and achieving a condensation reaction; The reaction formula is: 2-Chloro-3-aminopyridine + (1S,2S)-1,2-diphenyl-1,2-ethylenediamine → potassium carbonate, ethanol → 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylenediamine-bis-iminoethyl)]-bipyridine dichloride; The specific steps are as follows: 2-chloro-3-aminopyridine (8.5 g, 0.061 mol), (1S,2S)-1,2-diphenyl-1,2-ethylenediamine (5.8 g, 0.029 mol), potassium carbonate (16.8 g, 0.122 mol) and 100 mL of ethanol were added to a 250 mL three-necked flask equipped with a stirrer, a thermometer and a reflux condenser, and heated to reflux for reaction for 12 h; After the reaction, the mixture was cooled to room temperature, insoluble matter was removed by filtration, ethanol was removed by distillation under reduced pressure from the filtrate, water (50 mL) was added to the residue, and the mixture was extracted with dichloromethane (3×50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain 12.5 g of a yellow solid with a yield of 78%.

[0025] Step 5, coupling reaction with 6-tert-butylphenol: In the presence of a base and a palladium catalyst, the chlorine atom on the pyridine ring in 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bisiminoethyl)]-bipyridine dichloride first undergoes an oxidative addition reaction with the palladium catalyst to form a palladium intermediate, and then, 6-tert-butylphenol forms a phenol oxide anion under the action of a base, and the phenol oxide anion undergoes a metal transfer reaction with the palladium intermediate to generate a new intermediate, and finally, after a reduction elimination step, a carbon-oxygen bond is formed to obtain the target product 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bisiminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol; The reaction formula is: 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bis-iminoethyl)]-bipyridine dichloride + 6-tert-butylphenol → tetrakis(triphenylphosphine)palladium, potassium carbonate, toluene → 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bis-iminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol; The specific steps are as follows: 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bis(iminoethyl)]-bipyridine dichloride (12.5 g, 0.023 mol), 6-tert-butylphenol (7.8 g, 0.046 mol), potassium carbonate (12.7 g, 0.092 mol), tetrakis(triphenylphosphine)palladium (0.8 g, 0.0007 mol) and 150 mL of toluene are added to a 250 mL three-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a nitrogen inlet tube, and heated under reflux for reaction for 24 h under nitrogen protection; After the reaction, the mixture was cooled to room temperature and the insoluble matter was removed by filtration. The filtrate was washed with dilute hydrochloric acid (2×50 mL) and then with water (2×50 mL). The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The mixture was purified by column chromatography to obtain 10.2 g of a white solid with a yield of 60%.

[0026] Silica gel column was selected as stationary phase, and a mixed solvent of petroleum ether:ethyl acetate = 5:1 was used as eluent; The crude product was loaded onto a silica gel column, and the target product was separated from the impurities by the flow of the eluent. The eluent containing the target product was collected, and the eluent was removed by distillation under reduced pressure to obtain a white solid 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylidene-bisiminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol.

[0027] Comparison table of traditional technology and simple synthesis process Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A process for synthesizing high-purity 2,2'-[[(1S,2S)-1,2 - (-) - 1,2 - (-)]-bis[6-(1,1 - (-)]phenol, characterized in that: Using 3-aminopyridine as the starting material, the target product 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bisiminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol is finally synthesized through amino protection, chlorination, deprotection, condensation and coupling reactions; Specifically include: Step 1, amino protection of 3-aminopyridine: protecting the amino group by adding a protecting agent to obtain N-Boc-3-aminopyridine; Step 2, chlorination reaction of N-Boc-3-aminopyridine: Under the action of a suitable chlorination reagent, an electrophilic substitution reaction will occur at the ortho or para position of the 3-amino group on the pyridine ring to introduce a chlorine atom to obtain a crude N-Boc-2-chloro-3-aminopyridine; Step 3, deprotection reaction of N-Boc-2-chloro-3-aminopyridine: hydrochloric acid reacts with the Boc group in N-Boc-2-chloro-3-aminopyridine to remove it, generating 2-chloro-3-aminopyridine hydrochloride, and then alkalizing to obtain free 2-chloro-3-aminopyridine; Step 4: Condensation reaction of 2-chloro-3-aminopyridine and (1S,2S)-1,2-diphenyl-1,2-ethylenediamine: In the presence of a base, the lone pair of electrons on the amino nitrogen atom of (1S,2S)-1,2-diphenyl-1,2-ethylenediamine is nucleophilic and will attack the carbon atom connected to the chlorine atom in 2-chloro-3-aminopyridine, resulting in a nucleophilic substitution reaction. The chlorine atom leaves as a leaving group, thereby forming a carbon-nitrogen bond and achieving a condensation reaction; Step 5. Coupling reaction with 6-tert-butylphenol: In the presence of a base and a palladium catalyst, the chlorine atom on the pyridine ring in 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bisiminoethyl)]-bipyridine dichloride first undergoes an oxidative addition reaction with the palladium catalyst to form a palladium intermediate. Then, 6-tert-butylphenol forms a phenol oxide anion under the action of a base. The phenol oxide anion undergoes a metal transfer reaction with the palladium intermediate to generate a new intermediate. Finally, after a reduction elimination step, a carbon-oxygen bond is formed to obtain the target product 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bisiminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol.

