Method for synthesizing 2,2-difluoro-2-phenylethan-1-ol or 2,2-difluoroethyl phenyl ether compounds and analogs thereof

Abstract

The present application provides a method for synthesizing a 2,2-difluoro-2-phenylethan-1-ol or 2,2-difluoroethyl phenyl ether compound and an analog 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 carrying out reaction under an inert atmosphere to obtain a compound represented by formula (A). In the present application, by using the compounds represented by formula (1), formula (2), and formula (3) as starting materials, reaction is carried out under the action of a rhodium catalyst and a base in an inert atmosphere, and a 2,2-difluoro-2-phenylethan-1-ol or 2,2-difluoroethyl phenyl ether compound as shown in formula (A) and an analog thereof can be prepared in a single step. The described method greatly shortens the steps and time for synthesis, has a simple process of addition, uses readily available starting materials, and achieves high yield and high purity.

Description

Synthesis method of beta-difluoro phenethyl alcohol or beta-difluoro phenethyl ether compound and analogues thereof TECHNICAL FIELD

[0001] The present application relates to the technical field of chemical synthesis, in particular to a synthesis method of beta-difluoro phenethyl alcohol or beta-difluoro phenethyl ether compound and analogues thereof. BACKGROUND

[0002] Difluoro-containing fluorine building blocks have various important functions and play an important role in biological medicine, organic synthesis and chemical research.

[0003] The difluoro alcohol shown in formula (A) is a typical difluoro-containing fluorine building block, and the compound with the structure can be used to remove agricultural pests or be used as a mite repellent or moth repellent; and the beta adrenergic receptor antagonist against congenital lung disease or bronchitis also has a difluoro structure. Formula (A).

[0004] Chinese patent CN107337581A discloses a method for preparing difluoro alcohol by reacting aldehyde with fluorine-containing compound and then reducing with a reducing agent, but the difluoro alcohol prepared by the method has low purity. SUMMARY

[0005] Therefore, the purpose of the present application is to provide a synthesis method of beta-difluoro phenethyl alcohol or beta-difluoro phenethyl ether compound and analogues thereof, which has simple steps, less waste, high product purity and is suitable for industrial production.

[0006] The present application provides a synthesis method of beta-difluoro phenethyl alcohol or beta-difluoro phenethyl ether compound and analogues thereof, which comprises the following steps:

[0007] Rhodium catalyst, base, compound shown in formula (1), compound shown in formula (2) and compound shown in formula (3) are mixed and then reacted under inert atmosphere to obtain compound shown in formula (A); Formula (1); Formula (2); Formula (3); Formula (A);

[0008] Wherein, M is a boron-containing substituent, and the B atom of the boron-containing substituent is connected with the phenyl group;

[0009] X is halogen;

[0010] R1, R2, R3, R4, R5, R6, R7are independently selected from one of hydrogen, halogen, alkyl optionally substituted with one or more substituents, alkenyl optionally substituted with one or more substituents, alkynyl optionally substituted with one or more substituents, alkoxy optionally substituted with one or more substituents, cyano, amino, amido optionally substituted with one or more substituents, ester optionally substituted with one or more substituents, ketone optionally substituted with one or more substituents, phenyl optionally substituted with one or more substituents, naphthyl optionally substituted with one or more substituents, nitrogen-containing heterocycle optionally substituted with one or more substituents, oxygen-containing heterocycle optionally substituted with one or more substituents, sulfur-containing heterocycle optionally substituted with one or more substituents;

[0011] The substituents are selected from alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, halogen, alkenyl, haloalkenyl, alkenyloxy, alkylthio, haloalkylthio, alkyl- substituted boronate, alkanoate, benzyloxy, or aryl.

[0012] In some specific implementations, R1, R2, R3, R4, R5are not all hydrogen.

[0013] In some specific implementations, the rhodium catalyst is selected from one or more of acetylacetone bis(ethylene)rhodium(I), tris(triphenylphosphine)carbonylhydrido rhodium(I), dicarbonyl acetylacetone rhodium(I), carbonyl bis(triphenylphosphine) rhodium(I) chloride, (1,5-cyclooctadiene)chloro rhodium(I) dimer, bis(1,5- cyclooctadiene) rhodium tetrafluoroborate, bis(1,5-cyclooctadiene)- rhodium triflate, tris(triphenylphosphine) rhodium(I) bromide, (1,5- cyclooctadiene)2,4-pentanedione rhodium(I), bis[(1,5-cyclooctadiene)(methoxy) rhodium], chloro bis(ethylene) rhodium(I) dimer, dimeric hydroxo(1,5- cyclooctadiene) rhodium(I), 1,2-bis[(2S,5S)-2,5-diphenylphosphino]ethane(1,5- cyclooctadiene) rhodium(I) tetrafluoroborate, bis(1,5-cyclooctadiene) rhodium(I) antimony hexafluoride salt, (R)-(-)-t-butylmethyl(di-t-butylphosphinomethyl) phosphino(1,5-cyclooctadiene) rhodium(I) tetrafluoroborate.

