Benzopyran derivatives and methods for producing the same

Abstract

This invention provides benzopyran derivatives, which serve as raw materials or intermediates for physiologically active substances, and a method for producing them, in a short number of steps. [Solution] A compound (A) having a salicylaldehyde structure and a compound (B) having an acrylamide structure can be reacted to produce a compound (E) having a benzopyran-3-carboxylic acid amide structure in a single step.

Description

[Technical Field]

[0001] This invention relates to benzopyran derivatives and methods for producing the same. [Background technology]

[0002] Benzopyrane derivatives and dihydrobenzopyran derivatives are compounds obtained by introducing hydroxyl groups, alkoxy groups, halogen groups, carboxyl groups, ester groups, amino groups, sulfonyl groups, or sulfonamide groups, etc., into benzopyran or dihydrobenzopyran, and are widely studied as raw materials or intermediates for physiologically active substances, pharmaceuticals, or agrochemicals (Patent Documents 1-3). However, the synthesis of these compounds has been limited to multi-step reactions starting with benzopyran derivatives having cyano or epoxy groups, resulting in low total yields and very high manufacturing costs. For example, Patent Document 1 discloses a method for producing therapeutic drugs for the prevention and treatment of hyperlipidemia and hypercholesterolemia in mammals by hydrolyzing cyanobenzopyran to synthesize benzopyrancarboxylic acid, then esterifying the carboxylic acid, and further introducing chlorosulfonyl groups, mercapto groups, etc. Patent Document 2 discloses a method for producing antiarrhythmic drugs using benzopyran having an epoxide group as a raw material, reacting it with fluorophenylethylamine, reducing it with a reducing agent, and further introducing hydroxyl groups, cyano groups, nitro groups, etc. Patent Document 3 discloses the synthesis of an active substance suitable for the manufacture of drugs for the prevention and treatment of cardiovascular diseases and arrhythmias, the treatment of gastrointestinal ulcers, or the treatment of diarrheal diseases, by reacting a benzopyran having an epoxide group with a sulfonamide, and then introducing a benzyloxy group, a butoxy group, an acetoxy group, a hydroxyl group, etc. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] Special Publication No. 2005-527509 [Patent Document 2] Japanese Patent Publication No. 2003-081961 [Patent Document 3] Japanese Patent Application Publication No. 11-222485 [Overview of the project] [Problems that the invention aims to solve]

[0004] The first object of the present invention is to provide a compound having a benzopyran-3-carboxylic acid amide structure and a method for producing the same as a useful benzopyran derivative with a short number of steps, high yield, and low cost. The second object of the present invention is to provide a method for producing a compound having a benzopyran-3-carbonyl structure as a useful benzopyran derivative with a short number of steps, high yield, and low cost. The third object of the present invention is to provide a method for producing a compound having a dihydrobenzopyran-3-substituted structure as a useful dihydrobenzopyran derivative with a short number of steps and low cost. [Means for solving the problem]

[0005] As a result of diligent research to solve these problems, the present inventors have found that a compound (E) having a benzopyran-3-carboxylic acid amide structure can be obtained in a single step by reacting a compound (A) having a salicylaldehyde structure with a compound (B) having an acrylamide structure, and have thus found a method for producing a benzopyran derivative having a carboxylic acid amide group according to the first embodiment of this disclosure.

[0006] Furthermore, we discovered that a compound (F) having a benzopyran-3-carbonyl structure can be obtained by reacting a compound (E) having a benzopyran-3-carboxylic acid amide structure with an organometallic compound (G) or a metal hydride (G3), thus finding a method for producing a benzopyran derivative having a carbonyl group according to the second embodiment of this disclosure.

[0007] Furthermore, we discovered that a compound (H) having a dihydrobenzopyran-3-substituted structure can be obtained by reacting a compound (F) having a benzopyran-3-carbonyl structure with hydrogen, thus finding a method for producing a dihydrobenzopyran derivative according to the third embodiment of this disclosure.

