WO2021012479A1 - Hydrogenated cyclic [8] aromatic hydrocarbon compound and preparation method therefor - Google Patents

Hydrogenated cyclic [8] aromatic hydrocarbon compound and preparation method therefor Download PDF

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WO2021012479A1
WO2021012479A1 PCT/CN2019/116328 CN2019116328W WO2021012479A1 WO 2021012479 A1 WO2021012479 A1 WO 2021012479A1 CN 2019116328 W CN2019116328 W CN 2019116328W WO 2021012479 A1 WO2021012479 A1 WO 2021012479A1
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formula
compound represented
bromide
compound
reaction
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王梅祥
时谈浩
郭庆辉
佟硕
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清华大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
    • C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
    • C07C13/32—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings
    • C07C13/70—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with a condensed ring system consisting of at least two, mutually uncondensed aromatic ring systems, linked by an annular structure formed by carbon chains on non-adjacent positions of the aromatic ring, e.g. cyclophanes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/38—Separation; Purification; Stabilisation; Use of additives
    • C07C17/395—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to a chemical modification of at least one compound
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
    • C07C29/88—Separation; Purification; Use of additives, e.g. for stabilisation by treatment giving rise to a chemical modification of at least one compound
    • C07C29/92—Separation; Purification; Use of additives, e.g. for stabilisation by treatment giving rise to a chemical modification of at least one compound by a consecutive conversion and reconstruction
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2527/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
    • C07C2527/06—Halogens; Compounds thereof
    • C07C2527/128—Compounds comprising a halogen and an iron group metal or a platinum group metal
    • C07C2527/13—Platinum group metals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2531/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • C07C2531/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • C07C2531/04—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing carboxylic acids or their salts
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2531/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • C07C2531/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • C07C2531/22—Organic complexes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2531/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • C07C2531/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • C07C2531/24—Phosphines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/90—Ring systems containing bridged rings containing more than four rings

Definitions

  • the present invention relates to the field of organic chemistry. Specifically, the present invention relates to a hydrogenated ring zone [8] aromatic compound and a preparation method thereof.
  • Multicyclic compounds have the characteristics and advantages of good molecular structure designability and physical and chemical properties adjustable, and are widely used in many fields of chemistry, materials science and life science.
  • synthetic macrocyclic compounds can recognize anions, cations and neutral guest molecules, which can be used in separation, sensing and detection.
  • motifs or templates functionalized macrocyclic compounds are used in the construction of functional assemblies and nanomaterials and molecular machines. Macrocyclic compounds also provide unique research methods and approaches for exploring chemical reaction mechanisms and supramolecular catalysis.
  • an object of the present invention is to propose a hydrogenated ring-belt [8] arene compound and a preparation method thereof.
  • the compound has a barrel-shaped cavity structure, the cavity volume size is variable, and the cavity inner wall polarity is adjustable, and has broad application prospects.
  • the invention provides a compound.
  • the compound is a compound represented by formula (I) or a stereoisomer of a compound represented by formula (I),
  • R 1 , R 2 and R 3 are each independently a hydrogen atom, optionally substituted C 1-12 alkyl, optionally substituted C 1-12 heteroalkyl, optionally substituted C 2-12 alkenyl, any Optional substituted C 5-24 cycloalkyl or optionally substituted C 5-24 heterocyclic group.
  • the compounds of the above-mentioned embodiments are also called “hydrogenated annulus [8] arene compounds".
  • Such compounds have a barrel-shaped cavity structure, the cavity volume size is variable, and the cavity inner wall polarity is adjustable.
  • the hydrogenated ring band [8] aromatic hydrocarbon represented by formula (I) of the present invention can selectively recognize organic molecules from the mixed solution and form inclusion complexes, which are used in the selection of organic small molecules Sexual separation material.
  • R 1 , R 2 and R 3 are each independently a hydrogen atom, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 5-12 cycloalkane Group, C 5-12 heterocyclic group.
  • R 1 and R 2 are each independently a hydrogen atom, methyl, ethyl, n-propyl, n-butyl, phenyl or optionally substituted phenyl;
  • R 3 is ethyl, n Propyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, benzyl, p-methylbenzyl, o-methyl Benzyl or m-methylbenzyl.
  • the optionally substituted phenyl is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl Phenyl, 4-ethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 3,4-dimethylphenyl, 3,5-di Methylphenyl, 3,6-Dimethylphenyl, 2,3-Dimethylphenyl, 2,4-Dimethylphenyl, 2,5-Dimethylphenyl, 2,6-Dimethylphenyl Methylphenyl, 3,4-Diethylphenyl, 3,5-Diethylphenyl, 3,6-Diethylphenyl, 2,3-Diethylphenyl, 2,4-Diethylphenyl Ethylphenyl, 2,5-diethylphenyl, 2,5-diethylpheny
  • the compound has one of the following structures:
  • Ar 1 in formula (Ie-1) and formula (Ie-2) is 3,5-dimethylphenyl
  • Ar 2 in formula (If-1) and formula (If-2) is 2- Isopropylphenyl.
  • the present invention provides a method for preparing the compounds of the foregoing examples.
  • the method includes: contacting a compound represented by formula (II) or a compound represented by formula (III) with an acid to obtain a compound represented by formula (I),
  • R 1 and R 3 are as described above.
  • the compound represented by formula (II) or the compound represented by formula (III) can undergo intramolecular Friedel-Crafts alkylation reaction to form a ring under the action of acid to obtain the compound represented by formula (I) under mild reaction conditions,
  • the obtained product is stable in the air, easy to separate and purify, and has good practicability and application prospects.
  • the acid includes selected from polyphosphoric acid, hydrochloric acid, sulfuric acid, trifluoromethanesulfonic acid, trifluoromethanesulfonic anhydride, trimethylsilyl trifluoromethanesulfonate, methanesulfonic acid, p-methyl At least one of benzenesulfonic acid, perfluorosulfonic acid resin (Nafion resin), and scandium trifluoromethanesulfonate.
  • the reaction conditions can be made milder, and the product cyclization/polymerization ratio can be higher.
  • the acid includes at least one selected from trifluoromethanesulfonic acid and methanesulfonic acid.
  • the contact is carried out in a first solvent
  • the first solvent includes selected from benzene, toluene, benzotrifluoride, chlorobenzene, fluorobenzene, nitrobenzene, bromobenzene, dichloromethane, At least one of 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, and chloroform.
  • the first solvent is preferably 1,2-dichloroethane; the compound represented by formula (III)
  • the first solvent is preferably dichloromethane.
  • the contact is completed at -40 to 150°C for 0.1 to 48 hours.
  • the above-mentioned contact is preferably completed at 25 to 50°C for 2 hours; the compound represented by formula (III) is When preparing the compound represented by formula (I) from the raw materials, the above-mentioned contact is preferably completed at 0°C for 0.2h. As a result, the yield and selectivity of the product can be further improved.
  • the amount ratio of the compound represented by formula (II) to the acid is 0.01-1 mmol: 0.01-100 mmol, preferably 0.1 mmol: 0.3 mmol; the ratio of the compound represented by formula (III) to the acid
  • the dosage ratio is 0.01 to 1 mmol: 0.01 to 10 mL, preferably 0.1 mmol: 0.2 mL.
  • the amount of solvent used in the reaction is not particularly limited.
  • the amount ratio of the compound represented by formula (II), the acid and the first solvent may be 0.01-1mmol:0.01-100mmol:0.5-300mL , Preferably 0.1 mmol: 0.3 mmol: 5 mL; the amount ratio of the compound represented by formula (III), acid and first solvent can be 0.01-1 mmol: 0.01-10 mL: 2-500 mL, preferably 0.1 mmol: 0.2 mL-10 mL.
  • the compound represented by formula (II) can be prepared by cross-coupling the compound represented by formula (V) under the action of a metal catalyst.
  • the compound represented by the formula (II) can be prepared in large quantities from calix[4] rezoarene compounds as raw materials.
  • the metal catalyst may include palladium selected from palladium acetate, tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone) dipalladium, palladium chloride and [1,1'-bis(diphenyl) At least one of phosphono)ferrocene]palladium dichloride, preferably tetrakistriphenylphosphine palladium.
  • the cross-coupling reaction is carried out in a second solvent
  • the second solvent may include N,N-dimethylformamide, N,N-dimethylaniline, N, At least one of N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 1,4-dioxane, water, and dimethylsulfoxide.
  • the second solvent when R 1 in the target compound represented by formula (I) is H, the second solvent is preferably N,N-dimethylformamide; when the target compound represented by formula (I) When R 1 is another substituent, the second solvent is preferably a mixed solution of 1,4-dioxane and water.
  • the cross-coupling reaction is carried out under the action of additives and alkenylation reagents.
  • the additives may include those selected from potassium carbonate, cesium carbonate, lithium carbonate, sodium carbonate, sodium chloride, and At least one of lithium, the above additives can effectively participate in the catalytic cycle in the cross-coupling reaction, and improve the reaction efficiency.
  • the additive when R 1 in the target compound represented by formula (I) is H, the additive is preferably lithium chloride; when R 1 in the target compound represented by formula (I) is other substituents
  • the additive is preferably potassium carbonate.
  • the alkenylation agent may comprise selected from vinylmagnesium bromide, isopropenyl magnesium bromide, tributylvinylene, tributylisopropenylene, isopropenylboronic acid pinacol ester and vinylboronic acid pinacol At least one of alcohol esters.
  • R 1 in the target compound represented by formula (I) is H
  • the alkenylation reagent is preferably tributyl vinylene
  • R 1 is another substituent
  • the sylation agent is preferably isopropenyl boronic acid pinacol ester.
  • the cross-coupling reaction can be completed at 25-140°C for 6-36 hours.
  • the cross-coupling reaction when R 1 in the target compound represented by formula (I) is H, the cross-coupling reaction is preferably completed at 120° C. for 12 hours; when the target compound represented by formula (I), R When 1 is other substituents, the cross-coupling reaction is completed at 110°C for 24 hours. As a result, the yield of the product can be further improved.
  • the compound represented by the formula (III) can be prepared by the addition reaction of the compound represented by the formula (IV) with a Grignard reagent.
  • the compound represented by the formula (III) can be prepared in large quantities from calix[4] rezoarene compounds as raw materials;
  • the Grignard reagent may comprise selected from phenyl magnesium bromide, 2-methylphenyl magnesium bromide, 3-methylphenyl magnesium bromide, 4-methylphenyl magnesium bromide Magnesium, 2-ethylphenylmagnesium bromide, 3-ethylphenylmagnesium bromide, 4-ethylphenylmagnesium bromide, 2-isopropylphenylmagnesium bromide, 3-isopropylphenyl Magnesium bromide, 4-isopropylphenylmagnesium bromide, 3,4-dimethylphenylmagnesium bromide, 3,5-dimethylphenylmagnesium bromide, 3,6-dimethylphenyl Magnesium bromide, 2,3-dimethylphenyl magnesium bromide, 2,4-dimethylphenyl magnesium bromide, 2,5-dimethylphenyl magnesium bromide, 2,6-dimethyl Phen
  • the addition reaction is carried out in a third solvent, and the third solvent includes at least one selected from tetrahydrofuran and 1,4-dioxane, preferably tetrahydrofuran.
  • the addition reaction is completed at -78-60°C for 0.5-12 hours, preferably at -78°C for 1 hour.
  • the compound represented by formula (V) can be prepared by subjecting the compound represented by formula (VI) to trifluoromethanesulfonylation.
  • the trifluoromethanesulfonylation reaction is carried out under the action of a base, and the base used in the trifluoromethanesulfonylation reaction may include selected from pyridine, triethylamine, diethylamine, N, At least one of N-diisopropylethylamine, 2,6-lutidine and potassium carbonate is preferably pyridine.
  • the solvent used in the trifluoromethanesulfonylation reaction may include at least one selected from dichloromethane, trichloromethane, 1,2-dichloroethane, toluene, and benzene, and is preferably dichloromethane.
  • the trifluoromethanesulfonylation reaction can be completed at -78-45°C for 8 to 36 hours, preferably at 25°C for 12 hours.
  • the compound represented by formula (IV) can be prepared by subjecting the compound represented by formula (II) to an oxidation reaction.
  • the oxidation reaction is performed under the action of an oxidant, and the oxidant may include at least one selected from oxygen and ozone.
  • the oxidation reaction is performed in a fourth solvent
  • the fourth solvent includes at least one selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane and methanol, Preferably it is dichloromethane.
  • the oxidation reaction is completed at -78°C to -20°C for 1 to 24 hours, preferably at -78°C for 13 hours.
  • the present invention proposes the use of the compounds of the above embodiments in the selective inclusion of organic molecules, and the compounds are used to identify and selectively include organic molecules from a mixed solution.
  • the compound represented by formula (I) can be used as a macrocyclic host molecule to selectively recognize and include small organic molecules, thereby being applied to the separation of small organic molecules.
  • the above-mentioned mixed solution includes 1,2-dichloroethane, methanol, chloroform, and ethanol.
  • the inclusion compound formed by the compound of the present invention and an organic molecule includes: a compound represented by formula (If-1) and 1,2-dichloroethane, a compound represented by formula (VIIa) and ethanol , The compound represented by formula (VIIb) and 1,2-dichloroethane, the compound represented by formula (VIIc) and chloroform,
  • Figure 1 is a hydrogen nuclear magnetic spectrum of the compound represented by formula (Ia);
  • Figure 2 is a nuclear magnetic carbon spectrum of the compound represented by formula (Ia).
  • FIG 3 is the hydrogen nuclear magnetic spectrum of the compound represented by formula (Id-1);
  • FIG. 4 is the NMR spectrum of the compound represented by formula (Id-1);
  • FIG. 5 is a crystal structure diagram of the compound represented by formula (Ib);
  • FIG. 6 is a crystal structure diagram of the compound represented by formula (Ie-1);
  • Figure 7 is a crystal structure diagram of a complex formed by a compound represented by formula (If-1) and a guest 1,2-dichloroethane;
  • Figure 8 is a crystal structure diagram of the inclusion compound formed by the compound represented by formula (VIIa) and guest ethanol;
  • Figure 9 is a crystal structure diagram of a complex formed by a compound represented by formula (VIIb) and a guest 1,2-dichloroethane;
  • Figure 10 is a crystal structure diagram of a complex formed by the compound represented by formula (VIIc) and guest chloroform.
  • the specific preparation method is:
  • the specific preparation method is:
  • the specific preparation method is:
  • the specific preparation method is:
  • the aqueous phase was extracted with dichloromethane, the organic phases were combined and washed with 10% sodium hydroxide solution, 5% hydrogen peroxide solution and saturated sodium chloride solution, and then dried with anhydrous sodium sulfate.
  • Ar 1 in formula (Ie-1) and formula (Ie-2) is 3,5-dimethylphenyl.
  • the specific preparation method is:
  • Ar 2 in formula (If-1) and formula (If-2) is 2 -isopropylphenyl.
  • the specific preparation method is:
  • Rotate the solvent to dry, and use prefabricated thin-layer chromatography plate to separate can separate compounds of different configurations (If-1) and (If-2), 23.3 mg (If-1), 37.7 mg (If-2), the yields were 23% (If-1) and 38% (If-2), respectively.
  • Example 7 Selective inclusion of 1,2-dichloroethane by the compound represented by the hydrogenated ring zone [8] aromatic hydrocarbon formula (If-1)
  • Example 8 Selective inclusion of ethanol by the compound represented by the macrocyclic formula (VIIa)
  • the main force to maintain this structure is the hydrogen bond between ethanol molecules, the non-classical hydrogen bond between the alkyl part of the host molecule and the hydroxyl oxygen, and the CH bond of the ethanol molecule to the CH ... ⁇ interaction of the aromatic ring.
  • the chlorine atom on the chloroform in the cavity interacts with the alkyl chain of another host molecule to form a "sandwich” type sandwich structure.
  • the sandwich structure of "sandwich” can form one-dimensional long chains, which are connected by chloroform molecules outside the cavity to form a two-dimensional structure.
  • the main force to maintain this structure is the non-classical hydrogen bond between the chlorine atom and the main body C-H bond.

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Abstract

Provided are a hydrogenated cyclic [8] aromatic hydrocarbon compound and a preparation method therefor. The hydrogenated cyclic [8] aromatic hydrocarbon compound is a compound as represented by formula (I) or a stereoisomer of the compound as represented by formula (I), (I).

Description

氢化环带[8]芳烃化合物及其制备方法Hydrogenated ring zone [8] aromatic compound and preparation method thereof 技术领域Technical field
本发明涉及有机化学领域，具体而言，本发明涉及氢化环带[8]芳烃化合物及其制备方法。The present invention relates to the field of organic chemistry. Specifically, the present invention relates to a hydrogenated ring zone [8] aromatic compound and a preparation method thereof.
背景技术Background technique
人工合成大环化合物具有良好的分子结构可设计性以及理化性能可调节性的特点和优势，在化学、材料科学和生命科学诸多领域得到广泛应用。作为主体化合物，人工合成的大环化合物能识别阴阳离子和中性客体分子，从而应用于分离、传感和检测。作为基元或模板，官能团化大环化合物用于功能组装体和纳米材料和分子机器的构建。大环化合物还为探究化学反应机理和超分子催化提供了独特的研究手段和途径。Artificially synthesized macrocyclic compounds have the characteristics and advantages of good molecular structure designability and physical and chemical properties adjustable, and are widely used in many fields of chemistry, materials science and life science. As the host compound, synthetic macrocyclic compounds can recognize anions, cations and neutral guest molecules, which can be used in separation, sensing and detection. As motifs or templates, functionalized macrocyclic compounds are used in the construction of functional assemblies and nanomaterials and molecular machines. Macrocyclic compounds also provide unique research methods and approaches for exploring chemical reaction mechanisms and supramolecular catalysis.
迄今为止，文献中已经报道了大量的人工合成大环化合物，其中冠醚、球醚、化学修饰的环糊精衍生物、杯芳烃、杯雷琐芳烃、环三藜芦烃、杯吡咯、葫芦脲、杂杯芳烃、环对苯撑(CPPs)、柱芳烃、冠芳烃等正成为优势大环主体分子，得到比较深入和广泛的研究。由于不同的大环化合物具有不同的结构，其空腔大小、形状及电子特性均有差异，从而显示不一样的分子识别能力。因而，对于具有新结构和功能的大环化合物仍有待深入研究。So far, a large number of synthetic macrocyclic compounds have been reported in the literature, including crown ethers, globular ethers, chemically modified cyclodextrin derivatives, calixarene, calixorene, cyclotriveratrol, calixpyrrole, and cucurbits Urea, heterocalixarenes, cycloparaphenylenes (CPPs), pillared aromatics, crown aromatics, etc. are becoming dominant macrocyclic main molecules and have been studied in depth and extensively. Because different macrocyclic compounds have different structures, their cavity sizes, shapes, and electronic properties are different, thus showing different molecular recognition capabilities. Therefore, the macrocyclic compounds with new structures and functions still need to be studied in depth.
发明内容Summary of the invention
本发明旨在至少在一定程度上解决相关技术中的技术问题之一。为此，本发明的一个目的在于提出氢化环带[8]芳烃化合物及其制备方法。该化合物具有桶状空腔结构、空腔体积尺寸可变、空腔内壁极性可调，具有广阔的应用前景。The present invention aims to solve one of the technical problems in the related art at least to a certain extent. For this reason, an object of the present invention is to propose a hydrogenated ring-belt [8] arene compound and a preparation method thereof. The compound has a barrel-shaped cavity structure, the cavity volume size is variable, and the cavity inner wall polarity is adjustable, and has broad application prospects.
在本发明的一个方面，本发明提出了一种化合物。根据本发明的实施例，所述化合物为式(I)所示化合物或式(I)所示化合物的立体异构体，In one aspect of the invention, the invention provides a compound. According to an embodiment of the present invention, the compound is a compound represented by formula (I) or a stereoisomer of a compound represented by formula (I),
Figure PCTCN2019116328-appb-000001
Figure PCTCN2019116328-appb-000001
其中，among them,
R 1、R 2和R 3分别独立地为氢原子、任选取代的C 1-12烷基、任选取代的C 1-12杂烷基、任选取代的C 2-12烯基、任选取代的C 5-24环烷基或任选取代的C 5-24杂环基。 R 1 , R 2 and R 3 are each independently a hydrogen atom, optionally substituted C 1-12 alkyl, optionally substituted C 1-12 heteroalkyl, optionally substituted C 2-12 alkenyl, any Optional substituted C 5-24 cycloalkyl or optionally substituted C 5-24 heterocyclic group.
