WO2018024046A1 - 一种二氟烯丙基硼酸酯的制备方法及其应用 - Google Patents

一种二氟烯丙基硼酸酯的制备方法及其应用 Download PDF

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WO2018024046A1
WO2018024046A1 PCT/CN2017/089694 CN2017089694W WO2018024046A1 WO 2018024046 A1 WO2018024046 A1 WO 2018024046A1 CN 2017089694 W CN2017089694 W CN 2017089694W WO 2018024046 A1 WO2018024046 A1 WO 2018024046A1
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pinacol ester
preparation
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周宇涵
曲景平
柳阳
赵一龙
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Dalian University of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/40—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with ozone; by ozonolysis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the invention relates to a preparation method of difluoroallyl borate and application thereof, and belongs to the field of compound preparation.
  • 1,1-Difluoroolefins are an important class of fluorine-containing groups, often used in the construction of fluorine-containing compound skeletons, and 1,1-difluoroolefin functional groups can be defluorinated to form monofluoroolefins (Chem. Lett. 1979, 983). .), hydrogenation to form difluoromethyl (J. Chem. Soc., Chem. Commun. 1989, 1437.), fluoride to form trifluoromethyl (J. Org. Chem.
  • the unsaturated double bond can also undergo a nucleophilic addition reaction to form a fluorine-containing heterocyclic ring by intermolecular cycloaddition (Angew. Chem. Int. Ed. 2012, 51, 12059.).
  • the 1,1-difluoroolefin functional group is considered to be a carbonyl bioisostere in drug design (J. Chem. Soc., Chem. Commun.
  • 1,1 -Difluoroolefin functional organic molecules are also often used as enzyme inhibitors (Fluorine in Medicinal Chemistry and Chemical Biology; Wiley-Blackwell: West London, UK, 2009.), so that it is relatively easy to synthesize 1,1-difluoroolefins. Functional organic molecules are particularly important.
  • Alkyl borate and alkyl boric acid are very important intermediates in the field of organic synthesis (Boronic Acids: Preparation and Applications in Organic Synthesis and Medicine, Wiley-VCH, Weinheim, 2005), in various pharmaceutical and polymeric materials. It has been widely used in the synthesis of liquid crystal materials and fluorescent probe materials. Compounds containing borate or boric acid functional groups can be used in addition to the classical Suzuki-Miyaura coupling (Angew. Chem., Int. Ed. 2011, 50, 6722.), and can be easily converted into corresponding ones. Alcohols, aldehydes, amine functional groups, etc. (Chem. Commun. 2013, 49, 11230.).
  • the difluoroallyl borate compound containing both a 1,1-difluoroolefin functional group and a borate functional group in the molecule is an excellent organic synthetic building block, but the synthesis of the difluoroallyl borate compound is currently only one.
  • An example report (Angew. Chem. Int. Ed. 2011, 50, 7079.) requires a complex carbene copper complex as a catalyst and a low yield.
  • Compound III 3-(4-acetylphenyl)-1-(adamantan-1-yl)-2,2-difluoro-3-hydroxy-1-propanone (Compound III) is a gamma-aminobutyric acid receptor agonist (J.Med.Chem. 2013, 56, 2456), the existing synthetic route is based on 1-(adamantan-1-yl)-4,4,4-trifluoro-3-hydroxy-1-butanone It is obtained by fluorination with Selectfluor, detrifluoroacetyl group and addition with aldehyde, and the reagent used is relatively expensive (J. Am. Chem. Soc. 2011, 133, 5802).
  • the object of the present invention is to provide an inexpensive, commercially available iron salt directly as a catalyst, with borax Method for synthesizing difluoroallyl borate compound (compound of formula II) by using trifluoromethylene (compound of formula I) as raw material, using alcohol ester as boride reagent And used for the synthesis of ⁇ -aminobutyric acid receptor agonists.
  • a method for preparing a difluoroallyl boronic acid ester which comprises reacting a compound represented by the general formula II and a boronic acid pinacol ester in a solvent in the presence of an iron catalyst and a base according to the following reaction formula; a compound of the formula I,
  • R 2 is selected from the group consisting of H, C1-C6 alkyl
  • R 3 is selected from the group consisting of H, C1-C6 alkyl, phenyl, halogen, trifluoromethyl, trifluoromethoxy, C1-C4 alkoxy, and C2-C5 ester.
  • the iron catalyst is at least one of ferrous chloride, ferric chloride, ferrous bromide, iron bromide, iron acetylacetonate, ferrous acetylacetonate, and ferrous acetate.
  • the base is selected from the group consisting of potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, sodium methoxide, lithium methoxide, potassium methoxide, cesium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium phosphate. At least one.
  • the solvent of the present invention is preferably tetrahydrofuran (THF), acetonitrile, N,N-dimethylformamide, toluene, dichloromethane, 1,2-dichloromethane, anisole, methyl t-butyl ether, and At least one of oxyhexacyclohexane and ethylene glycol dimethyl ether.
  • THF tetrahydrofuran
  • acetonitrile N,N-dimethylformamide
  • toluene dichloromethane
  • 1,2-dichloromethane 1,2-dichloromethane
  • anisole methyl t-butyl ether
  • At least one of oxyhexacyclohexane and ethylene glycol dimethyl ether At least one of oxyhexacyclohexane and ethylene glycol dimethyl ether.
  • the solvent of the present invention may be used in an amount satisfying the reaction requirements.
  • the ratio of the compound of the formula II to the amount of the solvent is 1 mmol: 5 to 15 mL.
  • alkyl as used herein includes both straight chain alkyl and branched alkyl groups.
  • a single alkyl group such as "propyl”
  • a single branched-chain alkyl group such as "isopropyl”
  • alkyl group below C4 includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl and the like. Similar rules apply Other groups used in this specification.