[0008] This invention is based on the following configuration. (1) A method for producing a compound having a benzopyran-3-carboxylic acid amide structure as shown in general formula (3), by reacting a compound having a salicylaldehyde structure as shown in general formula (1) with a compound having an acrylamide structure as shown in general formula (2). JPEG2026062418000001.jpg35127JPEG2026062418000002.jpg25127JPEG2026062418000003.jpg35127(R 1 and R 2 R is attached to any position between positions 3 and 6 of general formula (1) or between positions 5 and 8 of general formula (3). In each formula, R 1 and R 2 Each of these independently represents a hydrogen atom, fluorine, chlorine, bromine, iodine, a saturated linear hydrocarbon group having 1 to 36 carbon atoms, an unsaturated linear hydrocarbon group having 2 to 36 carbon atoms, a saturated or unsaturated branched hydrocarbon group having 3 to 36 carbon atoms, an alkylcarboxyl group having 1 to 36 carbon atoms, an alkylcarboxyamide group having 1 to 36 carbon atoms, an alkyl ester group having 1 to 36 carbon atoms, an alkylamide group having 1 to 36 carbon atoms, an alkylthiol group having 1 to 36 carbon atoms, a thioalkoxy group having 1 to 36 carbon atoms, an alkoxy group having 1 to 36 carbon atoms, a carboalkoxy group having 2 to 4 carbon atoms, an alkylene oxide group having 2 to 18 repeating units, or an alkoxy group having 1 to 36 carbon atoms (a polyalkylene oxide having 2 to 18 repeating units of an alkylene oxide group having 2 to 4 carbon atoms). R 1 and R 2It may form a 5- to 12-membered saturated or unsaturated ring together with one side of the benzene ring carrying them, and carbon atoms other than one side of the benzene ring of the formed ring may be substituted with heteroatoms, and hydrogen atoms of the ring may be substituted with a saturated linear hydrocarbon group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms. R 3 and R 4 each independently represents a hydrogen atom, a saturated linear hydrocarbon group having 1 to 18 carbon atoms, an unsaturated linear hydrocarbon group having 2 to 18 carbon atoms, a saturated or unsaturated branched hydrocarbon group having 3 to 18 carbon atoms, a saturated or unsaturated cyclic hydrocarbon group having 6 to 18 carbon atoms, a primary, secondary or tertiary aminoalkyl group having 1 to 18 carbon atoms, a hydroxyalkyl group having 1 to 18 carbon atoms, an alkyl (having 1 to 18 carbon atoms) carbonyl alkylene (having 1 to 8 carbon atoms) group. R 3 and R 4 together with the nitrogen atom carrying them, forms a saturated or unsaturated ring having 5 to 18 members (the atoms forming the ring may have 1 to 6 heteroatoms, and hydrogen atoms of the ring may be substituted with a saturated linear hydrocarbon group having 1 to 6 carbon atoms or a saturated alkoxy group having 1 to 6 carbon atoms.) (2) A method for producing a compound having a benzopyran-3-carboxamide structure according to (1) above, wherein the reaction is carried out in the presence of a basic compound. (3) A method for producing a compound having a benzopyran-3-carboxamide structure according to (2) above, wherein the basic compound has a pKa value of the conjugate acid thereof of 8.0 to 18.0. (4) A method for producing a compound having a benzopyran-3-carboxamide structure according to (2) or (3) above, wherein the basic compound is an organic basic compound, an inorganic basic compound, an organic-inorganic hybrid basic compound, a basic ion exchange resin or a mixture thereof. (5) A method for producing a compound having a benzopyran-3-carboxamide structure according to any one of (2) to (4) above, wherein the basic compound is one or more metal salts selected from alkali metal salts and alkaline earth metal salts. (6) A method for producing a compound having a benzopyran-3-carboxylic acid amide structure according to any one of (1) to (5) above, wherein the reaction temperature is 40 to 150°C. (7) A method for producing a compound having a benzopyran-3-carboxylic acid amide structure according to any one of (1) to (6) above, carried out in the presence of a reaction solvent. (8) A compound having a benzopyran-3-carboxylic acid amide structure as shown in general formula (4). JPEG2026062418000004.jpg35127(R 5 and R 6 R is attached to any position between positions 5 and 8 in general formula (4). In the formula, R 5 and R 6 is R 1 and R 2 It is similar to R. 7 and R 8 is R 3 and R 4 It is similar to this. (9) A method for producing a compound having a benzopyran-3-carbonyl structure shown in general formula (5), by reacting a compound having a benzopyran-3-carboxylic acid amide structure as described in (8) above with an organometallic compound. JPEG2026062418000005.jpg35127(R 5 and R 6 R is attached to any position between the 5th and 8th positions in general formula (5). In the formula, R 5 and R 6 This is the same as above. R 9 (wherein 1 represents a hydrogen atom, a saturated linear hydrocarbon group having 1 to 18 carbon atoms, an unsaturated linear hydrocarbon group having 2 to 18 carbon atoms, a saturated or unsaturated branched hydrocarbon group having 3 to 18 carbon atoms, or a saturated or unsaturated cyclic hydrocarbon group having 6 to 18 carbon atoms.) Furthermore, the linear, branched, or cyclic hydrocarbon group may further contain fluorine, chlorine, bromine, iodine, an alkoxy group having 1 to 18 carbon atoms, a thioalkoxy group having 1 to 18 carbon atoms, an alkylene oxide group having 2 to 4 carbon atoms, or a polyalkylene oxide group having 2 to 18 repeating units of an alkylene oxide group having 2 to 4 carbon atoms. (10) A method for producing a compound having a benzopyran-3-carbonyl structure as described in (9), wherein the organometallic compound is an organometallic compound containing one or more metals selected from lithium, sodium, magnesium, aluminum, zinc, bismuth, and germanium. (11) A method for producing a compound having a benzopyran-3-carbonyl structure as described in (9) or (10), by reacting a compound having a benzopyran-3-carboxylic acid amide structure with an organomagnesium halide represented by general formula (6). JPEG2026062418000006.jpg11127 (in the formula, R 10 X represents a saturated linear hydrocarbon group having 1 to 18 carbon atoms, an unsaturated linear hydrocarbon group having 2 to 18 carbon atoms, a saturated or unsaturated branched hydrocarbon group having 3 to 18 carbon atoms, or a saturated or unsaturated cyclic hydrocarbon group having 6 to 18 carbon atoms. Furthermore, the linear, branched, or cyclic hydrocarbon group may further contain fluorine, chlorine, bromine, iodine, an alkoxy group having 1 to 18 carbon atoms, a thioalkoxy group having 1 to 18 carbon atoms, an alkylene oxide group having 2 to 4 carbon atoms, or a polyalkylene oxide group having 2 to 18 repeating units of an alkylene oxide group having 2 to 4 carbon atoms. (X represents a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.) (12) A method for producing a compound having a benzopyran-3-carbonyl structure as described in (9) or (10), by reacting a compound having a benzopyran-3-carboxylic acid amide structure with an organolithium represented by general formula (7). JPEG2026062418000007.jpg11127 (in the formula, R 11 (wherein represents a saturated linear hydrocarbon group having 1 to 18 carbon atoms, an unsaturated linear hydrocarbon group having 2 to 18 carbon atoms, a saturated or unsaturated branched hydrocarbon group having 3 to 18 carbon atoms, or a saturated or unsaturated cyclic hydrocarbon group having 6 to 18 carbon atoms. The linear, branched, or cyclic hydrocarbon group may further contain an alkoxy group or thioalkoxy group having 1 to 18 carbon atoms, an alkylene oxide group having 2 to 4 carbon atoms, or a polyalkylene oxide group having 2 to 18 repeating units of an alkylene oxide group having 2 to 4 carbon atoms.) (13) A method for producing a compound having a benzopyran-3-carbonyl structure according to any one of the above (9) to (12), characterized in that the method is carried out in an ether solvent. (14) A method for producing a compound having a benzopyran-3-carbonyl structure as described in (13), wherein the ether solvent is a linear ether and / or a cyclic ether. (15) A method for producing a compound having a benzopyran-3-carbonyl structure according to any one of the above items (9) to (14), wherein the reaction temperature is -100 to 60°C. (16) A method for producing a compound having a dihydrobenzopyran-3-substituted structure as described in general formula (8), by reacting a compound having a benzopyran-3-carbonyl structure as described in (9) above with hydrogen. JPEG2026062418000008.jpg26127(R 12 and R 13 R is attached to any position between the 5th and 8th positions in general formula (8). In the formula, R 12 and R 13 is R 1 and R 2 It is similar to that. R 14 (wherein 1 represents a hydrogen atom, a saturated linear hydrocarbon group having 1 to 18 carbon atoms, a saturated branched hydrocarbon group having 3 to 18 carbon atoms, or a saturated or unsaturated cyclic hydrocarbon group having 6 to 18 carbon atoms.) Furthermore, the linear, branched, or cyclic hydrocarbon group may further contain fluorine, chlorine, bromine, iodine, an alkoxy or thioalkoxy group having 1 to 18 carbon atoms, an alkylene oxide group having 2 to 4 carbon atoms, or a polyalkylene oxide group having 2 to 18 repeating units of the alkylene oxide group having 2 to 4 carbon atoms. (17) A method for producing a compound having a benzopyran-3-carbonyl structure as shown in general formula (12) by reacting a compound having a salicylaldehyde structure as shown in general formula (9) with a compound having an acrylamide structure as shown in general formula (10) to obtain a compound having a benzopyran-3-carboxylic acid amide structure as shown in general formula (11), and reacting the obtained compound having a benzopyran-3-carboxylic acid amide structure with an organometallic compound. JPEG2026062418000009.jpg35127JPEG2026062418000010.jpg24127JPEG2026062418000011.jpg34127JPEG2026062418000012.jpg34127(In each formula, R 15 and R 16 It is connected to any position in the 3rd to 6th positions of general formula (9), the 5th to 8th positions of general formula (11), or the 5th to 8th positions of general formula (12), R 15 and R 16 is R 1 and R 2 It is similar to that. R 17 and R 18 is R 3 and R 4 It is similar to that. R 19 is R 9 It is similar to this. (18) A method for producing a compound having a salicylaldehyde structure shown in general formula (13) and an acrylamide structure shown in general formula (14) by reacting them to obtain a compound having a benzopyran-3-carboxylic acid amide structure shown in general formula (15); reacting the obtained compound having a benzopyran-3-carboxylic acid amide structure with an organometallic compound to obtain a compound having a benzopyran-3-carbonyl structure shown in general formula (16); and reacting the obtained compound having a benzopyran-3-carbonyl structure with hydrogen to produce a compound having a dihydrobenzopyran-3-substituted structure shown in general formula (17). JPEG2026062418000013.jpg34127JPEG2026062418000014.jpg24127JPEG2026062418000 015.jpg34127JPEG2026062418000016.jpg34127JPEG2026062418000017.jpg24127(In each formula, R 20 and R 21 It is connected to any position from the 3rd to 6th positions of general formula (13), and from the 5th to 8th positions of general formulas (15) and (16), R 20 and R 21 is R 1 and R 2 It is similar to that. R22 and R 23 is R 3 and R 4 It is similar to R. 24 is R 9 It is similar to that. R 25 and R 26 It is connected to any position from the 5th to the 8th position in general formula (17), R 25 and R 26 is R 1 and R 2 It is similar to R. 27 is R 14 It is similar to this. [Effects of the Invention]

[0009] According to the present invention, a compound (E) having a benzopyran-3-carboxylic acid amide structure can be synthesized in a single step. Furthermore, a compound (F) having a benzopyran-3-carbonyl structure can be synthesized in a single step using compound (E). Moreover, a compound (H) having a dihydrobenzopyran-3-substituted structure can be synthesized in a single step using compound (F). [Modes for carrying out the invention]

[0010] The embodiments of this disclosure will be described in detail below, but the scope of the present invention is not limited to the embodiments described herein, and various modifications can be made without departing from the spirit of the invention. Furthermore, if multiple upper and lower limits are given for a particular parameter, any combination of these upper and lower limits can be used to create a suitable numerical range.

[0011] A first embodiment of the present invention involves reacting a compound (A) having a salicylaldehyde structure with a compound (B) having an acrylamide structure to obtain a compound (E) having a benzopyran-3-carboxylic acid amide structure.

[0012] Examples of compounds (A) having a salicylaldehyde structure include those represented by general formula (1). JPEG2026062418000018.jpg35127In formula, R 1 and R 2 This is the same as above.

