CN114671745A - Green method for synthesizing compound containing biaryl structure through Suzuki coupling reaction - Google Patents

Green method for synthesizing compound containing biaryl structure through Suzuki coupling reaction Download PDF

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CN114671745A
CN114671745A CN202011553254.8A CN202011553254A CN114671745A CN 114671745 A CN114671745 A CN 114671745A CN 202011553254 A CN202011553254 A CN 202011553254A CN 114671745 A CN114671745 A CN 114671745A
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compound
formula
reaction
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palladium
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CN114671745B (en
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吴玉成
赵李亮
徐爽
叶守陈
宋晓龙
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Jiangsu Hecheng Advanced Materials Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
    • C07B37/04—Substitution
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
    • C07C37/18—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms by condensation involving halogen atoms of halogenated compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Abstract

The invention discloses a green method for synthesizing a compound containing a biaryl structure through a Suzuki coupling reaction. Compared with the conventional anhydrous aprotic solvent, the organic solvent adopts the etherate of the dihydric alcohol, so that the generation of reaction byproducts can be effectively reduced, the reaction yield is higher, the product purity is higher, and the subsequent application of the product is not influenced; the product of the invention is easier to separate from the reaction system, thereby reducing the economic cost and time cost of post-treatment; the solvent used in the invention has the characteristics of high flash point and no odor, so that the danger is lower, and the requirements of green and environmental protection are met; therefore, the method for synthesizing the compound containing the biaryl structure by the Suzuki coupling reaction is beneficial to realizing industrial production and has extremely high industrial application value.

Description

Green method for synthesizing compound containing biaryl structure through Suzuki coupling reaction
Technical Field
The invention relates to the field of organic synthesis, in particular to a green method for synthesizing a compound containing a biaryl structure through a Suzuki coupling reaction.
Background
Suzuki coupling (also called Suzuki-Miyaura coupling, or Suzuki reaction, or Suzuki-Miyaura reaction) is a new type of cross-coupling reaction, and aryl or alkenyl boronic acid or borate is cross-coupled with chlorine, bromine, iodo-arene or olefin under the catalysis of a zero-valent palladium complex. The reaction is firstly reported in 1979 by Suzuki Chinese, has wide application range in organic synthesis, stronger substrate adaptability and functional group tolerance, and is commonly used for synthesizing derivatives of polyene, styrene and biphenyl, thereby being applied to the synthesis of a plurality of natural products and organic materials.
In recent years, the development of liquid crystal display materials has been advanced sufficiently, and various liquid crystal materials have been widely developed, in which a ring system is a skeleton of the display material, and a liquid crystal phase is impossible without the presence of the ring system. The ring system has a linear structure, and the ring system with practical value is mainly a six-membered ring, including (but not limited to): benzene ring, pyrimidine ring, pyridine ring, dioxane, cyclohexane ring, etc.
In the preparation process of liquid crystal materials, it is very common to prepare compounds containing biaryl structures by using Suzuki coupling reaction, for example, chinese patent application CN102307838A discloses that biphenyl structures are constructed by using Suzuki coupling reaction, however, the reaction yield can only reach about 70%, and since the product is difficult to be separated from the reaction solvent, post-treatment is required by processes such as extraction, which does not meet the high standard requirements of modern chemistry on green environmental protection.
Therefore, optimization and improvement of a method for synthesizing a compound containing a biaryl structure by a Suzuki coupling reaction are needed, so as to develop a green method with higher reaction yield, more convenient post-treatment, more economy and environmental protection.
Disclosure of Invention
The purpose of the invention is as follows: in order to solve the problems of low reaction yield, complex post-treatment, high three wastes and the like in the method for synthesizing the compound containing the biaryl structure through the Suzuki coupling reaction in the prior art, the invention aims to provide a green method for synthesizing the compound containing the biaryl structure through the Suzuki coupling reaction.