  • halogen as used herein includes fluoro, chloro, bromo, iodo.
  • the C2-C5 ester group described herein is a group having the structure: -COOR, wherein R is a C1-C4 alkyl group.
  • the C1-C4 alkoxy group described herein is a group having the structure: -OM 1 , wherein M 1 is a C1-C4 alkyl group such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group. , butoxy, tert-butoxy.
  • R 2 is selected from H, C 1 -C 6 alkyl, and further, R 2 is preferably H, n-propyl;
  • R 3 is selected from H, C1 ⁇ C6 alkyl, phenyl, halo, trifluoromethyl, trifluoromethoxy, C1 ⁇ C4 alkoxy, C2 ⁇ C5 ester group; further, R 3 is preferably H, Methyl, methoxy, halogen, trifluoromethyl, tert-butyl, trifluoromethoxy, phenyl;
  • the amount of the substance of the base is preferably 0.5 to 3 times the amount of the compound of the formula II, and further preferably the amount of the substance of the base is The amount of the compound represented by the above formula II is 1 to 2 times.
  • the amount of the substance of the bis-borate is preferably from 1 to 3 times the amount of the compound of the formula II, and further preferably The amount of the material of the boranoic acid pinacol ester is from 1 to 1.5 times the amount of the compound of the formula II.
  • the amount of the catalyst is preferably from 0.1% to 10%, preferably from 5% to 10%, based on the amount of the compound of the formula II.
  • the reaction temperature of the above reaction is preferably from 25 ° C to the reflux temperature of the solvent, and the reaction time is from 10 min to 48 h, preferably from 5 h to 24 h.
  • a method for preparing a difluoroallyl boronic acid ester which comprises reacting a compound represented by the general formula II and a boronic acid pinacol ester in a solvent in the presence of an iron catalyst and a base according to the following reaction formula; A compound of the formula I is obtained, wherein the reaction temperature is from 25 ° C to the reflux temperature of the solvent, and the reaction time is from 10 min to 48 h.
  • R 2 is selected from the group consisting of H, C1-C6 alkyl
  • R 3 is selected from the group consisting of H, C1-C6 alkyl, phenyl, halogen, trifluoromethyl, trifluoromethoxy, C1-C4 alkoxy, C2-C5 ester;
  • the iron catalyst is at least one of ferrous chloride, ferric chloride, ferrous bromide, iron bromide, iron acetylacetonate, ferrous acetylacetonate, and ferrous acetate.
  • the base is selected from the group consisting of potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, sodium methoxide, lithium methoxide, potassium methoxide, cesium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium phosphate. At least one.
  • the solvent is selected from the group consisting of tetrahydrofuran, acetonitrile, N,N-dimethylformamide, toluene, dichloromethane, 1,2-dichloromethane, anisole, methyl tert-butyl ether, dioxane, and B. At least one of the glycol dimethyl ethers.
  • a further object of the present invention is to provide the use of a compound prepared by the above synthetic method for the synthesis of a ⁇ -aminobutyric acid receptor agonist (III).
  • the difluoroallylboronic acid pinacol ester is then subjected to the following route:
  • 21-(4-Acetylphenyl)-3-(adamantan-1-yl)-2,2-difluorobut-3-en-1-ol is dissolved in dichloromethane/methanol mixed solvent, -78 ° C
  • the lower bubble was bubbled with ozone and kept in blue for 10 min, then moved to room temperature and bubbled with argon until the reaction system was a colorless clear solution; once again cooled to -78 ° C, argon was added to maintain argon atmosphere.
  • Table 1 lists the specific structures of the substituents of the respective starting compounds in the above reaction formula.
  • Table 2 lists the structures, physical properties and 1 H NMR data of the specific compounds 1 to 23 synthesized in the present invention, but the present invention is not limited to these compounds.
  • the invention has the beneficial effects that iron is the second highest metal element in the earth's crust and the indispensable trace element of the human body, and has the advantages of rich content, low cost, easy availability, low toxicity and environmental friendliness, and the catalyst is developed based on the invention. Current requirements for sustainable development and green chemistry.
  • the method of the present invention directly uses an inexpensive, commercially available metal iron salt as a catalyst to provide a convenient, low-cost method for the preparation of difluoroallyl borate, and is gamma-aminobutyric acid receptor agonist.
  • agent (III) provides a new and effective route.
  • test methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials are commercially available unless otherwise specified.
  • the organic phase was washed with brine (2 ⁇ 10 mL) and dried over anhydrous Na 2 SO 4
  • the title compound was obtained by chromatography.
  • the title compound was silica gel.
  • the eluent was petroleum ether: ethyl acetate (50:1).
  • the target compound was obtained in the same manner as in Example 1 except that the ⁇ -trifluoromethylstyrene in Example 1 was changed to the same molar amount of 2-methoxy- ⁇ -trifluoromethylstyrene.
  • the isolated yield was 89%.
  • the target compound was isolated in the same manner as in Example 1 except that the ⁇ -trifluoromethylstyrene in Example 1 was replaced by the same molar amount of 2-chloro- ⁇ -trifluoromethylstyrene. The rate is 72%.
  • the target compound was obtained in the same manner as in Example 1 except that the ⁇ -trifluoromethylstyrene in Example 1 was changed to the same molar amount of 3-methoxy- ⁇ -trifluoromethylstyrene.
  • the isolated yield was 90%.
  • the target compound was isolated in the same manner as in Example 1 except that the ⁇ -trifluoromethylstyrene in Example 1 was changed to the same molar amount of 3-chloro- ⁇ -trifluoromethylstyrene. The rate is 69%.
  • the target compound was obtained in the same manner as in Example 1 except that the ⁇ -trifluoromethylstyrene in Example 1 was changed to the same molar amount of 4-methoxy- ⁇ -trifluoromethylstyrene.