[0013] From the viewpoint of synthesizing compound (E) in high yield, the R of compound (A) 1 and R 2 Preferably, each of these is independently a hydrogen atom, fluorine, chlorine, bromine, iodine, a saturated linear hydrocarbon group having 1 to 36 carbon atoms, an unsaturated linear hydrocarbon group having 2 to 36 carbon atoms, a saturated or unsaturated branched hydrocarbon group having 3 to 36 carbon atoms, an alkylcarboxyl group having 1 to 36 carbon atoms, an alkylcarboxamide group having 1 to 36 carbon atoms, an alkyl ester group having 1 to 36 carbon atoms, an alkylamide group having 1 to 36 carbon atoms, an alkylthiol group having 1 to 36 carbon atoms, a thioalkoxy group having 1 to 36 carbon atoms, an alkoxy group having 1 to 36 carbon atoms, a carboalkoxy group having 2 to 4 carbon atoms, an alkylene oxide group having 2 to 18 repeating units of an alkylene oxide group having 1 to 36 carbon atoms, etc.

[0014] Preferably, such compounds include salicylaldehyde, halogenated salicylaldehyde, alkyl salicylaldehyde, N-alkylcarbosamide salicylaldehyde, salicylaldehyde carboxylate alkyl ester, salicylaldehyde carboxylate alkylamide, thioalkoxysalicyaldehyde, alkoxysalicyaldehyde, carboalkoxysalicyaldehyde, alkylene oxide salicylaldehyde, polyalkylene oxide salicylaldehyde, and alkoxypolyalkylene oxide salicylaldehyde.

[0015] Also, R 1 and R 2When these compounds join with one side of the supporting benzene ring to form a saturated or unsaturated ring of 5 to 12 members, the carbon atoms other than those on one side of the benzene ring of the formed ring may be substituted with heteroatoms, and the hydrogen atoms of the ring may be substituted with saturated linear hydrocarbon groups having 1 to 6 carbon atoms or alkoxy groups having 1 to 6 carbon atoms. From the viewpoint of synthesizing compound (E) in high yield, such compounds are preferably compounds such as methylenedioxysalicylic acid and 1-hydroxy-2-naphthaldehyde.

[0016] From the viewpoint of being able to purify compound (E) by a simple method and synthesize it in high yield, it is more preferable that compound (A) is water-soluble. For example, if compound (A) has R 1 and R 2 These can be independently a hydrogen atom, fluorine, chlorine, bromine, iodine, a saturated linear hydrocarbon group having 1 to 4 carbon atoms, a saturated branched hydrocarbon group having 3 to 4 carbon atoms, or an alkoxy group having 1 to 2 carbon atoms, with hydrogen atoms, fluorine, chlorine, a methyl group, and a methoxy group being more preferred. A water-soluble compound is a compound that can dissolve 1 g or more in 100 g of water at 25°C.

[0017] The following compounds are not limited to, but specifically include: salicylaldehyde, fluorosalicyaldehyde, difluorosalicyaldehyde, chlorosalicyaldehyde, dichlorosalicyaldehyde, bromosalicyaldehyde, dibromosalicyaldehyde, iodosalicylaldehyde, diiodosalicylaldehyde, chlorofluorosalicyaldehyde, bromochlorosalicyaldehyde, methylsalicyaldehyde, dimethylsalicyaldehyde, ethylsalicyaldehyde, diethylsalicyaldehyde, n-propylsalicyaldehyde, di(n-propyl)salicyaldehyde, i-propylsalicyaldehyde, di(i-propyl)salicyaldehyde, n-butylsalicyaldehyde, di(n-butyl)salicyaldehyde, i-butylsalicy Examples include aldehydes, di(i-butyl)salicyaldehyde, t-butylsalicyaldehyde, di(t-butyl)salicyaldehyde, methoxysalicyaldehyde, dimethoxysalicyaldehyde, ethoxysalicyaldehyde, diethoxysalicyaldehyde, methylethylsalicyaldehyde, methylmethoxysalicyaldehyde, ethylmethoxysalicyaldehyde, methylethoxysalicyaldehyde, ethylethoxysalicyaldehyde, fluoromethylsalicyaldehyde, bromomethylsalicyaldehyde, chloromethylsalicyaldehyde, iodomethylsalicyaldehyde, fluoromethoxysalicyaldehyde, bromomethoxysalicyaldehyde, chloromethoxysalicyaldehyde, iodomethoxysalicyaldehyde, and the like.

[0018] Examples of compounds (B) having an acrylamide structure include those represented by general formula (2). JPEG2026062418000019.jpg25127In formula, R 3 and R 4 This is the same as above.

[0019] From the viewpoint of synthesizing compound (E) in high yield, the R of compound (B) 3 and R 4Preferably, each of these is independently a hydrogen atom, a saturated linear hydrocarbon group having 1 to 18 carbon atoms, an unsaturated linear hydrocarbon group having 2 to 18 carbon atoms, a saturated or unsaturated branched hydrocarbon group having 3 to 18 carbon atoms, a saturated or unsaturated cyclic hydrocarbon group having 6 to 18 carbon atoms, a primary, secondary, or tertiary aminoalkyl group having 1 to 18 carbon atoms, a hydroxyalkyl group having 1 to 18 carbon atoms, or an alkyl (1 to 18 carbon atoms) carbonylalkylene (1 to 8 carbon atoms) group.

[0020] Examples of such compounds include acrylamide, N-alkylacrylamide, N,N-dialkylacrylamide, N-alkyl-N-alkyleneacrylamide, N-alkyl-N-cycloalkylacrylamide, N-alkyl-N-arylacrylamide, N-methylaminoalkylacrylamide, N,N-dimethylaminoalkylacrylamide, N-ethylaminoalkylacrylamide, N,N-diethylaminoalkylacrylamide, Nn-propylaminoalkylacrylamide, N,N-di(n-propyl)aminoalkylacrylamide, Ni-propylaminoalkylacrylamide, It is preferable that the compound is one of the following: N,N-di(i-propyl)aminoalkylacrylamide, N-(n-butyl)aminoalkylacrylamide, N,N-di(n-butyl)aminoalkylacrylamide, N-(i-butyl)aminoalkylacrylamide, N,N-di(i-butyl)aminoalkylacrylamide, N-(t-butyl)aminoalkylacrylamide, N,N-di(t-butyl)aminoalkylacrylamide, N-hydroxyalkylacrylamide, N,N-dihydroxyalkylacrylamide, N-alkyl-N-hydroxyalkylacrylamide, or diacetone acrylamide.

[0021] R 3 and R 4When these atoms, together with the nitrogen atoms supporting them, form a saturated or unsaturated ring of 5 to 18 members, the carbon atoms of the formed ring may be substituted with heteroatoms. From the viewpoint of synthesizing compound (E) in high yield, such compounds are preferably those such as pyrrolidine acrylamide, pyrroline acrylamide, pyrrole acrylamide, pyrazoline acrylamide, oxazole acrylamide, thiazole acrylamide, piperidine acrylamide, piperazine acrylamide, morpholin acrylamide, thiomorpholin acrylamide, thiomorpholin dioxide acrylamide, decahydroquinoline acrylamide, dihydroquinoline acrylamide, adenine acrylamide, azacycloalkyl acrylamide, (oxo-azacycloalkyl) acrylamide, azacrown ether acrylamide, etc.

[0022] From the viewpoint of being able to purify compound (E) by a simple method and synthesize it with high purity, it is more preferable that compound (B) is water-soluble. Furthermore, since compound (B) has an acrylamide structure, B may polymerize during the reaction, and a polymer of B may be formed as a byproduct. Therefore, it is even more preferable if the polymer of B is also water-soluble, as B and the polymer of B can be removed simultaneously during purification. For example, the R of compound (B) 3 and R 4 Each of these independently comprises a saturated linear hydrocarbon group having 1 to 4 carbon atoms, an alkylamino group having 1 to 3 carbon atoms, an alkylhydroxy group having 1 to 3 carbon atoms, or R 3 and R 4 Examples include 5-8 member saturated or unsaturated rings formed together with the nitrogen atoms supporting them.

[0023] The following compounds are not limited to those listed below, but specifically include N-dimethylacrylamide, N,N-dimethylacrylamide, N,N-diethylacrylamide, Ni-propylacrylamide, dimethylaminopropylacrylamide, N-hydroxyethylacrylamide, N-methyl-N-hydroxyethylacrylamide, acryloylmorpholine, piperidineacrylamide, and pyrrolidineacrylamide. Among these, acryloylmorpholine is more preferred.