根据本发明实施例上述实施例的化合物也称为“氢化环带[8]芳烃化合物”，该类化合物具有桶状空腔结构、空腔体积尺寸可变、空腔内壁极性可调。作为新型的人工合成大环分子，本发明中式(I)所示的氢化环带[8]芳烃能够从混合溶液中选择性识别有机分子，并形成包结复合物，应用于有机小分子的选择性分离材料。According to the embodiments of the present invention, the compounds of the above-mentioned embodiments are also called "hydrogenated annulus [8] arene compounds". Such compounds have a barrel-shaped cavity structure, the cavity volume size is variable, and the cavity inner wall polarity is adjustable. As a new type of artificially synthesized macrocyclic molecule, the hydrogenated ring band [8] aromatic hydrocarbon represented by formula (I) of the present invention can selectively recognize organic molecules from the mixed solution and form inclusion complexes, which are used in the selection of organic small molecules Sexual separation material.
另外，根据本发明实施例上述实施例的化合物还可以具有如下附加的技术特征：In addition, the compounds of the foregoing embodiments according to the embodiments of the present invention may also have the following additional technical features:
根据本发明的实施例，R 1、R 2和R 3分别独立地为氢原子、C 1-6烷基、C 1-6杂烷基、C 2-6烯基、C 5-12环烷基、C 5-12杂环基。 According to an embodiment of the present invention, R 1 , R 2 and R 3 are each independently a hydrogen atom, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 5-12 cycloalkane Group, C 5-12 heterocyclic group.
根据本发明的实施例，R 1和R 2分别独立地为氢原子、甲基、乙基、正丙基、正丁基、苯基或任选取代的苯基；R 3为乙基、正丙基、异丙基、正丁基、异丁基、正戊基、正己基、正庚基、正辛基、正壬基、正癸基、苄基、对甲基苄基、邻甲基苄基或间甲基苄基。 According to an embodiment of the present invention, R 1 and R 2 are each independently a hydrogen atom, methyl, ethyl, n-propyl, n-butyl, phenyl or optionally substituted phenyl; R 3 is ethyl, n Propyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, benzyl, p-methylbenzyl, o-methyl Benzyl or m-methylbenzyl.
根据本发明的实施例，所述任选取代的苯基为苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、2-乙基苯基、3-乙基苯基、4-乙基苯基、2-异丙基苯基、3-异丙基苯基、4-异丙基苯基、3,4-二甲基苯基、3,5- 二甲基苯基、3,6-二甲基苯基、2,3-二甲基苯基、2,4-二甲基苯基、2,5-二甲基苯基、2,6-二甲基苯基、3,4-二乙基苯基、3,5-二乙基苯基、3,6-二乙基苯基、2,3-二乙基苯基、2,4-二乙基苯基、2,5-二乙基苯基、2,6-二乙基苯基或3,4,5-三甲基苯基。According to an embodiment of the present invention, the optionally substituted phenyl is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl Phenyl, 4-ethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 3,4-dimethylphenyl, 3,5-di Methylphenyl, 3,6-Dimethylphenyl, 2,3-Dimethylphenyl, 2,4-Dimethylphenyl, 2,5-Dimethylphenyl, 2,6-Dimethylphenyl Methylphenyl, 3,4-Diethylphenyl, 3,5-Diethylphenyl, 3,6-Diethylphenyl, 2,3-Diethylphenyl, 2,4-Diethylphenyl Ethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl or 3,4,5-trimethylphenyl.
根据本发明的实施例，所述化合物具有以下其中之一的结构：According to an embodiment of the present invention, the compound has one of the following structures:
Figure PCTCN2019116328-appb-000002
Figure PCTCN2019116328-appb-000003
其中，式(Ie-1)和式(Ie-2)中的Ar 1为3,5-二甲基苯基，式(If-1)和式(If-2)中的Ar 2为2-异丙基苯基。
Figure PCTCN2019116328-appb-000002
Figure PCTCN2019116328-appb-000003
Among them, Ar 1 in formula (Ie-1) and formula (Ie-2) is 3,5-dimethylphenyl, and Ar 2 in formula (If-1) and formula (If-2) is 2- Isopropylphenyl.
在本发明的另一方面，本发明提出了一种制备上述实施例的化合物的方法。根据本发明的实施例，该方法包括：使式(II)所示化合物或式(III)所示化合物与酸接触，得到式(I)所示化合物，In another aspect of the present invention, the present invention provides a method for preparing the compounds of the foregoing examples. According to an embodiment of the present invention, the method includes: contacting a compound represented by formula (II) or a compound represented by formula (III) with an acid to obtain a compound represented by formula (I),
Figure PCTCN2019116328-appb-000004
Figure PCTCN2019116328-appb-000004
其中，R 1和R 3为如前所述的。 Wherein, R 1 and R 3 are as described above.
根据本发明的实施例，式(II)所示化合物或式(III)所示化合物可在酸作用下发生分子内傅克烷基化反应筑环，得到式(I)所示化合物，反应条件温和，所得产物在空气中稳定且易于分离纯化，具有很好的实用性和应用前景。According to the embodiment of the present invention, the compound represented by formula (II) or the compound represented by formula (III) can undergo intramolecular Friedel-Crafts alkylation reaction to form a ring under the action of acid to obtain the compound represented by formula (I) under mild reaction conditions, The obtained product is stable in the air, easy to separate and purify, and has good practicability and application prospects.
另外，根据本发明上述实施例的制备化合物的方法还可以具有如下附加的技术特征：In addition, the method for preparing a compound according to the foregoing embodiment of the present invention may also have the following additional technical features:
根据本发明的实施例，所述酸包括选自多聚磷酸、盐酸、硫酸、三氟甲磺酸、三氟甲磺酸酐、三氟甲磺酸三甲基硅酯、甲磺酸、对甲基苯磺酸、全氟磺酸树脂(Nafion树脂)、三氟甲磺酸钪中的至少之一。由此，可以使反应条件更为温和，产品成环/聚合比例更高。根据本发明的优选实施例，所述酸包括选自三氟甲磺酸和甲磺酸中的至少之一。According to an embodiment of the present invention, the acid includes selected from polyphosphoric acid, hydrochloric acid, sulfuric acid, trifluoromethanesulfonic acid, trifluoromethanesulfonic anhydride, trimethylsilyl trifluoromethanesulfonate, methanesulfonic acid, p-methyl At least one of benzenesulfonic acid, perfluorosulfonic acid resin (Nafion resin), and scandium trifluoromethanesulfonate. As a result, the reaction conditions can be made milder, and the product cyclization/polymerization ratio can be higher. According to a preferred embodiment of the present invention, the acid includes at least one selected from trifluoromethanesulfonic acid and methanesulfonic acid.
根据本发明的实施例，所述接触在第一溶剂中进行，所述第一溶剂包括选自苯、甲苯、三氟甲苯、氯苯、氟苯、硝基苯、溴苯、二氯甲烷、1,2-二氯乙烷、1,1,2,2-四氯乙烷和氯仿中的至少之一。根据本发明的一些实施例，以式(II)所示化合物为原料制备式(I)所示化合物时，第一溶剂优选为1,2-二氯乙烷；以式(III)所示化合物为原料制备式(I)所示化合物时，第一溶剂优选为二氯甲烷。由此，可以在为原料提供的良好溶解性的同时，满足反应温度对溶剂的要求。According to an embodiment of the present invention, the contact is carried out in a first solvent, and the first solvent includes selected from benzene, toluene, benzotrifluoride, chlorobenzene, fluorobenzene, nitrobenzene, bromobenzene, dichloromethane, At least one of 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, and chloroform. According to some embodiments of the present invention, when the compound represented by formula (II) is used as a raw material to prepare the compound represented by formula (I), the first solvent is preferably 1,2-dichloroethane; the compound represented by formula (III) When preparing the compound represented by formula (I) as a raw material, the first solvent is preferably dichloromethane. Thus, while providing good solubility for the raw materials, the requirements of the reaction temperature for the solvent can be met.
根据本发明的实施例，所述接触在-40～150℃下进行0.1～48h完成。根据本发明的一些实施例，以式(II)所示化合物为原料制备式(I)所示化合物时，上述接触优选在25～50℃下进行2h完成；以式(III)所示化合物为原料制备式(I)所示化合物时，上述接触优选在0℃下进行0.2h完成。由此，可以进一步提高产品的产率和选择性。According to an embodiment of the present invention, the contact is completed at -40 to 150°C for 0.1 to 48 hours. According to some embodiments of the present invention, when the compound represented by formula (II) is used as a raw material to prepare the compound represented by formula (I), the above-mentioned contact is preferably completed at 25 to 50°C for 2 hours; the compound represented by formula (III) is When preparing the compound represented by formula (I) from the raw materials, the above-mentioned contact is preferably completed at 0°C for 0.2h. As a result, the yield and selectivity of the product can be further improved.
根据本发明的实施例，式(II)所示化合物与所述酸的用量比为0.01～1mmol:0.01～100mmol，优选为0.1mmol:0.3mmol；式(III)所示化合物与所述酸的用量比为0.01～1mmol:0.01～10mL，优选为0.1mmol:0.2mL。另外，反应中溶剂的用量并不受特别限制，根据本发明的一些实施例，式(II)所示化合物、酸和第一溶剂的用量比可以为0.01～1mmol:0.01～100mmol:0.5～300mL，优选为0.1mmol:0.3mmol:5mL；式(III)所示化合物、酸和第一溶剂的用量比可以为0.01～1mmol:0.01～10mL:2～500mL，优选为0.1mmol: 0.2mL 10mL。According to an embodiment of the present invention, the amount ratio of the compound represented by formula (II) to the acid is 0.01-1 mmol: 0.01-100 mmol, preferably 0.1 mmol: 0.3 mmol; the ratio of the compound represented by formula (III) to the acid The dosage ratio is 0.01 to 1 mmol: 0.01 to 10 mL, preferably 0.1 mmol: 0.2 mL. In addition, the amount of solvent used in the reaction is not particularly limited. According to some embodiments of the present invention, the amount ratio of the compound represented by formula (II), the acid and the first solvent may be 0.01-1mmol:0.01-100mmol:0.5-300mL , Preferably 0.1 mmol: 0.3 mmol: 5 mL; the amount ratio of the compound represented by formula (III), acid and first solvent can be 0.01-1 mmol: 0.01-10 mL: 2-500 mL, preferably 0.1 mmol: 0.2 mL-10 mL.
根据本发明的实施例，式(II)所示化合物可以通过使式(V)所示化合物在金属催化剂的作用下发生交叉偶联反应制备得到。由此，式(II)所示化合物可以杯[4]雷琐芳烃类化合物为原料大量制备得到。According to an embodiment of the present invention, the compound represented by formula (II) can be prepared by cross-coupling the compound represented by formula (V) under the action of a metal catalyst. Thus, the compound represented by the formula (II) can be prepared in large quantities from calix[4] rezoarene compounds as raw materials.
Figure PCTCN2019116328-appb-000005
Figure PCTCN2019116328-appb-000005
根据本发明的实施例，所述金属催化剂可以包括选自醋酸钯、四三苯基膦钯、三(二亚苄基丙酮)二钯、氯化钯和[1,1’-双(二苯基膦基)二茂铁]二氯化钯中的至少之一，优选四三苯基膦钯。According to an embodiment of the present invention, the metal catalyst may include palladium selected from palladium acetate, tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone) dipalladium, palladium chloride and [1,1'-bis(diphenyl) At least one of phosphono)ferrocene]palladium dichloride, preferably tetrakistriphenylphosphine palladium.
根据本发明的实施例，所述交叉偶联反应在第二溶剂中进行，所述第二溶剂可以包括选自N,N-二甲基甲酰胺、N,N-二甲基苯胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、四氢呋喃、1,4-二氧六环、水和二甲基亚砜中的至少之一。根据本发明的一些实施例，当目标的式(I)所示化合物中R 1为H时，第二溶剂优选为N,N-二甲基甲酰胺；当目标的式(I)所示化合物中R 1为其他取代基时，第二溶剂优选为1,4-二氧六环与水的混合溶液。通过采用上述溶剂，可以进一步提高产品产率，并减少副反应，使产品易于分离。 According to an embodiment of the present invention, the cross-coupling reaction is carried out in a second solvent, and the second solvent may include N,N-dimethylformamide, N,N-dimethylaniline, N, At least one of N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 1,4-dioxane, water, and dimethylsulfoxide. According to some embodiments of the present invention, when R 1 in the target compound represented by formula (I) is H, the second solvent is preferably N,N-dimethylformamide; when the target compound represented by formula (I) When R 1 is another substituent, the second solvent is preferably a mixed solution of 1,4-dioxane and water. By using the above-mentioned solvent, the product yield can be further improved, side reactions can be reduced, and the product can be easily separated.
根据本发明的实施例，所述交叉偶联反应在添加剂和烯基化试剂的作用下进行，所述添加剂可以包括选自碳酸钾、碳酸铯、碳酸锂、碳酸钠、氯化钠和氯化锂中的至少之一，上述添加剂可以在交叉偶联反应中有效地参与催化循环，提高反应效率。根据本发明的一些实施例，当目标的式(I)所示化合物中R 1为H时，添加剂优选为氯化锂；当目标的式(I)所示化合物中R 1为其他取代基时，添加剂优选为碳酸钾。由此，可以进一步提高产品的产率、并减少副反应，使产品易于分离。所述烯基化试剂可以包括选自乙烯基溴化镁、异丙烯基溴化镁、三丁基乙烯基烯、三丁基异丙烯基烯、异丙烯基硼酸频哪醇酯和乙烯基硼酸频哪醇酯中的至少之一。当目标的式(I)所示化合物中R 1为H时，烯基化试剂优选为三丁基乙烯基烯；当目标的式(I)所示化合物中R 1为其他取代基时，烯基化试剂优选为异丙烯基硼酸频哪醇酯。由此，可以进一步提高产品的产率、并减少副反应，使产品易于分离。 According to an embodiment of the present invention, the cross-coupling reaction is carried out under the action of additives and alkenylation reagents. The additives may include those selected from potassium carbonate, cesium carbonate, lithium carbonate, sodium carbonate, sodium chloride, and At least one of lithium, the above additives can effectively participate in the catalytic cycle in the cross-coupling reaction, and improve the reaction efficiency. According to some embodiments of the present invention, when R 1 in the target compound represented by formula (I) is H, the additive is preferably lithium chloride; when R 1 in the target compound represented by formula (I) is other substituents The additive is preferably potassium carbonate. As a result, the yield of the product can be further improved, side reactions can be reduced, and the product can be easily separated. The alkenylation agent may comprise selected from vinylmagnesium bromide, isopropenyl magnesium bromide, tributylvinylene, tributylisopropenylene, isopropenylboronic acid pinacol ester and vinylboronic acid pinacol At least one of alcohol esters. When R 1 in the target compound represented by formula (I) is H, the alkenylation reagent is preferably tributyl vinylene; when the target compound represented by formula (I), R 1 is another substituent, the alkene The sylation agent is preferably isopropenyl boronic acid pinacol ester. As a result, the yield of the product can be further improved, side reactions can be reduced, and the product can be easily separated.
根据本发明的实施例，所述交叉偶联反应可以在25～140℃下进行6～36h完成。根据本发明的一些实施例，当目标的式(I)所示化合物中R 1为H时，交叉偶联反应优选在120℃下进行12h完成；当目标的式(I)所示化合物中R 1为其他取代基时，交叉偶联反应在110℃下进行24h完成。由此，可以进一步提高产品的产率。 According to an embodiment of the present invention, the cross-coupling reaction can be completed at 25-140°C for 6-36 hours. According to some embodiments of the present invention, when R 1 in the target compound represented by formula (I) is H, the cross-coupling reaction is preferably completed at 120° C. for 12 hours; when the target compound represented by formula (I), R When 1 is other substituents, the cross-coupling reaction is completed at 110°C for 24 hours. As a result, the yield of the product can be further improved.
根据本发明的实施例，式(III)所示化合物可以通过使式(IV)所示化合物与格氏试剂发生加成反应制备得到。由此，式(III)所示化合物可以杯[4]雷琐芳烃类化合物为原料大量制备得到；According to an embodiment of the present invention, the compound represented by the formula (III) can be prepared by the addition reaction of the compound represented by the formula (IV) with a Grignard reagent. Thus, the compound represented by the formula (III) can be prepared in large quantities from calix[4] rezoarene compounds as raw materials;
Figure PCTCN2019116328-appb-000006
Figure PCTCN2019116328-appb-000006
根据本发明的实施例，所述格氏试剂可以包括选自苯基溴化镁、2-甲基苯基溴化镁、3-甲基苯基溴化镁、4-甲基苯基溴化镁、2-乙基苯基溴化镁、3-乙基苯基溴化镁、4-乙基苯基溴化镁、2-异丙基苯基溴化镁、3-异丙基苯基溴化镁、4-异丙基苯基溴化镁、3,4-二甲基苯基溴化镁、3,5-二甲基苯基溴化镁、3,6-二甲基苯基溴化镁、2,3-二甲基苯基溴化镁、2,4-二甲基苯基溴化镁、2,5-二甲基苯基溴化镁、2,6-二甲基苯基溴化镁、3,4-二乙基苯基溴化镁、3,5-二乙基苯基溴化镁、3,6-二乙基苯基溴化镁、2,3-二乙基苯基溴化镁、2,4-二乙基苯基溴化镁、2,5-二乙基苯基溴化镁、2,6-二乙基苯基溴化镁和3,4,5-三甲基苯基溴化镁中的至少之一。According to an embodiment of the present invention, the Grignard reagent may comprise selected from phenyl magnesium bromide, 2-methylphenyl magnesium bromide, 3-methylphenyl magnesium bromide, 4-methylphenyl magnesium bromide Magnesium, 2-ethylphenylmagnesium bromide, 3-ethylphenylmagnesium bromide, 4-ethylphenylmagnesium bromide, 2-isopropylphenylmagnesium bromide, 3-isopropylphenyl Magnesium bromide, 4-isopropylphenylmagnesium bromide, 3,4-dimethylphenylmagnesium bromide, 3,5-dimethylphenylmagnesium bromide, 3,6-dimethylphenyl Magnesium bromide, 2,3-dimethylphenyl magnesium bromide, 2,4-dimethylphenyl magnesium bromide, 2,5-dimethylphenyl magnesium bromide, 2,6-dimethyl Phenylmagnesium bromide, 3,4-diethylphenylmagnesium bromide, 3,5-diethylphenylmagnesium bromide, 3,6-diethylphenylmagnesium bromide, 2,3-di Ethylphenyl magnesium bromide, 2,4-diethylphenyl magnesium bromide, 2,5-diethylphenyl magnesium bromide, 2,6-diethylphenyl magnesium bromide and 3,4 , At least one of 5-trimethylphenylmagnesium bromide.
根据本发明的实施例，所述加成反应在第三溶剂中进行，所述第三溶剂包括选自四氢呋喃和1,4-二氧六环中的至少之一，优选为四氢呋喃。According to an embodiment of the present invention, the addition reaction is carried out in a third solvent, and the third solvent includes at least one selected from tetrahydrofuran and 1,4-dioxane, preferably tetrahydrofuran.
根据本发明的实施例，所述加成反应在-78～60℃下进行0.5～12h完成，优选在-78℃下进行1h完成。According to the embodiment of the present invention, the addition reaction is completed at -78-60°C for 0.5-12 hours, preferably at -78°C for 1 hour.
