Chiral 2, 15-dihydroxy tetrabenzocyclooctadiene and preparation method thereof

Abstract

The invention provides chiral 2, 15-dihydroxy tetrabenzocyclooctadiene and a preparation method thereof, and belongs to the technical field of organic compounds and synthesis. The method comprises the following steps: separating 2, 15-dihydroxy tetrabenzocyclooctadiene by utilizing a chiral preparative column through high performance liquid chromatography, and then confirming by utilizing a chiral reagent to obtain optical isomers (S)-2, 15-dihydroxy tetrabenzocyclooctadiene and (R)-2, 15-dihydroxy tetrabenzocyclooctadiene, namely, the (S)-2, 15-dihydroxy tetrabenzocyclooctadiene and the (R)-2, 15-dihydroxy tetrabenzocyclooctadiene and the (R)-2, 15-dihydroxy tetrabenzocyclooctadiene; the chiral reagent comprises one of (+)-(S)-10-camphor sulfonyl chloride, (-)-(R)-10-camphor sulfonyl chloride, (+)-menthyl chloroformate, (-)-menthyl chloroformate, (R)-(+)-alpha-methylbenzylamine and (S)-(-)-alpha-methylbenzylamine. The preparation method disclosed by the invention is simple, mild in reaction condition, easy to obtain reaction raw materials or precursors, convenient to separate and purify and high in yield, and has very practical value.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic compounds and synthesis, and particularly relates to a chiral 2,15-dihydroxytetraphenylene and a preparation method thereof. BACKGROUND

[0002] Tetraphenylene is a polycyclic aromatic hydrocarbon with a unique saddle-shaped structure. It has attracted extensive attention due to its unique stereostructure and potential application prospects. In recent years, tetraphenylene derivatives have been well applied in asymmetric catalysis, supramolecular chemistry, liquid crystal materials, chiral helical molecules, molecular devices, organic light-emitting diodes, and covalent organic frameworks. In order to study the special properties of tetraphenylene and its derivatives and develop their potential application value, it is necessary to develop high-regioselective functionalization methods for synthesizing tetraphenylene, so as to synthesize more tetraphenylene derivatives.

[0003] Polyhydroxytetraphenylene is a derivative formed by introducing multiple hydroxyl functional groups into the tetraphenylene skeleton. The introduction of hydroxyl groups can significantly change the polarity and physical and chemical properties of the molecule. At the same time, the easy modification of hydroxyl groups also gives them more application potential, thereby expanding their applications in the fields of asymmetric catalysis, materials science, and drug chemistry, attracting more and more attention from chemists. For example, 1,16-dihydroxytetraphenylene has been widely used in asymmetric catalysis, supramolecular self-assembly, molecular recognition, chiral helical molecules, and liquid crystal materials.

[0004] Currently, the synthesis methods of tetraphenylene mainly include multi-step transition metal (such as palladium or nickel) catalyzed aromatic coupling reaction and cyclization reaction. The synthesis of polyhydroxytetraphenylene involves introducing the corresponding hydroxyl precursor on the raw material in advance and then reacting on the basis of synthesizing tetraphenylene. This process requires precise control of reaction conditions to avoid unnecessary side reactions and ensure that the introduction position and number of hydroxyl groups meet the design requirements. In order to improve the yield and purity, researchers continue to optimize the reaction conditions and post-processing process. Although the synthesis of tetraphenylene and polyhydroxytetraphenylene has made some progress, there are still many challenges to be overcome. For example, how to further improve the synthesis efficiency and product purity, how to more accurately control the introduction position and number of substituents (such as hydroxyl groups) to meet the design requirements, how to synthesize optically pure single enantiomers, and how to explore more novel application fields. Future research will pay more attention to interdisciplinary cooperation, combining knowledge from computational chemistry, materials science, and biology, to promote the overall development of these compounds.