  • the isolated yield was 80%.
  • the target compound was isolated in the same manner as in Example 1 except that the ⁇ -trifluoromethylstyrene in Example 1 was replaced with the same molar amount of 4-chloro- ⁇ -trifluoromethylstyrene. The rate is 96%.
  • the target compound was isolated in the same manner as in Example 1 except that the ⁇ -trifluoromethylstyrene in Example 1 was replaced with the same molar amount of 4-fluoro- ⁇ -trifluoromethylstyrene. The rate is 84%.
  • the target compound was isolated in the same manner as in Example 1 except that the ⁇ -trifluoromethylstyrene in Example 1 was replaced with the same molar amount of 4-bromo- ⁇ -trifluoromethylstyrene. The rate is 84%.
  • Example 2 The target was obtained in the same manner as in Example 1 except that the ⁇ -trifluoromethylstyrene in Example 1 was changed to the same molar amount of 4-trifluoromethyl- ⁇ -trifluoromethylstyrene.
  • the isolated yield of the compound was 86%.
  • Example 2 The same procedure as in Example 1 was carried out except that the ⁇ -trifluoromethylstyrene in Example 1 was replaced with the same molar amount of 4-trifluoromethoxy- ⁇ -trifluoromethylstyrene.
  • the isolated compound was obtained in an isolated yield of 97%.
  • the target compound was obtained in the same manner as in Example 1 except that the ⁇ -trifluoromethylstyrene in Example 1 was replaced with the same molar amount of 4-tert-butyl- ⁇ -trifluoromethylstyrene.
  • the isolated yield was 86%.
  • the target compound was isolated in the same manner as in Example 1 except that the ⁇ -trifluoromethylstyrene in Example 1 was replaced with the same molar amount of 4-phenyl- ⁇ -trifluoromethylstyrene. The yield was 95%.
  • the target compound was obtained in the same manner as in Example 1 except that the ⁇ -trifluoromethylstyrene in Example 1 was changed to the same molar amount of 4-methoxycarbonyl- ⁇ -trifluoromethylstyrene.
  • the isolated yield was 58%.
  • Example 2 The same procedure as in Example 1 was carried out except that the ⁇ -trifluoromethylstyrene in Example 1 was changed to the same molar amount of 3,4-methylenedioxy- ⁇ -trifluoromethylstyrene.
  • the target compound was obtained in an isolated yield of 99%.
  • Example 2 The same procedure as in Example 1 was carried out except that the ⁇ -trifluoromethylstyrene in Example 1 was changed to the same molar amount of 2,4-dimethyl- ⁇ -trifluoromethylstyrene. The isolated compound was isolated in a yield of 73%.
  • Example 2 The same procedure as in Example 1 was carried out except that the ⁇ -trifluoromethylstyrene in Example 1 was changed to the same molar amount of 3,5-dimethyl- ⁇ -trifluoromethylstyrene.
  • the isolated compound was isolated in a yield of 80%.
  • the target compound was isolated in the same manner as in Example 1 except that the ⁇ -trifluoromethylstyrene in Example 1 was changed to the same molar amount of ⁇ -trifluoromethyl-2-benzothiopheneethylene. The yield was 73%.
  • Example 2 The title compound was isolated in the same manner as in Example 1 except that the ⁇ -trifluoromethylstyrene in Example 1 was changed to the same molar amount of ⁇ -trifluoromethyl-1-naphthaleneethylene. 72%.
  • Example 2 The same procedure as in Example 1 was carried out except that the ⁇ -trifluoromethylstyrene in Example 1 was replaced with the same molar amount of 2-trifluoromethyl-4-phenyl-1-butene. The isolated compound was isolated in a yield of 94%.
  • Example 1 Except that the ⁇ -trifluoromethylstyrene in Example 1 was replaced by the same molar amount of 1-trifluoromethyl-1-phenylpentene (a mixture of cis-trans configuration, cis-conversion ratio of 1:2.16), The same procedure as in Example 1 was carried out to obtain a target compound isolated yield: 67%.
  • the target compound was isolated in the same manner as in Example 1 except that the ⁇ -trifluoromethylstyrene in Example 1 was replaced with the same molar amount of 2-trifluoromethyl-1-undecene. The rate is 91%.
  • Example 2 The same procedure as in Example 1 except that the ⁇ -trifluoromethylstyrene in Example 1 was replaced by the same molar amount of 3,3,3-trifluoro-2-(adamantan-1-yl)propene. The method was carried out to obtain an isolated compound yield of 76%.
  • Example 1 Except that the anhydrous THF in Example 1 was changed to anhydrous acetonitrile, the same procedure as in Example 1 was carried out to obtain a target compound having a hydrogen nuclear magnetic yield of 18% (1,1,2,2-tetrachloroethane). For internal standards).
  • Example 1 Except that the anhydrous THF in Example 1 was changed to anhydrous ethylene glycol dimethyl ether, the same procedure as in Example 1 was carried out to obtain a target compound having a hydrogen nuclear magnetic yield of 93% (1, 1, 2, 2). - Tetrachloroethane is an internal standard).
  • Example 1 Except that lithium t-butoxide in Example 1 was replaced with potassium methoxide, the same procedure as in Example 1 was carried out to obtain a target compound having a hydrogen nuclear magnetic yield of 45% (1,1,2,2-tetrachloroethane). For internal standards).
  • Example 1 Except that the lithium t-butoxide in Example 1 was reduced to 0.6 times the molar amount, the same procedure as in Example 1 was carried out to obtain a target compound having a hydrogen nuclear magnetic yield of 60% (1,1,2,2-tetrachloro). Ethane is an internal standard).
  • the hydrogen nucleus magnetic yield of the target compound was 59% (by 1,1,2,2- except that the boranoic acid pinacol ester in Example 1 was reduced to 0.6 times the molar amount, in the same manner as in Example 1. Tetrachloroethane is an internal standard).
