A method for synthesizing β-geminal difluorophenylethanol or β-geminal difluorophenyl ether compounds and analogs thereof

Abstract

The present application provides a method for synthesizing β-geminal difluorophenylethanol or β-geminal difluorophenyl ether compounds and analogs thereof, comprising the following steps: mixing a rhodium catalyst, a base, a compound represented by formula (1), a compound represented by formula (2) and a compound represented by formula (3) and reacting them under an inert atmosphere to obtain a compound represented by formula (A). The present application uses the compound represented by formula (1), the compound represented by formula (2) and the compound represented by formula (3) as raw materials, reacts them under the action of a rhodium catalyst and a base in an inert atmosphere, and can prepare β-geminal difluorophenylethanol or β-geminal difluorophenyl ether compounds and analogs thereof represented by formula (A) in one step, which greatly shortens the synthesis steps and time, has a simple feeding method, is easy to obtain the reaction raw materials, and has a high yield and high purity.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for synthesizing β-geminal difluorophenylethanol or β-geminal difluorophenyl ether compounds and analogs thereof. Background Art

[0002] Gem-difluoro fluorinated building blocks have many important functions and occupy an important position in biomedicine, organic synthesis and chemical research.

[0003] The difluoroalcohol shown in formula (A) is a typical geminal difluoro fluorine-containing building block. Compounds having this structure can be used to remove agricultural pests or as anthelmintics for mites or moths; and β-adrenergic receptor antagonists for combating congenital lung disease or bronchitis also have a difluoro structure.

[0004] Formula (A).

[0005] Chinese patent CN107337581A discloses a method for preparing difluoroalcohols by reacting aldehydes with fluorine-containing compounds and then reducing them with a reducing agent. However, the difluoroalcohols prepared by this method have low purity. Summary of the invention

[0006] In view of this, the purpose of the present application is to provide a method for synthesizing β-difluorophenylethanol or β-difluorophenyl ether compounds and their analogues. The synthesis method provided in the present application has simple steps, less waste, high product purity, and is suitable for industrial production.

[0007] The present application provides a method for synthesizing β-geminal difluorophenylethanol or β-geminal difluorophenyl ether compounds and analogs thereof, comprising the following steps:

[0008] A rhodium catalyst, a base, a compound represented by formula (1), a compound represented by formula (2) and a compound represented by formula (3) are mixed and reacted under an inert atmosphere to obtain a compound represented by formula (A);

[0009] Formula (1); Formula (2); Formula (3);

[0010] Formula (A);

[0011] Wherein, M is a boron-containing substituent, and the B atom of the boron-containing substituent is connected to a phenyl group;

[0012] X is a halogen;

[0013] R1, R2, R3, R4, R5, R6, R7 are independently selected from one of hydrogen, halogen, alkyl optionally substituted by one or more substituents, alkenyl optionally substituted by one or more substituents, alkynyl optionally substituted by one or more substituents, alkoxy optionally substituted by one or more substituents, cyano, amino, amide optionally substituted by one or more substituents, ester optionally substituted by one or more substituents, keto optionally substituted by one or more substituents, phenyl optionally substituted by one or more substituents, naphthyl optionally substituted by one or more substituents, nitrogen-containing heterocycle optionally substituted by one or more substituents, oxygen-containing heterocycle optionally substituted by one or more substituents, sulfur-containing heterocycle optionally substituted by one or more substituents;

[0014] The substituent is selected from alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, halogen, alkenyl, haloalkenyl, alkenyloxy, alkylthio, haloalkylthio, alkyl-substituted borate, alkanoate, benzyloxy or aromatic groups.

[0015] In some specific implementations, not all of R1, R2, R3, R4, and R5 are hydrogen.

[0016] In some specific implementations, the rhodium catalyst is selected from bis(ethylene)rhodium(I) acetylacetonate, tris(triphenylphosphine)carbonyl rhodium hydride(I), dicarbonyl acetylacetonate rhodium(I), carbonyl bis(triphenylphosphine)rhodium chloride(I) , (1,5-cyclooctadiene)chlororhodium (I) dimer, bis(1,5-cyclooctadiene)tetrafluoroborate rhodium, bis(1,5-cyclooctadiene)-trifluoromethanesulfonate rhodium, tri(triphenylphosphine)rhodium bromide (I), (1,5-cyclooctadiene)2,4-pentanedione rhodium (I), bis[(1,5-cyclooctadiene)(methoxy)rhodium], chlorobis(ethylene)rhodium (I) dimer, dipolymerized hydroxy(1,5-cyclooctadiene)rhodium (I), 1,2-bis[(2S,5S)-2,5-diphenylphosphino]ethane (1,5-cyclooctadiene)tetrafluoroborate rhodium (I), bis(1,5-cyclooctadiene)rhodium (I) hexafluoride antimony salt, (R)-(-)-tert-butylmethyl(di-tert-butylphosphinomethyl)phosphino(1,5-cyclooctadiene)rhodium (I) tetrafluoroborate or one or more thereof.

[0017] In some specific implementations, the base is selected from lithium trimethylsilanolate, potassium trimethylsilanolate, sodium trimethylsilanolate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium methoxide, sodium methoxide, potassium methoxide, lithium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, sodium thiosulfate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, sodium sulfate, potassium sulfate, potassium dihydrogen phosphate, potassium trihydrogen phosphate, potassium tetrahydrogen phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium trihydrogen phosphate, calcium tetrahydrogen phosphate, sodium phosphate, sodium dihydrogen phosphate, sodium trihydrogen phosphate, sodium tetrahydrogen phosphate, magnesium phosphate, magnesium dihydrogen phosphate, magnesium trihydrogen phosphate, magnesium tetrahydrogen phosphate, aluminum phosphate, aluminum dihydrogen phosphate, aluminum trihydrogen phosphate, aluminum tetrahydrogen phosphate, and one or more of copper phosphate, copper dihydrogen phosphate, copper trihydrogen phosphate and copper tetrahydrogen phosphate.