[0005] 2,15-dihydroxytetraphenylcyclooctatetraene has a unique spatial orientation due to its saddle-shaped spatial configuration and the substitution position of the two hydroxyl groups, and is an excellent skeleton for designing chiral macrocyclic molecules and chiral ligands / catalysts. Although the synthesis of 2,15-dihydroxytetraphenylcyclooctatetraene has been reported in the literature, the existing methods have the disadvantages of poor regioselectivity, difficulty in separating isomers and extremely low yield, and the existing methods only involve the synthesis of the racemate thereof, and the preparation of the optically pure enantiomers thereof which are more valuable in application has not been reported in the literature so far. Therefore, in order to study the special properties of 2,15-dihydroxytetraphenylcyclooctatetraene and its derivatives and the potential application prospect thereof, it is urgent to find a simple and efficient method to synthesize 2,15-dihydroxytetraphenylcyclooctatetraene and its optically pure enantiomers. SUMMARY

[0006] The present application aims to solve the problem that chiral 2,15-dihydroxytetraphenylcyclooctatetraene lacks an efficient and simple synthesis method, making it difficult to prepare optically pure enantiomers (S)-2,15-dihydroxytetraphenylcyclooctatetraene and (R)-2,15-dihydroxytetraphenylcyclooctatetraene, which has not been reported in the literature so far, seriously hindering the in-depth application of chiral 2,15-dihydroxytetraphenylcyclooctatetraene in the fields of asymmetric catalysis, supramolecular chemistry and material science. Therefore, the present application proposes a chiral 2,15-dihydroxytetraphenylcyclooctatetraene and a preparation method thereof.

[0007] The chiral 2,15-dihydroxytetraphenylcyclooctatetraene of the present application has the following formula I structure, and the optically active isomers (S)-2,15-dihydroxytetraphenylcyclooctatetraene and (R)-2,15-dihydroxytetraphenylcyclooctatetraene prepared by the preparation method of the present application have hydroxyl substituents at positions -2 and -15, and have the following formula (S)-I or (R)-I structure:

[0008]

[0009] To achieve the above-mentioned purpose, the present application provides the following technical solutions:

[0010] This invention proposes a method for preparing chiral 2,15-dihydroxytetrabenzocyclooctatetraene, comprising the following steps: chiral resolution of 2,15-dihydroxytetrabenzocyclooctatetraene to obtain optical isomers (S)-2,15-dihydroxytetrabenzocyclooctatetraene and (R)-2,15-dihydroxytetrabenzocyclooctatetraene; wherein, the chiral resolution process includes separation by high-performance liquid chromatography using a chiral preparative column, followed by chiral assay... The reagent confirmed the availability of the optical isomers (S)-2,15-dihydroxytetrabenzocyclooctatetraene and (R)-2,15-dihydroxytetrabenzocyclooctatetraene; the chiral reagent includes one of (+)-(S)-10-camphorsulfonyl chloride, (-)-(R)-10-camphorsulfonyl chloride, (+)-menthol chloroformate, (-)-menthol chloroformate, (R)-(+)-α-methylbenzylamine, and (S)-(-)-α-methylbenzylamine. Preferably, the chiral reagent is (+)-(S)-10-camphorsulfonyl chloride.

[0011] Furthermore, the preparation method of the 2,15-dihydroxytetrabenzocyclooctateteene includes the following steps:

[0012] Liquid bromine is mixed with 3,3'-dimethoxy-1,1'-biphenyl to undergo a bromination reaction, producing 2,2'-dibromo-5,5'-dimethoxy-1,1'-biphenyl;

[0013] After mixing n-butyllithium with the 2,2'-dibromo-5,5'-dimethoxy-1,1'-biphenyl and reacting with it to form a lithium, elemental iodine is added to generate 2,2'-diiodo-5,5'-dimethoxy-1,1'-biphenyl.

[0014] The 2,2'-diiodo-5,5'-dimethoxy-1,1'-biphenyl and 2,2'-diboronic anhydride-1,1'-biphenyl were mixed under palladium catalysis to undergo a Suzuki coupling reaction to construct an eight-membered ring structure and generate 2,15-dimethoxytetrabenzocyclooctatetraene.

[0015] The 2,15-dimethoxytetrabenzocyclooctatetraene was mixed with boron tribromide and subjected to a methyl removal reaction to generate 2,15-dihydroxytetrabenzocyclooctatetraene.

[0016] Furthermore, in the bromination reaction, the molar ratio of liquid bromine to 3,3'-dimethoxy-1,1'-biphenyl is 29:13.