根据本发明的实施例，式(V)所示化合物可以通过使式(VI)所示化合物发生三氟甲磺酰化反应制备得到。根据本发明的一些实施例，三氟甲磺酰化反应在碱的作用下进行，三氟甲磺酰化反应中所采用的碱可以包括选自吡啶、三乙胺、二乙胺、N,N-二异丙基乙胺、2,6-二甲基吡啶和碳酸钾中的至少之一，优选为吡啶。三氟甲磺酰化反应所采用的溶剂可以包括选自二氯甲烷、三氯甲烷、1,2-二氯乙烷、甲苯和苯中的至少之一，优选为二氯甲烷。三氟甲磺酰化反应可以在-78～45℃下进行8～36h完成，优选在25℃下进行12h完成。According to an embodiment of the present invention, the compound represented by formula (V) can be prepared by subjecting the compound represented by formula (VI) to trifluoromethanesulfonylation. According to some embodiments of the present invention, the trifluoromethanesulfonylation reaction is carried out under the action of a base, and the base used in the trifluoromethanesulfonylation reaction may include selected from pyridine, triethylamine, diethylamine, N, At least one of N-diisopropylethylamine, 2,6-lutidine and potassium carbonate is preferably pyridine. The solvent used in the trifluoromethanesulfonylation reaction may include at least one selected from dichloromethane, trichloromethane, 1,2-dichloroethane, toluene, and benzene, and is preferably dichloromethane. The trifluoromethanesulfonylation reaction can be completed at -78-45°C for 8 to 36 hours, preferably at 25°C for 12 hours.
Figure PCTCN2019116328-appb-000007
Figure PCTCN2019116328-appb-000007
根据本发明的实施例，式(IV)所示化合物可以通过使式(II)所示化合物发生氧化反应制备得到。According to an embodiment of the present invention, the compound represented by formula (IV) can be prepared by subjecting the compound represented by formula (II) to an oxidation reaction.
根据本发明的实施例，所述氧化反应在氧化剂的作用下进行，所述氧化剂可以包括选自氧气和臭氧中的至少之一。According to an embodiment of the present invention, the oxidation reaction is performed under the action of an oxidant, and the oxidant may include at least one selected from oxygen and ozone.
根据本发明的实施例，所述氧化反应在第四溶剂中进行，所述第四溶剂包括选自二氯甲烷，三氯甲烷，1,2-二氯乙烷和甲醇中的至少之一，优选为二氯甲烷。According to an embodiment of the present invention, the oxidation reaction is performed in a fourth solvent, and the fourth solvent includes at least one selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane and methanol, Preferably it is dichloromethane.
根据本发明的实施例，所述氧化反应在-78～-20℃下进行1～24h完成，优选在-78℃下进行13h完成。According to an embodiment of the present invention, the oxidation reaction is completed at -78°C to -20°C for 1 to 24 hours, preferably at -78°C for 13 hours.
在本发明的另一方面，本发明提出了上述实施例的化合物在在对有机分子选择性包合中的用途，所述化合物用于从混合溶液中识别并选择性包合有机分子。根据本发明的实施例，式(I)所示化合物能够作为大环主体分子，选择性识别和包合有机小分子，从而应用于有机小分子的分离。In another aspect of the present invention, the present invention proposes the use of the compounds of the above embodiments in the selective inclusion of organic molecules, and the compounds are used to identify and selectively include organic molecules from a mixed solution. According to an embodiment of the present invention, the compound represented by formula (I) can be used as a macrocyclic host molecule to selectively recognize and include small organic molecules, thereby being applied to the separation of small organic molecules.
根据本发明的实施例，上述混合溶液包括1,2-二氯乙烷、甲醇、氯仿和乙醇。根据本发明的具体示例，本发明的化合物与有机分子所形成的包合物包括：式(If-1)所示化合物与1,2-二氯乙烷，式(VIIa)所示化合物与乙醇，式(VIIb)所示化合物与1,2-二氯乙烷，式(VIIc)所示化合物与氯仿，According to an embodiment of the present invention, the above-mentioned mixed solution includes 1,2-dichloroethane, methanol, chloroform, and ethanol. According to a specific example of the present invention, the inclusion compound formed by the compound of the present invention and an organic molecule includes: a compound represented by formula (If-1) and 1,2-dichloroethane, a compound represented by formula (VIIa) and ethanol , The compound represented by formula (VIIb) and 1,2-dichloroethane, the compound represented by formula (VIIc) and chloroform,
Figure PCTCN2019116328-appb-000008
Figure PCTCN2019116328-appb-000008
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。The additional aspects and advantages of the present invention will be partly given in the following description, and part of them will become obvious from the following description, or be understood through the practice of the present invention.
附图说明Description of the drawings
附图是用来提供对本发明的进一步理解，并且构成说明书的一部分，与下面的具体实施方式一起用于解释本发明，但并不构成对本发明的限制。在附图中：The accompanying drawings are used to provide a further understanding of the present invention and constitute a part of the specification. Together with the following specific embodiments, they are used to explain the present invention, but do not constitute a limitation to the present invention. In the attached picture:
图1为式(Ia)所示化合物的核磁氢谱；Figure 1 is a hydrogen nuclear magnetic spectrum of the compound represented by formula (Ia);
图2为式(Ia)所示化合物的核磁碳谱。Figure 2 is a nuclear magnetic carbon spectrum of the compound represented by formula (Ia).
图3为式(Id-1)所示化合物的核磁氢谱；Figure 3 is the hydrogen nuclear magnetic spectrum of the compound represented by formula (Id-1);
图4为式(Id-1)所示化合物的核磁碳谱；Figure 4 is the NMR spectrum of the compound represented by formula (Id-1);
图5为式(Ib)所示化合物的晶体结构图；Figure 5 is a crystal structure diagram of the compound represented by formula (Ib);
图6为式(Ie-1)所示化合物的晶体结构图；Figure 6 is a crystal structure diagram of the compound represented by formula (Ie-1);
图7为式(If-1)所示化合物与客体1,2-二氯乙烷形成的复合物晶体结构图；Figure 7 is a crystal structure diagram of a complex formed by a compound represented by formula (If-1) and a guest 1,2-dichloroethane;
图8为式(VIIa)所示化合物与客体乙醇形成的包合物晶体结构图；Figure 8 is a crystal structure diagram of the inclusion compound formed by the compound represented by formula (VIIa) and guest ethanol;
图9为式(VIIb)所示化合物与客体1,2-二氯乙烷形成的复合物晶体结构图；Figure 9 is a crystal structure diagram of a complex formed by a compound represented by formula (VIIb) and a guest 1,2-dichloroethane;
图10为式(VIIc)所示化合物与客体氯仿形成的复合物晶体结构图。Figure 10 is a crystal structure diagram of a complex formed by the compound represented by formula (VIIc) and guest chloroform.
具体实施方式Detailed ways
下面详细描述本发明的实施例。下面描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。The embodiments of the present invention are described in detail below. The embodiments described below are exemplary, and are only used to explain the present invention, but should not be construed as limiting the present invention. Where specific techniques or conditions are not indicated in the examples, the procedures shall be carried out in accordance with the techniques or conditions described in the literature in the field or in accordance with the product specification. The reagents or instruments used without the manufacturer's indication are all conventional products that are commercially available.
实施例1：制备化合物(Ia)(对应式(I)中R 1为CH 3；R 2为CH 3；R 3为Et) Example 1: Preparation of compound (Ia) (corresponding to formula (I) where R 1 is CH 3 ; R 2 is CH 3 ; R 3 is Et)
反应式如下：The reaction formula is as follows:
Figure PCTCN2019116328-appb-000009
Figure PCTCN2019116328-appb-000009
具体制备方法是：The specific preparation method is:
在100mL史莱克瓶中加入0.3mmol(190mg)式(IIa)所示化合物与60mL二氯乙烷，室温下，使用微量进样器沿瓶壁缓慢加入0.15mmol(0.025mL)三氟甲磺酸酐，室温反应6h。反应完毕后，加水淬灭，用二氯甲烷萃取水相，合并有机相并用饱和氯化钠溶液洗涤，随后用无水硫酸钠干燥。将溶剂旋干柱层析(硅胶100～200目，淋洗剂：石油醚/二氯甲烷＝10/1)分离得到式(VIIa)所示化合物131mg，产率69％。Add 0.3mmol (190mg) of the compound represented by formula (IIa) and 60mL of dichloroethane into a 100mL Shrek bottle, and slowly add 0.15mmol (0.025mL) of trifluoromethanesulfonic anhydride along the wall of the bottle using a micro-injector at room temperature , Reaction at room temperature for 6h. After the completion of the reaction, it was quenched by adding water, the aqueous phase was extracted with dichloromethane, the organic phases were combined and washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. Solvent spin-drying column chromatography (silica gel 100-200 mesh, eluent: petroleum ether/dichloromethane = 10/1) was separated to obtain 131 mg of the compound represented by formula (VIIa) with a yield of 69%.
1H-NMR(400MHz,CHLOROFORM-D)δ7.31(d,J＝7.8Hz,4H),6.86(d,J＝7.8Hz,2H),6.81(s,2H),6.66(d,J＝7.8Hz,2H),5.22(s,2H),4.78(s,2H),3.99-4.07(m,4H),2.50-2.57(m,4H),2.31-2.38(m,4H),2.04(s,6H),1.60(d,J＝6.9Hz,12H),1.46(t,J＝7.3Hz,6H),1.09(t,J＝7.3Hz,6H)； 1 H-NMR(400MHz,CHLOROFORM-D)δ7.31(d,J=7.8Hz,4H), 6.86(d,J=7.8Hz,2H), 6.81(s,2H), 6.66(d,J= 7.8Hz, 2H), 5.22 (s, 2H), 4.78 (s, 2H), 3.99-4.07 (m, 4H), 2.50-2.57 (m, 4H), 2.31-2.38 (m, 4H), 2.04 (s , 6H), 1.60 (d, J = 6.9 Hz, 12H), 1.46 (t, J = 7.3 Hz, 6H), 1.09 (t, J = 7.3 Hz, 6H);
13C-NMR(101MHz,CHLOROFORM-D)δ146.1,145.6,145.0,143.9,143.6,142.3,139.9,139.2,125.0,123.3,122.7,120.6 119.6,115.5,48.4,42.4,40.4,27.0,26.0,25.3,20.7,13.4,13.3； 13 C-NMR (101MHz, CHLOROFORM-D) δ146.1, 145.6, 145.0, 143.9, 143.6, 142.3, 139.9, 139.2, 125.0, 123.3, 122.7, 120.6 119.6, 115.5, 48.4, 42.4, 40.4, 27.0, 26.0, 25.3, 20.7, 13.4, 13.3;
HRMS(APCI)calcd.for C 48H 57 +:[M+H] +m/z 633.4455,found 633.4446. HRMS(APCI)calcd.for C 48 H 57 + :[M+H] + m/z 633.4455,found 633.4446.
由上可知，上述化合物结构正确，为式(VIIa)所示化合物。It can be seen from the above that the above compound has a correct structure and is a compound represented by formula (VIIa).
随后将式(VIIa)所示化合物0.1mmol(63.3mg)置于25mL史莱克管中，加入5mL二氯乙烷溶解。室温下使用注射器沿瓶壁缓慢加入0.3mmol(0.06mL)三氟甲磺酸，40℃反应2h。反应完毕后，加水淬灭，用二氯甲烷萃取水相，合并有机相并用饱和氯化钠溶液洗涤，随后用无水硫酸钠干燥。将溶剂旋干柱层析(硅胶100～200目，淋洗剂：石油醚/二氯甲烷＝10/1)分离得到式(Ia)所示化合物10.4mg，产率16％。Subsequently, 0.1 mmol (63.3 mg) of the compound represented by formula (VIIa) was placed in a 25 mL Shrek tube, and 5 mL of dichloroethane was added to dissolve. Use a syringe to slowly add 0.3 mmol (0.06 mL) of trifluoromethanesulfonic acid along the bottle wall at room temperature, and react for 2 hours at 40°C. After the completion of the reaction, it was quenched by adding water, the aqueous phase was extracted with dichloromethane, the organic phases were combined and washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. Solvent spin-drying column chromatography (silica gel 100-200 mesh, eluent: petroleum ether/dichloromethane = 10/1) was separated to obtain 10.4 mg of the compound represented by formula (Ia) with a yield of 16%.
1H-NMR(400MHz,CHLOROFORM-D)δ7.03(s,4H),6.81(s,4H),4.18(t,J＝6.9Hz,4H),2.07-2.14(m,8H),1.75(s,12H),1.72(s,12H),1.33(t,J＝7.1Hz,12H)；(如图1) 1 H-NMR(400MHz,CHLOROFORM-D)δ7.03(s,4H), 6.81(s,4H), 4.18(t,J=6.9Hz,4H), 2.07-2.14(m,8H), 1.75( s,12H),1.72(s,12H),1.33(t,J=7.1Hz,12H); (Figure 1)
13C-NMR(101MHz,CHLOROFORM-D)δ148.1,144.4,120.6,119.8,43.6,42.4,28.1,24.1,20.7,13.1；(如图2) 13 C-NMR (101MHz, CHLOROFORM-D)δ148.1, 144.4, 120.6, 119.8, 43.6, 42.4, 28.1,24.1, 20.7, 13.1; (Figure 2)
HRMS(APCI)calcd.for C 48H 57 +:[M+H] +m/z 633.4446,found 633.4460. HRMS(APCI)calcd.for C 48 H 57 + :[M+H] + m/z 633.4446,found 633.4460.
由上可知，上述化合物结构正确，为式(Ia)所示化合物。It can be seen from the above that the above compound has a correct structure and is a compound represented by formula (Ia).
式(IIa)所示化合物的制备方法如下：The preparation method of the compound represented by formula (IIa) is as follows:
Figure PCTCN2019116328-appb-000010
Figure PCTCN2019116328-appb-000010
在250mL三口瓶中加入2.5mmol(2.67g)式Va，82mL二氧六环与水的混合溶液(v/v＝4.5/1)，2.5mmol(2.89g)四三苯基膦钯，40mmol(5.5g)碳酸钾，以及15mmol(2.9mL)异丙烯基硼酸频哪醇酯。随后将反应放于110℃的油浴中反应24h。反应结束后，用乙酸乙酯(EA)萃取反应体系，合并有机相后用5％过氧化氢与饱和氯化钠溶液洗涤。随后用无水硫酸钠干燥。将溶剂旋干柱层析(硅胶100～200目，淋洗剂：石油醚/二氯甲烷＝30/1)分离得到式IIa所示化合物943mg，产率60％。In a 250mL three-necked flask, add 2.5mmol (2.67g) of formula Va, 82mL of a mixed solution of dioxane and water (v/v=4.5/1), 2.5mmol (2.89g) palladium tetraphenylphosphine, 40mmol ( 5.5 g) potassium carbonate, and 15 mmol (2.9 mL) isopropenyl borate pinacol ester. The reaction was then placed in an oil bath at 110°C for 24 hours. After the reaction, the reaction system was extracted with ethyl acetate (EA), and the organic phases were combined and washed with 5% hydrogen peroxide and saturated sodium chloride solution. It was then dried with anhydrous sodium sulfate. Solvent spin-drying column chromatography (silica gel 100-200 mesh, eluent: petroleum ether/dichloromethane=30/1) was separated to obtain 943 mg of the compound represented by formula IIa with a yield of 60%.
1H-NMR(400MHz,CHLOROFORM-D)δ6.87(s,4H),6.83(d,J＝7.8Hz,4H),6.76(d,J＝7.8Hz,4H), 5.11(s,4H),4.68(s,4H),4.10(t,J＝7.3Hz,4H),2.04-2.11(m,4H),1.89-1.96(m,4H),1.82(s,12H),0.91(t,J＝7.3Hz,12H)； 1 H-NMR(400MHz,CHLOROFORM-D)δ6.87(s,4H), 6.83(d,J=7.8Hz,4H), 6.76(d,J=7.8Hz,4H), 5.11(s,4H) ,4.68(s,4H),4.10(t,J=7.3Hz,4H),2.04-2.11(m,4H),1.89-1.96(m,4H),1.82(s,12H),0.91(t,J =7.3Hz,12H);
13C-NMR(101MHz,CHLOROFORM-D)δ145.9,144.2,141.5,141.1,127.5,125.6,115.0,47.4,29.4,25.7,13.0； 13 C-NMR (101MHz, CHLOROFORM-D) δ145.9, 144.2, 141.5, 141.1, 127.5, 125.6, 115.0, 47.4, 29.4, 25.7, 13.0;
HRMS(APCI)calcd.for C 48H 57 +:[M+H] +m/z 633.4455,found 633.4445. HRMS(APCI)calcd.for C 48 H 57 + :[M+H] + m/z 633.4455,found 633.4445.
由上可知，上述化合物结构正确，为式IIa所示化合物。It can be seen from the above that the above compound has a correct structure and is a compound represented by formula IIa.
式(Va)所示化合物的合成参考文献：(a)P.C.B.Page,T.R.Bygrave,Y.Chan,H.Heaney,V.McKee.Eur.J.Org.Chem.2011,3016；(b)J.N.Smith,N.T.Lucas.Chem.Commun.2018,54,4716.References for the synthesis of the compound represented by formula (Va): (a) PCBPage, TRBygrave, Y. Chan, H. Heaney, V. McKee. Eur. J. Org. Chem. 2011, 3016; (b) JNSmith ,NTLucas.Chem.Commun.2018,54,4716.
实施例2：制备化合物(Ib)(对应式(I)中R 1为CH 3；R 2为CH 3；R 3为n-C 5H 11) Example 2: Preparation of compound (Ib) (corresponding to formula (I) where R 1 is CH 3 ; R 2 is CH 3 ; R 3 is nC 5 H 11 )
反应式如下：The reaction formula is as follows:
Figure PCTCN2019116328-appb-000011
Figure PCTCN2019116328-appb-000011
具体制备方法是：The specific preparation method is:
在100mL史莱克瓶中加入0.2mmol(160mg)式(IIb)所示化合物与40mL二氯乙烷，室温下，使用微量进样器沿瓶壁缓慢加入0.1mmol(0.017mL)三氟甲磺酸酐，室温下反应27h。反应完毕后，加水淬灭，用二氯甲烷萃取水相，合并有机相并用饱和氯化钠溶液洗涤，随后用无水硫酸钠干燥。将溶剂旋干柱层析(硅胶100～200目，淋洗剂：石油醚/二氯甲烷＝15/1)分离得到式(VIIb)所示化合物123mg，产率77％。Add 0.2mmol (160mg) of the compound represented by formula (IIb) and 40mL of dichloroethane into a 100mL Shrek bottle, and slowly add 0.1mmol (0.017mL) of trifluoromethanesulfonic anhydride along the wall of the bottle using a micro-injector at room temperature , React for 27h at room temperature. After the completion of the reaction, it was quenched by adding water, the aqueous phase was extracted with dichloromethane, the organic phases were combined and washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. Solvent spin-drying column chromatography (silica gel 100-200 mesh, eluent: petroleum ether/dichloromethane=15/1) was separated to obtain 123 mg of the compound represented by formula (VIIb) with a yield of 77%.
1H-NMR(400MHz,CHLOROFORM-D)δ7.31(s,2H),7.29(s,2H),6.86(d,J＝7.8Hz,2H),6.81(s,2H),6.65(d,J＝7.3Hz,2H),5.22(s,2H),4.78(s,2H),4.13(t,J＝6.6Hz,2H),4.09(t,J＝8.0Hz,2H),2.24-2.50(m,8H),2.04(s,6H),1.71-1.83(m,8H),1.60(s,6H),1.59(s,6H),1.33-1.65(m,16H),1.08(t,J＝7.3Hz,6H),0.91(t,J＝6.9Hz,6H)； 1 H-NMR(400MHz,CHLOROFORM-D)δ7.31(s,2H),7.29(s,2H),6.86(d,J=7.8Hz,2H),6.81(s,2H),6.65(d, J = 7.3Hz, 2H), 5.22 (s, 2H), 4.78 (s, 2H), 4.13 (t, J = 6.6 Hz, 2H), 4.09 (t, J = 8.0 Hz, 2H), 2.24-2.50 ( m,8H),2.04(s,6H),1.71-1.83(m,8H),1.60(s,6H),1.59(s,6H),1.33-1.65(m,16H),1.08(t,J= 7.3Hz, 6H), 0.91 (t, J=6.9Hz, 6H);
13C-NMR(101MHz,CHLOROFORM-D)δ146.3,145.7,145.2,144.2,143.9,142.7,140.3,139.2,125.1,123.4,122.8,120.9,119.9,115.6,46.7,40.7,40.6,34.2,33.1,32.4,28.6,28.5,28.0,27.1,26.1,25.4,23.2,22.7,14.4,14.4； 13 C-NMR (101MHz, CHLOROFORM-D) δ146.3, 145.7, 145.2, 144.2, 143.9, 142.7, 140.3, 139.2, 125.1, 123.4, 122.8, 120.9, 119.9, 115.6, 46.7, 40.7, 40.6, 34.2, 33.1, 32.4 ,28.6,28.5,28.0,27.1,26.1,25.4,23.2,22.7,14.4,14.4;
HRMS(APCI)calcd.for C 60H 81 +:[M+H] +801.6333.Found:801.6329. HRMS(APCI)calcd.for C 60 H 81 + :[M+H] + 801.6333.Found:801.6329.
