Method for producing aromatic compounds having an ethynyl group

Abstract

To produce an aromatic compound having an ethynyl group in high yield by a simple and inexpensive coupling reaction using an aromatic compound having an electron-donating substituent.SOLUTION: In the coupling reaction between an aromatic halogen compound represented by the following general formula (1) and an ethynyl compound represented by the following general formula (2), they are subjected to a coupling reaction together with palladium-on-charcoal, a phosphorus compound, and a copper compound in the presence of an amine to produce an aromatic compound having an ethynyl group represented by the following general formula (3) for performing coupling reaction in the nitrogen-containing organic solvent, wherein R is an electron-donating substituent, X is a halogen atom, A is a hydrocarbon group having a hydroxy group or a trialkylsilyl group, and n is an integer from 1 to 3.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing an aromatic compound having an ethynyl group. [Background technology]

[0002] Coupling reactions using aromatic halogen compounds and palladium catalysts are important reactions for forming novel carbon-carbon bonds. For example, in the Sonogashira coupling reaction, an aromatic halogen compound and an ethynyl compound are coupled using a palladium catalyst to synthesize an ethynylbenzene compound in which an ethynyl compound is bonded to an aromatic ring. The palladium catalyst used here is generally an organic palladium such as dichlorobis(triphenylphosphine)palladium or tetra(triphenylphosphine)palladium (see Patent Document 1).

[0003] For example, in the production of alkynyl-substituted heterocyclic compounds that act as FGFR (fibroblast growth factor receptor) inhibitors, the reaction of 1-bromo-3,5-dimethoxybenzene, which has an electron-donating dimethoxy group, with trimethylsilylacetylene uses expensive bis(triphenylphosphine)palladium chloride as a catalyst, and the amount of catalyst is 5 mol % relative to the starting material, 1-bromo-3,5-dimethoxybenzene, in order to carry out the synthesis. However, the bis(triphenylphosphine)palladium chloride used as the catalyst is a compound in which triphenylphosphine is coordinated to palladium, and is not only very expensive, but also unstable, decomposing in the presence of solvents and moisture in the air, making it difficult to handle industrially (see Patent Document 2).

[0004] In addition, in the reaction of 1-iodo-3,5-dimethoxybenzene, in which bromine has been replaced with highly reactive iodine, with trimethylacetylene, synthesis is carried out using bis(triphenylphosphine)palladium chloride as a catalyst. However, despite the presence of highly reactive iodine, a large amount of catalyst, 2 mol % relative to the raw material, is used (Patent Document 3).

[0005] Thus, there has been a demand for a method for producing an aromatic compound having an ethynyl group that can be synthesized simply and inexpensively in a coupling reaction of an aromatic compound having an electron-donating substituent such as a methoxy group. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Chinese Patent No. 103183722 [Patent Document 2] JP 2014-178400 A [Patent Document 3] Japanese Patent Application Publication No. 2019-529444 Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to produce an aromatic compound having an ethynyl group in high yield by a simple and inexpensive coupling reaction of an aromatic compound having an electron-donating substituent such as an alkoxy group or an alkyl group. [Means for solving the problem]

[0008] The following general formula (1) [ka] (wherein R represents an electron-donating substituent, X represents a halogen atom, and n represents an integer of 1 to 3). and an aromatic halogen compound represented by the following general formula (2): [ka] (wherein A represents a hydrocarbon group having a hydroxyl group or a trialkylsilyl group) In a coupling reaction with an ethynyl compound represented by and alkali metal saltsIn the presence of palladium carbon, a phosphorus compound, and a copper compound, a coupling reaction is carried out in a nitrogen-containing organic solvent, represented by the following general formula (3): [ka] (wherein R represents an electron-donating substituent, A represents a hydrocarbon group or a trialkylsilyl group having a hydroxyl group, and n represents an integer of 1 to 3). An aromatic compound having an ethynyl group represented by the formula: [Effects of the Invention]

[0009] The method for producing an aromatic compound having an ethynyl group of the present invention can synthesize the desired aromatic compound having an ethynyl group by performing Sonogashira coupling using palladium on carbon as a catalyst, and since the production can be performed by a simple procedure, it is possible to provide an aromatic compound having an ethynyl group industrially at low cost.