The technical scheme is as follows: in order to achieve the above object, the present invention provides a method for synthesizing a biaryl structure-containing compound by Suzuki coupling reaction, the biaryl structure-containing compound being a compound of formula a:
Figure BDA0002857784600000021
wherein the content of the first and second substances,
R1and R2Each independently represents hydrogen, cyano, thiocyano, isothiocyanato, nitro, amino, C1-C4Alkylamino, halogen, C1-C12Non-halogenated alkyl, or C1-C12Haloalkyl, and one or more-CH's in said alkyl2-may be independently replaced by-O-, -S-, -CO-, -CS-, -CH ═ CH-, or-C ≡ C-, respectively, wherein-O-and/or-S-are not directly linked;
Figure BDA0002857784600000022
each independently represents C3-C10Cycloalkyl radical, C5-C9Heterocyclic group, or C6-C10Aryl radical, said C3-C10Cycloalkyl radical, C5-C9Heterocyclic group, or C6-C10One or more-H in aryl is optionally substituted by 1,2 or 3 independently selected from cyano, thiocyano, isothiocyanato, nitro, amino, halogen, C1-C6Non-halogenated alkyl or C1-C6Haloalkyl, C1-C6Non-halogenated alkoxy and C1-C6Substituted with a halo-alkoxy group, and one or more-CH's in the alkyl group2-may be independently replaced by-O-, -S-, -CO-, -CS-, -CH ═ CH-, or-C ≡ C-, respectively, wherein-O-and/or-S-are not directly linked;
Figure BDA0002857784600000023
each independently represents C6-C10Aryl radical, said C6-C10One or more-H in aryl is optionally substituted by 1,2 or 3 independently selected from cyano, thiocyano, isothiocyanato, nitro, amino, halogen, C1-C6Non-halogenated alkyl, C1-C6Haloalkyl, C1-C6Non-halogenated alkoxy and C1-C6Substituted by a substituent of haloalkoxy, one or more-CH in said alkyl2-is independently replaced by-O-, -S-, -CO-, -CS-, -CH ═ CH-or-C ≡ C-, respectively, wherein-O-and/or-S-are not directly linked, and said C ≡ C-is6-C10One or more-CH-in aryl groups may each be independently replaced by-N ═ o;
Z1and Z2Each independently represents a single bond, -O-, -S-, -CO-O-, -O-CO-, - (CH)2)n-、-(CF2)n-、-CH＝CH-、-CF＝CH-、-CH＝CF-、-CF＝CF-、-C≡C-、-CH2O-、-OCH2-、-CF2O-or-OCF2-；
a and b each independently represent an integer of 0 to 2;
the method is characterized by comprising the following steps:
reacting a compound of formula I
Figure BDA0002857784600000024
With a compound of formula II in the presence of a base, a palladium catalyst, water and an organic solvent
Figure BDA0002857784600000025
Wherein the content of the first and second substances,
x represents chlorine, bromine or iodine;
L1and L2Each independently represents a hydroxyl group, or, L1And L2Together form a bridging group-O- (C (R)a)2)qO-, wherein q is 2 or 3, RaRepresents hydrogen or C1-C3An alkyl group;
R1、
Figure BDA0002857784600000026
Z1、Z2a and b are as defined above; and is
The organic solvent is an etherate of a dihydric alcohol.
In some embodiments of the invention, the organic solvent is one or more compounds of formula M:
Figure BDA0002857784600000031
wherein the content of the first and second substances,
r represents-H or C1-C5An alkyl group;
Rxand RyEach independently represents C1-C5An alkyl group; and is
n represents an integer from 1 to 8, where n represents an integer from 3 to 8, and structural fragments
Figure BDA0002857784600000032
Containing one or more-CH2When is, the one or more-CHs2-optionally each independently replaced by-O-, with the proviso that-O-is not directly attached.
In some embodiments of the invention, R preferably represents-H or methyl, and RxAnd RyEach independently represents C1-C3An alkyl group.