[0014] In some specific embodiments, 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, 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 copper phosphate, copper dihydrogen phosphate, copper trihydrogen phosphate, and copper tetrahydrogen phosphate.

[0015] In some specific embodiments, the solvent used in the reaction is selected from one or more of water, deuterium 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, diethyl ether, acetone, benzene, deuterated benzene, toluene, deuterated toluene, p-xylene, o-xylene, m-xylene, ethylbenzene, chlorobenzene, dichloromethane, deuterated dichloromethane, chloroform / deuterated chloroform, tetrahydrofuran, 1,4-dioxane.

[0016] In some specific embodiments, 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.

[0017] In some specific embodiments, the molar ratio of the compound represented by formula (1) to the base is 0.2-1:1-3.

[0018] The molar percentage of the rhodium catalyst with respect to the compound represented by formula (1) is 3%-15%.

[0019] In some specific embodiments, the temperature of the reaction is 0°C-200°C, and the time is 20 min-36 hours.

[0020] In some specific embodiments, the compound of formula (1) is selected from aryl boronic acid, (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aryl compound, potassium aryl trifluoroborate, aryl boronic acid neopentyl glycol ester, 2-aryl-1,3,2-benzodiol borane, such as (7-methoxynaphthalen-1-yl)boronic acid, (7-methoxynaphthalen-1-yl)potassium trifluoroborate (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)boronic acid, (4-(methoxycarbonyl)phenyl)boronic acid, (4-(diphenylamino)phenyl)boronic acid, naphthalen-2-ylboronic acid, and the like.

[0021] In some specific embodiments, in formula (2), X is selected from bromine, fluorine, chlorine.

[0022] The present application uses the compound of formula (1), the compound of formula (2) and the compound of formula (3) as raw materials, and reacts under the action of rhodium catalyst and base in an inert atmosphere to obtain the β-disubstituted difluoro phenethyl alcohol or β-disubstituted difluoro phenyl ether compound of formula (A) and the like in one step, greatly shortening the synthesis steps and time, and the feeding mode is simple, the raw materials are easy to obtain, and the yield and purity are high. BRIEF DESCRIPTION OF DRAWINGS

[0023] FIG. 1 is a hydrogen spectrum of 4-(1,1-difluoro-2-((3-methoxybenzyl)oxy)ethyl)-1,1'-biphenyl provided by Example 1 of the present application;

[0024] FIG. 2 is a fluorine spectrum of 4-(1,1-difluoro-2-((3-methoxybenzyl)oxy)ethyl)-1,1'-biphenyl provided by Example 1 of the present application;

[0025] FIG. 3 is a carbon spectrum of 4-(1,1-difluoro-2-((3-methoxybenzyl)oxy)ethyl)-1,1'-biphenyl provided by Example 1 of the present application;

[0026] FIG. 4 is a hydrogen spectrum of 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)-1-ethanol provided by Example 1 of the present application;

[0027] FIG. 5 is a fluorine spectrum of 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)-1-ethanol provided by Example 1 of the present application;

[0028] FIG. 6 is a carbon spectrum of 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)-1-ethanol provided by Example 1 of the present application;

[0029] Figure 7 is a hydrogen spectrum of the abediterol precursor provided in Example 3 of the present application;

[0030] Figure 8 is a fluorine spectrum of the abediterol precursor provided in Example 3 of the present application;

[0031] Figure 9 is a carbon spectrum of the abediterol precursor provided in Example 3 of the present application;

[0032] Figure 10 is a 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;

[0033] Figure 11 is a 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;

[0034] Figure 12 is a 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;

[0035] Figure 13 is a hydrogen spectrum of 2-((2-([1,1'-biphenyl]-4-yl)-2,2- difluoroethoxy)methyl)furan provided in Example 5 of the present application;

[0036] Figure 14 is a fluorine spectrum of 2-((2-([1,1'-biphenyl]-4-yl)-2,2- difluoroethoxy)methyl)furan provided in Example 5 of the present application;

[0037] Figure 15 is a 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

[0038] It should be understood that the expression "one or more of" includes each of the objects recited after the expression, individually, as well as various combinations of two or more of the recited objects, unless otherwise understood from the context and usage. The expression "and / or," in connection with three or more recited objects, should be understood to have the same meaning, unless otherwise understood from the context.