[0024] The reaction between compound (A) and compound (B) can be carried out using stoichiometric quantities. For example, using an excess of A or B is preferable because it accelerates the reaction and allows it to be completed quickly. Specifically, the molar ratio of B to A (B / A) is preferably 0.1 to 10.0, more preferably 1.0 to 7.0, and even more preferably 3.0 to 5.0.

[0025] In the reaction between compound (A) and compound (B), it is preferable to use an excess of B relative to A, from the viewpoint of obtaining E in a short time and in high yield. Specifically, the molar ratio of B to A (B / A) is preferably 1.1 or higher, and more preferably 3.0 or higher. Here, the excess compound (B) serves as both a raw material for the reaction and a reaction solvent, but it suppresses the polymerization of B and shortens the time required for purification after the reaction, so the molar ratio of B to A is preferably 10.0 or lower, and more preferably 5.0 or lower.

[0026] The reaction temperature between compound (A) and compound (B) is not particularly limited. For example, a reaction temperature of 40 to 150°C is preferred. The reaction proceeds easily at temperatures above 40°C. Also, below 150°C, the polymerization reaction of compound (B), which has an acrylamide structure, can be suppressed. From the viewpoint of a good balance between reaction rate and yield, a reaction temperature of 70°C to 130°C is more preferable.

[0027] The reaction pressure between compound (A) and compound (B) is not particularly limited. Generally, it can be carried out in the range of 0.101 to 0.981 MPa. If the boiling points of compounds (A) and (B) are higher than the required reaction temperature, the reaction can be carried out under pressure using a pressure-resistant reaction vessel.

[0028] The reaction time between compound (A) and compound (B) is not particularly limited. Specifically, it is preferable to carry out the reaction in the range of 10 to 30 hours. The reaction time can be appropriately adjusted by other reaction conditions such as reaction temperature and reaction pressure. If the reaction is mild, the reaction can be carried out for a longer time than the above range, and if the reaction is vigorous, the reaction can be carried out for a shorter time than the above range.

[0029] The reaction between compound (A) and compound (B) may be carried out while removing the water produced during the reaction as appropriate. Since this reaction produces compound (E) and equimolar water, removing the water produced during the reaction will lead to an improvement in yield.

[0030] The method for removing the generated water is not particularly limited. For example, it may be a method of distilling water out of the reaction system while the reaction is carried out under normal or reduced pressure, a method of removing water by passing an inert gas such as nitrogen through the reaction solution, a method of distilling water and solvent while the reaction is carried out using a solvent that can azeotrope with water, or a method of adding a dehydrating agent such as a molecular sieve or basic zeolite to the reaction solution or the packed column in the reflux section.

[0031] When using compound (B), which has a boiling point of 100°C or lower, the reaction can be completed by removing the water produced by the reaction of compound (A) and (B) under normal or reduced pressure, and then adding compound (B) further.

[0032] In the reaction between compound (A) and compound (B), unreacted compounds can be recovered by known methods. For example, the post-reaction solution can be distilled under atmospheric or reduced pressure, or the post-reaction solution can be washed with water or an organic solvent and then extracted and separated.

[0033] The obtained compound (E) may be purified by known methods such as precision distillation, recrystallization, or chromatography, depending on its structure and physical properties.

[0034] The reaction between compound (A) and compound (B) may be carried out in the presence of an acid or a base. This can accelerate the reaction. Specifically, it is preferable to use a basic compound (C). The basic compound (C) is preferably an organic basic compound, an inorganic basic compound, an organic-inorganic hybrid basic compound, a basic ion exchange resin, or a mixture thereof, more preferably an inorganic basic compound, and even more preferably an alkali metal salt or an alkaline earth metal salt. The basic compound (C) may be used alone or in combination of two or more types.

[0035] Basic compound (C) is an organic basic compound, an inorganic basic compound, or an organic-inorganic hybrid basic compound having basicity with a pKa value of 8.0 to 18.0 for its conjugate acid. From the viewpoint of facilitating the reaction between compound (A) and compound (B) and minimizing side reactions, it is more preferable that the pKa value of the conjugate acid of compound (C) is 10.0 to 18.0.

[0036] Organic basic compounds include pyrrole, pyrrolidine, 2-pyrroline, pyrazole, imidazolidine, imidazole, oxazole, pyrazole, pyridine, piperidine, pyrimidine, pyrazine, quinoline, isoquinoline, morpholin, piperazine, 1-azabicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane, diazabicycloundecene, 1,5,7-triazabicyclo[4.4.0]deca-5-ene, guanidine, trialkylamines with 1 to 18 carbon atoms, N-alkylpyrrole, N-alkyl Examples include pyrrolidine, N-alkyl-2-pyrroline, N-alkylpyrazole, 1-alkylimidazolidine, 1,3-dialkylimidazolidine, N-alkylimidazole, N-alkylpiperidine, N-alkylmorpholin, 1-alkylpiperazine, 1,4-dialkylpiperazine, 4-dialkylaminopyridine, 7-methyl-1,5,7-triazabicyclo[4.4.0]deca-5-ene, tetraalkylguanidine, alkali metal alkoxides having 1 to 18 carbon atoms, and alkaline earth metal dialkoxides. Among these, 1-azabicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane, diazabicycloundecene, 4-dimethylaminopyridine, or potassium t-butoxide are more preferred from the viewpoint of strong basicity and excellent solubility, with potassium t-butoxide being particularly preferred.

[0037] Examples of inorganic basic compounds include alkali metal salts such as alkali metal carbonates, alkali metal phosphates, alkali metal borates, and alkali metal hydroxides; alkaline earth metal salts such as alkaline earth metal carbonates, alkaline earth metal phosphates, alkaline earth metal borates, and alkaline earth metal hydroxides; basic zeolites; and hydrotalcite. Among these, alkali metal carbonates and phosphates are preferred, tripotassium phosphate, cesium carbonate, and potassium carbonate are more preferred, and potassium carbonate is particularly preferred.

[0038] Examples of organic-inorganic hybrid basic compounds include those in which organic basic compounds are supported on zeolites, silica, and other materials.

[0039] Examples of basic ion exchange resins include weakly basic anion exchange resins having primary to tertiary amines as exchange groups and strongly basic anion exchange resins having quaternary ammonium as exchange groups. For example, strongly basic anion exchange resins are preferred. Specifically, examples include the Diaion series manufactured by Mitsubishi Chemical Corporation and the Amberlite series manufactured by Organo Corporation.

[0040] The amount of basic compound (C) used is preferably such that the molar ratio of C to A (C / A) is 0.2 or higher. This allows the hydroxyl group of compound (A) to be activated as an anion by deprotonation. Furthermore, it is preferable that the molar ratio of C to A (C / A) is 2.0 or lower. This avoids the polymerization reaction of compound (B). The molar ratio of C / A is more preferably 0.5 to 1.5, and even more preferably 0.9 to 1.1.

[0041] The basic compound (C) may be removed as needed after the reaction between compound (A) and compound (B) is complete. For example, if C is dissolved, it can be adsorbed using an acidic ion exchange resin. Alternatively, C can be neutralized with an acidic compound such as sulfuric acid or hydrochloric acid, and the resulting neutralized salt can be filtered out. If C exhibits different solubility than compound (E), the solution containing C can be washed with water or an organic solvent to remove it. If C is not dissolved or if a basic ion exchange resin is used, the solution can be filtered after the reaction, and the filtered C can be recovered and reused.

[0042] The reaction method for compound (A) and compound (B) is not particularly limited. For example, it may be a batch method or a continuous method, and when using a basic compound (C), it may be a fixed-bed flow reactor or a suspension-bed reactor. In the case of a batch method, compound (A), compound (B), and basic compound (C) are charged into a reaction vessel, and if necessary, the inside of the reaction vessel and reaction solution are replaced with an inert gas. Then, while dissolving by stirring or maintaining a suspension state, the temperature is adjusted to a predetermined reaction temperature and the reaction is carried out for a predetermined time.

[0043] The reaction between compound (A) and compound (B) may use reaction solvent (D1) as needed. The reaction solvent is not particularly limited, and any common solvent can be used as long as it does not cause side reactions with compounds (A), (B), (E) and basic compound (C). Reaction solvent (D1) may be used alone or as a mixture of two or more.