  • Example 1 Except that the catalyst FeCl 2 in Example 1 was reduced to 1 mol%, the same procedure as in Example 1 was carried out to obtain a target compound having a hydrogen nuclear magnetic yield of 17% (1,1,2,2-tetrachloroethane). Internal standard).
  • Example 1 Except that the catalyst FeCl 2 in Example 1 was changed to 10 mol%, the same procedure as in Example 1 was carried out to obtain a target compound having a hydrogen nuclear magnetic yield of 99% (1,1,2,2-tetrachloroethane). Internal standard).
  • Example 1 Except that the reaction temperature in Example 1 was lowered to 25 ° C, the same procedure as in Example 1 was carried out to obtain a target compound having a hydrogen nuclear magnetic yield of 34% (with 1,1,2,2-tetrachloroethane). Standard).

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Abstract

公开了一种二氟烯丙基硼酸酯的制备方法及其应用，属于化合物制备领域。一种二氟烯丙基硼酸酯的制备方法，是于溶剂中，以通式（II）所示化合物和联硼酸频那醇酯为原料，在铁催化剂和碱存在下按下述反应式进行反应，得通式（I）所示化合物，所述方法直接使用便宜、市售的金属铁盐作为催化剂，为二氟烯丙基硼酸酯的制备提供了一种方便、低成本的方法，而且为γ-氨基丁酸受体激动剂（III）的合成提供了一种有效的途径。

Description

一种二氟烯丙基硼酸酯的制备方法及其应用 技术领域
本发明涉及一种二氟烯丙基硼酸酯的制备方法及其应用，属于化合物制备领域。
背景技术
在有机分子中引入氟原子通常可以改变化合物的物理、化学及生物活性相关的性质，因此，在各种药物、高分子材料、液晶材料中引入氟原子是提高物质性质常用的一种手段。
1,1-二氟烯烃是一类重要的含氟基团，常常用于含氟化合物骨架的构建，1,1-二氟烯烃官能团可以脱氟形成单氟烯烃(Chem.Lett.1979,983.)、加氢生成二氟甲基(J.Chem.Soc.,Chem.Commun.1989,1437.)、加氟生成三氟甲基(J.Org.Chem.1997,62,7758.)，不饱和双键还可以进行亲核加成反应、通过分子间环加成形成含氟杂环(Angew.Chem.Int.Ed.2012,51,12059.)。除此之外，1,1-二氟烯烃官能团在药物设计方面被认为是羰基的生物电子等排体(J.Chem.Soc.,Chem.Commun.1989,1437.)，并且含有1,1-二氟烯烃官能团的有机分子也常常作为酶抑制剂使用(Fluorine in Medicinal Chemistry and Chemical Biology；Wiley-Blackwell:West Sussex,UK,2009.)，因此能够较为简易合成含有1,1-二氟烯烃官能团的有机分子显得尤为重要。
烷基硼酸酯和烷基硼酸是有机合成领域一类非常重要的中间体(Boronic Acids:Preparation and Applications in Organic Synthesis and Medicine,Wiley-VCH,Weinheim,2005)，在各种药物、高分子材料、液晶材料、荧光探针材料的合成中都得到了广泛的应用。含有硼酸酯或硼酸官能团的化合物除了可以用于经典的Suzuki-Miyaura偶联之外(Angew.Chem.,Int.Ed.2011,50,6722.)，而且还能较为容易地转化为相应的醇、醛、胺官能团等(Chem.Commun.2013,49,11230.)。大多数含有硼酸酯或硼酸官能团的化合物相比于其它的金属有机亲核试剂(比如格氏试剂)有着良好的稳定性，能够直接在空气氛围下进行提纯或储存，因此合成官能团多样化的硼酸酯或硼酸化合物具有十分重要的意义。
分子中同时含有1,1-二氟烯烃官能团和硼酸酯官能团的二氟烯丙基硼酸酯化合物是优异的有机合成砌块，但是二氟烯丙基硼酸酯类化合物的合成目前只有一个实例报道(Angew.Chem.Int.Ed.2011,50,7079.)，该方法需要复杂的卡宾铜络合物作催化剂，并且产率也较低。
3-(4-乙酰苯基)-1-(金刚烷-1-基)-2,2-二氟-3-羟基-1-丙酮(化合物III)是一种γ-氨基丁酸受体激动剂(J.Med.Chem.2013,56,2456)，已有合成路线以1-(金刚烷-1-基)-4,4,4-三氟-3-羟基-1-丁酮为原料，经Selectfluor氟化，脱三氟乙酰基并与醛加成制得，所用试剂较贵(J.Am.Chem.Soc.2011,133,5802)。
发明内容
本发明的目的是提供一种使用便宜、市售的铁盐直接作为催化剂，以联硼酸频那 醇酯为硼化试剂，以三氟甲基烯(通式I所示化合物)为原料，高效、简便、经济的合成二氟烯丙基硼酸酯类化合物(通式II所示化合物)的方法，并将其用于γ-氨基丁酸受体激动剂的合成。
一种二氟烯丙基硼酸酯的制备方法，是于溶剂中，以通式II所示化合物和联硼酸频那醇酯为原料，在铁催化剂和碱存在下按下述反应式进行反应，得通式I所示化合物，
Figure PCTCN2017089694-appb-000001
其中，
R1选自C1～C10烷基、
Figure PCTCN2017089694-appb-000002
其中，m＝0～4，n＝1～5；
R2选自H、C1～C6烷基；
R3选自H、C1～C6烷基、苯基、卤素、三氟甲基、三氟甲氧基、C1～C4烷氧基、C2～C5酯基。
所述铁催化剂为氯化亚铁、氯化铁、溴化亚铁、溴化铁、乙酰丙酮铁、乙酰丙酮亚铁、乙酸亚铁中的至少1种。
所述碱选自叔丁醇钾、叔丁醇钠、叔丁醇锂、甲醇钠、甲醇锂、甲醇钾、碳酸铯、碳酸钾、碳酸钠、氢氧化钠、氢氧化钾、磷酸钾中的至少1种。