2. The synthesis process of high-purity 2,2'-[[(1S,2S)-1,2 - (-) - 1,2 - (-)]-bis[6-(1,1 - (-)]phenol according to claim 1, characterized in that: The reaction formula of step 1 is: 3-aminopyridine + di-tert-butyl dicarbonate → triethylamine → N-Boc-3-aminopyridine; The specific steps are as follows: add 3-aminopyridine (10 g, 0.109 mol) and 100 mL of dichloromethane into a three-necked flask, turn on the stirrer, and allow 3-aminopyridine to completely dissolve in dichloromethane. During this process, the solution is colorless and transparent; Under stirring conditions, slowly add di-tert-butyl dicarbonate (24.7 g, 0.114 mol) in dichloromethane (50 mL). During the addition process, the drop rate must be strictly controlled to ensure that the reaction temperature is maintained at 20-25°C. Because the reaction is an exothermic reaction, too fast a drop rate may cause a sharp rise in temperature and trigger side reactions; After the addition is complete, triethylamine (11.1 g, 0.109 mol) is added to the reaction system. Triethylamine, as a catalyst, can promote the reaction. After adding triethylamine, continue to stir the reaction for 4 hours. During the reaction, the color of the solution may gradually turn light yellow. After the reaction is completed, the reaction solution is transferred to a separatory funnel and first washed with 5% hydrochloric acid solution (2×50 mL) to remove unreacted triethylamine. At this time, stratification can be observed, with the lower layer being the organic phase and the upper layer being the aqueous phase. After the organic phase is separated, it is then washed with saturated sodium bicarbonate solution (2×50 mL) to remove possible residual acidic impurities, and finally washed with saturated brine (50 mL) to reduce the moisture in the organic phase for subsequent drying. The washed organic phase was transferred to a dry conical flask, and anhydrous sodium sulfate was added for drying. The anhydrous sodium sulfate can absorb the moisture in the organic phase. After standing for a period of time, the anhydrous sodium sulfate solid was removed by filtration. The filtrate was transferred to a rotary evaporator, and the dichloromethane solvent was removed by vacuum distillation to obtain a crude N-Boc-3-aminopyridine product, which was a light yellow oily liquid. The crude product was purified by column chromatography, and a mixed solvent of petroleum ether: ethyl acetate = 3:1 was selected as the eluent. The crude product was loaded onto a silica gel column. Different components were separated in the silica gel column by the flow of the eluent. The eluate containing the target product was collected, and the eluent was removed by distillation under reduced pressure to obtain white solid N-Boc-3-aminopyridine with a yield of 18.5 g and a yield of 85%.

3. The synthesis process of high-purity 2,2'-[[(1S,2S)-1,2 - (-) - 1,2 - (-)]-bis[6-(1,1 - (-)]phenol according to claim 1, characterized in that: The reaction formula of step 2 is: N-Boc-3-aminopyridine + N-chlorosuccinimide → azobisisobutyronitrile, carbon tetrachloride → N-Boc-2-chloro-3-aminopyridine; The specific steps are as follows: in a dry reaction bottle, dissolve N-Boc-3-aminopyridine in an appropriate amount of solvent such as toluene or dichloromethane, then slowly drop phosphorus oxychloride, and after the dropwise addition is completed, stir and react at a certain temperature for several hours, and the reaction temperature is between 50-100°C; After the reaction is completed, the reaction solution is slowly poured into ice water for hydrolysis to decompose the excess phosphorus oxychloride, and then the product is extracted with an organic solvent such as ethyl acetate. The organic phase is washed with water, saturated sodium bicarbonate solution and saturated brine in sequence, dried and concentrated to obtain the chlorinated product N-Boc-2-chloro-3-aminopyridine.