[0044] Examples of reaction solvents (D1) include ion-exchanged water, amides such as dimethylformamide, dimethylacetamide, 3-methoxydimethylpropionamide, and 3-butoxydimethylpropionamide, cyclic ethers such as tetrahydrofuran and 1,4-dioxane, sulfoxides such as dimethyl sulfoxide, aromatics such as benzene, toluene, and xylene, glycols such as ethylene glycol and propylene glycol, linear ethers such as diethyl ether and dibutyl ether, halogens such as chloroform, 1,2-dichloroethane, and carbon tetrachloride, and alcohols such as methanol, ethanol, i-propanol, n-butanol, and glycerin. Depending on the reaction temperature, it is preferable to use a reaction solvent with a boiling point of 80°C or higher.

[0045] The amount of reaction solvent (D1) used is not particularly limited. The higher the concentrations of compound (A) and compound (B) in the reaction system, the greater the reaction rate and the higher the reaction yield. Therefore, the less D1 used, the better, and it is even more preferable to use no solvent at all.

[0046] Polymerization inhibitors may be used in the reaction between compound (A) and compound (B). Polymerization inhibitors can prevent the homopolymerization of polymerizable compound (B), and are therefore preferably used when the reaction temperature of A and B is 100°C or higher. Examples of polymerization inhibitors include quinone-based polymerization inhibitors such as hydroquinone, methoxyhydroquinone, benzoquinone, and pt-butylcatechol; alkylphenol-based polymerization inhibitors such as 2,6-di-t-butylphenol, 2,4-di-t-butylphenol, 2-t-butyl-4,6-dimethylphenol, 2,6-di-t-butyl-4-methylphenol, and 2,4,6-tri-t-butylphenol; alkylated diphenylamine; and N,N'-diphenyl-p-phenyl Examples include amine polymerization inhibitors such as diamine and phenothiazine; TEMPO polymerization inhibitors such as 2,2,6,6-tetramethylpiperidine-N-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl, and 4-acetamido-2,2,6,6-tetramethylpiperidine-N-oxyl; and copper dithiocarbamate polymerization inhibitors such as copper dimethyldithiocarbamate, copper diethyldithiocarbamate, and copper dibutyldithiocarbamate.

[0047] The amount of polymerization inhibitor added is not particularly limited. Specifically, it is sufficient if it can prevent the homopolymerization of polymerizable compound (B) and reduce production costs. For example, it is preferably 0.0001 to 10.0% by mass, more preferably 0.001 to 5.0% by mass, and particularly preferably 0.01 to 2.0% by mass relative to compound (B).

[0048] Compounds (E) having a benzopyran-3-carboxylic acid amide structure include compounds represented by general formula (3). JPEG2026062418000020.jpg35127R 1 and R 2 R is attached to any position between positions 5 and 8 in general formula (3). In the formula, R 1 ~R 4 This is the same as above.

[0049] Compound (E) represented by general formula (3) can be synthesized using compound (A) represented by general formula (1) and compound (B) represented by general formula (2) by the method and conditions described above.

[0050] Specifically, compound (E) includes N,N-dimethyl-2H-1-benzopyran-3-carboxamide, N,N-diethyl-2H-1-benzopyran-3-carboxamide, N-isopropyl-2H-1-benzopyran-3-carboxamide, N-hydroxyethyl-2H-1-benzopyran-3-carboxamide, N-(dimethylaminopropyl)-2H-1-benzopyran-3-carboxamide, and 2H-1-benzopyran-3-yl-4-morpholi Nylmethanone, N-piperidinyl-2H-1-benzopyran-3-carboxamide, N-pyrrolidinyl-2H-1-benzopyran-3-carboxamide, 2H-1-(7,8-methylenedioxybenzopyran)-3-yl-4-morpholinylmethanone, 2H-1-naphthopyran-3-yl-4-morpholinylmethanone, N,N-dimethyl-2H-1-methylbenzopyran-3-carboxamide, N,N-dimethyl-2H-1-methoxybenzopyran-3 -Carboxamide, N,N-dimethyl-2H-1-fluoromethylbenzopyran-3-carboxamide, N,N-dimethyl-2H-1-chlorobenzopyran-3-carboxamide, N,N-dimethyl-2H-1-bromobenzopyran-3-carboxamide, N,N-dimethyl-2H-1-iodomethylbenzopyran-3-carboxamide, N,N-dimethyl-2H-1-dimethylbenzopyran-3-carboxamide, N,N-dimethyl-2H-1-dimethox Cibenzopyran-3-carboxamide, N,N-dimethyl-2H-1-difluoromethylbenzopyran-3-carboxamide, N,N-dimethyl-2H-1-dichlorobenzopyran-3-carboxamide, N,N-dimethyl-2H-1-dibromobenzopyran-3-carboxamide, N,N-dimethyl-2H-1-diiodomethylbenzopyran-3-carboxamide, N,N-dimethyl-2H-1-methylmethoxybenzopyran-3-carboxamide, N,N-dimethyl-2H-1-bromochlorobenzopyran-3-carboxamide, 2H-1-methylbenzopyran-3-yl-4-morpholinylmethanone, 2H-1-methoxybenzopyran-3-yl-4-morpholinylmethanone, 2H-1-fluoromethylbenzopyran-3-yl-4-morpholinylmethanone, 2H-1-chlorobenzopyran-3-yl-4-morpholinylmethanone, 2H-1-bromobenzopyran-3-yl-4-morpholinylmethanone, 2H-1-iodomethylbenzopyran-3-yl-4-morpholinylmethanone, 2H-1-dimethylbenzopyran-3-yl-4-morph Examples include morpholinylmethanone, 2H-1-dimethoxybenzopyran-3-yl-4-morpholinylmethanone, 2H-1-difluoromethylbenzopyran-3-yl-4-morpholinylmethanone, 2H-1-dichlorobenzopyran-3-yl-4-morpholinylmethanone, 2H-1-dibromobenzopyran-3-yl-4-morpholinylmethanone, 2H-1-diiodomethylbenzopyran-3-yl-4-morpholinylmethanone, 2H-1-methylmethoxybenzopyran-3-yl-4-morpholinylmethanone, and 2H-1-bromochlorobenzopyran-3-yl-4-morpholinylmethanone.

[0051] From the viewpoint of facilitating the purification of compound (E), it is preferable that compound (E) is N,N-dimethyl-2H-1-benzopyran-3-carboxamide, 2H-1-benzopyran-3-yl-4-morpholinylmethanone, or N,N-dimethyl-2H-1-benzopyran-3-carboxamide or 2H-1-benzopyran-3-yl-4-morpholinylmethanone having a methyl group, methoxy group, fluorine, chlorine, bromine, or iodine at any position between 5 and 8.

[0052] Among these, 2H-1-benzopyran-3-yl-4-morpholinylmethanone is preferred because it can be easily purified. Also, 2H-1-(6-fluoro)benzopyran-3-yl-4-morpholinylmethanone, 2H-1-(8-fluoro)benzopyran-3-yl-4-morpholinylmethanone, 2H-1-(6-chloro)benzopyran-3-yl-4-morpholinylmethanone, 2H-1-(7-chloro)benzopyran-3-yl-4-morpholinylmethanone, 2H-1-(6-bromo)benzopyran-3-yl-4-morpholinylmethanone, 2H-1-(8-bromo)benzopyran- 3-yl-4-morpholinylmethanone, 2H-1-(6-iodo)benzopyran-3-yl-4-morpholinylmethanone, 2H-1-(6,8-dichloro)6-chlorobenzopyran-3-yl-4-morpholinylmethanone, and 2H-1-(8-bromo-6-chloro)benzopyran-3-yl-4-morpholinylmethanone are even more preferable because they can be used as useful pharmaceutical intermediates by synthesizing new physiologically active substances through aromatic nucleophilic substitution reactions, coupling reactions, etc., utilizing the chlorine, bromine, or iodine contained in the benzopyran ring.

[0053] A second embodiment of the present invention is a production method that involves reacting a compound (E) having a benzopyran-3-carboxylic acid amide structure with an organometallic compound (G) or a metal hydride (G3) to obtain a compound (F) having a benzopyran-3-carbonyl structure.