[0018] In some specific implementations, the solvent used in the reaction is selected from one or more of water, deuterated water, ethanol, methanol, isopropanol, n-hexane, n-pentane, cyclopentane, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, methyl tert-butyl ether, ethyl ether, acetone, benzene, deuterated benzene, toluene, deuterated toluene, p-xylene, o-xylene, m-xylene, ethylbenzene, chlorobenzene, dichloromethane, deuterated dichloromethane, chloroform / deuterated chloroform, tetrahydrofuran, and 1,4-dioxane.

[0019] In some specific implementations, the molar ratio of the compound represented by formula (1), the compound represented by formula (2) and the compound represented by formula (3) is 0.2-1:0.5-4.0:0.2-100.

[0020] In some specific implementations, the molar ratio of the compound represented by formula (1) to the base is 0.2-1:1-3;

[0021] The molar percentage of the rhodium catalyst in the compound represented by formula (1) is 3% to 15%.

[0022] In some specific implementations, the reaction temperature is 0°C to 200°C, and the reaction time is 20 minutes to 36 hours.

[0023] In some specific implementations, the compound represented by formula (1) is selected from aryl boronic acid, (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) aryl compound, aryl trifluoroborate potassium, aryl boric acid neopentane glycol ester, 2-aryl-1,3,2-benzenediol borane, such as (7-methoxynaphthalen-1-yl) boronic acid, (7-methoxynaphthalen-1-yl) trifluoroborate potassium (I), 2 -(7-methoxynaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 2-(7-methoxynaphthalen-1-yl)-1,3,2-dioxaborolane, [1,1'-biphenyl]-4-ylboronic acid, (4-(trifluoromethyl)phenyl)boric acid, (4-(methoxycarbonyl)phenyl)boric acid, (4-(diphenylamino)phenyl)boric acid, naphth-2-ylboric acid, etc.

[0024] In some specific implementations, in formula (2), X is selected from bromine, fluorine, and chlorine.

[0025] The present application uses the compound represented by formula (1), the compound represented by formula (2) and the compound represented by formula (3) as raw materials, reacts in an inert atmosphere under the action of a rhodium catalyst and a base, and can prepare β-geminal difluorophenylethanol or β-geminal difluorophenylethyl ether compounds represented by formula (A) and their analogs in one step, which greatly shortens the synthesis steps and time, has a simple feeding method, is easy to obtain reaction raw materials, and has a high yield and high purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The hydrogen spectrum of 4-(1,1-difluoro-2-((3-methoxybenzyl)oxy)ethyl)-1,1'-biphenyl provided in Example 1 of the present application;

[0027] Figure 2 The fluorine spectrum of 4-(1,1-difluoro-2-((3-methoxybenzyl)oxy)ethyl)-1,1'-biphenyl provided in Example 1 of the present application;

[0028] Figure 3 The carbon spectrum of 4-(1,1-difluoro-2-((3-methoxybenzyl)oxy)ethyl)-1,1'-biphenyl provided in Example 1 of the present application;

[0029] Figure 4 The hydrogen spectrum of 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)-1-ethanol provided in Example 1 of the present application;

[0030] Figure 5 The fluorine spectrum of 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)-1-ethanol provided in Example 1 of the present application;

[0031] Figure 6The carbon spectrum of 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)-1-ethanol provided in Example 1 of the present application;

[0032] Figure 7 The hydrogen spectrum of the Abediterol precursor provided in Example 3 of the present application;

[0033] Figure 8 The fluorine spectrum of the Abediterol precursor provided in Example 3 of the present application;

[0034] Fig. 9 The carbon spectrum of the Abediterol precursor provided in Example 3 of the present application;

[0035] Fig.10 The hydrogen spectrum of (S)-2-(2,2-difluoro-2-(naphthalen-2-yl)ethoxy)methyl)-1,4-dioxane provided in Example 4 of the present application;

[0036] Fig.11 The fluorine spectrum of (S)-2-(2,2-difluoro-2-(naphthalen-2-yl)ethoxy)methyl)-1,4-dioxane provided in Example 4 of the present application;

[0037] Fig.12 The carbon spectrum of (S)-2-(2,2-difluoro-2-(naphthalen-2-yl)ethoxy)methyl)-1,4-dioxane provided in Example 4 of the present application;

[0038] Fig.13 The hydrogen spectrum of 2-((2-([1,1'-biphenyl]-4-yl)-2,2-difluoroethoxy)methyl)furan provided in Example 5 of the present application;

[0039] Fig.14 The fluorine spectrum of 2-((2-([1,1'-biphenyl]-4-yl)-2,2-difluoroethoxy)methyl)furan provided in Example 5 of the present application;

[0040] Fig.15 The carbon spectrum of 2-((2-([1,1'-biphenyl]-4-yl)-2,2-difluoroethoxy)methyl)furan provided in Example 5 of the present application. DETAILED DESCRIPTION

[0041] It should be understood that the expression "one or more of..." includes each of the items recited after the expression individually and in various different combinations of two or more of the recited items, unless otherwise understood from the context and usage. The expression "and / or" in combination with three or more recited items should be understood to have the same meaning, unless otherwise understood from the context.

[0042] The use of the terms "comprising", "having" or "containing", including their grammatical synonyms, should generally be understood as open and non-restrictive, for example not excluding other unrecited elements or steps, unless otherwise specifically stated or otherwise understood from the context.

[0043] It should be understood that the order of steps or the order in which certain actions are performed is not important as long as the present invention remains operable. In addition, two or more steps or actions may be performed simultaneously.

[0044] The use of any and all examples or exemplary language, such as "for example" or "including", herein is intended only to better illustrate the invention and does not limit the scope of the invention unless otherwise claimed. No language in this specification should be construed as indicating that any non-claimed element is essential to the practice of the invention.