[0010] Furthermore, the aromatic compounds having an ethynyl group obtained by the present invention have electron-donating substituents such as alkoxy groups and alkyl groups, and can be used as raw materials for fine chemicals, pharmaceuticals and agricultural chemicals, resins and plastics, and electronic and optical materials. DETAILED DESCRIPTION OF THE INVENTION

[0011] The production method of the present invention will be described in detail below. The raw material used in the present invention is a compound represented by the following general formula (1): [ka] (wherein R represents an electron-donating substituent, X represents a halogen atom, and n represents an integer of 1 to 3). It is an aromatic halogen compound represented by the formula:

[0012] Here, R represents an electron-donating substituent, and examples thereof include a hydroxyl group, an alkoxy group, an alkyl group, an amino group, and a carbonyloxy group. Preferred electron-donating substituents are alkoxy groups and alkyl groups. Preferred alkoxy groups include a methoxy group, an ethoxy group, an n-propyl group, an isopropyl group, and an n-butyl group. Preferred alkyl groups include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and an n-butyl group, which are easily available as raw materials industrially and are therefore particularly preferred.

[0013] n represents an integer of 1 to 3. Generally, compounds having three electron-donating substituents bonded to a benzene ring are difficult to obtain, and n is preferably 1 or 2.

[0014] X represents a halogen atom, and represents chlorine, bromine, or iodine. In terms of reactivity in the coupling reaction, iodine is usually the most reactive and chlorine the least reactive, but iodine compounds are expensive, so it is preferable to use bromine or chlorine. In general, chlorine atoms have low reactivity and the coupling reaction hardly proceeds, so bromine atoms are particularly preferred.

[0015] Particularly preferred aromatic compounds are aromatic compounds having an alkoxy group, such as 3-bromoanisole, 4-bromoanisole, 2-bromoanisole, 3-bromophenetole, 4-bromophenetole, 2-bromophenetole, 1-bromo-4-propoxybenzene, 1-bromo-3-propoxybenzene, 1-bromo-2-propoxybenzene, 1-bromo-4-isopropoxybenzene, 1-bromo-3-isopropoxybenzene, 1-bromo-2-isopropoxybenzene, 1-bromo-3,5-dimethoxybenzene, 1-bromo-2,4-dimethoxybenzene, 2-bromo-1,3-dimethoxybenzene, 1-bromo-2,5-dimethoxybenzene, and 4-bromo-1,2-dimethoxybenzene.

[0016] Examples of aromatic compounds having an alkyl group include 4-bromotoluene, 3-bromotoluene, 2-bromotoluene, 1-bromo-4-ethylbenzene, 1-bromo-3-ethylbenzene, 1-bromo-2-ethylbenzene, 1-bromo-4-propylbenzene, 1-bromo-3-propylbenzene, 1-bromo-2-propylbenzene, 1-bromo-4-isopropylbenzene, 1-bromo-3-isopropylbenzene, 1-bromo-2-isopropylbenzene, 4-bromo-m-xylene, 2-bromo-p-xylene, 5-bromo-m-xylene, 4-bromo-p-xylene, 4-bromo-o-xylene, 3-bromo-o-xylene, and 2-bromo-m-xylene.

[0017] In the present invention, the coupling reaction proceeds by adding raw materials, that is, an aromatic halogen compound having an electron-donating substituent, palladium on carbon, a phosphorus compound, a copper compound, and an amine, to a nitrogen-containing organic solvent as a reaction solvent, and then adding dropwise or pouring in an ethynyl compound represented by the following general formula (2) with stirring, and heating the mixture. [ka] (wherein A represents a hydrocarbon group having a hydroxyl group or a trialkylsilyl group)

[0018] Here, the nitrogen-containing organic solvent used as the reaction solvent is preferably N,N-dimethylacetamide, dimethylformamide, or N-methyl-2-pyrrolidone, and particularly preferably N,N-dimethylacetamide, which has a particularly high reactivity.

[0019] Because the halogen amine salt produced in the coupling reaction must be stirred in a slurry state, the nitrogen-containing organic solvent is preferably used in an amount 3 to 10 times by mass, and particularly preferably 3 to 7 times by mass, relative to the aromatic halogen compound having an electron-donating substituent as the raw material. If the amount of nitrogen-containing organic solvent used is less than 3 times by mass, compounds such as dimers formed by coupling of the ethynyl compounds used in the reaction are undesirably produced as by-products.