4. The synthesis process of high-purity 2,2'-[[(1S,2S)-1,2 - (-) - 1,2 - (-)]-bis[6-(1,1 - (-)]phenol according to claim 1, characterized in that: The reaction formula of step three is: N-Boc-2-chloro-3-aminopyridine+hydrochloric acid→dioxane→2-chloro-3-aminopyridine; The specific steps are: adding N-Boc-2-chloro-3-aminopyridine into a reaction bottle, then adding an appropriate amount of dioxane as a solvent, then passing dry hydrogen chloride gas or adding a dioxane solution of hydrochloric acid dropwise, and stirring the reaction at room temperature for several hours; After the reaction is completed, dioxane is first distilled off under reduced pressure, and then an appropriate amount of water is added to dissolve the product, and then the pH is adjusted to alkaline with alkali solution to free 2-chloro-3-aminopyridine, and finally extracted with an organic solvent, dried, and concentrated to obtain the target product 2-chloro-3-aminopyridine.

5. The process for synthesizing high-purity 2,2'-[[(1S,2S)-1,2 - (-) - 1,2 - (-)]-bis[6-(1,1 - (-)]phenol according to claim 1, characterized in that: The reaction formula of step 4 is: 2-chloro-3-aminopyridine+(1S,2S)-1,2-diphenyl-1,2-ethylenediamine→potassium carbonate, ethanol→2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bisiminoethyl)]-bipyridine dichloride; The specific steps are as follows: 2-chloro-3-aminopyridine (8.5 g, 0.061 mol), (1S,2S)-1,2-diphenyl-1,2-ethylenediamine (5.8 g, 0.029 mol), potassium carbonate (16.8 g, 0.122 mol) and 100 mL of ethanol were added to a 250 mL three-necked flask equipped with a stirrer, a thermometer and a reflux condenser, and heated to reflux for reaction for 12 h; After the reaction, the mixture was cooled to room temperature, insoluble matter was removed by filtration, ethanol was removed by distillation under reduced pressure from the filtrate, water (50 mL) was added to the residue, and the mixture was extracted with dichloromethane (3×50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain 12.5 g of a yellow solid with a yield of 78%.

6. The process for synthesizing high-purity 2,2'-[[(1S,2S)-1,2 - (-) - 1,2 - (-)]-bis[6-(1,1 - (-)]phenol according to claim 1, characterized in that: The reaction formula of step 5 is: 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bisiminoethyl)]-bipyridine dichloride + 6-tert-butylphenol → tetrakis(triphenylphosphine)palladium, potassium carbonate, toluene → 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bisiminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol; The specific steps are as follows: 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bis(iminoethyl)]-bipyridine dichloride (12.5 g, 0.023 mol), 6-tert-butylphenol (7.8 g, 0.046 mol), potassium carbonate (12.7 g, 0.092 mol), tetrakis(triphenylphosphine)palladium (0.8 g, 0.0007 mol) and 150 mL of toluene are added to a 250 mL three-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a nitrogen inlet tube, and heated under reflux for reaction for 24 h under nitrogen protection; After the reaction, the mixture was cooled to room temperature and the insoluble matter was removed by filtration. The filtrate was washed with dilute hydrochloric acid (2×50 mL) and then with water (2×50 mL). The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The mixture was purified by column chromatography to obtain 10.2 g of a white solid with a yield of 60%.

7. The process for synthesizing high-purity 2,2'-[[(1S,2S)-1,2 - (-) - 1,2 - (-)]-bis[6-(1,1 - (-)]phenol according to claim 6, characterized in that: In the column chromatography purification reaction in step 5, a silica gel column is selected as the stationary phase, and a mixed solvent of petroleum ether: ethyl acetate = 5:1 is used as the eluent; The crude product is loaded onto a silica gel column, and the target product is separated from the impurities by the flow of the eluent; the eluate containing the target product is collected, and the eluent is removed by distillation under reduced pressure to obtain a white solid 2,2'-[((1S,2S)-1,2-diphenyl-1,2-ethylene-bisiminoethyl)]-bis[6-(1,1-dimethylethyl)]phenol.