In some embodiments of the invention, the organic solvent is further preferably one or more of diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, diethylene glycol diethyl ether, ethylene glycol diethyl ether, dipropylene glycol dimethyl ether, dipropylene glycol diethyl ether, and dipropylene glycol diisopropyl ether; dipropylene glycol dimethyl ether is particularly preferable.
In the present invention, halogen represents fluorine, bromine, chlorine or iodine, particularly fluorine, bromine or chlorine.
In the present invention, C1-C12Non-halogenated alkyl represents a saturated straight-chain or branched-chain hydrocarbon group having 1 to 12 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2-dimethylpropyl, 1-ethylpropyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 2-trimethylpropyl, 1,2, 2-trimethylpropyl, 1-ethyl-1-methylpropyl, or 1-ethyl-2-methylpropyl, and the like.
In the present invention, C1-C12Haloalkyl denotes straight-chain or branched alkyl groups containing 1 to 12 carbon atoms, wherein one or more hydrogen atoms of these groups are substituted by halogen atoms as described above. C1-C12Examples of haloalkyl are, for example, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluorochloromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl1-fluoroethyl, 2, 2-difluoroethyl, 2,2, 2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2, 2-dichloroethyl, 2, 2-dichloro-2-fluoroethyl, 2,2, 2-trifluoroethyl, pentafluoroethyl, 1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 1, 1-difluoropropyl, 2, 2-difluoropropyl, 1, 2-difluoropropyl, 3,3, 3-trifluoropropyl, heptafluoropropyl, 1,1, 1-trifluoropropan-2-yl, 3-chloropropyl, 4-chlorobutyl and the like.
In the present invention, C3-C10Cycloalkyl means a saturated cyclic hydrocarbon group having 3 to 10 carbon atoms, for example, a monocyclic saturated hydrocarbon group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl), or a bicyclic saturated hydrocarbon group (e.g., bicyclo [3.1.0 ]]Hexyl, bicyclo [3.2.0]Heptyl, bicyclo [3.3.0]Octyl, bicyclo [4.2.0]Octyl, bicyclo [4.3.0]Nonyl, bicyclo [4.4.0]Decyl, bicyclo [2.2.1]Heptyl, bicyclo [3.1.1]Heptyl, bicyclo [2.2.2]Octyl, bicyclo [3.2.1]Octyl), and the like.
In the present invention, C5-C9Heterocyclyl represents a heteroaryl group having 5 to 9 carbon atoms containing 1,2,3 or 4 heteroatoms selected from N and O, for example, a monocyclic heteroaryl group (e.g., furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, pyridyl, oxopyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, etc.), or a bicyclic heteroaryl group (e.g., furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, pyridyl, oxopyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, etc.), or the like
Figure BDA0002857784600000041
Figure BDA0002857784600000042
Figure BDA0002857784600000043
Etc., wherein a denotes a point of attachment to the rest of the molecule, and the point of attachment is not limited to being on the ring shown, but may be on either ring).
In some embodiments of the invention, C6-C10Aryl radicalsFor example, it may be phenyl or naphthyl, etc., wherein C6-C10One or more-CH ═ in aryl groups can optionally each be independently replaced by-N ═ for example, C6-C10Each aryl group is independently substituted with-N ═ to form, for example, a pyridyl or pyrimidyl group, or C6-C10None of the-CH ═ groups in the aryl groups are replaced; wherein C is6-C10One or more-H in aryl groups may optionally each independently be substituted by halogen, -CN, C1-C5Alkyl, or C1-C5Alkoxy radicals substituted, e.g. C6-C10One or more-H in aryl is independently from each other halogen, -CN, C1-C5Alkyl, or C1-C5Alkoxy substituted, or C6-C10None of the-H groups in the aryl group are substituted.
In some embodiments of the invention, the base is an inorganic base, preferably an alkali metal carbonate, alkali metal bicarbonate, alkali metal phosphate, alkali metal hydrogen phosphate or alkali metal hydroxide, further preferably sodium bicarbonate, sodium carbonate or potassium carbonate.