[0020] The palladium-carbon used in coupling reactions is a carrier on which palladium (zerovalent) is dispersed and supported, also known as palladium-carbon. Palladium-carbon can be used in either dry or wet forms. Because palladium-carbon readily ignites in air, wet forms are preferred for industrial applications. The type of palladium-carbon affects the reactivity of the coupling reaction, and commercially available palladium-carbon from N.E. Chemcat Corporation is particularly preferred due to its high reactivity. Among the palladium-carbons from N.E. Chemcat Corporation, Type NE, Type K, and Type E are particularly preferred, as they offer high reaction yields. Type E is particularly preferred, as it allows for a reduced amount of palladium-carbon to be used.

[0021] Palladium carbon is an expensive catalyst, so it is preferably used in an amount of 1.0 mol % or less relative to the number of moles of the aromatic halogen compound, and more preferably 0.5 mol % or less, which allows for a smaller amount to be used and for inexpensive production.

[0022] The phosphorus compound used in the coupling reaction is preferably an organic phosphorus compound, and is preferably a hydrocarbon phosphine compound such as triphenylphosphine, trimethylphosphine, triethylphosphine, or tri-n-propylphosphine, which is widely available. Triphenylphosphine is particularly preferred because it is generally available at low cost and is easy to handle as a granular powder. The amount of the phosphorus compound used is preferably 4.0 equivalents or more relative to palladium carbon, and more preferably 4.0 to 8.0 equivalents, which is sufficient to form a palladium complex.

[0023] A copper compound is used as a reaction initiator, and copper iodide, which is widely available, is preferred. The amount of the copper compound used is preferably 0.1 to 1.0 equivalents, more preferably 0.1 to 0.5 equivalents, based on palladium carbon.

[0024] In the Sonogashira coupling reaction, amines are added to trap the halogen by-products produced in the reaction. As the amine, alkylamines are preferred, and tertiary amines such as trimethylamine, triethylamine, tri-n-propylamine, and tri-n-butylamine, and secondary amines such as diisobutylamine, diisopropylamine, and diethylamine are preferred. Triethylamine, diisopropylamine, and diisobutylamine are more preferred because they are inexpensive, easily available, have low boiling points, and can be removed by concentration.

[0025] The amount of the amine to be added is preferably 1.0 to 5.0 equivalents, more preferably 1.0 to 3.0 equivalents, relative to the aromatic halogen compound as the raw material.

[0026] The ethynyl compound used is a compound represented by the general formula (2) above. When R in the general formula (2) is a hydrocarbon group having a hydroxyl group, the ethynyl compound is preferably a compound represented by the following general formula (4): [ka] (In formula (4), R 1 , R 2 indicates a hydrogen atom or a hydrocarbon group) In general formula (4), R 1 , R 2 may be the same or different. 1 , R 2 is preferably a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, such as hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an n-pentyl group, etc. Preferred examples of the ethynyl compound represented by general formula (4) include 2-propen-1-ol, 2-methyl-3-butyn-2-ol, 3-butyn-2-ol, 3-methyl-4-pentyn-3-ol, 4-pentyn-3-ol, 4-methyl-5-hexyn-4-ol, 5-hexyn-4-ol, etc.

[0027] When R in the general formula (2) is a trialkylsilyl group, the ethynyl compound is preferably a compound represented by the following general formula (5): [ka] (In formula (5), R 1 ,R 2 ,R 3 indicates a hydrocarbon group) In general formula (6), R 1 ,R 2 ,R 3 may be the same or different. 1 ,R 2 ,R 3 is preferably an alkyl group having 1 to 5 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an n-pentyl group, etc. Preferred examples of the ethynyl compound represented by general formula (5) include trimethylsilylacetylene, triethylsilylacetylene, triisopropylsilylacetylene, etc.

[0028] In view of industrial availability, the ethynyl compound represented by the general formula (2) is more preferably 2-methyl-3-butyn-2-ol, 3-butyn-2-ol, or 2-propen-1-ol.

[0029] The amount of the ethynyl compound used is preferably 1.0 to 5.0 equivalents relative to the halogen of the aromatic halogen compound as a raw material, and more preferably 1.0 to 3.0 equivalents, since an excess amount will result in excessive by-production of compounds such as dimers of ethynyl compounds resulting from the reaction between ethynyl compounds.