[0045] In addition, the numerical ranges and parameters used to define the present invention are approximate values, and the relevant values ​​in the specific embodiments have been presented as accurately as possible. However, any numerical value inherently inevitably contains standard deviations due to individual test methods. Therefore, unless otherwise expressly stated, it should be understood that all ranges, quantities, values ​​and percentages used in this disclosure are modified by "about". Here, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a specific value or range.

[0046] The term "halogen" refers to fluorine, chlorine, bromine and iodine;

[0047] The term "alkyl" represents a saturated straight or branched hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylethyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl;

[0048] The term "alkenyl" represents an unsaturated straight-chain or branched hydrocarbon radical having 2 or 3 to 6 carbon atoms and having a double bond at any desired position, for example, C2-C6-alkenyl such as ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3- methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2 -methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1- dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3- dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl or 1-ethyl-2-methyl-2-propenyl;

[0049] The term "alkynyl" represents a straight-chain or branched hydrocarbon radical having 2 to 6 carbon atoms and having a triple bond at any desired position, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl- 2-Butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1- pentynyl, 3-methyl-4-pentynyl, 4-methyl-1-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl;

[0050] The term "alkoxy" represents a straight-chain or branched alkyl group (as described above) having 1 to 6 carbon atoms, which is bonded to the main structure via -O-;

[0051] The term "amide" represents a straight-chain or branched alkyl group (as described above) having 1 to 6 carbon atoms, which is bonded to the main structure via a -NH-CO- structure;

[0052] The term "ester group" represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms (as described above), which is bonded to the main structure via a -COO- structure;

[0053] The term "keto" represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms (as described above), which is bonded to the main structure via a -CO- structure;

[0054] The term "aromatic group" represents an unsaturated aromatic hydrocarbon group having 6 to 20 carbon atoms, such as phenyl, o-tolyl, 1-naphthyl (or α-naphthyl) or 2-naphthyl, etc.;

[0055] The term "heteroaryl" represents an aromatic group as described above, wherein at least one carbon atom is replaced by a heteroatom, such as N, O or S;

[0056] The term "nitrogen-containing heterocyclic group" represents a nitrogen-containing heterocyclic group, which is bonded to the main structure through -N-, and in addition to C and N, may also contain the group consisting of oxygen and sulfur as ring members, for example, it may be a 5-membered nitrogen-containing heterocyclic group containing one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom; the nitrogen-containing heterocyclic group may be a nitrogen-containing six-membered heterocyclic group, including carbon atoms and one to five nitrogen atoms, and in addition, may contain a sulfur atom or an oxygen atom as a ring member, etc.;

[0057] The term "oxygen-containing heterocyclic group" represents a heterocyclic group containing oxygen, which is bonded to the main structure through -O-, and in addition to C and O, may also contain the group consisting of nitrogen and sulfur as ring members, for example, it may be a 5-membered oxygen-containing heterocyclic group containing one to four oxygen atoms or one to three oxygen atoms and one sulfur or nitrogen atom; the oxygen-containing heterocyclic group may be an oxygen-containing six-membered heterocyclic group, including carbon atoms and one to five oxygen atoms, and in addition, may also contain a sulfur atom or a nitrogen atom as a ring member, etc.;

[0058] The term "sulfur-containing heterocyclic group" represents a sulfur-containing heterocyclic group, which is bonded to the main structure through -S-, and in addition to C and S, may also contain the group consisting of oxygen and nitrogen as ring members, for example, it may be a 5-membered nitrogen-containing heterocyclic group containing one to four sulfur atoms or one to three sulfur atoms and one nitrogen or oxygen atom; the sulfur-containing heterocyclic group may be a sulfur-containing six-membered heterocyclic group, including carbon atoms and one to five sulfur atoms, and in addition, may contain one sulfur atom or nitrogen atom as a ring member, etc.;

[0059] The term "borate" represents bonding to the main structure via a borate group (BO3-).

[0060] The present application provides a method for synthesizing β-geminal difluorophenylethanol or β-geminal difluorophenyl ether compounds and analogs thereof, comprising the following steps:

[0061] A rhodium catalyst, a base, a compound represented by formula (1), a compound represented by formula (2) and a compound represented by formula (3) are mixed and reacted under an inert atmosphere to obtain a compound represented by formula (A);

[0062] Formula (1); Formula (2); Formula (3);

[0063] Formula (A);

[0064] Wherein, M is a boron-containing substituent, and the B atom of the boron-containing substituent is connected to a phenyl group;

[0065] X is a halogen;

[0066] R1, R2, R3, R4, R5, R6, R7 are independently selected from one of hydrogen, halogen, alkyl optionally substituted by one or more substituents, alkenyl optionally substituted by one or more substituents, alkynyl optionally substituted by one or more substituents, alkoxy optionally substituted by one or more substituents, cyano, amino, amide optionally substituted by one or more substituents, ester optionally substituted by one or more substituents, keto optionally substituted by one or more substituents, phenyl optionally substituted by one or more substituents, naphthyl optionally substituted by one or more substituents, nitrogen-containing heterocycle optionally substituted by one or more substituents, oxygen-containing heterocycle optionally substituted by one or more substituents, sulfur-containing heterocycle optionally substituted by one or more substituents;

[0067] The substituent is selected from alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, halogen, alkenyl, haloalkenyl, alkenyloxy, alkylthio, haloalkylthio, alkyl-substituted borate, alkanoate, benzyloxy or aromatic groups.

[0068] The present application uses the compound represented by formula (1), the compound represented by formula (2) and the compound represented by formula (3) as raw materials, reacts in an inert atmosphere under the action of a rhodium catalyst and a base, and can prepare β-geminal difluorophenylethanol or β-geminal difluorophenylethyl ether compounds represented by formula (A) and their analogs in one step, which greatly shortens the synthesis steps and time, has a simple feeding method, is easy to obtain reaction raw materials, and has a high yield and high purity.