In the present invention, the base is used in an amount of 0.1 to 5 moles per mole of the compound of formula I or the compound of formula II which is not used in excess; preferably, the base is used in an amount of 0.1 to 3 moles.
In some embodiments of the invention, the palladium catalyst is a palladium (II) salt or palladium (0) complex, preferably dichloro-di-tert-butyl- (4-dimethylaminophenyl) phosphine palladium (II), bis (triphenylphosphine) palladium dichloride, tetrakis (triphenylphosphine) palladium, or palladium chloride. The catalysts can have better dispersibility and thermal stability in the organic solvent, so that the catalytic efficiency of the reaction is improved; in addition, the selectivity of the product obtained by catalyzing the catalyst is very high, and the purity of the product is further improved.
In some embodiments of the invention, the reaction is carried out at a temperature of from 50 ℃ to 140 ℃, preferably from 60 ℃ to 80 ℃. If the reaction temperature is too low, the activation energy of the reaction is difficult to reach, and the reaction duration and the reaction yield are influenced; if the reaction temperature is too high, the reaction yield and the product purity are not further improved, but the equipment requirements for industrial production are greatly improved, and the safety is also obviously reduced.
In some embodiments of the invention, the reaction time is from 1 to 12 hours, preferably from 4 to 8 hours. If the reaction time is too short, the reaction is incomplete, and the reaction yield is low; if the reaction time is too long, the reaction yield is not obviously improved, but by-products are gradually increased, and the product purity is influenced.
In some embodiments of the invention, the reaction may be carried out by standard procedures of the Suzuki reaction, for example, by mixing all reagents (including the catalyst or catalyst precursor and ligand, base and solvent mixture) and reacting them at the desired temperature; alternatively, the reagents may be added stepwise, especially in the case of a continuous or semi-continuous process. The reaction is carried out under the protection of an inert gas (e.g., under an argon or nitrogen atmosphere) to avoid the presence of oxygen.
In some embodiments of the invention, the molar ratio of the compound of formula I to the compound of formula II is from 1:1 to 1: 1.2.
In some embodiments of the present invention, the amount of the palladium catalyst used is 0.00001 to 0.05 mole calculated based on the Pd content, and the amount of the palladium catalyst used is determined with respect to 1 mole of the compound of formula I or the compound of formula II if the compound of formula I and the compound of formula II are used in equimolar amounts, or with respect to 1 mole of the compound of formula I or the compound of formula II not excessively used if the compound of formula I and the compound of formula II are not used in equimolar amounts.
In some embodiments of the present invention, the amount of the palladium catalyst used is 0.00001 to 0.001 mole, calculated based on the Pd content, and is determined with respect to 1 mole of the compound of formula I or the compound of formula II if the compound of formula I and the compound of formula II are used in equimolar amounts, or is determined with respect to 1 mole of the compound of formula I or the compound of formula II if the compound of formula I and the compound of formula II are not used in equimolar amounts.
In the present invention, water and an organic solvent constitute a solvent mixture, wherein water constitutes 0.1% to 20% of the total weight of the solvent mixture; preferably, water comprises 0.5% to 18% of the total weight of the solvent mixture; further preferably, water comprises 1% to 15% of the total weight of the solvent mixture; particularly preferably, water comprises from 1% to 10% by weight of the total solvent mixture.
In the present invention, the amount of the organic solvent used is not particularly limited, but is premised on dissolving the reactant.
Has the advantages that:
1. compared with the conventional anhydrous aprotic solvent, the organic solvent adopts the etherate of the dihydric alcohol, so that the generation of reaction byproducts can be effectively reduced, the reaction yield is higher, the product purity is higher, and the subsequent application of the product is not influenced;
2. the product of the invention is easier to separate from the reaction system, thereby reducing the economic cost and time cost of post-treatment;
3. the solvent used in the invention has the characteristics of high flash point and no odor, so that the danger is lower, and the requirements of green and environmental protection are met;
therefore, the method for synthesizing the compound containing the biaryl structure by the Suzuki coupling reaction is beneficial to realizing industrial production and has extremely high industrial application value.