[0030] In the Sonogashira coupling reaction, a nitrogen-containing compound (solvent), an aromatic halogen compound (raw material), palladium on carbon (catalyst), a copper compound (reaction initiator), an amine (halogen trap), and a phosphorus compound are charged into a reactor, followed by the dropwise addition of an ethynyl compound and heating. The reaction temperature is preferably 30°C or higher, at which the reaction proceeds easily, and more preferably 50°C or higher, at which the reaction proceeds more smoothly.

[0031] In addition, adding an alkali metal salt as an additive to the reaction is preferable because it improves the reaction yield. As the alkali metal salt, lithium salt, sodium salt, and potassium salt are preferred, which particularly improve the yield, and lithium chloride, lithium bromide, lithium iodide, sodium bromide, potassium bromide, etc. are more preferred, and lithium chloride, lithium bromide, lithium iodide, and sodium bromide are even more preferred, which allow the reaction to proceed more rapidly.

[0032] The amount of the alkali metal salt added is preferably 0.1 to 2.0 equivalents relative to the halogen of the aromatic halogen compound as the raw material, and more preferably 0.3 to 1.0 equivalents, which allows the Sonogashira coupling reaction to proceed more efficiently.

[0033] The coupling reaction can be monitored by analyzing the reaction with a gas chromatograph or high performance liquid chromatography. The reaction time for the coupling reaction is preferably 1 hour or more, more preferably 2 hours or more.

[0034] After the coupling reaction is completed, the mixture is cooled, water is added to dissolve the amine salt, and the amine salt is extracted with an organic solvent such as toluene or ethyl acetate to obtain a compound represented by the following general formula (3): [ka] (wherein R represents an electron-donating substituent, A represents a hydrocarbon group or a trialkylsilyl group having a hydroxyl group, and n represents an integer of 1 to 3). In this case, the palladium carbon used in the reaction can be easily removed by filtration.