[0017] Furthermore, the molar ratio of n-butyllithium, 2,2'-dibromo-5,5'-dimethoxy-1,1'-biphenyl to elemental iodine is 3:1:3.

[0018] Furthermore, the lithiation reaction is carried out at a temperature of -78°C for 3 hours.

[0019] Further, the palladium catalyst for the palladium catalysis includes at least one of Pd(OAc)2, PdCl2, Pd(PPh3)2Cl2, Pd(dppf)Cl2, Pd(dppb)Cl2, Pd(dppp)Cl2, Pd(PPh3)4, Pd2(dba)3 and Pd(dba)2. As a preferred, the palladium catalyst for the palladium catalysis is Pd(OAc)2, and forms a catalytic system with PPh3 (triphenylphosphine).

[0020] Further, in the Suzuki coupling reaction, the molar ratio of 2,2’-diiodo-5,5’-dimethoxy-1,1’-biphenyl and 2,2’-diboronic acid anhydride-1,1’-biphenyl is 27:32.2, the reaction temperature of the Suzuki coupling reaction is 90℃, and the reaction time is 36 hours.

[0021] Further, the methyl removal reaction is to dissolve 2,15-dimethoxy-tetraphenylcyclooctatetraene in dichloromethane, then add a dichloromethane solution of boron tribromide at 0℃, and stir at room temperature overnight.

[0022] Further, the concentration of the dichloromethane solution of boron tribromide is 1M, and the dosage ratio of 2,15-dimethoxy-tetraphenylcyclooctatetraene to the dichloromethane solution of boron tribromide is 1mmol:10mL.

[0023] Further, the present application provides a preparation method of chiral 2,15-dihydroxy-tetraphenylcyclooctatetraene, which specifically comprises the following steps:

[0024] (1) Preparation of 2,2’-dibromo-5,5’-dimethoxy-1,1’-biphenyl

[0025] The bromination reaction occurs when liquid bromine (Br2) is mixed with 3,3’-dimethoxy-1,1’-biphenyl (Formula 1) to generate 2,2’-dibromo-5,5’-dimethoxy-1,1’-biphenyl (Formula 2), which is then separated and purified, and the reaction process is as follows:

[0026]

[0027] (2) Preparation of 2,2’-diiodo-5,5’-dimethoxy-1,1’-biphenyl

[0028] The lithiation reaction occurs when the 2,2’-dibromo-5,5’-dimethoxy-1,1’-biphenyl (Formula 2) is dissolved in tetrahydrofuran (THF) at -78℃, then mixed with n-butyllithium (n-BuLi), and then added with elemental iodine (I2), to generate 2,2’-diiodo-5,5’-dimethoxy-1,1’-biphenyl (Formula 3), which is then separated and purified, and the reaction process is as follows:

[0029]

[0030] (3) Preparation of 2, 15-dimethoxy-tetraphenylcyclooctatetraene

[0031] Suzuki coupling reaction of 2, 2'-diiodo-5, 5'-dimethoxy-1, 1'-biphenyl (Formula 3) and 2, 2'-diboronic anhydride-1, 1'-biphenyl (Formula 4) under palladium catalysis to construct an eight-membered ring structure to generate 2, 15-dimethoxy-tetraphenylcyclooctatetraene (Formula 5), and separation and purification, the reaction process is as follows:

[0032]

[0033] (4) Preparation of 2, 15-dihydroxy-tetraphenylcyclooctatetraene

[0034] Methyl removal reaction of 2, 15-dimethoxy-tetraphenylcyclooctatetraene (Formula 5) dissolved in dichloromethane (CH2Cl2) and mixed with boron tribromide (BBr3) to generate 2, 15-dihydroxy-tetraphenylcyclooctatetraene (Formula I), and separation and purification, the reaction process is as follows:

[0035]

[0036] (5) Chiral resolution of 2, 15-dihydroxy-tetraphenylcyclooctatetraene

[0037] Chiral resolution of 2, 15-dihydroxy-tetraphenylcyclooctatetraene (Formula I) is separated by high performance liquid chromatography using a chiral preparation column, and then chiral reagents are used to confirm that optically active isomers (S)-2, 15-dihydroxy-tetraphenylcyclooctatetraene and (R)-2, 15-dihydroxy-tetraphenylcyclooctatetraene are obtained, the reaction process is as follows:

[0038]

[0039] Compared with the prior art, the present application has the following advantages and technical effects:

[0040] The application provides a method for simply and efficiently preparing optically pure chiral 2,15-dihydroxytetraphenylcyclooctatetraene, and can quickly resolve (S)-2,15-dihydroxytetraphenylcyclooctatetraene and (R)-2,15-dihydroxytetraphenylcyclooctatetraene, and solves the technical problem that the 2,15-dihydroxytetraphenylcyclooctatetraene is difficult to prepare. The optically pure (S)-2,15-dihydroxytetraphenylcyclooctatetraene and (R)-2,15-dihydroxytetraphenylcyclooctatetraene provided by the application have a unique stereo configuration, the hydroxyl group has excellent functional group conversion capability, and are expected to be widely applied in the fields of asymmetric catalysis, supramolecular chemistry and material science, and have important significance for promoting the application of chiral tetraphenylcyclooctatetraene compounds. In addition, the preparation method is simple, the reaction conditions are mild, the raw materials or precursors are easy to obtain, the separation and purification are convenient, the yield is high, and the method has very practical value. BRIEF DESCRIPTION OF DRAWINGS

[0041] The accompanying drawings, which form a part of the present application, are used to provide further understanding of the present application, and serve as an explanation of the illustrative embodiments of the present application, and do not constitute improper limitations to the present application. In the drawings:

[0042] Figure 1 A flow chart for preparing (S)-2,15-dihydroxytetraphenylcyclooctatetraene and (R)-2,15-dihydroxytetraphenylcyclooctatetraene from 5,5'-dimethoxy-1,1'-biphenyl as a starting material in the present application;

[0043] Figure 2 A nuclear magnetic hydrogen spectrum of 2,15-dimethoxytetraphenylcyclooctatetraene prepared in Example 3;

[0044] Figure 3 A nuclear magnetic carbon spectrum of 2,15-dimethoxytetraphenylcyclooctatetraene prepared in Example 3;

[0045] Figure 4 A nuclear magnetic hydrogen spectrum of 2,15-dihydroxytetraphenylcyclooctatetraene prepared in Example 4;

[0046] Figure 5 A nuclear magnetic carbon spectrum of 2,15-dihydroxytetraphenylcyclooctatetraene prepared in Example 4;

[0047] Figure 6 A chiral resolution flow chart of 2,15-dihydroxytetraphenylcyclooctatetraene in Example 5;

[0048] Figure 7 An HPLC spectrum determination result of (S)-2,15-dihydroxytetraphenylcyclooctatetraene;

[0049] Figure 8 An HPLC spectrum determination result of (R)-2,15-dihydroxytetraphenylcyclooctatetraene;

[0050] Figure 9 Circular dichroism curves for (S)-2, 15-dihydroxytetraphenylcyclooctatetraene and (R)-2, 15-dihydroxytetraphenylcyclooctatetraene. DETAILED DESCRIPTION

[0051] The following detailed description of various example embodiments of the application will not be considered to limit the application to these specific embodiments but rather to provide a more thorough description of the various aspects, features and embodiments of the application.

[0052] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. In addition, where particular ranges of values are given, understand that each intervening value, to the upper or lower limit of the ranges is also specifically included. Each smaller range that falls within the broader ranges is also specifically included. The upper and lower limits of these smaller ranges can independently be included or excluded in the range, and are also encompassed within the application, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of the limits are also included.

[0053] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although preferred methods and materials are described, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application. All documents mentioned herein are incorporated by reference to disclose and describe the methods and / or materials in connection with which the documents are cited. In case of conflict, the present specification will control.

[0054] Various modifications and changes can be made to the specific embodiments of the application described herein without departing from the scope or spirit of the application. Other embodiments of the application will be apparent to those of ordinary skill in the art from the description and examples presented herein. The description and examples are illustrative of the application and are not intended to limit the scope of the application.

[0055] As used herein, the terms "comprise", "comprising", "include", "including", "have", "having" and the like are open-ended and do not exclude additional elements or steps.