Detailed Description
The invention will be illustrated with reference to specific embodiments. It should be noted that the following examples are illustrative of the present invention, and are not intended to limit the present invention. Other combinations and various modifications within the spirit or scope of the present invention may be made without departing from the spirit or scope of the present invention.
The relevant reagents used in the following examples and comparative examples are commercially available.
Relevant data testing in examples and comparative examples the instruments and test methods used are as follows:
the GC test instrument is an Agilent 7820A gas chromatograph, the carrier gas is helium (2mL/min), the sample gasification chamber is set to be 280 ℃, and the flame ion detector is set to be 300 ℃. In separating the component compounds, the capillary column DB1 (length of 30m, inner diameter of 0.32mm, film thickness of 0.25 μm, fixed liquid phase of dimethylpolysiloxane, no polarity) was kept at 180 ℃ for 2 minutes, and then heated to 280 ℃ at a rate of 5 ℃/min. After preparing the sample to be tested into an acetone solution (0.1 wt%), 1. mu.L of the solution was injected into the sample vaporization chamber.
The MS testing instrument is an Agilent 7890B-5977A mass spectrometer, and the testing conditions are as follows: EI source, ionization voltage of 70eV, ion source temperature of 250 ℃ and scanning range of 30-600 m/z.
Example 1
Figure BDA0002857784600000061
A500 mL reaction flask was charged with 51.5g of 1-bromo-4- (4-propylcyclohexyl) benzene, 44.3g of (4-butoxy-2, 3-difluorophenyl) boronic acid, 14.3g of sodium carbonate, 300mL of dipropylene glycol dimethyl ether and 120mL of water, and 0.012g of dichlorodi-tert-butyl- (4-dimethylaminophenyl) phosphine palladium (II) was added thereto under nitrogen protection at 70 ℃ to 80 ℃ for 5 hours. The organic phase was subjected to liquid separation, direct freeze crystallization, suction filtration, recrystallization from dipropylene glycol dimethyl ether once, and suction filtration to give 64.93g of Compound A-1 as a white solid (purity: 99.96% (GC), yield: 91.8%).
MS data for Compound A-1: 219.1 (12%), 232.1 (24%), 245.1 (19%), 330.2 (31%), 386.3 (14%).
The following reaction formulas of examples 2 to 3 and comparative examples 1 to 2 are the same as example 1, and only specific reaction conditions are changed.
Example 2
A500 mL reaction flask was charged with 51.5g of 1-bromo-4- (4-propylcyclohexyl) benzene, 44.3g of (4-butoxy-2, 3-difluorophenyl) boronic acid, 14.3g of sodium carbonate, 300mL of dipropylene glycol diethyl ether, and 120mL of water, and 0.012g of dichlorodi-tert-butyl- (4-dimethylaminophenyl) phosphine palladium (II) was added thereto under nitrogen protection at 70 ℃ to 80 ℃ for 5 hours. The organic phase was subjected to liquid separation, direct freeze crystallization, suction filtration, and recrystallization from dipropylene glycol diethyl ether once, and suction filtration gave 64.08g of Compound A-1 (purity: 99.97% (GC), yield: 90.6%) as a white solid.
Example 3
A500 mL reaction flask was charged with 51.5g of 1-bromo-4- (4-propylcyclohexyl) benzene, 44.3g of (4-butoxy-2, 3-difluorophenyl) boronic acid, 14.3g of sodium carbonate, 300mL of dipropylene glycol diisopropyl ether and 120mL of water, and 0.012g of dichloro-di-tert-butyl- (4-dimethylaminophenyl) phosphine palladium (II) was added under nitrogen protection at 70 ℃ to 80 ℃ for 5 hours. The organic phase was subjected to liquid separation, direct freeze crystallization, suction filtration, recrystallization from dipropylene glycol diisopropyl ether and suction filtration to give 63.3g of Compound A-1 as a white solid (purity: 99.96% (GC), yield: 89.5%).