[0039] The use of the terms "including," "comprising," or "having" and variations thereof, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items not specifically recited, unless otherwise specified or understood from the context and usage.

[0040] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the application remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0041] The use of any and all examples, or exemplary language herein, for example, only the better elucidate the application, and unless otherwise stated, are to be construed as being without limitation to the application. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the application.

[0042] Further, the numerical ranges and parameters setting forth the broadest scope of the application are approximations, and are only used to convey generally understood precision. Numerical parameters are only expected to be useful as definitions in any judicial or administrative ruling, and are not to be used in a literal and / or strict sense unless expressly indicated otherwise. Unless otherwise indicated, all ranges, amounts, values and percentages stated in this disclosure are to be understood as "about" the stated ranges, amounts, values and percentages. Accordingly, unless indicated to the contrary, it should be understood that all

[0043] The term "halogen" represents fluorine, chlorine, bromine and iodine;

[0044] The term "alkyl" represents a saturated straight or branched chain hydrocarbon group having from 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;

[0045] The term "alkenyl" represents an unsaturated straight-chain or branched-chain hydrocarbon group having 2 or 3 to 6 carbon atoms and one double bond in 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;

[0046] The term "alkynyl" represents a straight or branched chain hydrocarbon group having from 2 to 6 carbon atoms and one triple bond in 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;

[0047] The term "alkoxy" represents a straight or branched chain alkyl group having from 1 to 6 carbon atoms, as described above, bonded to the main structure through an -O- linkage;

[0048] The term "amido" represents a straight or branched chain alkyl group having from 1 to 6 carbon atoms, as described above, bonded to the main structure through an -NH-CO- linkage;

[0049] The term "ester" represents a straight or branched chain alkyl group having from 1 to 6 carbon atoms, as described above, bonded to the main structure through a -COO- linkage;

[0050] The term "keto" represents a straight or branched chain alkyl group having from 1 to 6 carbon atoms, as described above, bonded to the main structure through a -CO- linkage;

[0051] The term "aryl" represents an unsaturated aromatic hydrocarbon group having from 6 to 20 carbon atoms, such as phenyl, o-tolyl, 1-naphthyl (or α-naphthyl), or 2-naphthyl, and the like;

[0052] The term "heteroaryl" represents an aryl group as described above wherein at least one carbon atom is replaced by a heteroatom, such as N, O, or S;

[0053] The term "nitrogen-containing heterocyclic group" represents a heterocyclic group containing nitrogen, which is bonded to the main structure through -N-, and can further contain, as ring members, in addition to C and N, a group of heteroatoms consisting of oxygen, sulfur, for example, can 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 can be a nitrogen-containing six-membered heterocyclic group containing carbon atoms and one to five nitrogen atoms, and can further contain, as ring members, a sulfur atom or an oxygen atom, and the like;

[0054] The term "oxygen-containing heterocyclic group" represents a heterocyclic group containing oxygen, which is bonded to the main structure through -O-, and can further contain, as ring members, in addition to C and O, a group of heteroatoms consisting of nitrogen, sulfur, for example, can 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 can be an oxygen-containing six-membered heterocyclic group containing carbon atoms and one to five oxygen atoms, and can further contain, as ring members, a sulfur atom or a nitrogen atom, and the like;

[0055] The term "sulfur-containing heterocyclic group" represents a heterocyclic group containing sulfur, which is bonded to the main structure through -S-, and can further contain, as ring members, in addition to C and S, a group of heteroatoms consisting of oxygen, nitrogen, for example, can 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 can be a sulfur-containing six-membered heterocyclic group containing carbon atoms and one to five sulfur atoms, and can further contain, as ring members, a sulfur atom or a nitrogen atom, and the like;

[0056] The term "boronate group" represents a boronate group (BO3-) bonded to the main structure.