由上可知，上述化合物结构正确，为式(VIIb)所示化合物。It can be seen from the above that the above compound has a correct structure and is a compound represented by formula (VIIb).
随后将式(VIIb)所示化合物0.1mmol(80.1mg)置于25mL史莱克管中，加入5mL二氯乙烷溶解。室温下使用微量进样器沿瓶壁缓慢加入0.3mmol(0.06mL)三氟甲磺酸，40℃反应2h。反应完毕后，加水淬灭，用二氯甲烷萃取水相，合并有机相并用饱和氯化钠溶液洗涤，随后用无水硫酸钠干燥。将溶剂旋干柱层析(硅胶100～200目，淋洗剂：石油醚/二氯甲烷＝10/1)分离得到式(Ib)所示化合物11.7mg，产率15％，其晶体结构如图5。Subsequently, 0.1 mmol (80.1 mg) of the compound represented by formula (VIIb) was placed in a 25 mL Shrek tube, and 5 mL of dichloroethane was added to dissolve. Slowly add 0.3mmol (0.06mL) of trifluoromethanesulfonic acid along the wall of the bottle using a micro-injector at room temperature, and react at 40°C for 2h. After the completion of the reaction, it was quenched by adding water, the aqueous phase was extracted with dichloromethane, the organic phases were combined and washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. Solvent spin-drying column chromatography (silica gel 100-200 mesh, eluent: petroleum ether/dichloromethane = 10/1) was separated to obtain 11.7 mg of the compound represented by formula (Ib) with a yield of 15%. Its crystal structure is as follows Figure 5.
1H-NMR(400MHz,CHLOROFORM-D)δ7.02(s,4H),6.77(s,4H),4.26(t,J＝6.9Hz,4H),2.02-2.07(m,8H),1.74(s,12H),1.71(s,12H),1.69-1.77(m,8H),1.55-1.62(m,8H),1.44-1.49(m,8H),1.00(t,J＝7.1Hz,12H)；(如图3) 1 H-NMR(400MHz,CHLOROFORM-D)δ7.02(s,4H), 6.77(s,4H), 4.26(t,J=6.9Hz,4H), 2.02-2.07(m,8H), 1.74( s,12H),1.71(s,12H),1.69-1.77(m,8H),1.55-1.62(m,8H),1.44-1.49(m,8H),1.00(t,J=7.1Hz,12H) ; (Figure 3)
13C-NMR(101MHz,CHLOROFORM-D)δ148.0,144.6,120.7,119.9,42.4,41.6,32.8,28.4,28.2,27.8,24.1,23.1,14.4；(如图4) 13 C-NMR (101MHz, CHLOROFORM-D)δ148.0, 144.6, 120.7, 119.9, 42.4, 41.6, 32.8, 28.4, 28.2, 27.8, 24.1,23.1, 14.4; (Figure 4)
HRMS(APCI)calcd.for C 60H 81 +:[M+H] +801.6333.Found:801.6320. HRMS(APCI)calcd.for C 60 H 81 + :[M+H] + 801.6333.Found:801.6320.
由上可知，上述化合物结构正确，为式(Ib)所示化合物。It can be seen from the above that the above compound has a correct structure and is a compound represented by formula (Ib).
式(IIb)所示化合物的制备方法如下：The preparation method of the compound represented by formula (IIb) is as follows:
Figure PCTCN2019116328-appb-000012
Figure PCTCN2019116328-appb-000012
在50mL三口瓶中加入0.53mmol(650mg)式(Vb)所示化合物，22mL二氧六环与水的混合溶液(v/v＝4.5/1)，0.53mmol(613mg)四三苯基膦钯，8.48mmol(1.17g)碳酸钾，以及3.18mmol(0.6mL)异丙烯基硼酸频哪醇酯。随后将反应放于110℃的油浴中反应24h。反应结束后，用乙酸乙酯萃取反应体系，合并有机相后用5％过氧化氢与饱和氯化钠溶液洗涤。随后用无水硫酸钠干燥。将溶剂旋干柱层析(硅胶100～200目，淋洗剂：石油醚)分离得到式(IIb)所示化合物341mg，产率80％。Add 0.53mmol (650mg) of the compound represented by formula (Vb), 22mL of a mixed solution of dioxane and water (v/v=4.5/1), 0.53mmol (613mg) of tetrakistriphenylphosphine palladium in a 50mL three-necked flask , 8.48mmol (1.17g) potassium carbonate, and 3.18mmol (0.6mL) isopropenyl borate pinacol ester. The reaction was then placed in an oil bath at 110°C for 24 hours. After the reaction, the reaction system was extracted with ethyl acetate, and the organic phases were combined and washed with 5% hydrogen peroxide and saturated sodium chloride solution. It was then dried with anhydrous sodium sulfate. Solvent spin-drying column chromatography (silica gel 100-200 mesh, eluent: petroleum ether) was separated to obtain 341 mg of the compound represented by formula (IIb) with a yield of 80%.
1H-NMR(400MHz,CHLOROFORM-D)δ6.83(d,J＝8.2Hz,4H),6.83(s,4H),6.75(dd,J＝8.0,1.6Hz,4H),5.10(s,4H),4.67(s,4H),4.18(t,J＝7.3Hz,4H),1.87-2.02(m,8H),1.82(s,12H),1.27-1.28(m,24H),0.85(t,J＝6.6Hz,12H)； 1 H-NMR (400MHz, CHLOROFORM-D) δ 6.83 (d, J = 8.2 Hz, 4H), 6.83 (s, 4H), 6.75 (dd, J = 8.0, 1.6 Hz, 4H), 5.10 (s, 4H), 4.67 (s, 4H), 4.18 (t, J = 7.3Hz, 4H), 1.87-2.02 (m, 8H), 1.82 (s, 12H), 1.27-1.28 (m, 24H), 0.85 (t ,J=6.6Hz,12H);
13C-NMR(101MHz,CHLOROFORM-D)δ145.7,144.1,141.2,141.0,127.4,127.3,125.7,114.8,45.6,36.6,32.1,28.0,25.6,22.6,14.1； 13 C-NMR (101MHz, CHLOROFORM-D) δ145.7, 144.1, 141.2, 141.0, 127.4, 127.3, 125.7, 114.8, 45.6, 36.6, 32.1,28.0, 25.6, 22.6, 14.1;
HRMS(APCI)calcd.for C 60H 81 +:[M+H] +801.6333Found:801.6326. HRMS(APCI)calcd.for C 60 H 81 + :[M+H] + 801.6333Found:801.6326.
由上可知，上述化合物结构正确，为式(IIb)所示化合物。It can be seen from the above that the above compound has a correct structure and is a compound represented by formula (IIb).
式(Vb)所示化合物的制备方法如下：The preparation method of the compound represented by formula (Vb) is as follows:
Figure PCTCN2019116328-appb-000013
Figure PCTCN2019116328-appb-000013
在500mL三口烧瓶中加入6mmol(4.2g)式(VIa)所示化合物，200mL二氯甲烷与48mmol(3.9mL)吡啶，室温搅拌均匀后将体系置于冰水浴中，使用10mL恒压滴液漏斗将36mmol(6mL)三氟甲磺酸酐缓慢加入体系。滴毕，将体系移至室温并继续反应12h。反应结束后，缓慢加入冰水淬灭，用二氯甲烷萃取水相，合并有机相后用饱和食盐水洗涤并用无水硫酸钠干燥。旋干溶剂后，用甲醇重结晶可得式(Vb)所示化合物6.3g，产率85％。Add 6mmol (4.2g) of the compound represented by formula (VIa), 200mL of dichloromethane and 48mmol (3.9mL) of pyridine into a 500mL three-necked flask. After stirring at room temperature, place the system in an ice-water bath and use a 10mL constant pressure dropping funnel. 36mmol (6mL) of trifluoromethanesulfonic anhydride was slowly added to the system. After dripping, the system was moved to room temperature and the reaction continued for 12 hours. After the reaction was completed, ice water was slowly added to quench, the aqueous phase was extracted with dichloromethane, and the organic phases were combined and washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was spin-dried, and recrystallized with methanol, 6.3 g of the compound represented by formula (Vb) was obtained with a yield of 85%.
1H-NMR(400MHz,CHLOROFORM-D,61℃)δ7.12(s,8H),6.92(s,4H),4.28(t,J＝7.6Hz,4H),1.96-2.02(m,8H),1.27-1.32(m,24H),0.87(t,J＝6.9Hz,12H)； 1 H-NMR(400MHz,CHLOROFORM-D,61℃)δ7.12(s,8H),6.92(s,4H),4.28(t,J=7.6Hz,4H),1.96-2.02(m,8H) ,1.27-1.32(m,24H),0.87(t,J=6.9Hz,12H);
19F-NMR(376MHz,CHLOROFORM-D)δ-73.78； 19 F-NMR(376MHz, CHLOROFORM-D)δ-73.78;
13C-NMR(101MHz,CHLOROFORM-D)δ146.1,143.5,136.8,130.0,126.3,123.29-121.3(J C,F＝322Hz,CF 3),113.7,43.2,35.2,31.7,27.3,22.5,14.0； 13 C-NMR (101MHz, CHLOROFORM-D) δ146.1 , 143.5, 136.8, 130.0, 126.3, 123.29-121.3 (J C, F = 322Hz, CF 3 ), 113.7, 43.2, 35.2, 31.7, 27.3, 22.5, 14.0;
HRMS(Maldi)calcd.for C 52H 60F 12O 12S 4Na +:[M+Na] +1255.2668.Found:1255.2662. HRMS(Maldi)calcd.for C 52 H 60 F 12 O 12 S 4 Na + :[M+Na] + 1255.2668.Found: 1255.2662.
由上可知，上述化合物结构正确，为式(Vb)所示化合物。It can be seen from the above that the above compound has the correct structure and is a compound represented by formula (Vb).
式(VIa)所示化合物的制备方法如下：The preparation method of the compound represented by formula (VIa) is as follows:
Figure PCTCN2019116328-appb-000014
Figure PCTCN2019116328-appb-000014
在250mL三口烧瓶中加入6.6mmol(5g)式(VIIIa)所示化合物，120mL二氯甲烷。室温搅拌均匀后将体系置于冰水浴中，使用10mL恒压滴液漏斗将40mmol(3.9mL)三溴化硼缓慢加入体系。滴毕，将体系移至室温并继续反应12h。反应结束后，缓慢加入冰水淬灭，用乙酸乙酯萃取水相，合并有机相后用饱和食盐水洗涤并用无水硫酸钠干燥。旋干溶剂后，用乙酸乙酯-石油醚重结晶可得式(VIa)所示化合物4.4g，产率95％。In a 250 mL three-necked flask were added 6.6 mmol (5 g) of the compound represented by formula (VIIIa) and 120 mL of dichloromethane. After stirring uniformly at room temperature, the system was placed in an ice-water bath, and 40 mmol (3.9 mL) of boron tribromide was slowly added to the system using a 10 mL constant pressure dropping funnel. After dripping, the system was moved to room temperature and the reaction continued for 12 hours. After the reaction was completed, ice water was slowly added to quench, the aqueous phase was extracted with ethyl acetate, and the organic phases were combined and washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was spin-dried, and recrystallized with ethyl acetate-petroleum ether, 4.4 g of the compound represented by formula (VIa) was obtained with a yield of 95%.
1H-NMR(400MHz,DMSO-D6)δ8.84(s,4H),7.32(d,J＝1.4Hz,4H),6.80(dd,J＝8.2,1.8Hz,4H),6.47(d,J＝8.2Hz,4H),4.15(t,J＝8.0Hz,4H),2.01-2.09(m,8H),1.13-1.31(m,24H),0.83(t,J＝7.1Hz,12H)； 1 H-NMR(400MHz,DMSO-D6)δ8.84(s,4H), 7.32(d,J=1.4Hz,4H), 6.80(dd,J=8.2,1.8Hz,4H), 6.47(d, J = 8.2 Hz, 4H), 4.15 (t, J = 8.0 Hz, 4H), 2.01-2.09 (m, 8H), 1.13-1.31 (m, 24H), 0.83 (t, J = 7.1 Hz, 12H);
13C-NMR(101MHz,DMSO-D6)δ151.9,136.0,132.0,127.1,123.3,113.9,40.9,33.9,31.5,27.5,22.2,14.0； 13 C-NMR(101MHz, DMSO-D6) δ151.9, 136.0, 132.0, 127.1, 123.3, 113.9, 40.9, 33.9, 31.5, 27.5, 22.2, 14.0;
HRMS(APCI)calcd.for C 48H 63O 4 -:[M-H] -703.4732.Found:703.4718. HRMS (APCI) calcd.for C 48 H 63 O 4 -: [MH] - 703.4732.Found: 703.4718.
由上可知，上述化合物结构正确，为式(VIa)所示化合物。It can be seen from the above that the above compound has the correct structure and is a compound represented by formula (VIa).
式(VIIIa)所示化合物的合成参考文献：P.C.B.Page,T.R.Bygrave,Y.Chan,H.Heaney,V.McKee.Eur.J.Org.Chem.2011,3016.References for the synthesis of the compound represented by formula (VIIIa): P.C.B. Page, T.R. Bygrave, Y. Chan, H. Heaney, V. McKee. Eur. J. Org. Chem. 2011, 3016.
实施例3：制备化合物(Ic)(对应式(I)中R 1为CH 3；R 2为CH 3；R 3为i-C 3H 7) Example 3: Preparation of compound (Ic) (corresponding to formula (I) where R 1 is CH 3 ; R 2 is CH 3 ; R 3 is iC 3 H 7 )
反应式如下：The reaction formula is as follows:
Figure PCTCN2019116328-appb-000015
Figure PCTCN2019116328-appb-000015
具体制备方法是：The specific preparation method is:
在25mL史莱克瓶中加入0.05mmol(34.4mg)式(IIc)所示化合物与10mL二氯乙烷，室温下，使用微量进样器沿瓶壁缓慢加入0.1mmol(0.017mL)三氟甲磺酸酐，室温下反应48h。反应完毕后，加水淬灭，用二氯甲烷萃取水相，合并有机相并用饱和氯化钠溶液洗涤，随后用无水硫酸钠干燥。将溶剂旋干柱层析(硅胶100～200目，淋洗剂：石油醚/二氯甲烷＝30/1)分离得到式(VIIc)所示化合物24.6mg，产率72％。Add 0.05mmol (34.4mg) of the compound represented by formula (IIc) and 10mL of dichloroethane into a 25mL Shrek bottle, and slowly add 0.1mmol (0.017mL) of trifluoromethanesulfonate along the wall of the bottle using a micro-injector at room temperature Acid anhydride, react for 48h at room temperature. After the completion of the reaction, it was quenched by adding water, the aqueous phase was extracted with dichloromethane, the organic phases were combined and washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. Solvent spin-drying column chromatography (silica gel 100-200 mesh, eluent: petroleum ether/dichloromethane=30/1) was separated to obtain 24.6 mg of the compound represented by formula (VIIc) with a yield of 72%.
1H-NMR(400MHz,CHLOROFORM-D)δ7.32-7.38(m,4H),6.84-6.94(m,2H),6.76(s,2H),6.50-6.60(m,2H),5.21(s,2H),4.75(s,2H),3.90(d,J＝10.5Hz,2H),3.61(d,J＝11.4Hz,2H),2.67-2.88(m,4H),2.00(s,6H),1.70-1.82(m,6H),1.43-1.50(m,12H),1.00-1.18(m,12H)； 1 H-NMR (400MHz, CHLOROFORM-D) δ 7.32-7.38 (m, 4H), 6.84-6.94 (m, 2H), 6.76 (s, 2H), 6.50-6.60 (m, 2H), 5.21 (s ,2H),4.75(s,2H),3.90(d,J=10.5Hz,2H),3.61(d,J=11.4Hz,2H),2.67-2.88(m,4H),2.00(s,6H) ,1.70-1.82(m,6H),1.43-1.50(m,12H),1.00-1.18(m,12H);
13C-NMR(101MHz,CHLOROFORM-D)δ146.5,146.0,144.1,143.0,142.8,138.8,138.6,124.8,123.4,122.9,121.9,121.2,115.6,54.4,49.2,41.0,32.5,27.6,26.3,25.6,25.5,23.2,23.1,22.0,21.9； 13 C-NMR (101MHz, CHLOROFORM-D) δ146.5, 146.0, 144.1, 143.0, 142.8, 138.8, 138.6, 124.8, 123.4, 122.9, 121.9, 121.2, 115.6, 54.4, 49.2, 41.0, 32.5, 27.6, 26.3, 25.6 ,25.5,23.2,23.1,22.0,21.9;
HRMS(APCI)calcd.for C 52H 65:[M+H] +689.5081.Found:689.5075. HRMS(APCI)calcd.for C 52 H 65 :[M+H] + 689.5081.Found:689.5075.
由上可知，上述化合物结构正确，为式(VIIc)所示化合物。It can be seen from the above that the above compound has a correct structure and is a compound represented by formula (VIIc).
随后将式(VIIc)所示化合物0.1mmol(68.9mg)置于25mL史莱克管中，加入5mL二氯乙烷溶解。室 温下使用微量进样器沿瓶壁缓慢加入0.3mmol(0.06mL)三氟甲磺酸，40℃反应2h。反应完毕后，加水淬灭，用二氯甲烷萃取水相，合并有机相并用饱和氯化钠溶液洗涤，随后用无水硫酸钠干燥。将溶剂旋干柱层析(硅胶100～200目，淋洗剂：石油醚/二氯甲烷＝20/1)分离得到式(Ic)所示化合物5.5mg，产率8％。Subsequently, 0.1 mmol (68.9 mg) of the compound represented by formula (VIIc) was placed in a 25 mL Shrek tube, and 5 mL of dichloroethane was added to dissolve. Use a micro-injector to slowly add 0.3mmol (0.06mL) trifluoromethanesulfonic acid along the wall of the bottle at room temperature, and react at 40°C for 2h. After the completion of the reaction, it was quenched by adding water, the aqueous phase was extracted with dichloromethane, the organic phases were combined and washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. Solvent spin-drying column chromatography (silica gel 100-200 mesh, eluent: petroleum ether/dichloromethane=20/1) was separated to obtain 5.5 mg of the compound represented by formula (Ic) with a yield of 8%.
1H-NMR(400MHz,CHLOROFORM-D)δ7.03(s,4H),6.93(s,4H),4.03(d,J＝10.5Hz,4H),2.52-2.57(m,4H),1.79(s,12H),1.69(s,12H),1.37(d,J＝6.4Hz,24H)； 1 H-NMR(400MHz, CHLOROFORM-D) δ7.03(s,4H), 6.93(s,4H), 4.03(d,J=10.5Hz,4H), 2.52-2.57(m,4H), 1.79( s,12H),1.69(s,12H),1.37(d,J=6.4Hz,24H);
13C-NMR(101MHz,CHLOROFORM-D)δ148.7,144.5,122.2,121.2,50.0,43.0,28.8,24.8,24.4,22.7； 13 C-NMR (101MHz, CHLOROFORM-D) δ148.7, 144.5, 122.2, 121.2, 50.0, 43.0, 28.8, 24.8, 24.4, 22.7;
HRMS(APCI)calcd.for C 52H 65:[M+H] +689.5081.Found:689.5079. HRMS(APCI)calcd.for C 52 H 65 :[M+H] + 689.5081.Found:689.5079.
由上可知，上述化合物结构正确，为式(Ic)所示化合物。It can be seen from the above that the above compound has a correct structure and is a compound represented by formula (Ic).