[0069] This application uses the compound represented by formula (1) as the raw material:

[0070] Formula (1);

[0071] Wherein, M is a boron-containing substituent, and the B atom of the boron-containing substituent is connected to a phenyl group, for example, it can be a boronic acid residue that has lost at least one hydroxyl group, a boric acid ester residue that has lost at least one hydroxyl group, or a boric acid salt residue that has lost at least one hydroxyl group, and optionally, the boric acid ester or boric acid salt can be substituted by a halogen. In the present application, the M group is used as a leaving group, and as long as the B atom is connected to the phenyl group, it can be removed under the action of a catalyst and a base, so that the phenyl group reacts with the double bond of the compound shown in formula (2). Therefore, the present application has no special restrictions on the boron-containing group.

[0072] In formula (1), R1, R2, R3, R4, and R5 are independently selected from the group consisting of hydrogen, halogen, alkyl optionally substituted by one or more substituents, alkenyl optionally substituted by one or more substituents, alkynyl optionally substituted by one or more substituents, alkoxy optionally substituted by one or more substituents, cyano, amino, amide optionally substituted by one or more substituents, ester optionally substituted by one or more substituents, keto optionally substituted by one or more substituents, phenyl optionally substituted by one or more substituents, naphthyl optionally substituted by one or more substituents, nitrogen-containing heterocycle optionally substituted by one or more substituents, oxygen-containing heterocycle optionally substituted by one or more substituents, and sulfur-containing heterocycle optionally substituted by one or more substituents;

[0073] The substituent is selected from alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, halogen, alkenyl, haloalkenyl, alkenyloxy, alkylthio, haloalkylthio, alkyl-substituted borate, alkanoate, benzyloxy or aromatic groups.

[0074] In some specific implementations, examples of the substituents are as follows: Examples of alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, isomers thereof, and cycloalkyl groups. Examples of alkenyl groups include vinyl, propenyl, butenyl, pentenyl, hexenyl, isomers thereof, and cycloalkenyl groups. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and isomers thereof. Alkoxy refers to a group formed by the above-mentioned alkyl group connected to an oxygen atom, such as methoxy, ethoxy, etc. Haloalkyl refers to a group formed by the above-mentioned alkyl group being substituted by one or more halogens, such as trifluoromethyl. Haloalkoxy refers to a group formed by the above-mentioned haloalkyl group being connected to an oxygen atom, such as trifluoromethoxy, etc. Halogen refers to fluorine, chlorine, bromine, and iodine. Haloalkenyl refers to a group formed by the above-mentioned alkenyl group being substituted by one or more halogens, such as difluorovinyl. Alkenyloxy refers to a group formed by the above-mentioned alkenyl group being connected to an oxygen atom, such as vinyloxy, propenyloxy, etc. Examples of alkylthio groups include methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio and isomers thereof and cycloalkylthio. Halogenated alkylthio refers to a group in which the above alkylthio is substituted by one or more halogens, such as trifluoromethylthio. Examples of alkyl-substituted borate groups include 3,4-tetramethyldioxaborolanyl, etc. Alkylcarboxyl refers to a group in which the above alkyl is substituted by one or more carboxyl groups. Examples of alkylalkanoate groups include methyl formate, etc. Examples of aromatic groups include naphthalene, biphenyl, etc.

[0075] In some specific implementations, the substituents may be 1, 2 or 3, and the substituents are preferably alkyl, halogenated alkyl, halogen, alkenyl and the like.

[0076] In some specific implementations, not all of R1, R2, R3, R4, and R5 are hydrogen.

[0077] In some specific implementations, the compound represented by formula (1) includes but is not limited to: aryl boronic acid, (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) aryl compound, aryl trifluoroborate potassium, aryl boric acid neopentane glycol ester, 2-aryl-1,3,2-benzenediol borane, such as (7-methoxynaphthalen-1-yl) boronic acid, (7-methoxynaphthalen-1-yl) trifluoroborate potassium (I ), 2-(7-methoxynaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 2-(7-methoxynaphthalen-1-yl)-1,3,2-dioxaborolane, [1,1'-biphenyl]-4-ylboronic acid, (4-(trifluoromethyl)phenyl)boric acid, (4-(methoxycarbonyl)phenyl)boric acid, (4-(diphenylamino)phenyl)boric acid, naphth-2-ylboric acid, etc.

[0078] This application uses the halogenated olefin represented by formula (2) as the raw material:

[0079] Formula (2);

[0080] Wherein, X is a halogen, preferably bromine.

[0081] R6 is selected from hydrogen, halogen, alkyl optionally substituted by one or more substituents, alkenyl optionally substituted by one or more substituents, alkynyl optionally substituted by one or more substituents, alkoxy optionally substituted by one or more substituents, cyano, amide optionally substituted by one or more substituents, ester group optionally substituted by one or more substituents, keto optionally substituted by one or more substituents, phenyl optionally substituted by one or more substituents, naphthyl optionally substituted by one or more substituents, nitrogen-containing heterocycle optionally substituted by one or more substituents, oxygen-containing heterocycle optionally substituted by one or more substituents, sulfur-containing heterocycle optionally substituted by one or more substituents, preferably independently selected from hydrogen or optionally substituted by one or more substituents alkyl. Each substituent has the definition as described above, and the application is not repeated here, preferably alkyl or alkoxy.

[0082] In some specific implementations, the compound represented by formula (2) includes, but is not limited to, one or more of 2-bromo-1,1-difluoroethylene, 1,1,2-trifluoroethylene, 2-chloro-1,1-difluoroethylene, and 2-bromo-1,1-difluoroprop-1-ene.

[0083] The present application uses the compound shown in formula (3) as a raw material, and its structural formula is as follows:

[0084] .