[0057] The present application provides a synthesis method of β- gem-difluorophenethyl alcohol or β- gem-difluorophenyl ether compound and its analogues, comprising the following steps:

[0058] Rhodium catalyst, base, compound represented by formula (1), compound represented by formula (2) and compound represented by formula (3) are mixed and reacted under inert atmosphere to obtain compound represented by formula (A); Formula (1); Formula (2); Formula (3); Formula (A);

[0059] Wherein, M is a boron-containing substituent, the B atom of the boron-containing substituent is connected with the phenyl group;

[0060] X is halogen;

[0061] R1, R2, R3, R4, R5, R6, R7are independently selected from one of hydrogen, halogen, alkyl optionally substituted with one or more substituents, alkenyl optionally substituted with one or more substituents, alkynyl optionally substituted with one or more substituents, alkoxy optionally substituted with one or more substituents, cyano, amino, amido optionally substituted with one or more substituents, ester optionally substituted with one or more substituents, ketone optionally substituted with one or more substituents, phenyl optionally substituted with one or more substituents, naphthyl optionally substituted with one or more substituents, nitrogen-containing heterocycle optionally substituted with one or more substituents, oxygen-containing heterocycle optionally substituted with one or more substituents, sulfur-containing heterocycle optionally substituted with one or more substituents;

[0062] said substituents are selected from alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, halogen, alkenyl, haloalkenyl, alkenyloxy, alkylthio, haloalkylthio, alkyl substituted boronate, alkanoate, benzyloxy or aryl.

[0063] The present application uses the compound shown in formula (1), the compound shown in formula (2) and the compound shown in formula (3) as raw materials, and carries out reaction in an inert atmosphere under the action of rhodium catalyst and base, to prepare the β-disubstituted difluoro phenethyl alcohol or β-disubstituted difluoro phenyl ether compound shown in formula (A) and its analogues in one step, greatly shortens the synthesis steps and time, the feeding mode is simple, the raw materials are easy to obtain, and the yield and purity are high.

[0064] The present application uses the compound shown in formula (1) as raw material: Formula (1);

[0065] wherein M is a boron-containing substituent, the B atom of the boron-containing substituent is connected with the phenyl group, for example, it can be a boronic acid residue losing at least one hydroxyl group, a boronic ester residue losing at least one hydroxyl group or a borate residue losing at least one hydroxyl group, optionally, the boronic ester or borate can be substituted by halogen. In the present application, the M group acts as a leaving group, as long as the B atom is connected with the phenyl group, it can be removed under the action of catalyst and base, so that the phenyl group reacts with the double bond of the compound shown in formula (2), therefore, the present application does not have special restrictions on the boron-containing group.

[0066] In formula (1), R1, R2, R3, R4, R5are independently selected from one of hydrogen, halogen, alkyl optionally substituted with one or more substituents, alkenyl optionally substituted with one or more substituents, alkynyl optionally substituted with one or more substituents, alkoxy optionally substituted with one or more substituents, cyano, amino, amido optionally substituted with one or more substituents, ester optionally substituted with one or more substituents, ketone optionally substituted with one or more substituents, phenyl optionally substituted with one or more substituents, naphthyl optionally substituted with one or more substituents, nitrogen-containing heterocycle optionally substituted with one or more substituents, oxygen-containing heterocycle optionally substituted with one or more substituents, and sulfur-containing heterocycle optionally substituted with one or more substituents;

[0067] The substituents are selected from alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, halogen, alkenyl, haloalkenyl, alkenyloxy, alkylthio, haloalkylthio, alkyl-substituted boronate, alkyl carboxylate, benzyloxy, or aryl.

[0068] In some specific implementations, examples of the substituents are as follows: examples of alkyl include methyl, ethyl, propyl, butyl, pentyl, hexyl, and isomers thereof and cycloalkyl. Examples of alkenyl include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and isomers thereof and cycloalkenyl. Examples of alkynyl include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and isomers thereof. Alkoxy refers to a group formed by connecting an alkyl group described above with an oxygen atom, such as methoxy, ethoxy, and the like. Haloalkyl refers to a group formed by substituting one or more halogens to an alkyl group described above, such as trifluoromethyl. Haloalkoxy refers to a group formed by connecting a haloalkyl group described above with an oxygen atom, such as trifluoromethoxy, and the like. Halogen refers to fluorine, chlorine, bromine, and iodine. Haloalkenyl refers to a group formed by substituting one or more halogens to an alkenyl group described above, such as difluoroethenyl. Alkenyloxy refers to a group formed by connecting an alkenyl group described above with an oxygen atom, such as ethenyloxy, propenyloxy, and the like. Examples of alkylthio include methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, and isomers thereof and cycloalkylthio. Haloalkylthio refers to a group formed by substituting one or more halogens to an alkylthio group described above, such as trifluoromethylthio. Examples of alkyl-substituted boronate include 3,4-tetramethyldioxolylboronate, and the like. Alkyl carboxylate refers to a group formed by substituting one or more carboxyl groups to an alkyl group described above. Examples of alkyl carboxylate include methyl carboxylate, and the like. Examples of aryl include naphthalene, biphenyl, and the like.