Comparative example 1
A500 mL reaction flask was charged with 51.5g of 1-bromo-4- (4-propylcyclohexyl) benzene, 44.3g of (4-butoxy-2, 3-difluorophenyl) boronic acid, 14.3g of sodium carbonate, 240mL of toluene, 120mL of water, and 120mL of ethanol, and 0.012g of dichloro-di-tert-butyl- (4-dimethylaminophenyl) phosphine palladium (II) was added under nitrogen protection at 70 ℃ to 80 ℃ for 5 hours. Separating, extracting the water phase with 50mL of toluene for 2 times, combining the filtrates, drying, passing the filtrate through silica gel column, spin-drying, adding 300mL of petroleum ether, pulping, filtering, recrystallizing with ethanol, and filtering to obtain 51.3g of compound A-1 (purity: 98.84% (GC), yield: 72.6%) as white solid.
Comparative example 2
A500 mL reaction flask was charged with 51.5g of 1-bromo-4- (4-propylcyclohexyl) benzene, 44.3g of (4-butoxy-2, 3-difluorophenyl) boronic acid, 14.3g of sodium carbonate, 360mL of tetrahydrofuran and 120mL of water, and 0.012g of dichlorodi-tert-butyl- (4-dimethylaminophenyl) phosphine palladium (II) was added thereto under nitrogen protection for 5 hours. Separating, extracting the water phase with 50mL of toluene for 2 times, combining the filtrates, drying, passing the filtrate through a silica gel column, spin-drying, adding 300mL of petroleum ether, pulping, filtering, recrystallizing with ethanol once, and filtering to obtain 52.97g of compound A-1 (purity: 99.26% (GC), yield: 74.9%) as a white solid.
Example 4
Figure BDA0002857784600000081
50g of 4-bromo-3-methylphenol, 38.72g of 4-hydroxyphenylboronic acid, 47.16g of sodium bicarbonate, 300mL of dipropylene glycol dimethyl ether and 120mL of water are added into a 500mL reaction flask, and 0.085g of palladium chloride is added for reaction for 5 hours under the condition of nitrogen protection and temperature control of 70-80 ℃. The organic phase was subjected to liquid separation, direct freeze crystallization, suction filtration, and recrystallization with dipropylene glycol dimethyl ether once, and suction filtration gave 44.10g of Compound A-2 (purity: 99.81% (GC), yield: 82.5%) as a white solid.
MS data for Compound A-2: 77.0 (5%), 115.1 (6%), 131.0 (4%), 157.1 (3%), 181.1 (5%), 200.1 (77%).
Example 5
Figure BDA0002857784600000082
A500 mL reaction flask was charged with 38g of 2-fluoro-6-bromophenol, 46g of (4-butoxy-2, 3-difluorophenyl) boronic acid, 50g of sodium bicarbonate, 300mL of dipropylene glycol dimethyl ether, and 120mL of water, and then, under a nitrogen blanket, 70 ℃ to 80 ℃ was controlled, and 0.025g of bis (triphenylphosphine) palladium dichloride was added and reacted for 5 hours. The organic phase was subjected to liquid separation, direct freeze crystallization, suction filtration, recrystallization with dipropylene glycol dimethyl ether once, and suction filtration to give 57.75g of Compound A-3 (purity: 99.73% (GC), yield: 87.8%) as a white solid.
MS data for Compound A-3: 143.1 (15%), 164.1 (20%), 191.1 (8%), 211.1 (11%), 240.1 (21%), 296.1 (25%).
Example 6
Figure BDA0002857784600000083
A500 mL reaction flask was charged with 14g of (4- (4-propylcyclohexyl) phenyl) boronic acid, 20g of 5- ((4-bromophenyl) difluoromethoxy) -1,2, 3-trifluorobenzene, 14.3g of sodium bicarbonate, 150mL of dipropylene glycol dimethyl ether, and 50mL of water, and 0.01g of dichlorodi-tert-butyl- (4-dimethylaminophenyl) phosphine palladium (II) was added under nitrogen protection at 60 ℃ to 70 ℃ for 8 hours. The organic phase was subjected to liquid separation, direct freeze crystallization, suction filtration, recrystallization with dipropylene glycol dimethyl ether once, and suction filtration to give 24.0g of Compound A-4 as a white solid (purity: 99.98% (GC), yield: 89.1%).