[0085] R7 is selected from hydrogen, halogen, alkyl optionally substituted by one or more substituents, alkenyl optionally substituted by one or more substituents, alkynyl optionally substituted by one or more substituents, alkoxy optionally substituted by one or more substituents, cyano, amide optionally substituted by one or more substituents, ester optionally substituted by one or more substituents, keto optionally substituted by one or more substituents, phenyl optionally substituted by one or more substituents, naphthyl optionally substituted by one or more substituents, nitrogen-containing heterocyclic ring optionally substituted by one or more substituents, oxygen-containing heterocyclic ring optionally substituted by one or more substituents, sulfur-containing heterocyclic ring optionally substituted by one or more substituents, preferably selected from phenyl optionally substituted by one or more substituents or keto optionally substituted by one or more substituents. Each substituent has the definition as described above, which is not repeated in this application, and is preferably alkyl or alkoxy. It can be understood by those skilled in the art that when R 7 When is H, the compound represented by formula (3) is water.

[0086] In some specific implementations, the compound represented by formula (3) includes but is not limited to: water, water- 18 O, deuterium oxide, methanol, isopropanol, 2-(6-hydroxyhexyl)isoindoline-1,3-dione, (Z)-3,7-dimethyloctan-2,6-diene-1-ol (nerol), 3-methylbut-2-ene-1-ol, trans-1,4-cyclohexanedimethanol, (3-methoxyphenyl)methanol, (R)-(1,4-dioxane-2-yl)methanol, and one or more of furan-2-ylmethanol.

[0087] In the preparation method provided in the present application, the solvent used in the reaction includes but is not limited to water, deuterated water, ethanol, methanol, isopropanol, n-hexane, n-pentane, cyclopentane, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, methyl tert-butyl ether, ethyl ether, acetone, benzene, deuterated benzene, toluene, deuterated toluene, p-xylene, o-xylene, m-xylene, ethylbenzene, chlorobenzene, dichloromethane, deuterated dichloromethane, chloroform, deuterated chloroform, tetrahydrofuran or 1,4-dioxane, and can be one or more of them, preferably p-xylene, tetrahydrofuran, dioxane or dimethyl sulfoxide.

[0088] The present application uses a rhodium-containing compound as a catalyst. In some specific implementations, the rhodium catalyst includes but is not limited to acetylacetonate bis(ethylene) rhodium (I), dicarbonyl acetylacetonate rhodium (I), (1,5-cyclooctadiene) chlororhodium (I) dimer, bis(1,5-cyclooctadiene)-trifluoromethanesulfonate rhodium, bis(1,5-cyclooctadiene) tetrafluoroborate rhodium, tri(triphenylphosphine) rhodium bromide (I), bis[(1,5-cyclooctadiene)(methoxy)rhodium], (1,5-cyclooctadiene) 2,4-pentanedione rhodium (I), chlorobis(ethylene) rhodium (I) dimer, dipolymerized hydroxy(1,5-cyclooctadiene) rhodium (I), 1,2-bis[(2S,5S)-2,5-diphenylphosphino]ethane (1,5-cyclooctadiene) tetrafluoroborate rhodium (I), carbonyl bis(triphenylphosphino) rhodium chloride (I) , bis(1,5-cyclooctadiene)rhodium(I) hexafluoride antimony salt, tri(triphenylphosphine)carbonyl rhodium(I) hydride, (R)-(-)-tert-butylmethyl(di-tert-butylphosphinomethyl)phosphino(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate or more, preferably bis(1,5-cyclooctadiene)rhodium tetrafluoroborate, chlorobis(ethylene)rhodium(I) dimer, acetylacetonatobis(ethylene)rhodium(I) or tri(triphenylphosphine)rhodium(I) bromide.

[0089] The preparation method provided in the present application also includes a base, and the base includes but is not limited to lithium trimethylsilanolate, sodium trimethylsilanolate, potassium trimethylsilanolate, lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, lithium methoxide, potassium methoxide, sodium methoxide, lithium carbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium thiosulfate, cesium carbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, sodium sulfate, potassium dihydrogen phosphate, potassium sulfate, potassium trihydrogen phosphate, calcium hydrogen phosphate, potassium tetrahydrogen phosphate, calcium tetrahydrogen phosphate, calcium dihydrogen phosphate, sodium phosphate, sodium trihydrogen phosphate, sodium dihydrogen phosphate, sodium tetrahydrogen phosphate, magnesium dihydrogen phosphate, magnesium phosphate, magnesium trihydrogen phosphate, aluminum dihydrogen phosphate, magnesium tetrahydrogen phosphate, aluminum trihydrogen phosphate, copper phosphate, aluminum tetrahydrogen phosphate, copper dihydrogen phosphate, copper trihydrogen phosphate and copper tetrahydrogen phosphate, preferably sodium carbonate, lithium tert-butoxide or cesium carbonate.

[0090] In the present application, the molar ratio of the compound represented by formula (1), the compound represented by formula (2) and the compound represented by formula (3) is 0.2~1:0.5~4.0:0.2~100, preferably 0.5~0.8:1~3.5:1~50. In some specific implementations, the molar ratio of the compound represented by formula (1) to the base is 0.2~1:1~3, preferably 0.5~0.8:1.5~3. In some specific implementations, the molar percentage of the rhodium catalyst in the compound represented by formula (1) is 3%~15%, preferably 5%~10%. In some specific implementations, the molar volume ratio of the compound represented by formula (1) to the reaction medium is 0.2mmol~1mmol:0.5mL~10mL, preferably 0.3mmol:2mL~6mL.

[0091] In the present application, the compound represented by formula (1), the compound represented by formula (2), the compound represented by formula (3), a rhodium catalyst and a base are uniformly mixed in a reaction medium and reacted to obtain β-geminal difluorophenylethanol or β-geminal difluorophenylethyl ether compounds and analogs thereof represented by formula (A). The reaction process is as follows:

[0092]

[0093] In some specific implementations, the reaction temperature is 0°C to 200°C, preferably 40°C to 150°C, more preferably 60°C to 120°C, more preferably 70°C to 100°C; the reaction time is 20min to 36h, preferably 5h to 30h, more preferably 6h to 24h. In some specific implementations, the reaction is preferably carried out in an oil bath.