[0054] From the viewpoint of synthesizing compound (F) in high yield, it is preferable that compound (E) is N,N-dimethyl-2H-1-benzopyran-3-carboxamide, 2H-1-benzopyran-3-yl-4-morpholinylmethanone, or N,N-dimethyl-2H-1-benzopyran-3-carboxamide or 2H-1-benzopyran-3-yl-4-morpholinylmethanone having a methyl group, methoxy group, fluorine, chlorine, bromine, or iodine at any position between 5 and 8.

[0055] Organometallic compounds (G) are compounds that contain a chemical bond between a metal and the carbon of an organic functional group. Specifically, examples include organometallic halides (G1) and organometallic compounds (G2).

[0056] The metal of the organometallic compound (G) is preferably lithium, sodium, magnesium, aluminum, zinc, bismuth, or germanium, and more preferably magnesium, lithium, sodium, and aluminum. In particular, organomagnesium halide is preferred as the organometallic halide (G1), and organolithium is preferred as the organometallic compound (G2). Among these, organolithium is more preferred because it yields a higher yield.

[0057] The organofunctional group of organometallic compound (G) may include saturated linear hydrocarbon groups having 1 to 18 carbon atoms, unsaturated linear hydrocarbon groups having 2 to 18 carbon atoms, saturated or unsaturated branched hydrocarbon groups having 3 to 18 carbon atoms, or saturated or unsaturated cyclic hydrocarbon groups having 6 to 18 carbon atoms. Furthermore, one or more hydrogen atoms of the linear, branched, or cyclic hydrocarbon groups may be substituted with fluorine, chlorine, bromine, iodine, alkoxy groups having 1 to 18 carbon atoms, thioalkoxy groups having 1 to 18 carbon atoms, alkylene oxide groups having 2 to 4 carbon atoms, or polyalkylene oxide groups having 2 to 18 repeating units of alkylene oxide groups having 2 to 18 carbon atoms.

[0058] The metal hydride (G3) may be a compound composed of one or more metals, or a compound containing boron in addition to the metal. Examples include metal hydrogen compounds and boron hydride metal compounds.

[0059] From the viewpoint of synthesizing compound (F) in high yield, the organometallic halide (G1) is more preferably alkylmagnesium chloride, alkylmagnesium bromide, alkylenemagnesium chloride, alkylenemagnesium bromide, cycloalkylmagnesium chloride, cycloalkylmagnesium bromide, arylmagnesium chloride, arylmagnesium bromide, phenylmagnesium chloride, methylmagnesium bromide, ethylmagnesium bromide, n-propylmagnesium bromide, i-propylmagnesium bromide, n-butylmagnesium bromide, i-butylmagnesium bromide, t-butylmagnesium bromide, allylmagnesium bromide, phenylmagnesium bromide, 3-methoxyphenylmagnesium bromide, 4-methoxyphenylmagnesium bromide, 2-methylphenylmagnesium bromide, 4-methoxy-2-methylphenylmagnesium bromide, 3-bromobenzylmagnesium bromide, or 3-chloro-4-fluorophenylmagnesium bromide, and these organomagnesium bromides are even more preferred.

[0060] From the viewpoint of synthesizing compound (F) in high yield, the organometallic compound (G2) is preferably alkyllithium, alkylenelithium, cycloalkyllithium, aryllithium, methyllithium, ethyllithium, n-propyllithium, i-propyllithium, n-butyllithium, i-butyllithium, t-butyllithium, allyllithium, or phenyllithium.

[0061] Examples of metal hydrides (G3) include lithium hydride, beryllium hydride, sodium hydride, magnesium hydride, potassium hydride, calcium hydride, sodium borohydride, lithium borohydride, zinc borohydride, lithium aluminum hydride, and nickel borohydride. Among these, sodium hydride is preferred. Furthermore, from the viewpoint of synthesizing compound (F) in high yield, it is preferable to use a metal halide corresponding to the metal hydride used, and the combination of sodium hydride and sodium iodide is most preferable.

[0062] Organometallic halides (G1), organometallic compounds (G2), and metal hydrides (G3) may be used individually or in any combination.

[0063] The amount of organometallic compound (G) or metal hydride (G3) used is not particularly limited. For example, if the amount is equal to or greater than that of compound (E) (a molar ratio of (G+G3) / E of 1.0 or more), it is preferable because it allows compound (E) to react almost completely. Furthermore, if the molar ratio of (G+G3) / E is 5.0 or less, it is more preferable because the reaction rate is fast, there are few side reactions, and it is economically advantageous. A molar ratio of (G+G3) / E between 1.1 and 3.0 is even more preferable.

[0064] The reaction temperature between compound (E) and organometallic compound (G) and / or metal hydride (G3) is not particularly limited. For example, from the viewpoint of improving the reaction yield, -100 to 60°C is preferred, -78 to 40°C is more preferred, and -78 to 25°C is even more preferred.

[0065] The reaction time between compound (E) and organometallic compound (G) and / or metal hydride (G3) is not particularly limited. Specifically, it is preferable to carry out the reaction in the range of 0.1 to 24 hours. The reaction time can be appropriately adjusted by other reaction conditions such as the reaction temperature. If the reaction is mild, the reaction can be carried out for a longer time than the above range, and if the reaction is vigorous, the reaction can be carried out for a shorter time than the above range.

[0066] The reaction between compound (E) and organometallic compound (G) and / or metal hydride (G3) may use a reaction solvent (D2) as needed. The reaction solvent is not particularly limited, and any common solvent can be used as long as it does not cause side reactions with the starting materials or catalyst. Furthermore, D2 may be used alone or as a mixture of two or more types.

[0067] Since organometallic compound (G) is highly reactive with water, it is preferable to use a solvent from which water has been removed as the reaction solvent (D2). Furthermore, from the viewpoint of coordinating with organometallic compound (G) to stabilize G and facilitate the reaction, it is even more preferable to use an ether-based solvent such as a linear ether or a cyclic ether.

[0068] Examples of linear ethers include dialkyl ethers having saturated linear hydrocarbon groups with 1 to 18 carbon atoms, alkylene oxide dialkyl ethers consisting of saturated alkyl groups with 1 to 4 carbon atoms and alkylene oxide groups with 2 to 4 carbon atoms, and polyalkylene oxide dialkyl ethers consisting of repeating units of saturated alkyl groups with 1 to 4 carbon atoms and alkylene oxide groups with 2 to 4 carbon atoms.

[0069] Specifically, examples include dimethyl ether, diethyl ether, di-n-butyl ether, ethylene oxide dimethyl ether, ethylene oxide diethyl ether, ethylene oxide dibutyl ether, propylene oxide dimethyl ether, propylene oxide diethyl ether, propylene oxide dibutyl ether, butylene oxide dimethyl ether, butylene oxide diethyl ether, butylene oxide dibutyl ether, polyethylene oxide dimethyl ether, polyethylene oxide diethyl ether, polyethylene oxide dibutyl ether, polypropylene oxide dimethyl ether, polypropylene oxide diethyl ether, polypropylene oxide dibutyl ether, polybutylene oxide dimethyl ether, polybutylene oxide diethyl ether, polybutylene oxide dibutyl ether, and the like.

[0070] Examples of the cyclic ether include saturated or unsaturated cyclic ethers having 5 to 18 members, and the hydrogen atoms of the cyclic ether may be substituted with a methyl group, an ethyl group, or a propyl group.

[0071] Specific examples include tetrahydrofuran, tetrahydropyran, 1,4-dioxane, 1,3,5-trioxane, 12-crown 4-ether, 15-crown 5-ether, 18-crown 6-ether, and the like.

[0072] From the viewpoint of easy separation and recovery after the reaction of the compound (E) and the organometallic compound (G), the reaction solvent (D2) is preferably diethyl ether or tetrahydrofuran.

[0073] The amount of the reaction solvent (D2) used is not particularly limited. For example, with respect to the compound (E), if it is equal to or more than the equivalent amount (the mass ratio of D2 / E is 1.0 or more), the reaction proceeds stably while maintaining the reaction temperature, which is preferable. Further, if the mass ratio of D2 / E is 10.0 or less, the reaction can proceed at a sufficient rate. The mass ratio of D2 / E is more preferably 1.1 to 8.0 or less.

[0074] The compound (F) having a benzopyran-3-carbonyl structure is a compound represented by the general formula (5). JPEG2026062418000021.jpg35127In the formula, R 5 , R 6 and R 9 are the same as above.