式(IIc)所示化合物的制备方法如下：The preparation method of the compound represented by formula (IIc) is as follows:
Figure PCTCN2019116328-appb-000016
Figure PCTCN2019116328-appb-000016
在50mL三口瓶中加入0.6mmol(672mg)式(Vc)所示化合物，22mL二氧六环与水的混合溶液(v/v＝4.5/1)，0.96mmol(1.1g)四三苯基膦钯，9.6mmol(1.3g)碳酸钾，以及4.8mmol(0.96mL)异丙烯基硼酸频哪醇酯。随后将反应放于110℃的油浴中反应24h。反应结束后，用乙酸乙酯萃取反应体系，合并有机相后用5％过氧化氢与饱和氯化钠溶液洗涤。随后用无水硫酸钠干燥。将溶剂旋干柱层析(硅胶100～200目，淋洗剂：石油醚)分离得到式(IIc)所示化合物187mg，产率45％。In a 50mL three-necked flask, add 0.6mmol (672mg) of the compound represented by formula (Vc), 22mL of a mixed solution of dioxane and water (v/v=4.5/1), 0.96mmol (1.1g) of tetratriphenylphosphine Palladium, 9.6 mmol (1.3 g) potassium carbonate, and 4.8 mmol (0.96 mL) isopropenyl borate pinacol ester. The reaction was then placed in an oil bath at 110°C for 24 hours. After the reaction, the reaction system was extracted with ethyl acetate, and the organic phases were combined and washed with 5% hydrogen peroxide and saturated sodium chloride solution. It was then dried with anhydrous sodium sulfate. Solvent spin-drying column chromatography (silica gel 100-200 mesh, eluent: petroleum ether) was separated to obtain 187 mg of the compound represented by formula (IIc) with a yield of 45%.
1H-NMR(400MHz,CHLOROFORM-D)δ7.63(s,4H),6.99(dd,J＝7.8,0.9Hz,4H),6.83(d,J＝7.8Hz,4H),5.30(s,4H),4.77(s,4H),3.79(d,J＝11.4Hz,4H),2.66-2.76(m,4H),2.02(s,12H),0.82-0.85(m,24H)； 1 H-NMR(400MHz,CHLOROFORM-D)δ7.63(s,4H), 6.99(dd,J=7.8,0.9Hz,4H), 6.83(d,J=7.8Hz,4H), 5.30(s, 4H), 4.77 (s, 4H), 3.79 (d, J = 11.4Hz, 4H), 2.66-2.76 (m, 4H), 2.02 (s, 12H), 0.82-0.85 (m, 24H);
13C-NMR(101MHz,CHLOROFORM-D)δ146.1,144.0,142.0,141.6,128.2,127.9,123.1,116.2,55.0,33.3,26.6,22.1,21.9； 13 C-NMR (101MHz, CHLOROFORM-D) δ146.1, 144.0, 142.0, 141.6, 128.2, 127.9, 123.1, 116.2, 55.0, 33.3, 26.6, 22.1,21.9;
HRMS(APCI)calcd.for C 52H 65 +:[M+H] +689.5081.Found:689.5082. HRMS(APCI)calcd.for C 52 H 65 + :[M+H] + 689.5081.Found:689.5082.
由上可知，上述化合物结构正确，为式(IIc)所示化合物。It can be seen from the above that the above compound has a correct structure and is a compound represented by formula (IIc).
式(Vc)所示化合物的制备方法如下：The preparation method of the compound represented by formula (Vc) is as follows:
Figure PCTCN2019116328-appb-000017
Figure PCTCN2019116328-appb-000017
在500mL三口烧瓶中加入1.6mmol(0.95g)式(VIc)所示化合物，100mL二氯甲烷与12.8mmol(1mL)吡啶，室温搅拌均匀后将体系置于冰水浴中，使用10mL恒压滴液漏斗将9.6mmol(1.6mL)三氟甲磺酸酐缓慢加入体系。滴毕，将体系移至室温并继续反应12h。反应结束后，缓慢加入冰水淬灭，用二氯甲烷萃取水相，合并有机相后用饱和食盐水洗涤并用无水硫酸钠干燥。旋干溶剂后，用甲醇重结晶可得式(Vc)所示化合物1.16g，产率65％。Add 1.6mmol (0.95g) of the compound represented by formula (VIc), 100mL of dichloromethane and 12.8mmol (1mL) of pyridine into a 500mL three-necked flask, stir well at room temperature, then place the system in an ice-water bath and use 10mL constant pressure drop 9.6 mmol (1.6 mL) of trifluoromethanesulfonic anhydride was slowly added to the funnel. After dripping, the system was moved to room temperature and the reaction continued for 12 hours. After the reaction was completed, ice water was slowly added to quench, the aqueous phase was extracted with dichloromethane, and the organic phases were combined and washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent is spin-dried, and recrystallized with methanol, 1.16 g of the compound represented by formula (Vc) can be obtained with a yield of 65%.
1H-NMR(400MHz,CHLOROFORM-D)δ7.40(d,J＝1.8Hz,4H),7.23(dd,J＝8.7,2.3Hz,4H),7.13(d,J＝8.2Hz,4H),3.91(d,J＝11.4Hz,4H),2.64-2.70(m,4H),0.93(d,J＝6.9Hz,12H),0.91(d,J＝6.4Hz, 12H)； 1 H-NMR(400MHz, CHLOROFORM-D) δ7.40(d,J=1.8Hz,4H), 7.23(dd,J=8.7,2.3Hz,4H), 7.13(d,J=8.2Hz,4H) ,3.91(d,J＝11.4Hz,4H),2.64-2.70(m,4H),0.93(d,J＝6.9Hz,12H),0.91(d,J＝6.4Hz, 12H);
19F-NMR(376MHz,CHLOROFORM-D)δ-73.75； 19 F-NMR(376MHz, CHLOROFORM-D)δ-73.75;
13C-NMR(101MHz,CHLOROFORM-D)δ146.6,143.5,136.9,130.5,124.6,123.4-113.9(J＝322Hz,CF 3),121.9,,51.4,31.8,21.6,21.1； 13 C-NMR (101MHz, CHLOROFORM-D) δ146.6, 143.5, 136.9, 130.5, 124.6, 123.4-113.9 (J=322Hz, CF 3 ), 121.9,, 51.4, 31.8, 21.6, 21.1;
HRMS(APCI)calcd.for C 44H 45F 12O 12S 4 +:[M+H] +1121.1597.Found:1121.1589. HRMS(APCI)calcd.for C 44 H 45 F 12 O 12 S 4 + :[M+H] + 1121.1597.Found:1121.1589.
由上可知，上述化合物结构正确，为式(Vc)所示化合物。It can be seen from the above that the above compound has a correct structure and is a compound represented by formula (Vc).
式(VIc)所示化合物的制备方法如下：The preparation method of the compound represented by formula (VIc) is as follows:
Figure PCTCN2019116328-appb-000018
Figure PCTCN2019116328-appb-000018
在100mL三口烧瓶中加入2mmol(1.3g)式(VIIIc)所示化合物，50mL二氯甲烷。室温搅拌均匀后将体系置于冰水浴中，使用10mL恒压滴液漏斗将12mmol(1.1mL)三溴化硼缓慢加入体系。滴毕，将体系移至室温并继续反应12h。反应结束后，缓慢加入冰水淬灭，用乙酸乙酯萃取水相，合并有机相后用饱和食盐水洗涤并用无水硫酸钠干燥。旋干溶剂后，用乙酸乙酯-石油醚重结晶可得式(VIc)所示化合物1.02g，产率88％。In a 100 mL three-necked flask were added 2 mmol (1.3 g) of the compound represented by formula (VIIIc) and 50 mL of dichloromethane. After stirring uniformly at room temperature, the system was placed in an ice-water bath, and 12 mmol (1.1 mL) of boron tribromide was slowly added to the system using a 10 mL constant pressure dropping funnel. After dripping, the system was moved to room temperature and the reaction continued for 12 hours. After the reaction was completed, ice water was slowly added to quench, the aqueous phase was extracted with ethyl acetate, and the organic phases were combined and washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was spin-dried, and recrystallized with ethyl acetate-petroleum ether, 1.02 g of the compound represented by formula (VIc) was obtained with a yield of 88%.
1H-NMR(400MHz,DMSO-D6)δ8.75(s,4H),7.55(s,4H),6.78(dd,J＝8.2,1.8Hz,4H),6.45(d,J＝8.2Hz,4H),3.76(d,J＝11.9Hz,4H),2.92-2.98(m,4H),0.82(d,J＝6.4Hz,12H),0.78(d,J＝6.4Hz,12H)； 1 H-NMR(400MHz,DMSO-D6)δ8.75(s,4H),7.55(s,4H),6.78(dd,J=8.2,1.8Hz,4H), 6.45(d,J=8.2Hz, 4H), 3.76 (d, J = 11.9 Hz, 4H), 2.92-2.98 (m, 4H), 0.82 (d, J = 6.4 Hz, 12H), 0.78 (d, J = 6.4 Hz, 12H);
13C-NMR(101MHz,DMSO-D6)δ152.0,135.9,131.8,127.2,124.1,113.7,49.7,29.76,21.9,21.5； 13 C-NMR (101MHz, DMSO-D6) δ 152.0, 135.9, 131.8, 127.2, 124.1, 113.7, 49.7, 29.76, 21.9, 21.5;
HRMS(APCI)calcd.for C 40H 47O 4 –:[M-H] –591.3480.Found:591.3483. HRMS(APCI)calcd.for C 40 H 47 O 4 – :[MH] – 591.3480.Found:591.3483.
由上可知，上述化合物结构正确，为式(VIc)所示化合物。It can be seen from the above that the above compound has a correct structure and is a compound represented by formula (VIc).
式(VIIIc)所示化合物的制备方法如下：The preparation method of the compound represented by formula (VIIIc) is as follows:
Figure PCTCN2019116328-appb-000019
Figure PCTCN2019116328-appb-000019
在250mL三口烧瓶中加入4mmol(3.68g)Pd 2(dba) 3与8mmol(5g)2,2’-双二苯膦基-1,1’-联萘(BINAP)并注入150mL预先鼓泡除氧的甲苯。将反应加热至回流，反应30min。冷却至室温，往体系中加入10mmol(12.4g)式(IXa)所示化合物，120mmol(16.6mL)三乙胺与120mmol(4.6mL)无水甲酸。室温搅拌均匀后将体系加热至回流，反应3d。反应结束后，旋干溶剂，加入乙酸乙酯溶解并用水，5％过氧化氢溶液与饱和氯化钠溶液洗涤有机相，随后用无水硫酸钠干燥。将溶剂旋干柱层析(硅胶100～200目，淋洗剂：石油醚/二氯甲烷＝3/1)分离得到式(VIIIc)所示化合物2.86g，产率44％。 Add 4mmol (3.68g) Pd 2 (dba) 3 and 8mmol (5g) 2,2'-bis-diphenylphosphino-1,1'-binaphthyl (BINAP) into a 250mL three-necked flask and inject 150mL into pre-bubble removal Oxygen in toluene. The reaction was heated to reflux and reacted for 30 min. After cooling to room temperature, 10 mmol (12.4 g) of the compound represented by formula (IXa), 120 mmol (16.6 mL) of triethylamine and 120 mmol (4.6 mL) of anhydrous formic acid were added to the system. After stirring uniformly at room temperature, the system was heated to reflux and reacted for 3d. After the reaction, the solvent was spin-dried, ethyl acetate was added to dissolve and the organic phase was washed with water, 5% hydrogen peroxide solution and saturated sodium chloride solution, and then dried with anhydrous sodium sulfate. Solvent spin-drying column chromatography (silica gel 100-200 mesh, eluent: petroleum ether/dichloromethane = 3/1) was separated to obtain 2.86 g of the compound represented by formula (VIIIc) with a yield of 44%.
1H-NMR(400MHz,CHLOROFORM-D)δ7.34(d,J＝1.8Hz,4H),7.04(dd,J＝8.2,1.8Hz,4H),6.60(d,J＝8.7Hz,4H),3.97(d,J＝11.9Hz,4H),3.74(s,12H),2.67-2.70(m,4H),0.90(d,J＝6.4Hz,12H),0.86(d,J＝6.4Hz,12H)； 1 H-NMR(400MHz,CHLOROFORM-D)δ7.34(d,J=1.8Hz,4H), 7.04(dd,J=8.2,1.8Hz,4H), 6.60(d,J=8.7Hz,4H) ,3.97(d,J=11.9Hz,4H),3.74(s,12H),2.67-2.70(m,4H),0.90(d,J=6.4Hz,12H),0.86(d,J=6.4Hz, 12H);
13C-NMR(101MHz,CHLOROFORM-D)δ155.1,137.3,133.8,128.4,123.3,110.5,55.8,49.6,31.3,22.0,21.6； 13 C-NMR (101MHz, CHLOROFORM-D) δ155.1, 137.3, 133.8, 128.4, 123.3, 110.5, 55.8, 49.6, 31.3, 22.0, 21.6;
HRMS(APCI)calcd.for C 44H 57O 4 +:[M+H] +649.4251.Found:649.4241. HRMS(APCI)calcd.for C 44 H 57 O 4 + :[M+H] + 649.4251.Found:649.4241.
由上可知，上述化合物结构正确，为式(VIIIc)所示化合物。It can be seen from the above that the above compound has the correct structure and is a compound represented by formula (VIIIc).
式(IXa)所示化合物的制备方法如下：The preparation method of the compound represented by formula (IXa) is as follows:
Figure PCTCN2019116328-appb-000020
Figure PCTCN2019116328-appb-000020
在1000mL三口烧瓶中加入22.5mmol(16.1g)式(Xa)所示化合物，800mL二氯甲烷与135mmol(22.5mL)吡啶，室温搅拌均匀后将体系置于冰水浴中，使用25mL恒压滴液漏斗将18mmol(14.7mL)三氟甲磺酸酐缓慢加入体系。滴毕，将体系移至室温并继续反应12h。反应结束后，缓慢加入冰水淬灭，用二氯甲烷萃取水相，合并有机相后用饱和食盐水洗涤并用无水硫酸钠干燥。旋干溶剂后，用甲醇重结晶可得式(IXa)所示化合物22.5g，产率80％。Add 22.5mmol (16.1g) of the compound represented by formula (Xa), 800mL of dichloromethane and 135mmol (22.5mL) of pyridine into a 1000mL three-necked flask, stir well at room temperature and place the system in an ice-water bath, using 25mL constant pressure drop In the funnel, 18 mmol (14.7 mL) of trifluoromethanesulfonic anhydride was slowly added to the system. After dripping, the system was moved to room temperature and the reaction continued for 12 hours. After the reaction was completed, ice water was slowly added to quench, the aqueous phase was extracted with dichloromethane, and the organic phases were combined and washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was spin-dried, and recrystallized with methanol, 22.5 g of the compound represented by formula (IXa) was obtained with a yield of 80%.
1H-NMR(400MHz,CHLOROFORM-D)δ7.10(s,4H),6.68(s,4H),4.33(d,J＝11.4Hz,4H),3.74(s,12H),2.36-2.42(m,4H),0.88(t,J＝6.6Hz,24H)； 1 H-NMR (400MHz, CHLOROFORM-D) δ 7.10 (s, 4H), 6.68 (s, 4H), 4.33 (d, J = 11.4 Hz, 4H), 3.74 (s, 12H), 2.36-2.42 ( m,4H),0.88(t,J=6.6Hz,24H);
19F-NMR(376MHz,CHLOROFORM-D)δ-73.91； 19 F-NMR(376MHz, CHLOROFORM-D)δ-73.91;
13C-NMR(101MHz,CHLOROFORM-D)δ156.4,147.5,131.3,126.7,126.60,123.5-113.9(J C,F＝321Hz,CF 3),103.3,77.5,77.4,77.2,76.8,55.6,41.8,32.1,21.2,21.0； 13 C-NMR (101MHz, CHLOROFORM-D) δ156.4, 147.5, 131.3, 126.7, 126.60, 123.5-113.9 (J C, F = 321Hz, CF 3 ), 103.3, 77.5, 77.4, 77.2, 76.8, 55.6, 41.8, 32.1,21.2,21.0;
HRMS(APCI)calcd.for C 48H 53F 12O 16S 4 +:[M+H] +1241.2019.Found:1241.2008. HRMS(APCI)calcd.for C 48 H 53 F 12 O 16 S 4 + :[M+H] + 1241.2019.Found:1241.2008.
由上可知，上述化合物结构正确，为式(IXa)所示化合物。It can be seen from the above that the above compound has a correct structure and is a compound represented by formula (IXa).
式(Xa)所示化合物的合成参考文献：J.Sun,L.L.Zhang,Y.Yao,C.G.Yan.J.Incl.Phenom.Macrocycl.Chem.2014,79,485.References for the synthesis of the compound represented by formula (Xa): J.Sun, L.L.Zhang, Y.Yao, C.G.Yan.J.Incl.Phenom.Macrocycl.Chem.2014,79,485.
实施例4：制备化合物(Id-1)、(Id-2)、(Id-3)(对应式(I)中R 1为Ph；R 2为H；R 3为Et) Example 4: Preparation of compounds (Id-1), (Id-2), (Id-3) (corresponding to formula (I) where R 1 is Ph; R 2 is H; R 3 is Et)
反应式如下：The reaction formula is as follows:
Figure PCTCN2019116328-appb-000021
Figure PCTCN2019116328-appb-000021
具体制备方法是：The specific preparation method is:
0℃下，在25mL史莱克瓶中加入0.1mmol(88.6mg)式(IIIa)所示化合物、10mL二氯甲烷与0.2mL甲磺酸，继续反应0.2h。反应结束后用水淬灭，用二氯甲烷萃取水相，合并有机相后用饱和食盐水洗涤并用无水硫酸钠干燥。旋干溶剂，使用制备级薄层色谱预制板分离(涂层厚度0.9-1.1mm，展开剂：石油醚/二氯甲烷＝3/1)，可分离得到不同构型的化合物(Id-1)、(Id-2)、(Id-3)，14.6mg(Id-1)、10.0mg(Id-2)、30.0mg(Id-3)，产率分别为18％(Id-1)、12％(Id-2)、36％(Id-3)。At 0° C., 0.1 mmol (88.6 mg) of the compound represented by formula (IIIa), 10 mL of dichloromethane and 0.2 mL of methanesulfonic acid were added to a 25 mL Shrek flask, and the reaction was continued for 0.2 h. After the reaction was completed, it was quenched with water, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. Rotate the solvent to dry, and use a prefabricated thin-layer chromatography plate for separation (coating thickness 0.9-1.1mm, developing agent: petroleum ether/dichloromethane = 3/1), and compounds of different configurations (Id-1) can be separated , (Id-2), (Id-3), 14.6mg(Id-1), 10.0mg(Id-2), 30.0mg(Id-3), the yields were 18%(Id-1), 12 % (Id-2), 36% (Id-3).
Id-1：Id-1:
1H-NMR(400MHz,CHLOROFORM-D)δ7.71(t,J＝7.6Hz,4H),7.56(t,J＝7.3Hz,2H),7.48(d,J＝6.9Hz,4H),7.08-7.13(m,10H),7.06(s,4H),6.89(s,4H),5.04(s,2H),4.90(s,2H),3.65(t,J＝6.9Hz,2H),3.33(t,J＝6.9Hz,2H),2.27-2.32(m,4H),1.98-2.05(m,4H),1.35(t,J＝7.3Hz,6H),1.10(t,J＝7.3Hz,6H)； 1 H-NMR(400MHz,CHLOROFORM-D)δ7.71(t,J=7.6Hz,4H), 7.56(t,J=7.3Hz,2H), 7.48(d,J=6.9Hz,4H), 7.08 -7.13(m,10H),7.06(s,4H),6.89(s,4H),5.04(s,2H),4.90(s,2H), 3.65(t,J=6.9Hz,2H),3.33( t,J=6.9Hz,2H),2.27-2.32(m,4H),1.98-2.05(m,4H),1.35(t,J=7.3Hz,6H),1.10(t,J=7.3Hz,6H );
13C-NMR(101MHz,CHLOROFORM-D)δ145.7,143.9,143.8,143.5,141.4,137.0,132.8,128.6,128.1,127.6,127.3,126.7,126.2,119.5,57.0,50.9,44.8,44.2,12.0,19.6,13.1,12.8； 13 C-NMR (101MHz, CHLOROFORM-D) δ145.7, 143.9, 143.8, 143.5, 141.4, 137.0, 132.8, 128.6, 128.1, 127.6, 127.3, 126.7, 126.2, 119.5, 57.0, 50.9, 44.8, 44.2, 12.0, 19.6 ,13.1,12.8;
HRMS(APCI)calcd.for C 64H 57 +:[M+H] +825.4455.Found:825.4435. HRMS(APCI)calcd.for C 64 H 57 + :[M+H] + 825.4455.Found:825.4435.