[0094] After the reaction is completed, the reaction medium, ie, the solvent, is removed, and the obtained residue is eluted by silica gel column chromatography to obtain the β-arylamine compound represented by formula (A) and its analogs.

[0095] The present application uses the compound represented by formula (1), the compound represented by formula (2) and the compound represented by formula (3) as raw materials, reacts in an inert atmosphere under the action of a rhodium catalyst and a base, and can prepare β-geminal difluorophenylethanol or β-geminal difluorophenylethyl ether compounds represented by formula (A) and their analogs in one step, which greatly shortens the synthesis steps and time, has a simple feeding method, is easy to obtain reaction raw materials, and has a high yield and high purity.

[0096] The synthesis method of β-geminal difluorophenylethanol or β-geminal difluorophenyl ether compounds and their analogs provided by the present application is further described below in conjunction with the examples.

[0097] Example 1 4-(1,1-difluoro-2-((3-methoxybenzyl)oxy)ethyl)-1,1'-biphenyl

[0098] Under the protection of an inert atmosphere, 0.1 mmol of [1,1'-biphenyl]-4-ylboronic acid, 0.18 mmol of 2-bromo-1,1-difluoroethylene, 0.6 mmol of (3-methoxyphenyl)methanol, 0.003 mmol of tris(triphenylphosphine)rhodium bromide (I) and 0.3 mmol of sodium carbonate were mixed, and 2 mL of p-xylene was added, and the mixture was stirred in an oil bath at 50 °C for 15 h. After the reaction was completed, the solvent was removed, the residue was eluted by silica gel column chromatography, and the product was collected to obtain 4-(1,1-difluoro-2-((3-methoxybenzyl)oxy)ethyl)-1,1'-biphenyl, which had a structure of formula (a), a purity of 93%, and a yield of 63%.

[0099] Formula (a)

[0100] The 4-(1,1-difluoro-2-((3-methoxybenzyl)oxy)ethyl)-1,1'-biphenyl was subjected to nuclear magnetic resonance analysis. The results are shown in Figure 1 , Figure 2 and Figure 3 , Figure 1 The hydrogen spectrum of 4-(1,1-difluoro-2-((3-methoxybenzyl)oxy)ethyl)-1,1'-biphenyl provided in Example 1 of the present application, Figure 2 The fluorine spectrum of 4-(1,1-difluoro-2-((3-methoxybenzyl)oxy)ethyl)-1,1'-biphenyl provided in Example 1 of the present application, Figure 3 This is the carbon spectrum of 4-(1,1-difluoro-2-((3-methoxybenzyl)oxy)ethyl)-1,1'-biphenyl provided in Example 1 of the present application.

[0101] 4-(1,1-difluoro-2-((3-methoxybenzyl)oxy)ethyl)-1,1'-biphenyl: 1 H NMR(500 MHz, Chloroform-d) δ 7.65 (d, J = 8.15 Hz, 2H), 7.62-7.56 (m, 4H), 7.46(t, J = 7.58 Hz, 2H), 7.42-7.34 (m, 1H), 7.24 (dd, J = 7.35, 1.91 Hz, 1H), 6.87- 6.80 (m, 3H), 4.62 (s, 2H), 3.90 (t, J = 12.88 Hz, 2H), 3.76 (s, 3H).19 F NMR (471 MHz, Chloroform-d) δ -103.16 (t, J = 12.88 Hz). 13 C NMR (126 MHz, Chloroform-d) δ 159.8, 143.1, 140.3, 138.8, 133.9 (t, J = 25.64 Hz), 129.5,128.9, 127.8, 127.3, 127.1, 126.1 (t, J = 6.15 Hz), 120.5 (t, J = 244.13 Hz), 119.9, 113.7, 112.8, 73.7, 72.0 (t, J = 32.87 Hz), 55.2. HRMS (EI) m / z: [(M)+] Calcd for C 22 H 20 F2O2 + 354.1431; Found 354.1420.

[0102] Example 2 2,2-Difluoro-2-(4-(trifluoromethyl)phenyl)-1-ethanol

[0103] Under the protection of an inert atmosphere, 0.1 mmol of (4-(trifluoromethyl)phenyl)boric acid, 0.18 mmol of 2-bromo-1,1-difluoroethylene, 5 mmol of water, 0.003 mmol of dicarbonyl acetylacetonate rhodium (I) and 0.3 mmol of cesium carbonate were mixed, and 2 mL of dioxane was added, and the mixture was stirred in an oil bath at 100 °C for 12 h. After the reaction was completed, the solvent was removed, the residue was eluted by silica gel column chromatography, and the product was collected to obtain 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)-1-ethanol, which had a structure of formula (b), a purity of 95%, and a yield of 42%.

[0104] Formula (b)

[0105] The 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)-1-ethanol was subjected to nuclear magnetic resonance analysis. The results are shown in Figure 4 , Figure 5 and Figure 6 , Figure 4 The hydrogen spectrum of 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)-1-ethanol provided in Example 1 of the present application, Figure 5 The fluorine spectrum of 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)-1-ethanol provided in Example 1 of the present application, Figure 6This is the carbon spectrum of 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)-1-ethanol provided in Example 1 of the present application.

[0106] 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)ethan-1-ol: 1 H NMR (400MHz, Chloroform-d) δ 7.73 (d, J = 8.24 Hz, 2H), 7.66 (d, J = 8.24 Hz, 2H), 3.99 (t, J = 13.00 Hz, 2H). 19 F NMR (376 MHz, Chloroform-d) δ -62.99, -107.40 (t, J = 13.00 Hz). 13 C NMR (101 MHz, Chloroform-d) δ 138.1 (t, J = 25.86 Hz), 132.3 (t, J = 32.65 Hz), 126.2 (t, J = 6.19 Hz), 125.6 (q, J = 3.79 Hz), 123.7 (q, J = 272.26 Hz), 120.0 (t, J = 244.36 Hz), 65.8 (t, J = 32.62 Hz).HRMS (EI) m / z: [(M)+] Calcd for C9H7F5O+ 226.0417; Found 226.0410.