[0075] Compound (F) includes 2H-1-benzopyran-3-carboxyaldehyde, 2H-1-benzopyran-3-yl-alkylmethanone, 2H-1-benzopyran-3-yl-alkylenemethanone, 2H-1-benzopyran-3-yl-cycloalkylmethanone, 2H-1-benzopyran-3-yl-arylmethanone, 2H-1-(7,8-methylenedioxybenzopyran)-3-carboxyaldehyde, 2H-1-(7,8-methylenedioxybenzopyran)-3-yl-alkylmethanone, and 2H-1-(7,8-methylenedioxybenzo Examples include pyran-3-yl alkylenemethanone, 2H-1-(7,8-methylenedioxybenzopyran)-3-ylcycloalkylmethanone, 2H-1-(7,8-methylenedioxybenzopyran)-3-ylarylmethanone, 2H-1-naphthopyran-3-carboxyaldehyde, 2H-1-naphthopyran-3-ylalkylmethanone, 2H-1-naphthopyran-3-ylalkylenemethanone, 2H-1-naphthopyran-3-ylcycloalkylmethanone, and 2H-1-naphthopyran-3-ylarylmethanone.

[0076] In particular, from the viewpoint of synthesizing compound (F) in high yield, 2H-1-benzopyran-3-yl-methylmethanone, 2H-1-benzopyran-3-yl-ethylmethanone, 2H-1-benzopyran-3-yl-(n-propyl)methanone, 2H-1-benzopyran-3-yl-(isopropyl)methanone, 2H-1-benzopyran-3-yl-(n-butyl)methanone, 2H-1-benzopyran-3-yl-arylmethanone, 2H-1-benzopyran-3-ylcyclohexanemethanone, and 2H-1-benzopyran-3-ylphenylmethanone are preferred.

[0077] A compound (F) having a benzopyran-3-carbonyl structure can be reacted with hydrogen to obtain a compound (H) having a dihydrobenzopyran-3-substituted structure represented by general formula (8). JPEG2026062418000022.jpg26127In formula, R 12 , R 13 and R 14This is the same as above.

[0078] R of compound (H) 14 Preferably, the linear hydrocarbon group is a hydrogen atom, a saturated linear hydrocarbon group having 1 to 18 carbon atoms, a saturated branched hydrocarbon group having 3 to 18 carbon atoms, or a saturated or unsaturated cyclic hydrocarbon group having 6 to 18 carbon atoms. Furthermore, the linear, branched, or cyclic hydrocarbon group may further contain fluorine, chlorine, bromine, iodine, an alkoxy or thioalkoxy group having 1 to 18 carbon atoms, an alkylene oxide group having 2 to 4 carbon atoms, or a polyalkylene oxide group having 2 to 18 repeating units of an alkylene oxide group having 2 to 4 carbon atoms.

[0079] Examples of such compounds include 3-alkyl-3,4-dihydro-benzopyran, 3-alkylene-3,4-dihydro-benzopyran, 3-cycloalkyl-3,4-dihydro-benzopyran, and 3-aryl-3,4-dihydro-benzopyran.

[0080] Specifically, as compound (H), these include 3-methyl-3,4-dihydro-benzopyran, 3-ethyl-3,4-dihydro-benzopyran, 3-butyl-3,4-dihydro-benzopyran, 3-cyclohexylmethyl-3,4-dihydro-benzopyran, 3-benzyl-3,4-dihydro-benzopyran, 3-benzyl-3,4-dihydro-7-methylbenzopyran, 3-benzyl-3,4-dihydro-6-methoxybenzopyran, 3-benzyl-3, Examples include 4-dihydro-5-methoxy-6-methylbenzopyran, 3-ethyl-3,4-dihydro-7,8-methylenedioxybenzopyran, 3-butyl-3,4-dihydro-7,8-methylenedioxybenzopyran, 3-benzyl-3,4-dihydro-7,8-methylenedioxybenzopyran, 3-ethyl-3,4-dihydro-naphthopyrane, 3-butyl-3,4-dihydro-naphthopyrane, and 3-benzyl-3,4-dihydro-naphthopyrane.

[0081] In the reaction between compound (F) and hydrogen, the reaction conditions are not particularly limited. For example, it is preferable to react with hydrogen under mild conditions that do not easily proceed with the hydrogenation of the aromatic ring, and specifically, a reaction at 1 to 5 atmospheres and 0°C to 100°C or lower is preferred.

[0082] In the above reaction, a catalyst may be used as needed. The catalyst used is not particularly limited as long as it has hydrogenation ability. Examples include metal catalysts, supported metal catalysts, and metal complex catalysts. One type may be used alone, or two or more types may be used in mixture. Examples of metal species that can be used as catalysts include lithium, nickel, palladium, platinum, rhodium, and ruthenium. Among these, nickel, palladium, and platinum are preferred.

[0083] The metal catalyst may be a single-metal catalyst or a binary-metal catalyst. The support used for the supported metal catalyst is not particularly limited. Examples include silica, alumina, silica-alumina, titania, magnesia, zeolite, and carbon, with carbon support being preferred. The method for supporting the metal on the support can be carried out by known methods.

[0084] Among these, nickel-supported carbon catalysts, palladium-supported carbon catalysts, and platinum-supported carbon catalysts are preferred.

[0085] The compound (E) having a benzopyran-3-carboxamide structure and the compound (F) having a benzopyran-3-carbonyl structure obtained by the above production method can be utilized as physiologically active substances themselves. Further, the compound (H) having a dihydrobenzopyran-3-substituted structure found in pharmacologically active natural products has a homoisoflavan skeleton and can be used as a raw material for pharmaceuticals and agricultural chemicals and a synthetic intermediate. Specifically, various substituents can be introduced into the benzopyran ring of (E), (F) and (H), and various physiologically active substances can be synthesized. In particular, by using (E), (F) and (H) and performing an oxidation reaction to introduce a carbonyl group at the 2-position of the benzopyran ring, a coumarin compound can be synthesized. By introducing a substituent at the 4-position of (E) and (F), derivatives of 3,4-dihydrobenzopyran-3-carboxamide and derivatives of 3,4-dihydrobenzopyran-3-carbonyl can be used as intermediates of physiologically active substances. Incidentally, the uses of (E), (F) and (H) are not limited to these.

Example

[0086] Hereinafter, the present invention will be described in detail with reference to examples, but these examples are merely illustrative for preferably explaining the present invention and do not limit the present invention in any way. In the following, "parts" and "%" are all based on mass unless otherwise specified.

[0087] Hereinafter, the analytical methods used in the examples and comparative examples of the present invention will be described, including the equipment and analytical conditions used. Nuclear magnetic resonance spectroscopy ( 1 H-NMR analysis) 1 The 1H-NMR analysis was performed using a 400 MHz instrument manufactured by JEOL Ltd., and the resonance frequency of the methyl group of tetramethylsilane was set to 0.

[0088] The various raw materials and reaction solvents used in the examples and comparative examples are shown below. (1) Compound (A) A-1: Salicylaldehyde A-2: 3-Methylsalicylaldehyde A-3: 4-Methylsalicyaldehyde A-4: 5-Methoxysalicyaldehyde A-5:6-Methoxysalicyaldehyde A-6: 3-t-butylsalicyaldehyde A-7:3-Methoxysalicylic acid A-8:4-Methoxysalicyaldehyde A-9:5-Methoxysalicylic acid A-10: 6-Methoxysalicylic acid A-11: 3-Fluorosalicylaldehyde A-12: 5-Fluorosalicylaldehyde A-13: 4-Chlorosalicyaldehyde A-14: 5-Chlorosalicyaldehyde A-15:3-Bromosalicylaldehyde A-16:5-Bromosalicylaldehyde A-17: 5-iodosalicylaldehyde A-18: 3,5-Dichlorosalicyaldehyde A-19: 3-bromo-5-chlorosalicyaldehyde (2) Compound (B) B-1: Acroylmorpholin B-2: Dimethylacrylamide B-3: N-isopropylacrylamide B-4: Hydroxyethylacrylamide B-5: Dimethylaminopropylacrylamide (3) Basic compounds (C) C-1: 1,4-Diazabicyclo[2.2.2]octane (pKa of conjugate acid = 8.8) C-2: Diazabicycloundecene (pKa of conjugate acid = 12.0) C-3: Sodium carbonate (pKa of conjugate acid = 10.3) C-4: Cesium carbonate (pKa of conjugate acid = 10.3) C-5: Potassium carbonate (pKa of conjugate acid = 10.3) C-6: Potassium t-butoxide (pKa of conjugate acid = 17.0) C-7: Tripotassium phosphate (pKa of conjugate acid = 12.4) (4) Reaction solvent (D) D1-1: Dimethylformamide D1-2: 1,4-dioxane D1-3: Dimethyl sulfoxide D1-4: Toluene D1-5: Ethylene glycol D1-6: Ion-exchanged water D1-7: Chloroform D2-1: Tetrahydrofuran D2-2: Diethyl ether (5) Organometallic compounds (G) or metal hydrides G1-1: Phenylmagnesium chloride 1.5M tetrahydrofuran solution G1-2: Ethyl magnesium chloride 1.5M tetrahydrofuran solution G1-3: Allyl magnesium chloride 1.5M tetrahydrofuran solution G2-1: Phenyllithium 1.5M tetrahydrofuran solution G2-2: Methyllithium 1.5M tetrahydrofuran solution G2-3: N-butyllithium 1.5M tetrahydrofuran solution G3-1: Sodium hydride 1.5M tetrahydrofuran solution