[0056] Embodiments of the present application, with 5,5'-dimethoxy-1,1'-biphenyl as starting material, bromination reaction with liquid bromine, 2,2'-dibromo-5,5'-dimethoxy-1,1'-biphenyl is generated, and then the key intermediate 2,2'-diiodo-5,5'-dimethoxy-1,1'-biphenyl is prepared. The eight-membered ring structure is constructed by Suzuki coupling reaction of 2,2'-diiodo-5,5'-dimethoxy-1,1'-biphenyl and 2,2'-diboric anhydride-1,1'-biphenyl, and 2,15-dimethoxy-tetraphenylcyclooctatetraene is prepared efficiently and accurately. This step avoids the problem of difficult separation of isomers in the old method, solves the purification problem of the compound and improves the yield. Subsequently, 2,15-dimethoxy-tetraphenylcyclooctatetraene is subjected to demethylation reaction to obtain 2,15-dihydroxy-tetraphenylcyclooctatetraene racemate, and then optical pure (S)-2,15-dihydroxy-tetraphenylcyclooctatetraene and (R)-2,15-dihydroxy-tetraphenylcyclooctatetraene are obtained by chiral resolution operation, respectively. The detailed preparation flow chart is shown in Figure 1 .

[0057] In the embodiments of the present application, all raw materials are commercially available.

[0058] In the embodiments of the present application, room temperature refers to "25±3℃".

[0059] The technical solutions of the present application are further illustrated by the following examples.

[0060] Example 1

[0061] 2,2'-dibromo-5,5'-dimethoxy-1,1'-biphenyl is prepared, including the following steps:

[0062] 3,3'-dimethoxy-1,1'-biphenyl (Formula 1) (14.0 g, 65.0 mmol) is dissolved in 210 mL of acetic acid (AcOH), liquid bromine (Br2) (7.5 mL, 145.0 mmol) is slowly added at room temperature, after stirring for 2 hours, saturated sodium sulfite aqueous solution (40 mL) is added to the reaction system, then stirring is continued for 30 min, then the crude product is extracted with chloroform, the organic layers obtained by multiple extractions are combined, anhydrous sodium sulfate is added for drying treatment, after drying is completed, the organic layer is concentrated by reduced pressure distillation, and the concentrated crude product is purified by ethanol washing to obtain white solid product (15.7 g, yield 65%), and the reaction flow chart is as follows:

[0063]

[0064] 1H NMR (600 MHz, CHCI3) δ 7.53 (d, J = 8.8 Hz, 1 H), 6.83 (dd, J = 8.8, 3.1 Hz, 1 H), 6.79 (d, J = 3.1 Hz, 1 H), 3.81 (s, 3 H). 13 C NMR (125 MHz, CDCI3) δ 158.6, 142.7, 133.2, 116.3, 115.5, 113.8, 55.6.

[0065] The white solid product obtained in Example 1 was 2,2'-dibromo-5,5'-dimethoxy-1,1'- biphenyl.

[0066] Example 2

[0067] Preparation of 2,2'-diiodo-5,5'-dimethoxy-1,1'-biphenyl, comprising the steps of:

[0068] At -78°C, 2,2'-dibromo-5,5'-dimethoxy-1,1'-biphenyl (Formula 2, 16.3 g, 43.8 mmol) prepared in Example 1 was dissolved in 200 mL of tetrahydrofuran (THF), and then n-butyllithium (n-BuLi, 55 mL, 131.4 mmol) was slowly added dropwise to the solution. After the addition was completed, the reaction temperature was maintained at -78°C, and the reaction system was continuously stirred for 3 hours. Subsequently, elemental iodine (I2) (34.0 g, 131.4 mmol) was dissolved in 50 mL of tetrahydrofuran solution and added to the above reaction system. After the addition was completed, the temperature of the reaction system was gradually increased to room temperature and continuously stirred for 2 hours. A saturated ammonium chloride solution (80 mL) was added to the reaction system, and then extracted with ethyl acetate. The organic layers were combined, washed with a sodium thiosulfate solution, and then dried with anhydrous sodium sulfate. After drying, the organic solution was filtered to remove the drying agent anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to remove most of the solvent. Finally, the concentrated product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 6 / 1, volume ratio), and the purified product was recrystallized with ethyl acetate to obtain a white solid of the pure product (14.3 g, yield 70%).