[0107] Example 3 Abediterol Precursor

[0108] Under the protection of an inert atmosphere, 0.3 mmol of phenylboronic acid, 1 mmol of 2-bromo-1,1-difluoroethylene, 1.1 mmol of 2-(6-hydroxyhexyl)isoindoline-1,3-dione, 0.03 mmol of tris(triphenylphosphine)rhodium bromide (I) and 1.5 mmol of sodium carbonate were mixed, and 6 mL of p-xylene was added, and the mixture was stirred in an oil bath at 100 °C for 20 h. After the reaction was completed, the solvent was removed, the residue was eluted by silica gel column chromatography, and the product was collected to obtain the compound of formula (c) with a purity of 95% and a yield of 56%.

[0109] Formula (c);

[0110] The compound of formula (c) was subjected to NMR analysis, and the results are shown in Figure 7 , Figure 8 and Fig. 9, Figure 7 This is the hydrogen spectrum of the Abediterol precursor provided in Example 3 of the present application, Figure 8 The fluorine spectrum of the Abediterol precursor provided in Example 3 of the present application, Fig. 9 This is the carbon spectrum of the Abediterol precursor provided in Example 3 of the present application. Its NMR data are as follows:

[0111] 2-(6-(2,2-difluoro-2-phenylethoxy)hexyl)isoindoline-1,3-dione: 1 H NMR(500 MHz, Chloroform-d) δ 7.83 (dd, J = 5.5, 3.0 Hz, 2H), 7.69 (dd, J = 5.5,3.0 Hz, 2H), 7.50 (dd, J = 7.2, 2.6 Hz, 2H), 7.45-7.40 (m, 3H), 3.82 (t, J =13.0 Hz, 2H), 3.64 (t, J = 7.3 Hz, 2H), 3.49 (t, J = 6.5 Hz, 2H), 1.63 (p, J= 7.2 Hz, 2H), 1.52 (p, J = 6.6 Hz, 2H), 1.36-1.28 (m, 4H). 19 F NMR (471 MHz, Chloroform-d) δ -103.69 (t, J = 13.0 Hz). 13 C NMR (126 MHz, Chloroform-d) δ168.5, 135.1 (t, J = 25.33 Hz), 133.9, 132.2, 130.0 (d, J = 1.82 Hz), 128.3,125.5 (t, J = 6.21 Hz), 123.2, 120.4 (t, J = 244.32 Hz), 73.2 (t, J = 32.49Hz), 72.4, 37.9, 29.3, 28.5, 26.6, 25.5.

[0112] Example 4 (S)-2-(2,2-difluoro-2-(naphthalen-2-yl)ethoxy)methyl)-1,4-dioxane

[0113] Under the protection of an inert atmosphere, 0.1 mmol of naphthalene-2-ylboronic acid, 0.18 mmol of 2-bromo-1,1-difluoroethylene, 0.6 mmol of (R)-(1,4-dioxane-2-yl)methanol, 0.003 mmol of bis(1,5-cyclooctadiene)rhodium tetrafluoroborate and 0.3 mmol of sodium carbonate were mixed, and 2 mL of p-xylene was added, and the mixture was stirred in an oil bath at 50 °C for 12 h. After the reaction was completed, the solvent was removed, the residue was eluted by silica gel column chromatography, and the product was collected to obtain the compound of formula (d) with a purity of 97% and a yield of 43%.

[0114] Formula (d);

[0115] The compound of formula (d) was subjected to NMR analysis, and the results are shown in Fig.10 , Fig.11 and Fig.12 , Fig.10 The hydrogen spectrum of (S)-2-(2,2-difluoro-2-(naphthalen-2-yl)ethoxy)methyl)-1,4-dioxane provided in Example 4 of the present application, Fig.11 The fluorine spectrum of (S)-2-(2,2-difluoro-2-(naphthalen-2-yl)ethoxy)methyl)-1,4-dioxane provided in Example 4 of the present application, Fig.12 The carbon spectrum of (S)-2-(2,2-difluoro-2-(naphthalen-2-yl)ethoxy)methyl)-1,4-dioxane provided in Example 4 of the present application. Its NMR data are as follows:

[0116] (S)-2-((2,2-difluoro-2-(naphthalen-2-yl)ethoxy)methyl)-1,4-dioxane: 1 HNMR (500 MHz, Chloroform-d) δ 8.04 (d, J = 9.7 Hz, 1H), 7.93 – 7.85 (m, 3H), 7.61 – 7.51 (m, 3H), 4.01 (t, J = 13.0 Hz, 2H), 3.79 – 3.63 (m, 5H), 3.64 –3.51 (m, 3H), 3.35 (dd, J = 11.4, 9.9 Hz, 1H). 19 F NMR (471 MHz, Chloroform-d)δ -103.27 (t, J = 13.0 Hz). 13C NMR (126 MHz, Chloroform-d) δ 133.9, 132.5,132.1 (t, J = 25.2 Hz), 128.6, 128.4, 127.8, 127.3, 126.7, 125.6 (t, J = 7.0Hz), 122.5 (t, J = 5.7 Hz), 120.6 (t, J = 244.7 Hz), 74.3, 73.9 (t, J = 32.6Hz), 72.2, 68.4, 66.7, 66.4.

[0117] Example 5 2-((2-([1,1'-biphenyl]-4-yl)-2,2-difluoroethoxy)methyl)furan

[0118] Under the protection of an inert atmosphere, 0.1 mmol of [1,1'-biphenyl]-4-ylboronic acid, 0.18 mmol of 2-bromo-1,1-difluoroethylene, 0.6 mmol of furan-2-ylmethanol, 0.003 mmol of chlorobis(ethylene)rhodium(I) dimer and 0.3 mmol of lithium tert-butoxide were mixed, and 2 mL of toluene was added, and the mixture was stirred in an oil bath at 50 °C for 12 h. After the reaction was completed, the solvent was removed, the residue was eluted by silica gel column chromatography, and the product was collected to obtain the compound of formula (e) with a purity of 92% and a yield of 59%.