[0035] R in the general formula (3) is the same as R in the general formula (1), and A is the same as A in the general formula (2), and therefore, the explanation for each is omitted. In addition, examples of aromatic compounds having an ethynyl group represented by the general formula (3) include 2-methyl-4-(4-methoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(3-methoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(2-methoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(4-ethoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(3-ethoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(2-ethoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(4-n-propoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(3-n-propoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(2-n-propoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(4-isopropoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(3-isopropoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(2-isopropoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(2,3-dimethoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(2,4-dimethoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(2,5-dimethoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(2,6-dimethoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(3,4-dimethoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(3,5 -dimethoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(2,3-diethoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(2,4-diethoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(2,5-diethoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(2,6-diethoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(3,4-diethoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(3,5-diethoxyphenyl)-3-butyn-2-ol, 2-methyl-4-(4-tolyl)-3-butyn-2-ol, 2-methyl-4-(3-tolyl)-3-butyn-2-ol, 2-methyl-4-(2-tolyl)-3-butyn-2-ol, 2-methyl-4-(4-ethylphenyl)-3-butyn-2-ol, 2-methyl-4-(3-ethylphenyl)-3-butyn-2-ol, 2-methyl-4-(2-ethylphenyl)-3-butyn-2-ol 2-methyl-4-(4-n-propylphenyl)-3-butyn-2-ol, 2-methyl-4-(3-n-propylphenyl)-3-butyn-2-ol, 2-methyl-4-(2-n-propylphenyl)-3-butyn-2-ol, 2-methyl-4-(4-isopropylphenyl)-3-butyn-2-ol, 2-methyl-4-(3-isopropylphenyl)-3-butyn-2-ol, 2-methyl-4-(2-isopropylphenyl)-3- Butyn-2-ol, 2-methyl-4-(2,3-dimethylphenyl)-3-butyn-2-ol, 2-methyl-4-(2,4-dimethylphenyl)-3-butyn-2-ol, 2-methyl-4-(2,5-dimethylphenyl)-3-butyn-2-ol, 2-methyl-4-(2,6-dimethylphenyl)-3-butyn-2-ol, 2-methyl-4-(3,4-dimethylphenyl)-3-butyn-2-ol, 2-methyl-4-(3,5-dimethylphenyl) 2-methyl-4-(2,3-diethylphenyl)-3-butyn-2-ol, 2-methyl-4-(2,4-diethylphenyl)-3-butyn-2-ol, 2-methyl-4-(2,5-diethylphenyl)-3-butyn-2-ol, 2-methyl-4-(2,6-diethylphenyl)-3-butyn-2-ol, 2-methyl-4-(3,4-diethylphenyl)-3-butyn-2-ol, 2-methyl-4-(3,5-Diethylphenyl)-3-butyn-2-ol, 4-(2-trimethylsilylethynyl)anisole, 3-(2-trimethylsilylethynyl)anisole, 2-(2-trimethylsilylethynyl)anisole, 4-(2-trimethylsilylethynyl)phenetole, 3-(2-trimethylsilylethynyl)phenetole, 2-(2-trimethylsilylethynyl)phenetole, n-propyl-[4-(2-trimethylsilylethynyl)phenyl]ether, n-propyl-[3-(2-trimethylsilylethynyl)phenyl]ether, n-propyl- [2-(2-trimethylsilylethynyl)phenyl]ether, isopropyl-[4-(2-trimethylsilylethynyl)phenyl]ether, isopropyl-[3-(2-trimethylsilylethynyl)phenyl]ether, isopropyl-[2-(2-trimethylsilylethynyl)phenyl]ether, 3-(2-trimethylsilylethynyl)-1,2-dimethoxybenzene, 4-(2-trimethylsilylethynyl)-1,2-dimethoxybenzene, 2-(2-trimethylsilylethynyl)-1,3-dimethoxybenzene, 4-(2-trimethylsilylethynyl)- (2-Trimethylsilylethynyl)-1,3-dimethoxybenzene, 5-(2-trimethylsilylethynyl)-1,3-dimethoxybenzene, 6-(2-trimethylsilylethynyl)-1,3-dimethoxybenzene, 2-(2-trimethylsilylethynyl)-1,4-dimethoxybenzene, 3-(2-trimethylsilylethynyl)-1,4-dimethoxybenzene, 3-(2-triethoxysilylethynyl)-1,2-dimethoxybenzene, 4-(2-trimethylsilylethynyl)-1,2-diethoxybenzene, 2-(2-trimethylsilylethynyl)-1,3-diethoxybenzene , 4-(2-trimethylsilylethynyl)-1,3-diethoxybenzene, 5-(2-trimethylsilylethynyl)-1,3-diethoxybenzene, 6-(2-trimethylsilylethynyl)-1,3-diethoxybenzene, 2-(2-trimethylsilylethynyl)-1,4-diethoxybenzene, 3-(2-trimethylsilylethynyl)-1,4-diethoxybenzene, 3-(2-trimethylsilylethynyl)-1,2-dimethylbenzene, 4-(2-trimethylsilylethynyl)-1,2-dimethylbenzene, 2-(2-trimethylsilylethynyl)-1,3-Dimethylbenzene, 4-(2-trimethylsilylethynyl)-1,3-dimethylbenzene, 5-(2-trimethylsilylethynyl)-1,3-dimethylbenzene, 6-(2-trimethylsilylethynyl)-1,3-dimethylbenzene, 2-(2-trimethylsilylethynyl)-1,4-dimethylbenzene, 3-(2-trimethylsilylethynyl)-1,4-dimethylbenzene, 3-(2-triethoxysilylethynyl)-1,2-dimethylbenzene, 3-(2-trimethylsilylethynyl)-1,2-diethylbenzene, 4-(2-trimethylsilylethynyl)-1,4-dimethylbenzene, 3-(2-trimethylsilylethynyl)-1,2-diethylbenzene, Examples of suitable silylethynyl compounds include 2-(2-trimethylsilylethynyl)-1,2-diethylbenzene, 2-(2-trimethylsilylethynyl)-1,3-diethylbenzene, 4-(2-trimethylsilylethynyl)-1,3-diethylbenzene, 5-(2-trimethylsilylethynyl)-1,3-diethylbenzene, 6-(2-trimethylsilylethynyl)-1,3-diethylbenzene, 2-(2-trimethylsilylethynyl)-1,4-diethylbenzene, 3-(2-trimethylsilylethynyl)-1,4-diethylbenzene, and 3-(2-triethoxysilylethynyl)-1,2-diethylbenzene.

[0036] From the obtained aromatic compound having an ethynyl group, the A group at the ethynyl terminal can be more easily removed under alkaline conditions, etc. In this way, the Sonogashira coupling of the present invention can synthesize an aromatic compound having an ethynyl group simply by introducing palladium on carbon and carrying out the reaction, making it possible to provide useful aromatic compounds having an ethynyl group. [Example]

[0037] The present invention will be specifically described below with reference to examples. In the examples, the reaction yield (%) of the aromatic compound having an ethynyl group represented by the general formula (3) and the dimer content (area %) of the ethynyl compound represented by the general formula (2) were analyzed using GC (gas chromatography) under the following conditions, and the fraction of the peak area of ​​each compound relative to the total peak area minus the peak area of ​​the nitrogen-containing organic solvent was measured.