本发明所述溶剂优选为四氢呋喃(THF)、乙腈、N,N-二甲基甲酰胺、甲苯、二氯甲烷、1,2-二氯甲烷、苯甲醚、甲基叔丁基醚、二氧六环、乙二醇二甲醚中的至少1种。
本发明所述溶剂，其用量满足反应要求即可，优选通式Ⅱ所示化合物与溶剂的量之比为1mmol:5～15 mL。
除另有说明外，本文中使用的术语具有以下含义。
本文中使用的术语“烷基”包括直链烷基和支链烷基。如提及单个烷基如“丙基”，则只特指直链烷基，如提及单个支链烷基如“异丙基”，则只特指支链烷基。例如，“C4以下烷基”包括甲基、乙基、正丙基、异丙基、正丁基和叔丁基等。类似的规则也适用 于本说明书中使用的其它基团。
本文中使用术语“卤素”包括氟、氯、溴、碘。
本文中所述C2～C5酯基为具有如下结构的基团：-COOR，其中，R为C1～C4烷基。
本文中所述C1～C4烷氧基为具有如下结构的基团：-O-M1，其中，M1为C1～C4烷基，如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基。
上述技术方案中，所述
Figure PCTCN2017089694-appb-000003
(m＝0～4，n＝1～5)，其中，(R3)n中，n＝1～5指R3在苯基上的取代可为单取代或多位取代，可为1、2、3、4或5取代。n＝1时为单取代，单取代的取代位可为2、3或4位；n＝2、3、4或5时，为多位取代，其中，n＝2为双取代，双取代的取代位为2,3-、2,4-、2,5-、2,6-、3,4-、3,5-；n＝3为三取代，三取代的取代位为2,3,4-、2,3,5-、2,3,6-、3,4,5-。
本发明所述二氟烯丙基硼酸酯的制备方法优选R1选自C1～C10烷基、
Figure PCTCN2017089694-appb-000004
其中，m＝0、1、2、3、4，进一步地，m＝0或2；n＝1、2、3、4、5；
R2选自H、C1～C6烷基，进一步地，R2优选为H、正丙基；
R3选自H、C1～C6烷基、苯基、卤素、三氟甲基、三氟甲氧基、C1～C4烷氧基、C2～C5酯基；进一步地，R3优选为H、甲基、甲氧基、卤素、三氟甲基、叔丁基、三氟甲氧基、苯基；
本发明所述二氟烯丙基硼酸酯的制备方法优选所述碱的物质的量为通式II所示化合物物质的量的0.5～3倍，进一步优选所述碱的物质的量为所述通式II所示化合物物质的量的1～2倍。
本发明所述二氟烯丙基硼酸酯的制备方法优选所述联硼酸频那醇酯的物质的量为所述通式II所示化合物物质的量的1～3倍，进一步优选所述联硼酸频那醇酯的物质的量为所述通式II所示化合物物质的量的1～1.5倍。
本发明所述二氟烯丙基硼酸酯的制备方法优选所述催化剂的物质的量为所述通式II所示化合物物质的量的0.1％～10％，优选5％～10％。
本发明所述二氟烯丙基硼酸酯的制备方法优选上述反应的反应温度为25℃～溶剂回流温度，反应时间为10min～48h，优选5h～24h。
本发明一个优选的技术方案为：
一种二氟烯丙基硼酸酯的制备方法，是于溶剂中，以通式II所示化合物和联硼酸频那醇酯为原料，在铁催化剂和碱存在下按下述反应式进行反应，得通式I所示化合物，其中，反应温度为25℃～溶剂回流温度，反应时间为10min～48h，
Figure PCTCN2017089694-appb-000005
其中，
R1选自C1～C10烷基、
Figure PCTCN2017089694-appb-000006
其中，m＝0～4，n＝1～5；
R2选自H、C1～C6烷基；
R3选自H、C1～C6烷基、苯基、卤素、三氟甲基、三氟甲氧基、C1～C4烷氧基、C2～C5酯基；
所述铁催化剂为氯化亚铁、氯化铁、溴化亚铁、溴化铁、乙酰丙酮铁、乙酰丙酮亚铁、乙酸亚铁中的至少1种。
所述碱选自叔丁醇钾、叔丁醇钠、叔丁醇锂、甲醇钠、甲醇锂、甲醇钾、碳酸铯、碳酸钾、碳酸钠、氢氧化钠、氢氧化钾、磷酸钾中的至少1种。
所述溶剂选自四氢呋喃、乙腈、N,N-二甲基甲酰胺、甲苯、二氯甲烷、1,2-二氯甲烷、苯甲醚、甲基叔丁基醚、二氧六环、乙二醇二甲醚中的至少1种。
本发明的又一目的是提供上述合成方法制得的化合物在合成γ-氨基丁酸受体激动剂(III)中的应用。
一种以二氟烯丙基硼酸酯为原料合成γ-氨基丁酸受体激动剂(III)的制备方法，先利用上述方法合成2-(金刚烷-1-基)-3,3-二氟烯丙基硼酸频哪醇酯，再按下述路线进行：
Figure PCTCN2017089694-appb-000007
包括以下两步反应：
①2-(金刚烷-1-基)-3,3-二氟烯丙基硼酸频哪醇酯与4-乙酰基苯甲醛在磷酸二苯酯和苯甲酸催化下，甲苯溶剂中，60℃反应10h～30h，2-(金刚烷-1-基)-3,3-二氟烯丙基硼酸频哪醇酯、4-乙酰基苯甲醛、磷酸二苯酯、苯甲酸的物质的量之比为1:(1～1.5):0.1:0.1；
②1-(4-乙酰苯基)-3-(金刚烷-1-基)-2,2-二氟丁-3-烯-1-醇溶于二氯甲烷/甲醇混合溶剂中，-78℃下鼓泡通入臭氧，并保持蓝色10min，之后移至室温并鼓泡鼓入氩气直至反应体系为无色清液；再次冷却至-78℃下保持氩气氛围加入二甲硫醚，自然升至室温反应10h～24h；1-(4-乙酰苯基)-3-(金刚烷-1-基)-2,2-二氟丁-3-烯-1-醇与二甲硫醚的物质的量之比为1:2；混合溶剂中二氯甲烷/甲醇的体积比为1:1～3:1。
表1中列举了上述反应式中各个原料化合物取代基的具体结构。
表1
Figure PCTCN2017089694-appb-000008
Figure PCTCN2017089694-appb-000009
Figure PCTCN2017089694-appb-000010
Figure PCTCN2017089694-appb-000011
Figure PCTCN2017089694-appb-000012
Figure PCTCN2017089694-appb-000013
Figure PCTCN2017089694-appb-000014
Figure PCTCN2017089694-appb-000015
Figure PCTCN2017089694-appb-000016
Figure PCTCN2017089694-appb-000017
表2列举了本发明合成的具体化合物1～23的结构、物理性质及1H NMR数据，但本发明并不仅限于这些化合物。
表2
Figure PCTCN2017089694-appb-000018
Figure PCTCN2017089694-appb-000019
Figure PCTCN2017089694-appb-000020