[0069] In some specific implementations, the substituents can be 1, 2, or 3, and the substituents are preferably alkyl, haloalkyl, halogen, alkenyl, and the like.

[0070] In some specific implementations, R1, R2, R3, R4, R5are not all hydrogen.

[0071] In some specific embodiments, the compound of formula (1) includes, but is not limited to, aryl boronic acid, (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aryl compound, aryl potassium trifluoroborate, aryl boronic acid neopentyl glycol ester, 2-aryl-1,3,2-benzene diol borane, such as (7-methoxynaphthalen-1-yl)boronic acid, (7-methoxynaphthalen-1-yl)potassium trifluoroborate (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)boronic acid, (4-(methoxycarbonyl)phenyl)boronic acid, (4-(diphenylamino)phenyl)boronic acid, naphthalen-2-ylboronic acid, and the like.

[0072] The present application uses a halogenated alkene of formula (2) as a raw material: Formula (2);

[0073] wherein X is halogen, preferably bromine.

[0074] R6is selected from one of hydrogen, halogen, alkyl optionally substituted with one or more substituents, alkenyl optionally substituted with one or more substituents, alkynyl optionally substituted with one or more substituents, alkoxy optionally substituted with one or more substituents, cyano, amido optionally substituted with one or more substituents, ester optionally substituted with one or more substituents, ketone optionally substituted with one or more substituents, phenyl optionally substituted with one or more substituents, naphthyl optionally substituted with one or more substituents, nitrogen-containing heterocycle optionally substituted with one or more substituents, oxygen-containing heterocycle optionally substituted with one or more substituents, sulfur-containing heterocycle optionally substituted with one or more substituents, preferably independently selected from hydrogen or alkyl optionally substituted with one or more substituents. Each substituent has the definition as described above, which is not repeated here, preferably alkyl or alkoxy.

[0075] In some specific embodiments, the compound of 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, 2-bromo-1,1-difluoroprop-1-ene.

[0076] The present application uses a compound of formula (3) as a raw material, which has the following structural formula: .

[0077] R7 is selected from hydrogen, halogen, alkyl optionally substituted with one or more substituents, alkenyl optionally substituted with one or more substituents, alkynyl optionally substituted with one or more substituents, alkoxy optionally substituted with one or more substituents, cyano, amide optionally substituted with one or more substituents, ester optionally substituted with one or more substituents, ketone optionally substituted with one or more substituents, phenyl optionally substituted with one or more substituents, naphthyl optionally substituted with one or more substituents, nitrogen-containing heterocycle optionally substituted with one or more substituents, oxygen-containing heterocycle optionally substituted with one or more substituents, and sulfur-containing heterocycle optionally substituted with one or more substituents, preferably phenyl optionally substituted with one or more substituents or ketone optionally substituted with one or more substituents. Each substituent has the definition described above, and will not be repeated here, but is preferably alkyl or alkoxy. Those skilled in the art will understand that when R... 7 When H is present, the compound shown in formula (3) is water.

[0078] In some specific implementations, the compound represented by formula (3) includes, but is not limited to: water, water- 18 One or more of the following: O, heavy water-D2 (deuterium oxide), methanol, isopropanol, 2-(6-hydroxyhexyl)isoindoline-1,3-dione, (Z)-3,7-dimethyloct-2,6-dien-1-ol (nerol), 3-methylbut-2-en-1-ol, trans-1,4-cyclohexanediethanol, (3-methoxyphenyl)methanol, (R)-(1,4-dioxane-2-yl)methanol, and furan-2-ylmethanol.

[0079] The solvent used in the preparation method provided in this application 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, diethyl 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 may be one or more of these, preferably p-xylene, tetrahydrofuran, dioxane, or dimethyl sulfoxide.