MS data for Compound A-4: 327 (75%), 363.1 (5%), 455.2 (6%), 474.2 (6%), 476.2 (8%).
As can be seen from the comparison between the above examples 1-3 and the comparative examples 1-2, the present invention selects the etherate of the dihydric alcohol as the reaction solvent, which can effectively reduce the generation of reaction byproducts, improve the reaction yield, and has higher product purity and no influence on the subsequent application of the product. In addition, the above examples show that the product of the invention is easy to separate from the reaction system, and the post-reaction treatment method is simpler, thereby reducing the economic cost and time cost of post-treatment; the solvent used in the invention has the characteristics of high flash point and no odor, so that the danger is lower, and the requirements of environmental protection are met better. Therefore, the method for synthesizing the compound containing the biaryl structure by the Suzuki coupling reaction is beneficial to realizing industrial production and has extremely high industrial application value.
The above embodiments are merely illustrative of the technical concept and features of the present invention, and the present invention is not limited thereto, and equivalent changes and modifications made according to the spirit of the present invention should be covered thereby.

Claims (10)

1. A method of synthesizing a biaryl structure containing compound by Suzuki coupling reaction, the biaryl structure containing compound being of formula a:
Figure FDA0002857784590000011
wherein the content of the first and second substances,
R1and R2Each independently represents hydrogen, cyano, thiocyano, isothiocyanato, nitro, amino, C1-C4Alkylamino, halogen, C1-C12Non-halogenated alkyl, or C1-C12Haloalkyl, and one or more-CH's in said alkyl2-are each independently replaceable by-O-, -S-, -CO-, -CS-, -CH ═ CH-, or-C ≡ C-, wherein-O-and/or-S-are not directly linked;
ring (C)
Figure FDA0002857784590000014
And ring
Figure FDA0002857784590000015
Each independently represents C3-C10Cycloalkyl radical, C5-C9Heterocyclic group, or C6-C10Aryl radical, said C3-C10Cycloalkyl radical, C5-C9Heterocyclic group, or C6-C10One or more-H in aryl is optionally substituted by 1,2 or 3 independently selected from cyano, thiocyano, isothiocyanato, nitro, amino, halogen, C1-C6Non-halogenated alkyl or C1-C6Haloalkyl, C1-C6Non-halogenated alkoxy and C1-C6Substituted with a halo-alkoxy group, and one or more-CH's in the alkyl group2-may be independently replaced by-O-, -S-, -CO-, -CS-, -CH ═ CH-, or-C ≡ C-, respectively, wherein-O-and/or-S-are not directly linked;
ring (C)
Figure FDA0002857784590000016
And ring
Figure FDA0002857784590000017
Each independently represents C6-C10Aryl radical, said C6-C10One or more-H in aryl is optionally substituted by 1One, 2 or 3 are independently selected from cyano, thiocyano, isothiocyanato, nitro, amino, halogen, C1-C6Non-halogenated alkyl, C1-C6Haloalkyl, C1-C6Non-halogenated alkoxy and C1-C6Substituted by a substituent of haloalkoxy, one or more-CH in said alkyl2-is independently replaced by-O-, -S-, -CO-, -CS-, -CH ═ CH-or-C ≡ C-, respectively, wherein-O-and/or-S-are not directly linked, and said C ≡ C-is6-C10One or more-CH-in aryl groups may each be independently replaced by-N ═ o;
Z1and Z2Each independently represents a single bond, -O-, -S-, -CO-O-, -O-CO-, - (CH)2)n-、-(CF2)n-、-CH＝CH-、-CF＝CH-、-CH＝CF-、-CF＝CF-、-C≡C-、-CH2O-、-OCH2-、-CF2O-or-OCF2-；
a and b each independently represent an integer of 0 to 2;
characterized in that the method comprises the following steps:
reacting a compound of formula I
Figure FDA0002857784590000012
With a compound of formula II in the presence of a base, a palladium catalyst, water and an organic solvent
Figure FDA0002857784590000013
Wherein, the first and the second end of the pipe are connected with each other,
x represents chlorine, bromine or iodine;
L1and L2Each independently represents a hydroxyl group, or, L1And L2Together form a bridging group-O- (C (R)a)2)qO-, wherein q is 2 or 3, RaRepresents hydrogen or C1-C3An alkyl group;
R1ring of
Figure FDA0002857784590000023
Ring(s)
Figure FDA0002857784590000024
Ring(s)
Figure FDA0002857784590000025
Ring (C)
Figure FDA0002857784590000026
Z1、Z2A and b are as defined above; and is provided with
The organic solvent is an etherate of dihydric alcohol.