Id-2：Id-2:
1H-NMR(400MHz,TETRACHLOROETHAN)δ7.62(t,J＝7.6Hz,4H),7.47(d,J＝7.3Hz,6H),7.33(s,1H),7.29(d,J＝7.3Hz,4H),7.18-7.23(m,6H),7.14(s,2H),6.95(s,1H),6.89(s,2H),6.82(d,J＝5.5Hz,2H),5.03(s,2H),5.01(s,2H),3.70(t,J＝6.6Hz,2H),3.31(t,J＝7.1Hz,2H),2.29-2.36(m,4H),1.98-2.06(m,4H),1.39(t,J＝7.1Hz,6H),1.09(t,J＝6.9Hz,6H)； 1 H-NMR(400MHz,TETRACHLOROETHAN)δ7.62(t,J=7.6Hz,4H), 7.47(d,J=7.3Hz,6H),7.33(s,1H),7.29(d,J=7.3Hz ,4H),7.18-7.23(m,6H),7.14(s,2H),6.95(s,1H),6.89(s,2H),6.82(d,J=5.5Hz,2H),5.03(s, 2H),5.01(s,2H),3.70(t,J=6.6Hz,2H),3.31(t,J=7.1Hz,2H),2.29-2.36(m,4H),1.98-2.06(m,4H ), 1.39(t,J=7.1Hz,6H), 1.09(t,J=6.9Hz,6H);
13C-NMR(101MHz,TETRACHLOROETHAN)δ145.7,145.3,144.0,143.9,143.6,143.0,142.9,142.5,140.8,136.0,132.2,130.9,128.2,127.8,127.2,126.0,125.7,120.2,112.0,119.3,118.3,56.12,50.8,44.5,43.7,19.7,19.2,12.9,12.5； 13 C-NMR (101MHz, TETRACHLOROETHAN) δ145.7, 145.3, 144.0, 143.9, 143.6, 143.0, 142.9, 142.5, 140.8, 136.0, 132.2, 130.9, 128.2, 127.8, 127.2, 126.0, 125.7, 120.2, 112.0, 119.3, 118.3 ,56.12,50.8,44.5,43.7,19.7,19.2,12.9,12.5;
HRMS(APCI)calcd.for C 64H 57 +:[M+H] +825.4455.Found:825.4434. HRMS(APCI)calcd.for C 64 H 57 + :[M+H] + 825.4455.Found:825.4434.
Id-3：Id-3:
1H-NMR(400MHz,CHLOROFORM-D)δ7.73(t,J＝7.6Hz,4H),7.46-7.55(m,10H),7.31(t,J＝7.1Hz,1H),7.09-7.12(m,7H),6.95(s,2H),6.91(s,2H),6.88(s,2H),5.00(s,1H),4.99(s,2H),4.94(s,1H),3.76(t,J＝6.6Hz,1H),3.64(t,J＝7.1Hz,2H),3.31(t,J＝6.9Hz,1H),2.29-2.36(m,6H),2.00-2.07(m,2H),1.41(t,J＝7.3Hz,3H),1.36(t,J＝7.3Hz,6H),1.10(t,J＝7.1Hz,3H)； 1 H-NMR (400MHz, CHLOROFORM-D) δ7.73 (t, J = 7.6Hz, 4H), 7.46-7.55 (m, 10H), 7.31 (t, J = 7.1Hz, 1H), 7.09-7.12 ( m, 7H), 6.95 (s, 2H), 6.91 (s, 2H), 6.88 (s, 2H), 5.00 (s, 1H), 4.99 (s, 2H), 4.94 (s, 1H), 3.76 (t ,J=6.6Hz,1H),3.64(t,J=7.1Hz,2H),3.31(t,J=6.9Hz,1H),2.29-2.36(m,6H),2.00-2.07(m,2H) ,1.41(t,J=7.3Hz,3H),1.36(t,J=7.3Hz,6H),1.10(t,J=7.1Hz,3H);
13C-NMR(101MHz,CHLOROFORM-D)δ148.9,147.0,147.0,146.9,146.7,146.4,146.4,146.1,144.2,139.7,139.2,135.8,135.6,131.7,131.5,131.2,130.8,130.6,130.5,129.6,129.4,123.4,122.7,121.8,59.9,54.6,54.2,48.0,47.8,47.1,23.2,23.1,22.7,16.4,16.3,16.0； 13 C-NMR (101MHz, CHLOROFORM-D) δ148.9, 147.0, 147.0, 146.9, 146.7, 146.4, 146.4, 146.1, 144.2, 139.7, 139.2, 135.8, 135.6, 131.7, 131.5, 131.2, 130.8, 130.6, 130.5, 129.6 ,129.4,123.4,122.7,121.8,59.9,54.6,54.2,48.0,47.8,47.1,23.2,23.1,22.7,16.4,16.3,16.0;
HRMS(APCI)calcd.for C 64H 57 +:[M+H] +825.4455.Found:825.4437. HRMS(APCI)calcd.for C 64 H 57 + :[M+H] + 825.4455.Found:825.4437.
由上可知，上述化合物结构正确，分别为式(Id-1)、(Id-2)、(Id-3)所示化合物。It can be seen from the above that the above-mentioned compounds have correct structures and are compounds represented by formulas (Id-1), (Id-2) and (Id-3).
式(IIIa)所示化合物的制备方法如下：The preparation method of the compound represented by formula (IIIa) is as follows:
Figure PCTCN2019116328-appb-000022
Figure PCTCN2019116328-appb-000022
在250mL三口烧瓶中加入0.5mmol(290mg)式(XIa)所示化合物与100mL四氢呋喃，冷却至-78℃，用10mL恒压滴液漏斗缓慢滴加3mL格氏试剂(1mol/L的四氢呋喃溶液)。体系在-78℃下反应1h后，加入饱和氯化铵溶液淬灭。使用乙酸乙酯萃取水相，合并有机相后用饱和氯化钠溶液洗涤并用无水硫酸钠干燥。将溶剂旋干柱层析(硅胶100-200目，淋洗剂：二氯甲烷/乙酸乙酯＝5/1至3/1)分离得到式(IIIa)所示化合物213mg，产率47％。Add 0.5mmol (290mg) of the compound represented by formula (XIa) and 100mL of tetrahydrofuran into a 250mL three-necked flask, cool to -78°C, slowly drop 3mL Grignard reagent (1mol/L tetrahydrofuran solution) with a 10mL constant pressure dropping funnel . After the system was reacted at -78°C for 1 hour, it was quenched by adding saturated ammonium chloride solution. The aqueous phase was extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Solvent spin-drying column chromatography (silica gel 100-200 mesh, eluent: dichloromethane/ethyl acetate = 5/1 to 3/1) was separated to obtain 213 mg of the compound represented by formula (IIIa) with a yield of 47%.
1H-NMR(400MHz,DMSO-D6)δ7.25-7.41(m,28H),6.94(d,J＝7.3Hz,4H),6.03(s,4H),5.68(d,J＝3.2Hz,4H),3.95(t,J＝6.4Hz,4H),1.80-1.96(m,8H),0.48(t,J＝6.9Hz,12H)； 1 H-NMR(400MHz,DMSO-D6)δ7.25-7.41(m,28H), 6.94(d,J=7.3Hz,4H), 6.03(s,4H), 5.68(d,J=3.2Hz, 4H), 3.95(t,J=6.4Hz,4H),1.80-1.96(m,8H),0.48(t,J=6.9Hz,12H);
13C-NMR(101MHz,DMSO-D6)δ144.9,142.8,141.8,139.7,128.1,127.1,126.9,126.6,124.3,71.2,46.4,28.6,12.2； 13 C-NMR(101MHz,DMSO-D6)δ144.9,142.8,141.8,139.7,128.1,127.1,126.9,126.6,124.3,71.2,46.4,28.6,12.2;
HRMS(APCI)calcd.for C 64H 63O 4 -:[M-H] -895.4732.Found:895.4752. HRMS (APCI) calcd.for C 64 H 63 O 4 -: [MH] - 895.4732.Found: 895.4752.
由上可知，上述化合物结构正确，为式(IIIa)所示化合物。It can be seen from the above that the above compound has a correct structure and is a compound represented by formula (IIIa).
式XIa所示化合物的制备方法如下：The preparation method of the compound represented by formula XIa is as follows:
Figure PCTCN2019116328-appb-000023
Figure PCTCN2019116328-appb-000023
在100mL梨形瓶中加入0.8mmol(460mg)式(XIIId)所示化合物并加入25mL二氯甲烷溶解。将体系移至-78℃，使用臭氧发生器通入臭氧(Anseros Ozone Generator COM-AD-01，功率35W)。反应体系变为蓝色后，停止臭氧输入，使用氮气鼓泡30min并缓慢升至室温。加入5mL三乙胺，室温反应过夜。将溶剂旋干柱层析(硅胶100～200目，淋洗剂：二氯甲烷/乙酸乙酯＝40/1)分离得到式(XIa)所示化合物290mg，产率62％。In a 100 mL pear-shaped flask, 0.8 mmol (460 mg) of the compound represented by formula (XIIId) was added and 25 mL of dichloromethane was added to dissolve. Move the system to -78°C and use an ozone generator to pass in ozone (Anseros Ozone Generator COM-AD-01, power 35W). After the reaction system turned blue, the ozone input was stopped, and nitrogen was used to bubble for 30 minutes and slowly rise to room temperature. Add 5 mL of triethylamine and react at room temperature overnight. Solvent spin-drying column chromatography (silica gel 100-200 mesh, eluent: dichloromethane/ethyl acetate=40/1) was separated to obtain 290 mg of the compound represented by formula (XIa) with a yield of 62%.
1H-NMR(400MHz,CHLOROFORM-D)δ10.10(s,4H),7.62(d,J＝7.8Hz,4H),7.26(dd,J＝8Hz,J＝1.4Hz,4H),7.01(s,4H),5.10(t,J＝7.6Hz,4H),2.01-2.15(m,8H),0.95(t,J＝7.1Hz,12H)； 1 H-NMR (400MHz, CHLOROFORM-D) δ10.10 (s, 4H), 7.62 (d, J = 7.8 Hz, 4H), 7.26 (dd, J = 8 Hz, J = 1.4 Hz, 4H), 7.01 ( s, 4H), 5.10 (t, J = 7.6 Hz, 4H), 2.01-2.15 (m, 8H), 0.95 (t, J = 7.1 Hz, 12H);
13C-NMR(101MHz,CHLOROFORM-D)δ192.5,150.9,146.1,133.8,131.7,128.99,126.4,45.9,28.6,12.4； 13 C-NMR (101MHz, CHLOROFORM-D) δ 192.5, 150.9, 146.1, 133.8, 131.7, 128.99, 126.4, 45.9, 28.6, 12.4;
HRMS(APCI)calcd.for C 40H 41O 4 +:[M+H] +m/z 585.2999,found 585.2991. HRMS(APCI)calcd.for C 40 H 41 O 4 + :[M+H] + m/z 585.2999,found 585.2991.
由上可知，上述化合物结构正确，为式(XIa)所示化合物。It can be seen from the above that the above compound has a correct structure and is a compound represented by formula (XIa).
式(XIIId)所示化合物的制备方法如下：The preparation method of the compound represented by formula (XIIId) is as follows:
Figure PCTCN2019116328-appb-000024
Figure PCTCN2019116328-appb-000024
在100mL史莱克瓶中加入3mmol(3.2g)式(Va)所示化合物，1.5mmol(1.74g)四三苯基膦钯，1.5mmol(0.40g)三苯基膦。将反应瓶转移至手套箱中，加入36mmol(1.53g)无水氯化锂与30mL重蒸DMF。将体系密封，移出手套箱并加入15mmol(4.4mL)三丁基乙烯基锡。120℃反应一天后，加水淬灭。使用二氯甲烷萃取水相，合并有机相并用10％氢氧化钠溶液，5％过氧化氢溶液与饱和氯化钠溶液洗涤，随后用无水硫酸钠干燥。将旋干溶剂柱层析(硅胶200-300目，淋洗剂：石油醚/二氯甲烷＝10/1)分离得到式(XIIId)所示化合物1.12g，产率65％。Add 3 mmol (3.2 g) of the compound represented by formula (Va), 1.5 mmol (1.74 g) palladium tetraphenylphosphine, and 1.5 mmol (0.40 g) triphenylphosphine into a 100 mL Shrek flask. Transfer the reaction flask to the glove box, add 36mmol (1.53g) of anhydrous lithium chloride and 30mL of redistilled DMF. The system was sealed, removed from the glove box, and 15 mmol (4.4 mL) of tributyl vinyl tin was added. After reacting at 120°C for one day, it was quenched by adding water. The aqueous phase was extracted with dichloromethane, the organic phases were combined and washed with 10% sodium hydroxide solution, 5% hydrogen peroxide solution and saturated sodium chloride solution, and then dried with anhydrous sodium sulfate. Spin-drying solvent column chromatography (silica gel 200-300 mesh, eluent: petroleum ether/dichloromethane = 10/1) was separated to obtain 1.12 g of the compound represented by formula (XIIId) with a yield of 65%.
1H-NMR(400MHz,CHLOROFORM-D)δ7.26(s,4H),6.98(dd,J＝16.8Hz,J＝10.8Hz,4H),6.94(dd,J＝8.0Hz,J＝1.2Hz,4H),6.82(d,J＝1.4Hz,4H),5.50(dd,J＝17.2,1.6Hz,4H),5.19(dd,J＝11.0,1.4Hz,4H),4.06(t,J＝7.6Hz,4H),2.00(dtd,J＝38.8,14.2,7.3Hz,8H),0.90(t,J＝7.3Hz,12H)； 1 H-NMR(400MHz,CHLOROFORM-D)δ7.26(s,4H), 6.98(dd,J=16.8Hz,J=10.8Hz,4H), 6.94(dd,J=8.0Hz,J=1.2Hz , 4H), 6.82 (d, J = 1.4 Hz, 4H), 5.50 (dd, J = 17.2, 1.6 Hz, 4H), 5.19 (dd, J = 11.0, 1.4 Hz, 4H), 4.06 (t, J = 7.6 Hz, 4H), 2.00 (dtd, J = 38.8, 14.2, 7.3 Hz, 8H), 0.90 (t, J = 7.3 Hz, 12H);
13C-NMR(101MHz,CHLOROFORM-D)δ144.2,142.2,135.2,134.6,127.4,125.8,125.5,115.2,47.7,28.5,12.7； 13 C-NMR (101MHz, CHLOROFORM-D) δ144.2, 142.2, 135.2, 134.6, 127.4, 125.8, 125.5, 115.2, 47.7, 28.5, 12.7;
HRMS(APCI)calcd.for C 44H 49 +:[M+H] +m/z 577.3829,found 577.3819. HRMS(APCI)calcd.for C 44 H 49 + :[M+H] + m/z 577.3829,found 577.3819.
由上可知，上述化合物结构正确，为式(XIIId)所示化合物。It can be seen from the above that the above compound has the correct structure and is a compound represented by formula (XIIId).
实施例5：制备化合物(Ie-1)、(Ie-2)(对应式(I)中R 1为3,5-二甲基苯基；R 2为H；R 3为Et) Example 5: Preparation of compounds (Ie-1), (Ie-2) (corresponding to formula (I) where R 1 is 3,5-dimethylphenyl; R 2 is H; R 3 is Et)
反应式如下：The reaction formula is as follows:
Figure PCTCN2019116328-appb-000025
Figure PCTCN2019116328-appb-000025
式(Ie-1)和式(Ie-2)中的Ar 1为3,5-二甲基苯基。 Ar 1 in formula (Ie-1) and formula (Ie-2) is 3,5-dimethylphenyl.
具体制备方法是：The specific preparation method is:
0℃下，在25mL史莱克瓶中加入0.1mmol(101mg)式(IIIb)所示化合物、10mL二氯甲烷与0.2mL甲磺酸，继续反应0.2h。反应结束后用水淬灭，用二氯甲烷萃取水相，合并有机相后用饱和食盐水洗涤并用无水硫酸钠干燥。旋干溶剂，使用制备级薄层色谱预制板分离(涂层厚度0.9-1.1mm，展开剂石油醚/二氯甲烷＝10/1)，可分离得到不同构型的化合物(Ie-1)和(Ie-2)，18mg(Ie-1)、25.3mg(Ie-2)，产率分别为19％(Ie-1)、27％(Ie-2)，其中式(Ie-1)所示化合物的晶体结构如图6。At 0° C., 0.1 mmol (101 mg) of the compound represented by formula (IIIb), 10 mL of dichloromethane and 0.2 mL of methanesulfonic acid were added to a 25 mL Shrek flask, and the reaction was continued for 0.2 h. After the reaction was completed, it was quenched with water, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. Rotate the solvent to dry, use prefabricated thin-layer chromatography to separate (coating thickness 0.9-1.1mm, developing solvent petroleum ether/dichloromethane = 10/1), can be separated to obtain different configuration compounds (Ie-1) and (Ie-2), 18mg (Ie-1), 25.3mg (Ie-2), the yields were 19% (Ie-1), 27% (Ie-2), and the formula (Ie-1) The crystal structure of the compound is shown in Figure 6.
Ie-1:Ie-1:
1H-NMR(400MHz,CHLOROFORM-D)δ7.26(s,4H),7.23(s,4H),7.13(s,2H),6.89(s,4H),6.75(s,4H),6.73(s,2H),5.10(s,2H),4.81(s,2H),3.77(t,J＝6.9Hz,2H),3.31(t,J＝7.1Hz,2H),2.53(s,12H),2.26-2.33(m,4H),2.10(s,12H),2.00-2.07(m,4H),1.39(t,J＝7.3Hz,6H),1.10(t,J＝7.1Hz,6H)； 1 H-NMR (400MHz, CHLOROFORM-D) δ 7.26 (s, 4H), 7.23 (s, 4H), 7.13 (s, 2H), 6.89 (s, 4H), 6.75 (s, 4H), 6.73 ( s, 2H), 5.10 (s, 2H), 4.81 (s, 2H), 3.77 (t, J = 6.9 Hz, 2H), 3.31 (t, J = 7.1 Hz, 2H), 2.53 (s, 12H), 2.26-2.33(m,4H), 2.10(s,12H), 2.00-2.07(m,4H), 1.39(t,J=7.3Hz,6H), 1.10(t,J=7.1Hz,6H);
13C-NMR(101MHz,CHLOROFORM-D)δ145.3,144.4,144.0,143.3,141.1,138.0,137.6,136.6,130.4,129.3,127.9,125.6,125.2,119.5,56.7,51.0,45.3,43.7,22.4,21.3,20.1,19.6,13.2,12.7； 13 C-NMR (101MHz, CHLOROFORM-D) δ145.3, 144.4, 144.0, 143.3, 141.1, 138.0, 137.6, 136.6, 130.4, 129.3, 127.9, 125.6, 125.2, 119.5, 56.7, 51.0, 45.3, 43.7, 22.4, 21.3 ,20.1,19.6,13.2,12.7;
HRMS(APCI)calcd.for C 72H 73 +:[M+H] +937.5707.Found:937.5703. HRMS(APCI)calcd.for C 72 H 73 + :[M+H] + 937.5707.Found:937.5703.