[0080] The present application uses a rhodium-containing compound as a catalyst, and in some specific implementations, the rhodium catalyst includes, but is not limited to, one or more of acetylacetonebis(ethylene)rhodium(I), dicarbonylacetone rhodium(I), (1,5-cyclooctadiene)chlororhodium(I) dimer, bis(1,5-cyclooctadiene)-trifluoromethanesulfonic acid rhodium, bis(1,5-cyclooctadiene)tetrafluoroboric acid rhodium, tris(triphenylphosphine)rhodium(I) bromide, bis[(1,5-cyclooctadiene)(methoxy)rhodium], (1,5-cyclooctadiene)2,4-pentanedione rhodium(I), chlorobis(ethylene)rhodium(I) dimer, dimeric hydroxy(1,5-cyclooctadiene)rhodium(I), 1,2-bis[(2S,5S)-2,5-diphenylphosphino]ethane(1,5-cyclooctadiene)tetrafluoroboric acid rhodium(I), carbonylbis(triphenylphosphine)rhodium(I) chloride, bis(1,5-cyclooctadiene)rhodium(I) hexafluoroantimonate, tris(triphenylphosphine)carbonylhydrido rhodium(I), (R)-(-)-t-butylmethyl(di-t-butylphosphinomethyl)phosphino(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate, preferably bis(1,5-cyclooctadiene)tetrafluoroboric acid rhodium, chlorobis(ethylene)rhodium(I) dimer, acetylacetonebis(ethylene)rhodium(I), or tris(triphenylphosphine)rhodium(I) bromide.

[0081] The present application also includes a base in the preparation method, and the base includes, but is not limited to, one or more of 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 dihydrogen phosphate, calcium tetrahydrogen phosphate, calcium trihydrogen 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 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.

[0082] 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 embodiments, 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 embodiments, the molar percentage of the rhodium catalyst in the compound represented by formula (1) is 3%-15%, preferably 5%-10%. In some specific embodiments, the molar volume ratio of the compound represented by formula (1) to the reaction medium is 0.2 mmol-1 mmol:0.5 mL-10 mL, preferably 0.3 mmol:2 mL-6 mL.

[0083] In the present application, the compound represented by formula (1), the compound represented by formula (2) and the compound represented by formula (3), the rhodium catalyst and the base are mixed uniformly in a reaction medium, and then reacted to obtain the β-arylamines compound represented by formula (A) or the like, and the reaction process is as follows: 。

[0084] In some specific embodiments, the reaction temperature is 0 ℃-200 ℃, preferably 40 ℃-150 ℃, more preferably 60 ℃-120 ℃, and more preferably 70 ℃-100 ℃; the reaction time is 20 min-36 h, preferably 5 h-30 h, and more preferably 6 h-24 h. In some specific embodiments, the reaction is preferably carried out in an oil bath.

[0085] After the reaction is completed, the reaction medium, i.e., the solvent, is removed, and the obtained residue is eluted by silica gel column chromatography to obtain the β-arylamines compound represented by formula (A) or the like.

[0086] In the present application, the compound represented by formula (1), the compound represented by formula (2) and the compound represented by formula (3) are used as raw materials, and the reaction is carried out in an inert atmosphere under the action of a rhodium catalyst and a base to obtain the β-arylamines compound represented by formula (A) or the like in one step, which greatly shortens the synthesis steps and time, has a simple feeding mode, and has raw materials that are easy to obtain, and has a high yield and high purity.

[0087] The synthesis method of the β-arylamines compound represented by formula (A) or the like provided in the present application is further described below in combination with examples.

[0088] Example 1 4-(1,1-Difluoro-2-((3-methoxybenzyl)oxy)ethyl)-1,1'-biphenyl

[0089] Under the protection of 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(I) bromide and 0.3 mmol of sodium carbonate were mixed and 2 mL of p-xylene was added, and the reaction was stirred in a 50 °C oil bath 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 having the structure of formula (a), with a purity of 93% and a yield of 63%. Formula (a)

[0090] The 4-(1,1-difluoro-2-((3-methoxybenzyl)oxy)ethyl)-1,1'-biphenyl was subjected to nuclear magnetic analysis, and the results are shown in FIG. 1, FIG. 2 and FIG. 3, FIG. 1 is the hydrogen spectrum of 4-(1,1-difluoro-2-((3-methoxybenzyl)oxy)ethyl)-1,1'-biphenyl provided by Example 1 of the present application, FIG. 2 is the fluorine spectrum of 4-(1,1-difluoro-2-((3-methoxybenzyl)oxy)ethyl)-1,1'-biphenyl provided by Example 1 of the present application, and FIG. 3 is the carbon spectrum of 4-(1,1-difluoro-2-((3-methoxybenzyl)oxy)ethyl)-1,1'-biphenyl provided by Example 1 of the present application.

[0091] 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). 13C 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.