[0069]

[0070] 1 H NMR (500 MHz, CHCI3): δ 7.68 (d, J = 9.0 Hz, 1 H), 6.76 (d, J = 3.0 Hz, 1 H), 6.69 (dd, J = 5.5, 3.0 Hz, 1 H), 3.81 (s, 3 H). 13C NMR (125 MHz, CDC13) δ 159.8, 149.7, 139.6, 116.0, 115.7, 88.0, 55.6.

[0071] The pure product obtained in Example 2 as a white solid was 2,2'-diiodo-5,5'-dimethoxy-1,1'-biphenyl.

[0072] Example 3

[0073] The preparation of 2,15-dimethoxy-tetraphenocyclooctatetraene included the following steps:

[0074] The 2,2'-diiodo-5,5'-dimethoxy-1,1'-biphenyl (Formula 3, 12.6 g, 27.0 mmol) prepared in Example 2, 2,2'-diboronic anhydride-1,1'-biphenyl (7.2 g, 32.2 mmol), potassium carbonate (28.0 g, 202.5 mmol), Pd(OAc)2(380 mg, 1.7 mmol), and PPh3(2.7 g, 10.1 mmol) were dissolved in a mixed solvent of 1,4-dioxane (300 mL) and water (60 mL), and then the flask was frozen in liquid nitrogen, and argon was exchanged 6 times under vacuum. Subsequently, the reaction mixture was heated and stirred at 90°C for 36 hours, after the reaction was completed, the reaction mixture was cooled to room temperature, and 100 mL of brine was added for dilution, followed by the addition of dichloromethane for multiple extractions, the organic layers were combined, washed with brine, dried with anhydrous sodium sulfate, and after drying was completed, the organic layer was concentrated by reduced pressure distillation. The crude product was purified by silica gel column chromatography (eluent: n-hexane / dichloromethane = 2 / 1, volume ratio) to obtain a white solid product (3.6 g, yield 37%), and the reaction scheme is as follows:

[0075]

[0076] 1 H NMR (400 MHz, CHCl3): δ 7.28-7.25 (m, 2H), 7.15-7.13 (m, 2H), 7.07 (d, J = 8.4 Hz, 1H), 6.82 (dd, J = 5.7, 2.7 Hz, 1H), 6.72 (d, J = 2.6 Hz, 1H), 3.76 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 158.5, 142.6, 141.9, 141.2, 134.2, 130.2, 129.3, 129.0, 127.1, 127.0, 114.2, 113.0, 55.2. HRMS (ESI) m / z calcd for C 26 H21 O2[M+H] + 365.1536, found 365.1534.

[0077] The white solid product obtained in Example 3 is 2,15-dimethoxy-tetraphenylcyclooctetraene. The1H NMR and13C NMR spectra of 2,15-dimethoxy-tetraphenylcyclooctetraene (Formula 5) obtained in Example 3 are shown in Figures 1 and 2, respectively. Figure 2 and Figure 3 .

[0078] Example 4

[0079] 2,15-dihydroxy-tetraphenylcyclooctetraene was prepared by the following steps:

[0080] The 2,15-dimethoxy-tetraphenylcyclooctetraene (Formula 5, 5.9 g, 16 mmol) prepared in Example 3 was dissolved in 400 mL of dichloromethane (CH2Cl2), and then a solution of BBr3in dichloromethane (160 mL, 1.0 M) was slowly added at 0 °C. Subsequently, the mixture was continuously stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched with 200 mL of water at 0 °C. Then, most of the dichloromethane was removed by distillation under reduced pressure, and ethyl acetate was added for multiple extraction operations. The organic layers obtained by each extraction were combined, washed with saturated sodium bicarbonate solution and brine, and then dried with anhydrous sodium sulfate. After drying was completed, the drying agent was removed by filtration, and the organic layer was concentrated by distillation under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1, volume ratio), and a white solid product (5.4 g, yield 100%) was finally obtained. The reaction scheme is as follows:

[0081]

[0082] 1 H NMR (400 MHz, CD3OD): δ 7.25-7.23 (m, 2H), 7.09-7.05 (m, 2H), 6.90 (d, J = 8.3 Hz, 1H), 6.69 (dd, J = 5.7, 2.6 Hz, 1H), 6.53 (d, J = 2.5 Hz, 1H). 13 C NMR (100 MHz, CD3OD) δ 157.5, 144.2, 143.5, 143.0, 134.4, 131.1, 130.2, 129.9, 128.1, 127.9, 116.4, 115.2. HRMS (ESI) m / z calcd for C 24 H 15 O2[M-H]- 335.1078, found 335.1077.