Ie-2:Ie-2:
1H-NMR(400MHz,CHLOROFORM-D)δ7.17(s,2H),7.10(s,1H),7.06(s,2H),7.03(s,2H),6.96(s,2H),6.89(s,4H),6.86(s,3H),6.85(s,2H),6.80(s,2H),4.96(s,2H),4.87(d,J＝6.9Hz,2H),3.65(t,J＝6.6Hz,1H),3.44(t,J＝6.4Hz,3H),2.46(s,6H),2.23-2.31(m,2H),2.28(s,6H),2.19(s,12H),1.97-2.04(m,6H),1.35(t,J＝7.3Hz,3H),1.12(t,J＝7.1Hz,9H)； 1 H-NMR (400MHz, CHLOROFORM-D) δ 7.17 (s, 2H), 7.10 (s, 1H), 7.06 (s, 2H), 7.03 (s, 2H), 6.96 (s, 2H), 6.89 ( s, 4H), 6.86 (s, 3H), 6.85 (s, 2H), 6.80 (s, 2H), 4.96 (s, 2H), 4.87 (d, J = 6.9 Hz, 2H), 3.65 (t, J =6.6Hz,1H),3.44(t,J=6.4Hz,3H),2.46(s,6H),2.23-2.31(m,2H),2.28(s,6H),2.19(s,12H),1.97 -2.04 (m, 6H), 1.35 (t, J = 7.3 Hz, 3H), 1.12 (t, J = 7.1 Hz, 9H);
13C-NMR(101MHz,CHLOROFORM-D)δ146.4,146.1,145.7,144.8,143.9,143.88,143.8,143.3,141.2,141.1,137.8,137.6,137.6,136.8,131.7,130.8,128.9,128.1,128.0,127.4,125.4,125.3,120.5,119.3,57.1,56.6,50.6,44.8,44.2,44.1,21.8,21.6,21.4,20.0,19.7,19.6,13.2,12.9,12.8； 13 C-NMR (101MHz, CHLOROFORM-D) δ146.4, 146.1, 145.7, 144.8, 143.9, 143.88, 143.8, 143.3, 141.2, 141.1, 137.8, 137.6, 137.6, 136.8, 131.7, 130.8, 128.9, 128.1, 128.0, 127.4 ,125.4,125.3,120.5,119.3,57.1,56.6,50.6,44.8,44.2,44.1,21.8,21.6,21.4,20.0,19.7,19.6,13.2,12.9,12.8;
HRMS(APCI)calcd.for C 72H 73 +:[M+H] +937.5707.Found:937.5699. HRMS(APCI)calcd.for C 72 H 73 + :[M+H] + 937.5707.Found:937.5699.
由上可知，上述化合物结构正确，分别为式(Ie-1)、(Ie-2)所示化合物。It can be seen from the above that the above-mentioned compounds have correct structures and are compounds represented by formula (Ie-1) and (Ie-2) respectively.
式(IIIb)所示化合物的制备方法如下：The preparation method of the compound represented by formula (IIIb) is as follows:
Figure PCTCN2019116328-appb-000026
Figure PCTCN2019116328-appb-000026
在10mL史莱克瓶中加入1.92mmol(47mg)金属镁，2mL四氢呋喃与1.6mmol(0.22mL)3,5-二甲基溴苯，室温搅拌1h，静置待用。在100mL三口烧瓶中加入0.2mmol(116mg)式(XIa)所示化合物与30mL 四氢呋喃，冷却至-78℃，将上述新制格氏试剂转移至用10mL恒压滴液漏斗中并缓慢滴加到反应体系中。在-78℃下反应1h后，加入饱和氯化铵溶液淬灭。使用乙酸乙酯萃取水相，合并有机相后用饱和氯化钠溶液洗涤并用无水硫酸钠干燥。将溶剂旋干柱层析(硅胶100～200目，淋洗剂：二氯甲烷/乙酸乙酯＝10/1至9/1)分离得到式(IIIb)所示化合物136mg，产率67％。Add 1.92mmol (47mg) of magnesium metal, 2mL of tetrahydrofuran and 1.6mmol (0.22mL) of 3,5-dimethyl bromobenzene into a 10mL Shrek flask, stir at room temperature for 1h, and stand for later use. Add 0.2mmol (116mg) of the compound represented by formula (XIa) and 30mL of tetrahydrofuran into a 100mL three-necked flask, cool to -78°C, transfer the freshly prepared Grignard reagent to a 10mL constant pressure dropping funnel and slowly add dropwise to the reaction System. After reacting at -78°C for 1 h, it was quenched by adding saturated ammonium chloride solution. The aqueous phase was extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Solvent spin-drying column chromatography (silica gel 100-200 mesh, eluent: dichloromethane/ethyl acetate=10/1 to 9/1) was separated to obtain 136 mg of the compound represented by formula (IIIb) with a yield of 67%.
1H-NMR(400MHz,DMSO-D6)δ7.41(s,4H),7.36(d,J＝7.8Hz,4H),7.05(d,J＝7.8Hz,4H),6.93(s,8H),6.88(s,4H),5.99(d,J＝3.7Hz,4H),5.58(d,J＝4.1Hz,4H),4.00(t,J＝7.1Hz,4H),2.24(s,24H),1.93-2.02(m,4H),1.81-1.88(m,4H),0.54(t,J＝7.1Hz,12H)； 1 H-NMR(400MHz,DMSO-D6)δ7.41(s,4H), 7.36(d,J=7.8Hz,4H), 7.05(d,J=7.8Hz,4H), 6.93(s,8H) ,6.88(s,4H),5.99(d,J=3.7Hz,4H), 5.58(d,J=4.1Hz,4H), 4.00(t,J=7.1Hz,4H), 2.24(s,24H) ,1.93-2.02(m,4H),1.81-1.88(m,4H),0.54(t,J=7.1Hz,12H);
13C-NMR(101MHz,DMSO-D6)δ144.8,142.8,141.7,139.9,136.9,128.2,127.4,126.4,125.2,124.0,70.9,46.2,28.6,21.0,12.2； 13 C-NMR (101MHz, DMSO-D6)δ144.8, 142.8, 141.7, 139.9, 136.9, 128.2, 127.4, 126.4, 125.2, 124.0, 70.9, 46.2, 28.6, 21.0, 12.2;
HRMS(APCI)calcd.for C 72H 79O 4 -:[M-H] –1007.5984.Found:1007.5996. HRMS(APCI)calcd.for C 72 H 79 O 4 - :[MH] – 1007.5984.Found:1007.5996.
由上可知，上述化合物结构正确，为式(IIIb)所示化合物。It can be seen from the above that the above compound has a correct structure and is a compound represented by formula (IIIb).
实施例6：制备化合物(If-1)、(If-2)(对应式(I)中R 1为2-异丙基苯基；R 2为H；R 3为Et) Example 6: Preparation of compounds (If-1), (If-2) (corresponding to formula (I) where R 1 is 2-isopropylphenyl; R 2 is H; R 3 is Et)
反应式如下：The reaction formula is as follows:
Figure PCTCN2019116328-appb-000027
Figure PCTCN2019116328-appb-000027
式(If-1)和式(If-2)中的Ar 2为2-异丙基苯基。 Ar 2 in formula (If-1) and formula (If-2) is 2 -isopropylphenyl.
具体制备方法是：The specific preparation method is:
0℃下，在25mL史莱克瓶中加入0.1mmol(107mg)式(IIIc)所示化合物、10mL二氯甲烷与0.2mL甲磺酸，继续反应0.2h。反应结束后用水淬灭，用二氯甲烷萃取水相，合并有机相后用饱和食盐水洗涤并用无水硫酸钠干燥。旋干溶剂，使用制备级薄层色谱预制板分离(涂层厚度0.9～1.1mm，展开剂石油醚/二氯甲烷＝10/1)，可分离得到不同构型的化合物(If-1)和(If-2)，23.3mg(If-1)、37.7mg(If-2)，产率分别为23％(If-1)、38％(If-2)。At 0°C, 0.1 mmol (107 mg) of the compound represented by formula (IIIc), 10 mL of dichloromethane and 0.2 mL of methanesulfonic acid were added to a 25 mL Shrek flask, and the reaction was continued for 0.2 h. After the reaction was completed, it was quenched with water, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. Rotate the solvent to dry, and use prefabricated thin-layer chromatography plate to separate (coating thickness 0.9～1.1mm, developing solvent petroleum ether/dichloromethane=10/1), can separate compounds of different configurations (If-1) and (If-2), 23.3 mg (If-1), 37.7 mg (If-2), the yields were 23% (If-1) and 38% (If-2), respectively.
If-1:If-1:
1H-NMR(400MHz,CHLOROFORM-D)δ7.75(t,J＝7.3Hz,2H),7.51-7.58(m,4H),7.29(d,J＝7.8Hz,2H),7.19(t,J＝9.2Hz,4H),7.11(t,J＝7.4Hz,2H),7.07(s,4H),6.89(d,J＝10.1Hz,6H),5.46(s,2H),5.03(s,2H),3.69(t,J＝7.1Hz,2H),3.61(t,J＝7.1Hz,2H),3.54(q,J＝6.7Hz,2H),3.29-3.36(m,2H),2.31(m,4H),2.03(m,4H),1.37(t,J＝7.1Hz,6H),1.26(d,J＝6.4Hz,12H),1.16(t,J＝7.3Hz,6H),0.83(d,J＝6.9Hz,12H)； 1 H-NMR(400MHz,CHLOROFORM-D)δ7.75(t,J=7.3Hz,2H),7.51-7.58(m,4H),7.29(d,J=7.8Hz,2H),7.19(t, J = 9.2Hz, 4H), 7.11 (t, J = 7.4Hz, 2H), 7.07 (s, 4H), 6.89 (d, J = 10.1Hz, 6H), 5.46 (s, 2H), 5.03 (s, 2H), 3.69 (t, J = 7.1 Hz, 2H), 3.61 (t, J = 7.1 Hz, 2H), 3.54 (q, J = 6.7 Hz, 2H), 3.29-3.36 (m, 2H), 2.31 ( m, 4H), 2.03 (m, 4H), 1.37 (t, J = 7.1 Hz, 6H), 1.26 (d, J = 6.4 Hz, 12H), 1.16 (t, J = 7.3 Hz, 6H), 0.83 ( d, J = 6.9 Hz, 12H);
13C-NMR(101MHz,CHLOROFORM-D)δ148.9,148.5,146.8,144.4,143.5,136.2,133.3,128.24 127.3,126.8,126.1,124.8,124.1,119.1,56.6,44.8,44.2,43.1,29.5,28.8,24.0,23.7,20.1,19.6,13.1,12.7； 13 C-NMR (101MHz, CHLOROFORM-D) δ148.9, 148.5, 146.8, 144.4, 143.5, 136.2, 133.3, 128.24 127.3, 126.8, 126.1, 124.8, 124.1, 119.1, 56.6, 44.8, 44.2, 43.1,29.5, 28.8, 24.0, 23.7, 20.1, 19.6, 13.1, 12.7;
HRMS(APCI)calcd.for C 76H 81 +:[M+H] +993.6333.Found:993.6315. HRMS(APCI)calcd.for C 76 H 81 + :[M+H] + 993.6333.Found:993.6315.
If-2:If-2:
1H-NMR(400MHz,CHLOROFORM-D)δ7.87-7.91(m,2H),7.74(d,J＝7.8Hz,1H),7.57(t,J＝7.3Hz,1H),7.46-7.53(m,4H),7.40(d,J＝7.3Hz,2H),7.29-7.33(m,2H),7.17(d,J＝9.6Hz,2H),7.10(t,J＝6.9Hz,1H),7.05(s,2H),7.02(s,2H),6.99(s,2H),6.86-6.92(m,3H),5.60(s,1H),5.44(s,2H),5.03(s,1H),3.82(t,J＝6.9Hz,1H),3.68(t,J＝6.9Hz,1H),3.62(t,J＝6.9Hz,2H),3.28-3.48(m,4H),2.34-2.39(m,6H),2.03-2.18(m,2H),1.46(t,J＝7.3Hz,3H),1.39(t,J＝7.3Hz,6H),1.19(d,J＝6.0Hz,12H),1.17(t,J＝7.3Hz,3H),1.12(d,J＝6.9Hz,6H),0.82(d,J＝6.4Hz,6H)； 1 H-NMR(400MHz, CHLOROFORM-D)δ7.87-7.91(m,2H), 7.74(d,J=7.8Hz,1H), 7.57(t,J=7.3Hz,1H),7.46-7.53( m, 4H), 7.40 (d, J = 7.3 Hz, 2H), 7.29-7.33 (m, 2H), 7.17 (d, J = 9.6 Hz, 2H), 7.10 (t, J = 6.9 Hz, 1H), 7.05(s, 2H), 7.02(s, 2H), 6.99(s, 2H), 6.86-6.92(m, 3H), 5.60(s, 1H), 5.44(s, 2H), 5.03(s, 1H) , 3.82(t,J=6.9Hz,1H), 3.68(t,J=6.9Hz,1H), 3.62(t,J=6.9Hz,2H), 3.28-3.48(m,4H),2.34-2.39( m,6H),2.03-2.18(m,2H),1.46(t,J=7.3Hz,3H), 1.39(t,J=7.3Hz,6H), 1.19(d,J=6.0Hz,12H), 1.17(t,J=7.3Hz,3H), 1.12(d,J=6.9Hz,6H), 0.82(d,J=6.4Hz,6H);
13C-NMR(101MHz,CHLOROFORM-D)δ148.6,148.0,146.9,144.2,144.2,144.1,143.7,143.6,143.4,142.9,136.2,133.8,133.6,133.2,132.8,128.3,127.3,127.1,127.0,126.9,126.2,126.2,125.8,125.2,124.9, 124.4,121.2,119.1,118.4,56.4,45.2,44.9,44.2,43.5,43.4,29.7,29.60 28.8,24.2,24.0,23.8,23.7,20.4,20.2,19.8,13.2,13.2,12.8； 13 C-NMR (101MHz, CHLOROFORM-D) δ148.6, 148.0, 146.9, 144.2, 144.2, 144.1, 143.7, 143.6, 143.4, 142.9, 136.2, 133.8, 133.6, 133.2, 132.8, 128.3, 127.3, 127.1, 127.0, 126.9 ,126.2,126.2,125.8,125.2,124.9, 124.4,121.2,119.1,118.4,56.4,45.2,44.9,44.2,43.5,43.4,29.7,29.60 28.8,24.2,24.0,23.8,23.7,20.4,20.2,19.8, 13.2, 13.2, 12.8;
HRMS(APCI)calcd.for C 76H 81 +:[M+H] +993.6333.Found:993.6315. HRMS(APCI)calcd.for C 76 H 81 + :[M+H] + 993.6333.Found:993.6315.
由上可知，上述化合物结构正确，分别为式(If-1)、(If-2)所示化合物。It can be seen from the above that the above-mentioned compounds have the correct structure and are compounds represented by formulas (If-1) and (If-2) respectively.
式(IIIc)所示化合物的制备方法如下：The preparation method of the compound represented by formula (IIIc) is as follows:
Figure PCTCN2019116328-appb-000028
Figure PCTCN2019116328-appb-000028
在25mL史莱克瓶中加入4.8mmol(117mg)金属镁，10mL四氢呋喃与4mmol(0.62mL)2-异丙基溴苯，室温搅拌1h，静置待用。在250mL三口烧瓶中加入0.4mmol(232mg)式(XIa)所示化合物与80mL四氢呋喃，冷却至-20℃，将上述新制格氏试剂转移至用25mL恒压滴液漏斗中并缓慢滴加到反应体系中。滴毕，将体系转移至室温并继续反应12h。反应完成后，加入饱和氯化铵溶液淬灭。使用乙酸乙酯萃取水相，合并有机相后用饱和氯化钠溶液洗涤并用无水硫酸钠干燥。将溶剂旋干柱层析(硅胶100～200目，淋洗剂：二氯甲烷/乙酸乙酯＝10/1至8/1)分离得到式(IIIc)所示化合物186mg，产率44％。Add 4.8 mmol (117 mg) of magnesium metal, 10 mL of tetrahydrofuran and 4 mmol (0.62 mL) of 2-isopropyl bromobenzene into a 25 mL Shrek flask, stir at room temperature for 1 h, and let it stand for use. Add 0.4mmol (232mg) of the compound represented by the formula (XIa) and 80mL of tetrahydrofuran into a 250mL three-necked flask, cool to -20°C, transfer the freshly prepared Grignard reagent to a 25mL constant pressure dropping funnel and slowly add dropwise to the reaction System. After dropping, the system was transferred to room temperature and the reaction continued for 12 hours. After the reaction was completed, it was quenched by adding saturated ammonium chloride solution. The aqueous phase was extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Solvent spin-drying column chromatography (silica gel 100-200 mesh, eluent: dichloromethane/ethyl acetate=10/1 to 8/1) was separated to obtain 186 mg of the compound represented by formula (IIIc) with a yield of 44%.
1H-NMR(400MHz,DMSO-D6)δ7.52(s,4H),7.36(d,J＝6.9Hz,4H),7.27(t,J＝6.9Hz,4H),7.10-7.16(m,12H),7.02(d,J＝7.8Hz,4H),6.32(d,J＝6.0Hz,4H),5.54(d,J＝6.0Hz,4H),3.88(t,J＝7.8Hz,4H),3.30(q,J＝6.9Hz,4H),2.03-2.10(m,4H),1.84-1.91(m,4H),1.20(d,J＝6.9Hz,12H),1.11(d,J＝6.9Hz,12H),0.55(t,J＝7.1Hz,12H)； 1 H-NMR(400MHz,DMSO-D6)δ7.52(s,4H), 7.36(d,J=6.9Hz,4H), 7.27(t,J=6.9Hz,4H), 7.10-7.16(m, 12H), 7.02(d,J=7.8Hz,4H), 6.32(d,J=6.0Hz,4H), 5.54(d,J=6.0Hz,4H), 3.88(t,J=7.8Hz,4H) , 3.30(q,J=6.9Hz,4H),2.03-2.10(m,4H),1.84-1.91(m,4H),1.20(d,J=6.9Hz,12H),1.11(d,J=6.9 Hz,12H),0.55(t,J=7.1Hz,12H);
13C-NMR(101MHz,DMSO-D6)δ146.8,142.9,142.3,140.7,139.5,127.5,127.2,127.1,127.0,125.5,125.1,124.2,67.6,46.6,28.7,27.8,24.6,23.4,12.2； 13 C-NMR (101MHz, DMSO-D6) δ146.8, 142.9, 142.3, 140.7, 139.5, 127.5, 127.2, 127.1, 127.0, 125.5, 125.1, 124.2, 67.6, 46.6, 28.7, 27.8, 24.6, 23.4, 12.2;
HRMS(APCI)calcd.for C 76H 87O 4 -:[M-H] -1063.6610.Found:1063.6627. HRMS (APCI) calcd.for C 76 H 87 O 4 -: [MH] - 1063.6610.Found: 1063.6627.
由上可知，上述化合物结构正确，为式(IIIc)所示化合物。It can be seen from the above that the above compound has the correct structure and is a compound represented by formula (IIIc).
实施例7：氢化环带[8]芳烃式(If-1)所示化合物对1,2-二氯乙烷的选择性包合Example 7: Selective inclusion of 1,2-dichloroethane by the compound represented by the hydrogenated ring zone [8] aromatic hydrocarbon formula (If-1)
取上述式(If-1)所示化合物2mg溶解于0.5mL 1,2-二氯乙烷中，使用气相扩散法向其中缓慢扩散甲醇，可以得到透明块状的晶体。单晶X-衍射实验结果如图7所示，客体分子1,2-二氯乙烷与大环主体形成了1:1包合物结构，客体分子的氯原子与主体分子上的2-异丙基苯基部分的C-H键存在相互作用。此外，该客体分子还与其他主体分子相互作用，形成“夹合”式结构。维持该结构的主要作用力为氯原子与主体上氢原子的非经典氢键与溶剂分子C-H键对芳环的C-H …π相互作用。 2 mg of the compound represented by the above formula (If-1) was dissolved in 0.5 mL of 1,2-dichloroethane, and methanol was slowly diffused into it using the gas phase diffusion method to obtain transparent massive crystals. The results of the single crystal X-ray diffraction experiment are shown in Figure 7. The guest molecule 1,2-dichloroethane and the macrocyclic host formed a 1:1 clathrate structure. The CH bond of the propylphenyl moiety interacts. In addition, the guest molecule also interacts with other host molecules to form a "sandwich" structure. The main force to maintain the structure is the non-classical hydrogen bond between the chlorine atom and the hydrogen atom on the host and the CH bond of the solvent molecule to the CH … π interaction of the aromatic ring.