[0092] Example 2 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)ethan-1-ol

[0093] Under the protection of inert atmosphere, 0.1 mmol of (4-(trifluoromethyl)phenyl)boronic acid, 0.18 mmol of 2-bromo-1,1-difluoroethylene, 5 mmol of water, 0.003 mmol of dicarbonyl acetylacetone rhodium (I) and 0.3 mmol of cesium carbonate were mixed and 2 mL of dioxane was added, and the reaction was stirred in a 100 °C oil bath 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 has the structure of formula (b), purity 95%, yield 42%. Formula (b)

[0094] The 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)-1-ethanol was subjected to nuclear magnetic analysis, and the results are shown in FIG. 4, FIG. 5 and FIG. 6, FIG. 4 is the hydrogen spectrum of 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)-1-ethanol provided by Example 1 of the present application, FIG. 5 is the fluorine spectrum of 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)-1-ethanol provided by Example 1 of the present application, and FIG. 6 is the carbon spectrum of 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)-1-ethanol provided by Example 1 of the present application.

[0095] 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)ethan-1-ol: 1H NMR (400 MHz, 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.

[0096] Example 3 Abediterol precursor

[0097] Under the protection of 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(I) bromide and 1.5 mmol of sodium carbonate were mixed and 6 mL of p-xylene was added, and the reaction was stirred in a 100 °C oil bath 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%. Formula (c);

[0098] The compound of formula (c) was subjected to nuclear magnetic analysis, and the results are shown in FIG. 7, FIG. 8 and FIG. 9. FIG. 7 is the hydrogen spectrum of the Abediterol precursor provided in Example 3 of the present application, FIG. 8 is the fluorine spectrum of the Abediterol precursor provided in Example 3 of the present application, and FIG. 9 is the carbon spectrum of the Abediterol precursor provided in Example 3 of the present application. The nuclear magnetic data thereof are as follows:

[0099] 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) δ 168.5, 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 = 32.49 Hz), 72.4, 37.9, 29.3, 28.5, 26.6, 25.5.

[0100] Example 4 (S)-2-(2,2-difluoro-2-(naphthyl-2-yl)ethoxy)methyl)-1,4-dioxane

[0101] Under an inert atmosphere, 0.1 mmol of naphth-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)tetrafluoroborate and 0.3 mmol of sodium carbonate were mixed, and 2 mL of p-xylene was added. The mixture was stirred in an oil bath at 50 °C for 12 h. After the reaction was complete, the solvent was removed, and the residue was eluted by silica gel column chromatography. The product was collected to give compound (d) with a purity of 97% and a yield of 43%. Formula (d);

[0102] The compound of Formula (d) was subjected to nuclear magnetic analysis, and the results are shown in FIG. 10, FIG. 11 and FIG. 12, FIG. 10 is 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 is 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, and FIG. 12 is 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. The nuclear magnetic data thereof are as follows:

[0103] (S)-2-((2,2-difluoro-2-(naphthalen-2-yl)ethoxy)methyl)-1,4-dioxane: 1 H NMR (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). 13 C 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 = 7.0 Hz), 122.5 (t, J = 5.7 Hz), 120.6 (t, J = 244.7 Hz), 74.3, 73.9 (t, J = 32.6 Hz), 72.2, 68.4, 66.7, 66.4.

[0104] Example 5 2-((2-([1,1'-biphenyl]-4-yl)-2,2-difluoroethoxy)methyl)furan

[0105] Under the protection of 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 reaction was stirred in a 50 °C oil bath 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%. Formula (e);

[0106] The compound of formula (e) was subjected to nuclear magnetic analysis, and the results are shown in FIG. 13, FIG. 14 and FIG. 15. FIG. 13 is 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 is the fluorine spectrum of 2-((2-([1,1'-biphenyl]-4-yl)-2,2-difluoroethoxy)methyl)furan provided in Example 5 of the present application, and FIG. 15 is the carbon spectrum of 2-((2-([1,1'-biphenyl]-4-yl)-2,2-difluoroethoxy)methyl)furan provided in Example 5 of the present application. The nuclear magnetic data thereof are as follows:

[0107] 2-((2-([1,1'-biphenyl]-4-yl)-2,2-difluoroethoxy)methyl)furan: 1 H 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). 13C NMR (126 MHz, Chloroform-d) δ 150.8, 143.2, 143.1 (t, J = 1.9 Hz), 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.

[0108] The above description is merely preferred embodiments of the present application, and it is to be noted that, for the ordinary skilled in the art, certain improvements and refinements can be made without departing from the principles of the present application, and these improvements and refinements shall also be considered as falling within the scope of the present application.