[0038] Here, the reaction yield of the aromatic compound having an ethynyl group represented by general formula (3) (referred to as the "coupling product" in the following calculation formula) is a numerical value indicating the extent to which the reaction of obtaining the target coupling product from the raw material, an aromatic halogen compound having an electron-donating substituent (referred to as the "raw material" in the following calculation formula), has progressed, and was calculated as follows: Area% of coupling body / (area% of coupling body + area% of raw material) x 100(%)

[0039] <Purity analysis> Column: DB-5 (0.25 mm x 30 m x 0.25 μm) (Agilent J&W) Carrier gas: Helium Inlet temperature: 300℃ Detector temperature: 300℃ Column temperature: 50°C (hold for 2 minutes) → 10°C / min → 300°C (hold for 3 minutes) Column flow rate: 3.65 mL / min Purge flow rate: 5.0 mL / min Split ratio: 20 Sample volume: 1 μL Sample preparation: 0.5 g of sample was weighed into a 10 mL volumetric flask and made up to volume with acetonitrile.

[0040] The reagents used in the experiments were commercially available. Palladium on carbon (Pd / C) manufactured by N.E. Chemcat Corporation was purchased from Fujifilm Wako Pure Chemical Industries.

[0041] [Example 1] A 200 mL flask equipped with a stirrer and a condenser was charged with 25 g of N,N-dimethylacetamide (DMAc) (5 times by weight / 3-BT), 5.0 g (29.2 mmol) of 3-bromotoluene (3-BT), 0.610 g (0.146 mmol, 0.5 mol% / 3-BT) of 5% palladium on carbon (Pd / C; Type E, Pd content 5.1 wt%, 50 wt% water content), 0.192 g (0.731 mmol) of triphenylphosphine, 0.0348 g (0.183 mmol) of copper(I) iodide, and 5.92 g (58.5 mmol, 2.0 equivalents / 3-BT) of diisopropylamine. 4.92 g (58.5 mmol, 2.0 equivalents / 3-BT) of 2-methyl-3-butyn-2-ol was added dropwise at 20 to 30 °C. After the dropwise addition, the mixture was placed in an oil bath and reacted at a reaction temperature of 70-75°C for 24 hours. After 24 hours, the reaction mixture was analyzed by gas chromatography (GC). The reaction yield of the target 2-methyl-4-(2-tolyl)-3-butyn-2-ol was 99.4%, and the GC purity was 84.1%. The GC retention time of 2-methyl-3-butyn-2-ol was 17.1 minutes, and the m / z was 174 by GC / MS analysis. Similarity analysis revealed that the product was 2-methyl-4-(2-tolyl)-3-butyn-2-ol.

[0042] [Example 2] A 200 mL flask equipped with a stirrer and a condenser was charged with 25 g of N,N-dimethylacetamide (DMAc) (5 times by mass / 3-BA), 5.0 g (26.7 mmol) of 3-bromoanisole (3-BA), 0.558 g (0.134 mmol, 0.5 mol% / 3-BA) of 5% palladium on carbon (Pd / C; Type E, Pd content 5.1 mass%, 50% water content), and triflate. 0.175 g (0.668 mmol) of phenylphosphine, 0.0318 g (0.167 mmol) of copper (I) iodide, and 5.41 g (53.5 mmol, 2.0 equivalents / 3-BA) of diisopropylamine were added, and 4.50 g (53.5 mmol, 2.0 equivalents / 3-BA) of 2-methyl-3-butyn-2-ol was added dropwise at 20 to 30 ° C., and the reaction was carried out in the same manner as in Example 1. After 24 hours, the reaction solution was analyzed by gas chromatography (GC). As a result, the reaction yield of the target 2-methyl-4-(3-methoxyphenyl)-3-butyn-2-ol was 93.0%, and the GC purity was 83.8%. The GC retention time of 2-methyl-4-(3-methoxyphenyl)-3-butyn-2-ol was 17.1 minutes, m / z 190 was determined from GC / MS analysis, and the compound was determined to be 2-methyl-4-(3-methoxyphenyl)-3-butyn-2-ol from a similarity search.