实施例8：大环分子式(VIIa)所示化合物对乙醇的选择性包合Example 8: Selective inclusion of ethanol by the compound represented by the macrocyclic formula (VIIa)
取上述式(VIIa)所示化合物2mg溶于0.5mL氯仿中，使用气相扩散法向其中缓慢扩散乙醇，可以得到透明块状的晶体。单晶X-衍射实验结果如图8所示，客体分子乙醇与主体分子形成1:1包合物结构。如图8所示，乙醇分子以其疏水的一端竖直地插入式(VIIa)所示化合物地碗状空腔中。此外，乙醇分子之间可以用羟基以氢键相连，形成1:2:1形式的“夹心”结构。维持该结构的主要作用力为乙醇分子之间的氢键、主体分子烷基部分与羟基氧之间的非经典氢键与乙醇分子C-H键对芳环的C-H …π相互作用。 Dissolve 2 mg of the compound represented by the above formula (VIIa) in 0.5 mL of chloroform, and slowly diffuse ethanol into it using a gas phase diffusion method to obtain transparent massive crystals. The results of single crystal X-ray diffraction experiments are shown in Figure 8. The guest molecule ethanol and the host molecule form a 1:1 inclusion structure. As shown in Figure 8, the ethanol molecule is vertically inserted into the bowl-shaped cavity of the compound represented by formula (VIIa) with its hydrophobic end. In addition, the ethanol molecules can be connected by hydrogen bonds with hydroxyl groups to form a "sandwich" structure in the form of 1:2:1. The main force to maintain this structure is the hydrogen bond between ethanol molecules, the non-classical hydrogen bond between the alkyl part of the host molecule and the hydroxyl oxygen, and the CH bond of the ethanol molecule to the CH ... π interaction of the aromatic ring.
实施例9：大环分子式(VIIb)所示化合物对1,2-二氯乙烷的选择性包合Example 9: Selective inclusion of 1,2-dichloroethane by the compound represented by the macrocyclic formula (VIIb)
取上述式(VIIb)所示化合物1.5mg溶于0.5mL 1,2-二氯乙烷中，用气相扩散法向其中缓慢扩散甲醇，可以得到透明块状的晶体。单晶X-衍射实验结果如图9所示，客体分子1,2-二氯乙烷与主体分子形成1:1包合物结构，客体分子以其C-H键的一端坐落于主体分子的碗状空腔中。此外，其氯原子部分又可以与另外三个主体分子相互作用，组成向心式的结构。维持该结构的主要作用力为客体分子对主体芳环的 C-H …π相互作用与氯原子与主体烷基链之间的非经典氢键。 Take 1.5 mg of the compound represented by the above formula (VIIb) and dissolve it in 0.5 mL of 1,2-dichloroethane, and slowly diffuse methanol into it by a gas phase diffusion method to obtain transparent massive crystals. The single crystal X-ray diffraction experiment results are shown in Figure 9. The guest molecule 1,2-dichloroethane and the host molecule form a 1:1 clathrate structure, and the guest molecule is located in the bowl of the host molecule with one end of the CH bond. In the cavity. In addition, the chlorine atom part can interact with the other three main molecules to form a centripetal structure. The main force to maintain this structure is the CH … π interaction of the guest molecule on the host aromatic ring and the non-classical hydrogen bond between the chlorine atom and the host alkyl chain.
实施例10：大环分子式(VIIc)所示化合物对1,2-二氯乙烷的选择性包合Example 10: Selective inclusion of 1,2-dichloroethane by the compound represented by the macrocyclic formula (VIIc)
取上述式(VIIc)所示化合物2mg溶于0.5mL氯仿中，用气相扩散法向其中缓慢扩散甲醇，可以得到透明块状的晶体。单晶X-衍射实验结果如图10所示，客体分子氯仿与主体分子形成1:2包合物。如图10所示，氯仿分子以其C-H键的一端插入主体分子得碗状空腔中，在主体空腔之外，另有一氯仿分子通过非经典氢键与主体分子相连。此外，空腔中的氯仿上的氯原子与另一主体分子的烷基链相互作用形成“三明治”型的夹心结构。这其中，“三明治”的夹心结构可以形成一维长链，长链之间通过空腔外的氯仿分子相连，组成二维结构。维持该结构的主要作用力为与氯原子与主体C-H键之间的非经典氢键。Dissolve 2 mg of the compound represented by the above formula (VIIc) in 0.5 mL of chloroform, and slowly diffuse methanol into it by the gas phase diffusion method to obtain transparent massive crystals. The results of single crystal X-ray diffraction experiments are shown in Figure 10. The guest molecule chloroform forms a 1:2 inclusion compound with the host molecule. As shown in Figure 10, the chloroform molecule is inserted into the bowl-shaped cavity of the host molecule with one end of its C-H bond. Outside the main cavity, another chloroform molecule is connected to the host molecule through a non-classical hydrogen bond. In addition, the chlorine atom on the chloroform in the cavity interacts with the alkyl chain of another host molecule to form a "sandwich" type sandwich structure. Among them, the sandwich structure of "sandwich" can form one-dimensional long chains, which are connected by chloroform molecules outside the cavity to form a two-dimensional structure. The main force to maintain this structure is the non-classical hydrogen bond between the chlorine atom and the main body C-H bond.
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。In the description of this specification, descriptions with reference to the terms "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" etc. mean specific features described in conjunction with the embodiment or example , Structure, materials or features are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the described specific features, structures, materials or characteristics can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine the different embodiments or examples and the characteristics of the different embodiments or examples described in this specification without contradicting each other.
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。Although the embodiments of the present invention have been shown and described above, it can be understood that the above-mentioned embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can comment on the foregoing within the scope of the present invention. The embodiment undergoes changes, modifications, substitutions and modifications.

Claims (25)

  1. 一种化合物，其特征在于，所述化合物为式(I)所示化合物或式(I)所示化合物的立体异构体，A compound characterized in that the compound is a compound represented by formula (I) or a stereoisomer of a compound represented by formula (I),
    Figure PCTCN2019116328-appb-100001
    Figure PCTCN2019116328-appb-100001
    其中，among them,
    R 1、R 2和R 3分别独立地为氢原子、任选取代的C 1-12烷基、任选取代的C 1-12杂烷基、任选取代的C 2-12烯基、任选取代的C 5-24环烷基或任选取代的C 5-24杂环基。 R 1 , R 2 and R 3 are each independently a hydrogen atom, optionally substituted C 1-12 alkyl, optionally substituted C 1-12 heteroalkyl, optionally substituted C 2-12 alkenyl, any Optional substituted C 5-24 cycloalkyl or optionally substituted C 5-24 heterocyclic group.
  2. 根据权利要求1所述的化合物，其特征在于，The compound of claim 1, wherein:
    R 1、R 2和R 3分别独立地为氢原子、C 1-6烷基、C 1-6杂烷基、C 2-6烯基、C 5-12环烷基、C 5-12杂环基。 R 1 , R 2 and R 3 are each independently a hydrogen atom, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 5-12 cycloalkyl, C 5-12 hetero Ring base.
  3. 根据权利要求1所述的化合物，其特征在于，The compound of claim 1, wherein:
    R 1和R 2分别独立地为氢原子、甲基、乙基、正丙基、正丁基、苯基或任选取代的苯基； R 1 and R 2 are each independently a hydrogen atom, methyl, ethyl, n-propyl, n-butyl, phenyl, or optionally substituted phenyl;
    R 3为乙基、正丙基、异丙基、正丁基、异丁基、正戊基、正己基、正庚基、正辛基、正壬基、正癸基、苄基、对甲基苄基、邻甲基苄基或间甲基苄基。 R 3 is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, benzyl, p-methyl Benzyl, o-methylbenzyl or m-methylbenzyl.
  4. 根据权利要求1所述的化合物，其特征在于，所述任选取代的苯基为苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、2-乙基苯基、3-乙基苯基、4-乙基苯基、2-异丙基苯基、3-异丙基苯基、4-异丙基苯基、3,4-二甲基苯基、3,5-二甲基苯基、3,6-二甲基苯基、2,3-二甲基苯基、2,4-二甲基苯基、2,5-二甲基苯基、2,6-二甲基苯基、3,4-二乙基苯基、3,5-二乙基苯基、3,6-二乙基苯基、2,3-二乙基苯基、2,4-二乙基苯基、2,5-二乙基苯基、2,6-二乙基苯基或3,4,5-三甲基苯基。The compound of claim 1, wherein the optionally substituted phenyl is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethyl Phenyl, 3-ethylphenyl, 4-ethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 3,4-dimethylphenyl , 3,5-dimethylphenyl, 3,6-dimethylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl , 2,6-Dimethylphenyl, 3,4-Diethylphenyl, 3,5-Diethylphenyl, 3,6-Diethylphenyl, 2,3-Diethylphenyl , 2,4-Diethylphenyl, 2,5-Diethylphenyl, 2,6-Diethylphenyl or 3,4,5-Trimethylphenyl.
  5. 根据权利要求1所述的化合物，其特征在于，具有以下其中之一的结构：The compound according to claim 1, characterized in that it has one of the following structures:
    Figure PCTCN2019116328-appb-100002
    Figure PCTCN2019116328-appb-100002
    Figure PCTCN2019116328-appb-100003
    Figure PCTCN2019116328-appb-100004
    其中，式(Ie-1)和式(Ie-2)中的Ar 1为3,5-二甲基苯基，式(If-1)和式(If-2)中的Ar 2为2-异丙基苯基。
    Figure PCTCN2019116328-appb-100003
    Figure PCTCN2019116328-appb-100004
    Among them, Ar 1 in formula (Ie-1) and formula (Ie-2) is 3,5-dimethylphenyl, and Ar 2 in formula (If-1) and formula (If-2) is 2- Isopropylphenyl.
  6. 一种制备权利要求1～5任一项所述的化合物的方法，其特征在于，包括：A method for preparing the compound according to any one of claims 1 to 5, characterized in that it comprises:
    使式(II)所示化合物或式(III)所示化合物与酸接触，得到式(I)所示化合物，The compound represented by formula (II) or the compound represented by formula (III) is contacted with an acid to obtain the compound represented by formula (I),
    Figure PCTCN2019116328-appb-100005
    Figure PCTCN2019116328-appb-100005
    其中，R 1和R 3为权利要求1所限定的。 Wherein, R 1 and R 3 are defined in claim 1.
  7. 根据权利要求6所述的方法，其特征在于，所述酸包括选自多聚磷酸、盐酸、硫酸、三氟甲磺酸、三氟甲磺酸酐、三氟甲磺酸三甲基硅酯、甲磺酸、对甲基苯磺酸、全氟磺酸树脂、三氟甲磺酸钪中的至少之一。The method of claim 6, wherein the acid is selected from the group consisting of polyphosphoric acid, hydrochloric acid, sulfuric acid, trifluoromethanesulfonic acid, trifluoromethanesulfonic anhydride, trimethylsilyl trifluoromethanesulfonate, At least one of methanesulfonic acid, p-toluenesulfonic acid, perfluorosulfonic acid resin, and scandium trifluoromethanesulfonate.
  8. 根据权利要求6所述的方法，其特征在于，所述接触在第一溶剂中进行，所述第一溶剂包括选自 苯、甲苯、三氟甲苯、氯苯、氟苯、硝基苯、溴苯、二氯甲烷、1,2-二氯乙烷、1,1,2,2-四氯乙烷和氯仿中的至少之一。The method according to claim 6, wherein the contact is carried out in a first solvent, and the first solvent comprises benzene, toluene, benzotrifluoride, chlorobenzene, fluorobenzene, nitrobenzene, bromine At least one of benzene, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, and chloroform.
  9. 根据权利要求6所述的方法，其特征在于，所述接触在-40～150℃下进行0.1～48h完成。The method according to claim 6, wherein the contact is completed at -40 to 150°C for 0.1 to 48 hours.
  10. 根据权利要求6所述的方法，其特征在于，式(II)所示化合物与所述酸的用量比为0.01～1mmol:0.01～100mmol，式(III)所示化合物与所述酸的用量比为0.01～1mmol:0.01～10mL。The method according to claim 6, characterized in that the ratio of the amount of the compound represented by formula (II) to the acid is 0.01-1 mmol: 0.01-100 mmol, and the ratio of the amount of the compound represented by formula (III) to the acid It is 0.01～1mmol:0.01～10mL.
  11. 根据权利要求6所述的方法，其特征在于，式(II)所示化合物通过使式(V)所示化合物在金属催化剂的作用下发生交叉偶联反应制备得到。The method according to claim 6, wherein the compound represented by formula (II) is prepared by cross-coupling the compound represented by formula (V) under the action of a metal catalyst.
  12. 根据权利要求6所述的方法，其特征在于，式(III)所示化合物通过使式(IV)所示化合物与格氏试剂发生加成反应制备得到，式(V)所示化合物通过使式(VI)所示化合物发生三氟甲磺酰化反应制备得到；The method according to claim 6, wherein the compound represented by formula (III) is prepared by the addition reaction of the compound represented by formula (IV) with a Grignard reagent, and the compound represented by formula (V) is prepared by making The compound shown in (VI) is prepared by trifluoromethanesulfonylation reaction;
    Figure PCTCN2019116328-appb-100006
    Figure PCTCN2019116328-appb-100006
  13. 根据权利要求6所述的方法，其特征在于，式(IV)所示化合物通过使式(II)所示化合物发生氧化反应制备得到。The method according to claim 6, wherein the compound represented by formula (IV) is prepared by subjecting the compound represented by formula (II) to an oxidation reaction.
  14. 根据权利要求11所述的方法，其特征在于，所述金属催化剂包括选自醋酸钯、四三苯基膦钯、三(二亚苄基丙酮)二钯、氯化钯和[1,1’-双(二苯基膦基)二茂铁]二氯化钯中的至少之一。The method according to claim 11, wherein the metal catalyst comprises palladium selected from the group consisting of palladium acetate, tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium, palladium chloride and [1,1' -At least one of bis(diphenylphosphino)ferrocene]palladium dichloride.
  15. 根据权利要求11所述的方法，其特征在于，所述交叉偶联反应在第二溶剂中进行，所述第二溶剂包括选自N,N-二甲基甲酰胺、N,N-二甲基苯胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、四氢呋喃、1,4-二氧六环、水和二甲基亚砜中的至少之一。The method according to claim 11, wherein the cross-coupling reaction is carried out in a second solvent, and the second solvent comprises N,N-dimethylformamide, N,N-dimethylformamide and N,N-dimethylformamide. At least one of aniline, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 1,4-dioxane, water, and dimethylsulfoxide.
  16. 根据权利要求11所述的方法，其特征在于，所述交叉偶联反应在添加剂和烯基化试剂的作用下进行，所述添加剂包括选自碳酸钾、碳酸铯、碳酸锂、碳酸钠、氯化钠和氯化锂中的至少之一；所述烯基化试剂包括选自乙烯基溴化镁、异丙烯基溴化镁、三丁基乙烯基烯、三丁基异丙烯基烯、异丙烯基硼酸频哪醇酯和乙烯基硼酸频哪醇酯中的至少之一。The method of claim 11, wherein the cross-coupling reaction is carried out under the action of additives and alkenylation reagents, and the additives include those selected from potassium carbonate, cesium carbonate, lithium carbonate, sodium carbonate, and chlorine. At least one of sodium chloride and lithium chloride; the alkenylation reagent includes selected from vinylmagnesium bromide, isopropenyl magnesium bromide, tributylvinylene, tributylisopropenylene, isopropenyl At least one of boric acid pinacol ester and vinyl boric acid pinacol ester.
  17. 根据权利要求11所述的方法，其特征在于，所述交叉偶联反应在25～140℃下进行6～36h完成。The method of claim 11, wherein the cross-coupling reaction is completed at 25-140°C for 6-36 hours.
  18. 根据权利要求12所述的方法，其特征在于，所述格氏试剂包括选自苯基溴化镁、2-甲基苯基溴化镁、3-甲基苯基溴化镁、4-甲基苯基溴化镁、2-乙基苯基溴化镁、3-乙基苯基溴化镁、4-乙基苯基溴化镁、2-异丙基苯基溴化镁、3-异丙基苯基溴化镁、4-异丙基苯基溴化镁、3,4-二甲基苯基溴化镁、3,5-二甲基苯基溴化镁、3,6-二甲基苯基溴化镁、2,3-二甲基苯基溴化镁、2,4-二甲基苯基溴化镁、2,5-二甲基苯基溴化镁、2,6-二甲基苯基溴化镁、3,4-二乙基苯基溴化镁、3,5-二乙基苯基溴化镁、3,6-二乙基苯基溴化镁、2,3-二乙基苯基溴化镁、2,4-二乙基苯基溴化镁、2,5-二乙基苯基溴化镁、2,6-二乙基苯基溴化镁和3,4,5-三甲基苯基溴化镁中的至少之一。The method according to claim 12, wherein the Grignard reagent comprises selected from phenylmagnesium bromide, 2-methylphenylmagnesium bromide, 3-methylphenylmagnesium bromide, 4-methyl Phenyl magnesium bromide, 2-ethylphenyl magnesium bromide, 3-ethylphenyl magnesium bromide, 4-ethylphenyl magnesium bromide, 2-isopropylphenyl magnesium bromide, 3- Isopropylphenyl magnesium bromide, 4-isopropylphenyl magnesium bromide, 3,4-dimethylphenyl magnesium bromide, 3,5-dimethylphenyl magnesium bromide, 3,6- Dimethylphenylmagnesium bromide, 2,3-dimethylphenylmagnesium bromide, 2,4-dimethylphenylmagnesium bromide, 2,5-dimethylphenylmagnesium bromide, 2, 6-Dimethylphenylmagnesium bromide, 3,4-diethylphenylmagnesium bromide, 3,5-diethylphenylmagnesium bromide, 3,6-diethylphenylmagnesium bromide, 2,3-Diethylphenylmagnesium bromide, 2,4-diethylphenylmagnesium bromide, 2,5-diethylphenylmagnesium bromide, 2,6-diethylphenylmagnesium bromide At least one of magnesium and 3,4,5-trimethylphenylmagnesium bromide.
  19. 根据权利要求12所述的方法，其特征在于，所述加成反应在第三溶剂中进行，所述第三溶剂包括选自四氢呋喃和1,4-二氧六环中的至少之一。The method according to claim 12, wherein the addition reaction is performed in a third solvent, and the third solvent includes at least one selected from tetrahydrofuran and 1,4-dioxane.
  20. 根据权利要求12所述的方法，其特征在于，所述加成反应在-78～60℃下进行0.5～12h完成。The method of claim 12, wherein the addition reaction is completed at -78-60°C for 0.5-12h.
  21. 根据权利要求13所述的方法，其特征在于，所述氧化反应在氧化剂的作用下进行，所述氧化剂包括选自氧气和臭氧中的至少之一。The method according to claim 13, wherein the oxidation reaction is carried out under the action of an oxidant, and the oxidant includes at least one selected from oxygen and ozone.
  22. 根据权利要求13所述的方法，其特征在于，所述氧化反应在第四溶剂中进行，所述第四溶剂包括选自二氯甲烷，三氯甲烷，1,2-二氯乙烷和甲醇中的至少之一。The method according to claim 13, wherein the oxidation reaction is carried out in a fourth solvent, and the fourth solvent is selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, and methanol At least one of.
  23. 根据权利要求13所述的方法，其特征在于，所述氧化反应在-78～-20℃下进行1～24h完成。The method of claim 13, wherein the oxidation reaction is completed at -78 to -20°C for 1 to 24 hours.
  24. 权利要求1～5任一项所述的化合物在对有机分子选择性包合中的用途，所述化合物用于从混合溶液中识别并选择性包合有机分子。The use of the compound according to any one of claims 1 to 5 in the selective inclusion of organic molecules, wherein the compound is used to identify and selectively include organic molecules from a mixed solution.
  25. 根据权利要求24所述的用途，其特征在于，所述混合溶液包括1,2-二氯乙烷、甲醇、氯仿和乙醇。The use according to claim 24, wherein the mixed solution comprises 1,2-dichloroethane, methanol, chloroform and ethanol.
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