Claims

1. A method for synthesizing a β- gem-difluorophenethyl alcohol or β- gem-difluorophenyl ether compound and analogs thereof, comprising the steps of: a) reacting a compound of formula (A) ; wherein M is a boron-containing substituent, the B atom of the boron-containing substituent is attached to the phenyl group; X is a halogen; R1, R2, R3, R4, R5, R6, R7 are independently selected from one of hydrogen, halogen, alkyl optionally substituted with one or more substituents, alkenyl optionally substituted with one or more substituents, alkynyl optionally substituted with one or more substituents, alkoxy optionally substituted with one or more substituents, cyano, amino, amido optionally substituted with one or more substituents, ester optionally substituted with one or more substituents, ketone optionally substituted with one or more substituents, phenyl optionally substituted with one or more substituents, naphthyl optionally substituted with one or more substituents, nitrogen-containing heterocycle optionally substituted with one or more substituents, oxygen-containing heterocycle optionally substituted with one or more substituents, sulfur-containing heterocycle optionally substituted with one or more substituents; the substituents are selected from alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, halogen, alkenyl, haloalkenyl, alkenyloxy, alkylthio, haloalkylthio, alkyl substituted boronate, alkanoate, benzyloxy, or aryl; b) reacting the compound of step (a) with a rhodium catalyst; and c) isolating the β- gem-difluorophenethyl alcohol or β- gem-difluorophenyl ether compound. Rhodium catalyst, base, compound represented by formula (1), compound represented by formula (2) and compound represented by formula (3) are mixed and reacted under inert atmosphere to obtain compound represented by formula (A); Formula (1); formula (2); formula (3); R1, R2, R3, R4, R5 are not all hydrogen. the rhodium catalyst is selected from one or more of acetylacetonebis(ethylene)rhodium(I), tris(triphenylphosphine)carbonylhydridorhodium(I), dicarbonylacetone rhodium(I), carbonylbis(triphenylphosphine)rhodium(I) chloride, (1,5-cyclooctadiene)chlororhodium(I) dimer, bis(1,5-cyclooctadiene)rhodium tetrafluoroborate, bis(1,5-cyclooctadiene)-rhodium triflate, tris(triphenylphosphine)rhodium(I) bromide, (1,5-cyclooctadiene)2,4-pentanedionerhodium(I), bis[(1,5-cyclooctadiene)(methoxy)rhodium], chlorobis(ethylene)rhodium(I) dimer, dimeric hydroxy(1,5-cyclooctadiene)rhodium(I), 1,2-bis[(2S,5S)-2,5-diphenylphosphino]ethane(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate, bis(1,5-cyclooctadiene)rhodium(I) hexafluoroantimonate, (R)-(-)-t-butylmethyl(di-t-butylphosphinomethyl)phosphino(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate. ​ ​ ​ 2. The method of claim 1, wherein, ​ 3. The production method according to claim 1 or 2, characterized by, ​ 4. The production method according to claim 1 or 2, characterized by, 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, 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 copper phosphate, copper dihydrogen phosphate, copper trihydrogen phosphate, and copper tetrahydrogen phosphate.

5. The production method according to claim 1 or 2, characterized by, The solvent used in the reaction is selected from one or more of water, deuterium 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, diethyl ether, acetone, benzene, deuterated benzene, toluene, deuterated toluene, p-xylene, o-xylene, m-xylene, ethylbenzene, chlorobenzene, dichloromethane, deuterated dichloromethane, chloroform, deuterated chloroform, tetrahydrofuran, 1,4-dioxane.

6. The production method according to claim 1 or 2, characterized by, 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.

7. The production method according to claim 1 or 2, characterized by, The molar ratio of the compound represented by formula (1) to the base is 0.2-1:1-3; The molar percentage of the rhodium catalyst with respect to the compound represented by formula (1) is 3%-15%.

8. The production method according to claim 1 or 2, characterized by, The temperature of the reaction is 0 ℃-200 ℃, and the time is 20 min-36 hours.

9. The production method according to claim 1 or 2, characterized by, The compound represented by formula (1) is selected from one or more of (7-methoxynaphthalen-1-yl)boronic acid, potassium (7-methoxynaphthalen-1-yl)trifluoroborate (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)boronic acid, (4-(methoxycarbonyl)phenyl)boronic acid, (4-(diphenylamino)phenyl)boronic acid, or naphthalen-2-ylboronic acid.

10. The production method according to claim 1 or 2, characterized by, In formula (2), X is selected from bromine.

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