[0043] [Example 3] A 200 mL flask equipped with a stirrer and a condenser was charged with 25 g of N,N-dimethylacetamide (DMAc) (5 mass % / DMBB), 5.0 g (23.0 mmol) of 3,5-dimethoxybromobenzene (DMBB), and 0.0481 g (0.115 mmol, 0.5 mol% / DMBB) of 5% palladium on carbon (Pd / C; Type E, Pd content 5.1 mass %, 50 mass % water). ), 0.151 g (0.576 mmol) of triphenylphosphine, 0.0274 g (0.144 mmol) of copper (I) iodide, and 4.66 g (46.1 mmol, 2.0 equivalents / DMBB) of diisopropylamine were added, and 3.88 g (46.1 mmol, 2.0 equivalents / DMBB) of 2-methyl-3-butyn-2-ol was added dropwise at 20 to 30 ° C., and the reaction was carried out in the same manner as in Example 1. After 24 hours, the reaction solution was analyzed by gas chromatography (GC). As a result, the reaction yield of 2-methyl-4-(3,5-dimethoxyphenyl)-3-butyn-2-ol was 98.9%, and the GC purity was 85.4%. The GC retention time of 2-methyl-4-(3,5-dimethoxyphenyl)-3-butyn-2-ol was 20.2 minutes, and the m / z was 220 by GC / MS analysis. Similarity search determined that the compound was 2-methyl-4-(3,5-dimethoxyphenyl)-3-butyn-2-ol.

[0044] [Example 4] A 200 mL flask equipped with a stirrer and a condenser was charged with 25 g of N,N-dimethylacetamide (DMAc) (5 times by mass / DMBB), 5.0 g (23.0 mmol) of 3,5-dimethoxybromobenzene (DMBB), 0.0.196 g (0.0461 mmol, 0.2 mol% / DMBB) of 5% palladium carbon (Pd / C; Type E, Pd content 5.1 mass%, 50 mass% water content) of 0.0.196 g (0.0461 mmol, 0.2 mol% / DMBB). The same amount of raw materials as in Example 3 were charged, and the reaction was carried out in the same manner as in Example 1. After 24 hours, the reaction solution was analyzed by gas chromatography (GC). The reaction yield of 2-methyl-4-(3,5-dimethoxyphenyl)-3-butyn-2-ol was 87.1%, and the GC purity was 75.2%.

[0045] [Example 5] In a 200 mL flask equipped with a stirrer and a condenser, DMAc, DMBB, 5% palladium carbon, triphenylphosphine, copper (I) iodide, and diisopropylamine were charged as in Example 4, and then 1.20 g of lithium bromide (13.8 mmol, 0.6 mol% / DMBB) was added as an additive. 3.88 g of 2-methyl-3-butyn-2-ol (46.1 mmol, 2.0 equivalents / DMBB) was added dropwise at 20 to 30 ° C. as in Example 4, and the reaction was carried out in the same manner as in Example 1. After 24 hours, the reaction solution was analyzed by gas chromatography (GC). The reaction yield of 2-methyl-4-(3,5-dimethoxyphenyl)-3-butyn-2-ol was 91.5%, and the GC purity was 77.8%.

[0046] [Comparative Example 1] A 200 mL flask equipped with a stirrer and a condenser was charged with 25 g of N,N-dimethylacetamide (DMAc) (5 times by mass / 3-BT), 5.0 g (29.2 mmol) of 3-bromotoluene (3-BT), and 0.103 g (0.146 mmol, 0.5 mol% / 3-BT) of bis(triphenylphosphine)palladium dichloride (BTPD) instead of 5% palladium carbon and triphenylphosphine. The raw materials described in Example 1 were added and reacted for 24 hours. After 24 hours, the reaction solution was analyzed by gas chromatography (GC). The reaction yield of the target 2-methyl-4-(2-tolyl)-3-butyn-2-ol was 75.5%, and the GC purity was 63.5%.

[0047] Comparative Example 2 The reaction was carried out for 24 hours in the same manner as in Example 2, except that 0.0938 g (0.134 mmol, 0.5 mol% / 3-BA) of bis(triphenylphosphine)palladium dichloride (BTPD) was added instead of the palladium carbon and triphenylphosphine described in Example 2. Analysis of the reaction solution after 24 hours by gas chromatography (GC) revealed that the reaction yield of the target 2-methyl-4-(3-methoxyphenyl)-3-butyn-2-ol was 62.1%, and the GC purity was 50.3%.