Figure PCTCN2017089694-appb-000021
本发明的有益效果为：铁作为地壳含量第二高的金属元素和人体不可缺少的微量元素，具有含量丰富、价廉、易得、低毒、环境友好的优点，以其为基础开发催化剂符合当前可持续发展与绿色化学的要求。本发明所述方法直接使用便宜、市售的金属铁盐作为催化剂，为二氟烯丙基硼酸酯的制备提供了一种方便、低成本的方法，而且为γ-氨基丁酸受体激动剂(III)的合成提供了一种新的有效的途径。
具体实施方式
下述非限制性实施例可以使本领域的普通技术人员更全面地理解本发明，但不以任何方式限制本发明。
下述实施例中所述试验方法，如无特殊说明，均为常规方法；所述试剂和材料，如无特殊说明，均可从商业途径获得。
实施例1
2-苯基-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物1)
室温下，向氩气保护的25mLSchlenk瓶中依次加入催化剂FeCl2 6.3mg(0.05mmol，α-三氟甲基苯乙烯物质的量的5％，记为5mol％)、无水THF 8mL、α-三氟甲基苯乙烯172mg(1mmol)、α-三氟甲基苯乙烯1.1倍摩尔量的联硼酸频那醇酯279mg(1.1mmol)、α-三氟甲基苯乙烯1.1倍摩尔量的叔丁醇锂88mg(1.1mmol)，反应体系为浅黄色浑浊液，置于65℃反应12小时。后处理通过旋转蒸发仪除去溶剂，再加入25mL水，用乙酸乙酯萃取(3×15mL)，合并有机相用饱和食盐水洗涤(2×10mL)后用无水Na2SO4干燥，通过柱层析获得目标化合物，填充料为硅胶，洗脱剂为石油醚:乙酸乙酯(50:1)，分离收率92％。
实施例2
2-(2-甲氧基苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物2)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的2-甲氧基-α-三氟甲基苯乙烯外，按与实施例1同样的方法进行，获得目标化合物分离收率89％。
实施例3
2-(2-氯苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物3)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的2-氯-α-三氟甲基苯乙烯外，按与实施例1同样的方法进行，获得目标化合物分离收率72％。
实施例4
2-(3-甲氧基苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物4)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的3-甲氧基-α-三氟甲基苯乙烯外，按与实施例1同样的方法进行，获得目标化合物分离收率90％。
实施例5
2-(3-氯苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物5)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的3-氯-α-三氟甲基苯乙烯外，按与实施例1同样的方法进行，获得目标化合物分离收率69％。
实施例6
2-(4-甲氧基苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物6)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的4-甲氧基-α-三氟甲基苯乙烯外，按与实施例1同样的方法进行，获得目标化合物分离收率80％。
实施例7
2-(4-氯苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物7)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的4-氯-α-三氟甲基苯乙烯外，按与实施例1同样的方法进行，获得目标化合物分离收率96％。
实施例8
2-(4-氟苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物8)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的4-氟-α-三氟甲基苯乙烯外，按与实施例1同样的方法进行，获得目标化合物分离收率84％。
实施例9
2-(4-溴苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物9)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的4-溴-α-三氟甲基苯乙烯外，按与实施例1同样的方法进行，获得目标化合物分离收率84％。
实施例10
2-(4-三氟甲基苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物10)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的4-三氟甲基-α-三氟甲基苯乙烯外，按与实施例1同样的方法进行，获得目标化合物分离收率86％。
实施例11
2-(4-三氟甲氧基苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物11)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的4-三氟甲氧基-α-三氟甲基苯乙烯外，按与实施例1同样的方法进行，获得目标化合物分离收率97％。
实施例12
2-(4-叔丁基苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物12)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的4-叔丁基-α-三氟甲基苯乙烯外，按与实施例1同样的方法进行，获得目标化合物分离收率86％。
实施例13
2-(4-苯基苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物13)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的4-苯基-α-三氟甲基苯乙烯外，按与实施例1同样的方法进行，获得目标化合物分离收率95％。
实施例14
2-(4-甲氧羰基苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物14)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的4-甲氧羰基-α-三氟甲基苯乙烯外，按与实施例1同样的方法进行，获得目标化合物分离收率58％。