[0119] Formula (e);

[0120] The compound of formula (e) was subjected to NMR analysis, and the results are shown in Fig.13 , Fig.14 and Fig.15 , Fig.13 The hydrogen spectrum of 2-((2-([1,1'-biphenyl]-4-yl)-2,2-difluoroethoxy)methyl)furan provided in Example 5 of the present application, Fig.14 The fluorine spectrum of 2-((2-([1,1'-biphenyl]-4-yl)-2,2-difluoroethoxy)methyl)furan provided in Example 5 of the present application, Fig.15 The carbon spectrum of 2-((2-([1,1'-biphenyl]-4-yl)-2,2-difluoroethoxy)methyl)furan provided in Example 5 of the present application. Its NMR data are as follows:

[0121] 2-((2-([1,1'-biphenyl]-4-yl)-2,2-difluoroethoxy)methyl)furan: 1H NMR(500 MHz, Chloroform-d) δ 7.66 (d, J = 8.2 Hz, 2H), 7.64 – 7.57 (m, 4H), 7.48(t, J = 7.7 Hz, 2H), 7.44 – 7.37 (m, 2H), 6.49 – 5.99 (m, 2H), 4.60 (s, 2H), 3.94 (t, J = 13.0 Hz, 2H). 19 F NMR (471 MHz, Chloroform-d) δ -102.97 (t, J =13.0 Hz). 13 C NMR (126 MHz, Chloroform-d) δ 150.8, 143.2, 143.1 (t, J = 1.9Hz), 140.3, 133.8 (t, J = 25.6 Hz), 128.9, 127.9, 127.3, 127.2, 126.1 (t, J =6.2 Hz), 120.5 (t, J = 244.1 Hz), 110.4, 110.1, 71.7 (t, J = 32.6 Hz), 65.7.

[0122] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for synthesizing β-geminal difluorophenylethanol or β-geminal difluorophenyl ether compounds and analogs thereof, comprising the following steps: A rhodium catalyst, a base, a compound represented by formula (1), a compound represented by formula (2) and a compound represented by formula (3) are mixed and reacted under an inert atmosphere to obtain a compound represented by formula (A); Formula (1); Formula (2); Formula (3); Formula (A); wherein M is a boron-containing substituent, and the B atom of the boron-containing substituent is connected to a phenyl group; the compound represented by formula (1) is selected from one or more of [1,1'-biphenyl]-4-ylboronic acid, (4-(trifluoromethyl)phenyl)boronic acid, phenylboronic acid or naphth-2-ylboronic acid; X is a halogen; R7 is selected from one of hydrogen, alkyl optionally substituted by one or more substituents, and phenyl optionally substituted by one or more substituents; R6 is selected from hydrogen; The substituent is selected from an alkoxy group or an aromatic group.

2. The preparation method according to claim 1, characterized in that: The rhodium catalyst is selected from bis(ethylene)rhodium acetylacetonate (I), tris(triphenylphosphine)carbonyl rhodium hydride (I), dicarbonyl acetylacetonate rhodium (I), carbonyl bis(triphenylphosphine)rhodium chloride (I) , (1,5-cyclooctadiene)chlororhodium (I) dimer, bis(1,5-cyclooctadiene)tetrafluoroborate rhodium, bis(1,5-cyclooctadiene)-trifluoromethanesulfonate rhodium, tri(triphenylphosphine)rhodium bromide (I), (1,5-cyclooctadiene)2,4-pentanedione rhodium (I), bis[(1,5-cyclooctadiene)(methoxy)rhodium], chlorobis(ethylene)rhodium (I) dimer, dipolymerized hydroxy(1,5-cyclooctadiene)rhodium (I), 1,2-bis[(2S,5S)-2,5-diphenylphosphino]ethane (1,5-cyclooctadiene)tetrafluoroborate rhodium (I), bis(1,5-cyclooctadiene)rhodium (I) hexafluoride antimony salt, (R)-(-)-tert-butylmethyl(di-tert-butylphosphinomethyl)phosphino(1,5-cyclooctadiene)rhodium (I) tetrafluoroborate or one or more thereof.

3. The preparation method according to claim 1, characterized in that: The base is selected from one or more of lithium trimethylsilanolate, potassium trimethylsilanolate, sodium trimethylsilanolate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium methoxide, sodium methoxide, potassium methoxide, lithium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, and magnesium hydroxide.

4. The preparation method according to claim 1, characterized in that: The solvent used in the reaction is selected from one or more of n-hexane, n-pentane, cyclopentane, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N-methylpyrrolidone, methyl tert-butyl ether, ethyl ether, acetone, benzene, deuterated benzene, toluene, deuterated toluene, p-xylene, o-xylene, m-xylene, ethylbenzene, chlorobenzene, dichloromethane, deuterated dichloromethane, chloroform, deuterated chloroform, tetrahydrofuran, and 1,4-dioxane.

5. The preparation method according to claim 1, characterized in that: The molar ratio of the compound represented by formula (1), the compound represented by formula (2) and the compound represented by formula (3) is 0.2-1:0.5-4.0:0.2-100.

6. The preparation method according to claim 1, characterized in that: The molar ratio of the compound represented by the formula (1) to the base is 0.2-1:1-3; The molar percentage of the rhodium catalyst in the compound represented by formula (1) is 3% to 15%.

7. The preparation method according to claim 1, characterized in that: The reaction temperature is 0°C to 200°C, and the reaction time is 20 minutes to 36 hours.

8. The preparation method according to claim 1, characterized in that: In formula (2), X is selected from bromine.

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