[0083] The white solid product prepared in Example 4 is 2,15-dihydroxytetraphenocyclooctetraene. The1H NMR and13C NMR spectra of 2,15-dihydroxytetraphenocyclooctetraene (Formula I) prepared in Example 4 are shown in Figures 1 and 2, respectively. Figure 4 and Figure 5 .

[0084] Example 5

[0085] Chiral resolution of 2,15-dihydroxytetraphenocyclooctetraene, comprising the steps of:

[0086] The 2,15-dihydroxytetraphenocyclooctetraene (Formula I) prepared in Example 4 was subjected to chiral resolution and separated by high performance liquid chromatography using a chiral preparative column. The optically active isomers (S)-2,15-dihydroxytetraphenocyclooctetraene and (R)-2,15-dihydroxytetraphenocyclooctetraene were confirmed by reaction with (+)-(S)-10-camphorsulfonyl chloride. The reaction scheme is shown in Figure 3. Figure 6 .

[0087] Results analysis:

[0088] The absolute configuration of (R)-2,15-dihydroxytetraphenocyclooctetraene was confirmed to be R-configuration by single crystal structure of the derivative 6 formed by reaction of the enantiomer with retention time of 9.21 min with (+)-(S)-10-camphorsulfonyl chloride. From this result, it was inferred that the other enantiomer with retention time of 11.25 min was (S)-2,15-dihydroxytetraphenocyclooctetraene.

[0089] The ee values and retention times (tR) of (S)-2,15-dihydroxytetraphenocyclooctetraene and (R)-2,15-dihydroxytetraphenocyclooctetraene were measured by high performance liquid chromatography (HPCL). The test conditions were: Daicel Chiralpak AD-H, n-hexane / i-propanol = 80 / 20, flow rate = 0.6 mL / min, T = 30 °C, 220 nm, and the results are as follows: R ). The test conditions were: Daicel Chiralpak AD-H, n-hexane / i-propanol = 80 / 20, flow rate = 0.6 mL / min, T = 30 °C, 220 nm, and the results are as follows:

[0090] (S)-2,15-dihydroxytetraphenocyclooctetraene: ee > 99%, t R (major) = 11.25 min, t R (minor) = 9.22 min. The HPLC spectrum measurement results are shown in Figure 4. Figure 7 .

[0091] (R)-2,15-dihydroxytetraphenocyclooctetraene: ee > 99%, t R(major) = 9.21 min, t R (minor) = 11.25 min. The HPLC spectrum determination results are shown in Table 1. Figure 8 .

[0092] Their specific optical rotations [α] were determined by using a polarimeter. The results are as follows:

[0093] (S)-2, 15-dihydroxytetraphenylcyclooctetraene: [α]D= -11.9 (c = 1.00, CH3OH). D 25 = -11.9 (c = 1.00, CH3OH).

[0094] (R)-2, 15-dihydroxytetraphenylcyclooctetraene: [α]D= +12.1 (c = 1.00, CH3OH). D 25 = +12.1 (c = 1.00, CH3OH).

[0095] The circular dichroism curves of (S)-2, 15-dihydroxytetraphenylcyclooctetraene and (R)-2, 15-dihydroxytetraphenylcyclooctetraene were determined by using a circular dichroism spectrometer, and the results are shown in Table 2. Figure 9 It can be seen that the two enantiomers obtained by chiral resolution present a good mirror image relationship.

[0096] The above merely describes the preferred specific embodiments of the present application, but the protection scope of the present application is not limited thereto, and any person skilled in the art can easily think of changes or replacements within the technical scope disclosed by the present application, which should be covered within the protection scope of the present application.