实施例15
2-(2,4-二甲基苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物15)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的3,4-亚甲二氧基-α-三氟甲基苯乙烯外，按与实施例1同样的方法进行，获得目标化合物分离收率99％。
实施例16
2-(3,5-二甲基苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物16)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的2,4-二甲基-α-三氟甲基苯乙烯外，按与实施例1同样的方法进行，获得目标化合物分离收率73％。
实施例17
2-(3,4-亚甲二氧基苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物17)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的3,5-二甲基-α-三氟甲基苯乙烯外，按与实施例1同样的方法进行，获得目标化合物分离收率80％。
实施例18
2-(苯并噻吩-2-基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物18)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的α-三氟甲基-2-苯并噻吩乙烯外，按与实施例1同样的方法进行，获得目标化合物分离收率73％。
实施例19
2-(1-萘基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物19)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的α-三氟甲基-1-萘乙烯外，按与实施例1同样的方法进行，获得目标化合物分离收率72％。
实施例20
2-(2-苯基乙基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物20)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的2-三氟甲基-4-苯基-1-丁烯外，按与实施例1同样的方法进行，获得目标化合物分离收率94％。
实施例21
2-苯基-3-硼酸频哪醇酯-1,1-二氟-1-己烯的制备(化合物21)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的1-三氟甲基-1-苯戊烯(顺反构型的混合物，顺反比例为1:2.16)外，按与实施例1同样的方法进行，获得目标化合物分离收率67％。
实施例22
2-二氟甲叉基-1-十一烷硼酸频哪醇酯的制备(化合物22)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的2-三氟甲基-1-十一烯外，按与实施例1同样的方法进行，获得目标化合物分离收率91％。
实施例23
2-(金刚烷-1-基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物23)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的3,3,3-三氟-2-(金刚烷-1-基)丙烯外，按与实施例1同样的方法进行，获得目标化合物分离收率76％。
实施例24
2-苯基-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物1)
除了将实施例1中的无水THF换成无水乙腈外，按与实施例1同样的方法进行，获得目标化合物氢核磁收率18％(以1,1,2,2-四氯乙烷为内标)。
实施例25
2-苯基-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物1)
除了将实施例1中的无水THF换成无水乙二醇二甲醚外，按与实施例1同样的方法进行，获得目标化合物氢核磁收率93％(以1,1,2,2-四氯乙烷为内标)。
实施例26
2-苯基-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物1)
除了将实施例1中的叔丁醇锂换成甲醇钾外，按与实施例1同样的方法进行，获得目标化合物氢核磁收率45％(以1,1,2,2-四氯乙烷为内标)。
实施例27
2-苯基-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物1)
除了将实施例1中的叔丁醇锂降为0.6倍摩尔量外，按与实施例1同样的方法进行，获得目标化合物氢核磁收率60％(以1,1,2,2-四氯乙烷为内标)。
实施例28
2-苯基-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物1)
除了将实施例1中的联硼酸频那醇酯降为0.6倍摩尔量外，按与实施例1同样的方法进行，获得目标化合物氢核磁收率59％(以1,1,2,2-四氯乙烷为内标)。
实施例29
2-苯基-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物1)
除了将实施例1中的催化剂FeCl2降为1mol％外，按与实施例1同样的方法进行，获得目标化合物氢核磁收率17％(以1,1,2,2-四氯乙烷为内标)。
实施例30
2-苯基-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物1)
除了将实施例1中的催化剂FeCl2改为10mol％外，按与实施例1同样的方法进行，获得目标化合物氢核磁收率99％(以1,1,2,2-四氯乙烷为内标)。
实施例31
2-苯基-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物1)
除了将实施例1中的反应温度降至25℃外，按与实施例1同样的方法进行，获得目标化合物氢核磁收率34％(以1,1,2,2-四氯乙烷为内标)。
实施例32
3-(4-乙酰苯基)-1-(金刚烷-1-基)-2,2-二氟-3-羟基-1-丙酮的合成(化合物III)