2. The process according to claim 1, characterized in that the organic solvent is one or more compounds of formula M:
Figure FDA0002857784590000021
wherein the content of the first and second substances,
r represents-H or C1-C5An alkyl group;
Rxand RyEach independently represents C1-C5An alkyl group; and is
n represents an integer from 1 to 8, where n represents an integer from 3 to 8, and structural fragments
Figure FDA0002857784590000022
Containing one or more-CH2When is said one or more-CH2-optionally each independently replaced by-O-, with the proviso that-O-is not directly attached;
preferably, R represents-H or methyl, and RxAnd RyEach independently represents C1-C3An alkyl group;
further preferably, the organic solvent is one or more of diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, diethylene glycol diethyl ether, ethylene glycol diethyl ether, dipropylene glycol dimethyl ether, dipropylene glycol diethyl ether and dipropylene glycol diisopropyl ether; particularly preferably, the organic solvent is dipropylene glycol dimethyl ether.
3. The process according to claim 1, characterized in that the base is an inorganic base, preferably an alkali metal carbonate, alkali metal bicarbonate, alkali metal phosphate, alkali metal hydrogen phosphate or alkali metal hydroxide, further preferably sodium bicarbonate, sodium carbonate or potassium carbonate.
4. The process according to claim 1, characterized in that the palladium catalyst is a palladium (II) salt or a palladium (0) complex, preferably dichloro-di-tert-butyl- (4-dimethylaminophenyl) phosphine palladium (II), bis (triphenylphosphine) palladium dichloride, tetrakis (triphenylphosphine) palladium, or palladium chloride.
5. The process according to claim 1, characterized in that the reaction is carried out at a temperature of 50-140 ℃, preferably 60-80 ℃.
6. The process according to claim 1, wherein the reaction time is 1 to 12 hours, preferably 4 to 8 hours.
7. The method of claim 1, wherein the reaction is carried out under the protection of an inert gas.
8. The method of claim 1, wherein the molar ratio of the compound of formula I to the compound of formula II is from 1:1 to 1: 1.2.
9. The method according to claim 1, wherein the amount of the palladium catalyst used is 0.00001 to 0.05 mole calculated based on the Pd content, and is determined with respect to 1 mole of the compound of formula I or the compound of formula II if the compound of formula I and the compound of formula II are used in equimolar amounts, or is determined with respect to 1 mole of the compound of formula I or the compound of formula II not used in excess if the compound of formula I and the compound of formula II are not used in equimolar amounts.
10. The method according to claim 9, wherein the palladium catalyst is used in an amount of 0.00001 to 0.001 mole calculated based on the Pd content, and the amount of the palladium catalyst is determined with respect to 1 mole of the compound of formula I or the compound of formula II if the compound of formula I and the compound of formula II are used in equimolar amounts, or the amount of the palladium catalyst is determined with respect to 1 mole of the compound of formula I or the compound of formula II that is not used in excess if the compound of formula I and the compound of formula II are not used in equimolar amounts.
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