Claims

1. A method for preparing chiral 2,15-dihydroxytetrabenzocyclooctatetraene, characterized in that, Includes the following steps: 2,15-dihydroxytetrabenzocyclooctatetraene was separated by high performance liquid chromatography using a chiral preparative column, and then the optical isomers (S)-2,15-dihydroxytetrabenzocyclooctatetraene and (R)-2,15-dihydroxytetrabenzocyclooctatetraene were confirmed by chiral reagents. The chiral reagent includes one of (+)-(S)-10-camphorsulfonyl chloride, (-)-(R)-10-camphorsulfonyl chloride, (+)-menthol chloroformate, (-)-menthol chloroformate, (R)-(+)-α-methylbenzylamine, and (S)-(-)-α-methylbenzylamine.

2. The method for preparing chiral 2,15-dihydroxytetrabenzocyclooctatetraene according to claim 1, characterized in that, The preparation method of the 2,15-dihydroxytetrabenzocyclooctate includes the following steps: Liquid bromine is mixed with 3,3'-dimethoxy-1,1'-biphenyl to undergo a bromination reaction, producing 2,2'-dibromo-5,5'-dimethoxy-1,1'-biphenyl; After mixing n-butyllithium with the 2,2'-dibromo-5,5'-dimethoxy-1,1'-biphenyl and reacting with it to form a lithium, elemental iodine is added to generate 2,2'-diiodo-5,5'-dimethoxy-1,1'-biphenyl. The 2,2'-diiodo-5,5'-dimethoxy-1,1'-biphenyl and 2,2'-diboronic anhydride-1,1'-biphenyl were mixed under palladium catalysis to undergo a Suzuki coupling reaction to generate 2,15-dimethoxytetrabenzocyclooctatetraene. The 2,15-dimethoxytetrabenzocyclooctatetraene was mixed with boron tribromide and subjected to a methyl removal reaction to generate the 2,15-dihydroxytetrabenzocyclooctatetraene.

3. The method for preparing chiral 2,15-dihydroxytetrabenzocyclooctatetraene according to claim 2, characterized in that, In the bromination reaction, the molar ratio of liquid bromine to 3,3'-dimethoxy-1,1'-biphenyl is 29:

13.

4. The method for preparing chiral 2,15-dihydroxytetrabenzocyclooctatetetraene according to claim 2, characterized in that, The molar ratio of n-butyllithium, 2,2'-dibromo-5,5'-dimethoxy-1,1'-biphenyl to elemental iodine is 3:1:

3.

5. The method for preparing chiral 2,15-dihydroxytetrabenzocyclooctatetraene according to claim 2, characterized in that, The lithiation reaction was carried out at a temperature of -78°C for 3 hours.

6. The method for preparing chiral 2,15-dihydroxytetrabenzocyclooctatetraene according to claim 2, characterized in that, The palladium catalyst for palladium catalysis includes at least one of Pd(OAc)2, PdCl2, Pd(PPh3)2Cl2, Pd(dppf)Cl2, Pd(dppb)Cl2, Pd(dppp)Cl2, Pd(PPh3)4, Pd2(dba)3, and Pd(dba)2.

7. The method for preparing chiral 2,15-dihydroxytetrabenzocyclooctatetraene according to claim 2, characterized in that, In the Suzuki coupling reaction, the molar ratio of 2,2'-diiodo-5,5'-dimethoxy-1,1'-biphenyl to 2,2'-diboronic anhydride-1,1'-biphenyl is 27:32.2, the reaction temperature is 90°C, and the reaction time is 36 hours.

8. The method for preparing chiral 2,15-dihydroxytetrabenzocyclooctatetraene according to claim 2, characterized in that, The methyl removal reaction involves dissolving 2,15-dimethoxytetrabenzocyclooctatetraene in dichloromethane, then adding a dichloromethane solution of boron tribromide at 0°C, and stirring overnight at room temperature.

9. The method for preparing chiral 2,15-dihydroxytetrabenzocyclooctatete according to claim 8, characterized in that, The concentration of the boron tribromide dichloromethane solution is 1M, and the volume ratio of 2,15-dimethoxytetrabenzocyclooctateteene to the boron tribromide dichloromethane solution is 1 mmol: 10 mL.

10. A chiral 2,15-dihydroxytetrabenzocyclooctatetraene, characterized in that, The chiral 2,15-dihydroxytetrabenzocyclooctatetraene, prepared according to any one of claims 1-9, comprises (S)-2,15-dihydroxytetrabenzocyclooctatetraene and (R)-2,15-dihydroxytetrabenzocyclooctatetraene.

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