①25mL Schlenk瓶中，氩气保护下，依次加入2-(金刚烷-1-基)-3,3-二氟烯丙基硼酸频哪醇酯85mg(0.2513mmol)，甲苯3mL，4-乙酰基苯甲醛37mg(0.2513mmol)，10mol％的磷酸二苯酯6mg(0.02513mmol)，10mol％的苯甲酸3mg(0.02513mmol)，封闭后移至油浴锅60℃反应24h。降温，后处理直接拌硅胶柱层析，洗脱剂为石油醚:乙酸乙酯(5:1)，得到1-(4-乙酰苯基)-3-(金刚烷-1-基)-2,2-二氟丁-3-烯-1-醇58mg，产率64％。
白色固体，m.p.116～118℃，1H NMR:δ7.94(d,J＝7.9Hz,2H,ArH),7.53(d,J＝7.9Hz,2H,ArH),5.36(s,1H,1/2CCH2),5.25(s,1H,1/2CCH2),5.04(dd,J＝10.0Hz,J＝13.6Hz,1H,ArCH),3.61(br,4H,OH+CH3),2.02(br,3H,3CH),1.80(br,6H,3CH2),1.70(m,6H,3CH2)。
②25mL Schlenk瓶中依次加入1-(4-乙酰苯基)-3-(金刚烷-1-基)-2,2-二氟丁-3-烯-1-醇20mg(0.05553mmol)，二氯甲烷3mL，甲醇1.5mL，冷却至-78℃下鼓泡鼓入臭氧，并保持蓝色10min，之后移至室温并鼓泡鼓入氩气直至反应体系为无色清液。再次冷却至-78℃下保持氩气氛围加入二甲硫醚7mg(0.1110mmol)，自然升至室温反应18h。后处理直接拌硅胶柱层析，洗脱剂为石油醚:乙酸乙酯(5:1)，得到化合物III 19mg，产率95％。
白色固体，m.p.97～99℃，1H NMR:δ7.94(d,J＝7.4Hz,2H,ArH),7.52(d,J＝7.9Hz,2H,ArH),5.32(dd,J＝6.1Hz,J＝18.0Hz,1H,ArCH),3.28(br,1H,OH),2.59(s,3H,CH3),2.02(br,3H,3CH),1.89(br,6H,3CH2),1.70(m,6H,3CH2)。
实施例33
3-(4-乙酰苯基)-1-(金刚烷-1-基)-2,2-二氟-3-羟基-1-丙酮的合成(化合物III)
①25mL Schlenk瓶中，氩气保护下，依次加入2-(金刚烷-1-基)-3,3-二氟烯丙基硼酸频哪醇酯169mg(0.5mmol)，甲苯3mL，4-乙酰基苯甲醛111mg(0.75mmol)，10mol％的磷酸二苯酯12mg(0.05mmol)，10mol％的苯甲酸6mg(0.05mmol)，封闭后移至油浴锅65℃反应13h。降温，后处理直接拌硅胶柱层析，洗脱剂为石油醚:乙酸乙酯(5:1)，得到1-(4-乙酰苯基)-3-(金刚烷-1-基)-2,2-二氟丁-3-烯-1-醇166mg，产率92％。
②25mL Schlenk瓶中依次加入1-(4-乙酰苯基)-3-(金刚烷-1-基)-2,2-二氟丁-3-烯-1-醇20mg(0.05553mmol)，二氯甲烷3mL，甲醇1.5mL，冷却至-78℃下鼓泡鼓入臭氧，并保持蓝色10min，之后移至室温并鼓泡鼓入氩气直至反应体系为无色清液。再次冷却至-78℃下保持氩气氛围加入二甲硫醚7mg(0.1110mmol)，自然升至室温反应18h。后处理直接拌硅胶柱层析，洗脱剂为石油醚:乙酸乙酯(5:1)，得到化合物III 19mg，产率95％。

Claims (10)

  1. 一种二氟烯丙基硼酸酯的制备方法，是于溶剂中，以通式II所示化合物和联硼酸频那醇酯为原料，在铁催化剂和碱存在下按下述反应式进行反应，得通式I所示化合物，
    Figure PCTCN2017089694-appb-100001
    其中，
    R1选自C1～C10烷基、
    Figure PCTCN2017089694-appb-100002
    其中，m＝0～4，n＝1～5；
    R2选自H、C1～C6烷基；
    R3选自H、C1～C6烷基、苯基、卤素、三氟甲基、三氟甲氧基、C1～C4烷氧基、C2～C5酯基；
    所述铁催化剂为氯化亚铁、氯化铁、溴化亚铁、溴化铁、乙酰丙酮铁、乙酰丙酮亚铁、乙酸亚铁中的至少1种；
    所述碱选自叔丁醇钾、叔丁醇钠、叔丁醇锂、甲醇钠、甲醇锂、甲醇钾、碳酸铯、碳酸钾、碳酸钠、氢氧化钠、氢氧化钾、磷酸钾中的至少1种。
  2. 根据权利要求1所述的方法，其特征在于：所述R2为H、丙基。
  3. 根据权利要求1所述的方法，其特征在于：所述R3为H、甲基、甲氧基、卤素、三氟甲基、叔丁基、三氟甲氧基、苯基。
  4. 根据权利要求1所述的方法，其特征在于：所述碱的物质的量为通式II所示化合物的0.5～3倍。
  5. 根据权利要求4所述的方法，其特征在于：所述碱的物质的量为所述通式II所示化合物的1～2倍。
  6. 根据权利要求1所述的方法，其特征在于：所述联硼酸频那醇酯的物质的量所述为通式II所示化合物的1～3倍。
  7. 根据权利要求6所述的方法，其特征在于：所述联硼酸频那醇酯的物质的量为 所述通式II所示化合物的1～1.5倍。
  8. 根据权利要求1所述的方法，其特征在于：所述催化剂的物质的量为所述通式II所示化合物物质的量的0.1％～10％。
  9. 根据权利要求1～8任一项所述的方法，其特征在于：所述反应的反应温度为25℃～溶剂回流温度，反应时间为10min～48h。
  10. 权利要求1所述的方法制备所述通式I所示化合物在γ-氨基丁酸受体激动剂(III)合成中的应用，其特征在于：先按权利要求1所述方法合成2-(金刚烷-1-基)-3,3-二氟烯丙基硼酸频哪醇酯，再按下述路线进行：
    Figure PCTCN2017089694-appb-100003
    包括以下两步反应：
    ①2-(金刚烷-1-基)-3,3-二氟烯丙基硼酸频哪醇酯与4-乙酰基苯甲醛在磷酸二苯酯和苯甲酸催化下，甲苯溶剂中，60℃反应10h～30h，2-(金刚烷-1-基)-3,3-二氟烯丙基硼酸频哪醇酯、4-乙酰基苯甲醛、磷酸二苯酯、苯甲酸的物质的量之比为1:(1～1.5):0.1:0.1；
    ②1-(4-乙酰苯基)-3-(金刚烷-1-基)-2,2-二氟丁-3-烯-1-醇溶于二氯甲烷/甲醇混合溶剂中，-78℃下鼓泡通入臭氧，并保持蓝色10min，之后移至室温并鼓泡鼓入氩气直至反应体系为无色清液；再次冷却至-78℃下保持氩气氛围加入二甲硫醚，自然升至室温反应10h～24h；1-(4-乙酰苯基)-3-(金刚烷-1-基)-2,2-二氟丁-3-烯-1-醇与二甲硫醚的物质的量之比为1:2；混合溶剂中二氯甲烷/甲醇的体积比为1:1～3:1。
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