[0048] Comparative Example 3 The reaction was carried out for 24 hours in the same manner as in Example 3, except that 0.0809 g (0.115 mmol, 0.5 mol% / DMBB) of bis(triphenylphosphine)palladium dichloride (BTPD) was added instead of the palladium carbon and triphenylphosphine described in Example 3. After 24 hours, the reaction solution was analyzed by gas chromatography (GC), and the reaction yield of 2-methyl-4-(3,5-dimethoxyphenyl)-3-butyn-2-ol was 72.0%, and the GC purity was 59.5%.

[0049] The results of the examples and comparative examples are summarized in the table below. Furthermore, the usefulness of each production method was rated with a symbol × to ⊚ to judge the usefulness when carried out industrially. The evaluation criteria were as follows: ◎ indicates a high reaction yield, high GC purity, and little impurity generation, and is considered easy to industrialize; ◯ indicates a relatively high yield and high GC purity; and × indicates a low reaction yield, low GC purity, and much impurity generation, making industrialization difficult.

[0050] [Table 1]

[0051] As shown in the table above, the use of palladium carbon (Pd / C) as the catalyst resulted in high reaction yields and high GC purity. Furthermore, as shown in Example 4, it was found that even when the amount of catalyst used was reduced, a reaction yield of 80% or more and a GC purity of 70% or more could be maintained. Furthermore, as shown in Example 5, it was found that the addition of lithium bromide as an additive improved the reaction yield and GC purity. The method for producing an aromatic compound having an ethynyl group of the present invention can achieve a high reaction yield even when the amount of catalyst is reduced, thereby enabling inexpensive production.

[0052] After the coupling reaction, the reaction mixture is cooled, extracted with a non-aqueous organic solvent such as ethyl acetate, washed with water several times, and the organic solvent is concentrated. After that, recrystallization or distillation can be performed to obtain the desired aromatic ethynyl compounds such as 2-methyl-4-(2-tolyl)-3-butyn-2-ol, 4-(3-methoxyphenyl)-3-butyn-2-ol, and 2-methyl-4-(3,5-dimethoxyphenyl)-3-butyn-2-ol. [Industrial Applicability]

[0053] The method for producing an aromatic compound having an ethynyl group of the present invention uses an aromatic compound having an electron-donating substituent such as an alkoxy group or an alkyl group as a raw material and palladium on carbon as a catalyst, thereby enabling the Sonogashira coupling reaction to proceed efficiently and in high yield.

[0054] The aromatic compounds having an ethynyl group obtained by the present invention can be used to synthesize aromatic compounds having an ethynyl group that are useful as raw materials for pharmaceuticals and electronic materials, and can be used as useful compounds as raw materials for fine chemicals, pharmaceutical and agricultural chemicals, resins and plastics, electronic information materials, and optical materials.

Claims

1. The following general formula (1) 【Chemistry 1】 (wherein R represents an electron-donating substituent, X represents a halogen atom, and n represents an integer of 1 to 3). and an aromatic halogen compound represented by the following general formula (2): 【Chemistry 2】 (wherein A represents a hydrocarbon group having a hydroxyl group or a trialkylsilyl group) In a coupling reaction with an ethynyl compound represented by the following general formula (3), the coupling reaction is carried out in a nitrogen-containing organic solvent together with palladium carbon, a phosphorus compound, and a copper compound in the presence of an amine and an alkali metal salt: 【Transformation 3】 (wherein R represents an electron-donating substituent, A represents a hydrocarbon group having a hydroxyl group or a trialkylsilyl group, and n represents an integer of 1 to 3). A method for producing an aromatic compound having an ethynyl group represented by the formula:

2. 2. The method for producing an aromatic compound having an ethynyl group according to claim 1, wherein the electron-donating substituent is an alkoxy group and / or an alkyl group.

3. 3. The method for producing an aromatic compound having an ethynyl group according to claim 1, wherein the amount of palladium on carbon used is 1.0 mol % or less based on the amount of the aromatic halogen compound.

4. 4. The method for producing an aromatic compound having an ethynyl group according to claim 1, wherein the halogen atom is bromine or iodine.

5. 5. The method for producing an aromatic compound having an ethynyl group according to claim 1, wherein the nitrogen-containing organic solvent is N,N-dimethylacetamide or N-methyl-2-pyrrolidone.

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