[0089] Example 1: Preparation of 2H-1-benzopyran-3-yl-4-morpholinylmethanone (E-1) Salicylaldehyde (A-1) (6.14 g, 50 mmol), acroylmorpholine (B-1) (35.29 g, 250 mmol), and 1,4-diazabicyclo[2.2.2]octane (C-1) (6.11 g, 50 mmol) were charged into a 100 mL flask and mixed. Under a nitrogen atmosphere, the mixture was heated to 100 °C with stirring and reacted at 100 °C for 18 hours. The reaction mixture was then cooled to 25 °C, extracted with ethyl acetate, and the water in the organic layer was removed with sodium sulfate. The mixture was concentrated using an evaporator to obtain a pale yellow oily product. 1¹H-NMR analysis confirmed the presence of protons derived from benzopyran (position 2: 4.89 ppm, d, 2H; position 4: 6.59 ppm, s, 1H; position 5: 6.86 ppm, d, 1H; position 6: 7.21 ppm, dd, 1H; position 7: 6.93 ppm, ddd, 1H; position 8: 7.07 ppm, dd, 1H) and protons derived from the morpholin ring (3.72 ppm, 8H), and the product was identified as the target compound 2H-1-benzopyran-3-yl-4-morpholinylmethanone (1.96 g, yield 16%) (E-1).

[0090] Examples 2-19: Preparation of Compound (E-1) The raw materials (A) (50 mmol), raw materials (B), and basic compound (C) were reacted and purified in the same manner as in Example 1, according to the charging ratio, reaction temperature, and reaction time shown in Table 1-1, to obtain compound (E-1). The identification of E-1 was carried out in the same manner as in Example 1. 1 Analysis was performed by 1H-NMR. The yields for each example are shown in Table 1-1.

[0091] Example 20: Preparation of compound (E-1) Starting material (A) (50 mmol), starting material (B), and basic compound (C) were added to a 100 mL flask connected to a Dean-Stark dehydrator in the charging ratios shown in Table 1-1, and mixed. The reaction was carried out under a nitrogen atmosphere with stirring at 110°C for 18 hours, while dehydrating. Subsequently, the compound (E-1) was obtained in the yield shown in Table 1-1 by purification in the same manner as in Example 1. Identification of E-1 was performed in the same manner as in Example 1. 1 This was performed by 1H-NMR analysis.

[0092] Examples 21-26: Preparation of Compound (E-1) The starting material (A) (50 mmol), starting material (B), basic compound (C), and reaction solvent (D1) (25 mL) were reacted and purified under the conditions shown in Table 1-1, in the same manner as in Example 1, to obtain compound (E-1) in the yield shown in Table 1-1. The identification of E-1 was carried out in the same manner as in Example 1. 1 This was performed by 1H-NMR analysis.

[0093] Example 27 Preparation of compound (E-2) Starting material (A) (1 mmol), starting material (B), and basic compound (C) were reacted and purified in the same manner as in Example 1, according to the charging ratio, reaction temperature, and reaction time shown in Table 1-2, to obtain compound (E-2) in the yield shown in Table 1-2. Identification of E-2 was carried out in the same manner as in Example 1. 1 ¹H-NMR analysis confirmed the presence of protons derived from benzopyran (position 2: 4.90 ppm, d, 2H; position 4: 6.60 ppm, s, 1H; position 5: 7.06 ppm, dd, 1H; position 6: 6.91 ppm, td, 1H; position 7: 6.19 ppm, td, 1H; position 8: 6.85 ppm, d, 1H) and a proton from the methyl group of the dimethylamide group (3.11 ppm, brs, 6H). The product was confirmed to be the target compound N,N-dimethyl-2H-1-benzopyran-3-carboxamide (41 mg, yield 20%) (E-2).

[0094] Example 28: Preparation of Compound (E-3) Starting material (A) (1 mmol), starting material (B), and basic compound (C) were reacted and purified in the same manner as in Example 1, according to the charging ratio, reaction temperature, and reaction time shown in Table 1-2, to obtain compound (E-3) in the yield shown in Table 1-2. Identification of E-3 was carried out in the same manner as in Example 1. 1 ¹H-NMR analysis confirmed the presence of protons derived from benzopyran (position 2: 5.00 ppm, d, 2H; position 4: 6.90 ppm, s, 1H; position 5: 7.08 ppm, dd, 1H; position 6: 6.92 ppm, td, 1H; position 7: 7.20 ppm, td, 1H; position 8: 6.84 ppm, d, 1H) and protons of the isopropylamide group (methyl group: 1.23 ppm, d, 6H; methine group: 4.18 ppm, m, 1H). The product was confirmed to be the target compound N-isopropyl-2H-1-benzopyran-3-carboxamide (42 mg, yield 20%) (E-3).

[0095] Example 29 Preparation of compound (E-4) Starting material (A) (1 mmol), starting material (B), and basic compound (C) were reacted and purified in the same manner as in Example 1, according to the charging ratio, reaction temperature, and reaction time shown in Table 1-2, to obtain compound (E-4) in the yield shown in Table 1-2. Identification of E-4 was carried out in the same manner as in Example 1.1 ¹H-NMR analysis confirmed the presence of protons derived from benzopyran (position 2: 5.01 ppm, d, 2H; position 4: 7.00 ppm, s, 1H; position 5: 7.10 ppm, dd, 1H; position 6: 6.92 ppm, td, 1H; position 7: 7.22 ppm, td, 1H; position 8: 6.85 ppm, d, 1H) and protons from the methylene group of the hydroxyethylamide group (methylene group adjacent to the hydroxyl group: 3.81 ppm, t, 2H; methylene group adjacent to the amide group: 3.56 ppm, dd, 2H). The product was confirmed to be the target compound N-hydroxyethyl-2H-1-benzopyran-3-carboxamide (52 mg, yield 24%) (E-4).

[0096] Example 30: Preparation of compound (E-5) Starting material (A) (1 mmol), starting material (B), and basic compound (C) were reacted and purified in the same manner as in Example 1, according to the charging ratio, reaction temperature, and reaction time shown in Table 1-2, to obtain compound (E-5) in the yield shown in Table 1-2. Identification of E-5 was carried out in the same manner as in Example 1. 1 ¹H-NMR analysis confirmed the presence of protons derived from benzopyran (position 2: 4.99 ppm, d, 2H; position 4: 6.99 ppm, s, 1H; position 5: 7.08 ppm, dd, 1H; position 6: 6.91 ppm, td, 1H; position 7: 7.19 ppm, td, 1H; position 8: 6.84 ppm, d, 1H) and protons of the dimethylaminopropylamide group (methyl group: 2.30 ppm, s, 6H; methylene group adjacent to amide group: 3.48 ppm, dd, 2H; methylene group adjacent to amino group: 2.50 ppm, t, 2H; methylene group: 1.72 ppm, dt, 2H). The product was confirmed to be the target compound N-(N,N-dimethylaminopropyl)-2H-1-benzopyran-3-carboxamide (25 mg, yield 10%) (E-5).

[0097] Example 31: Preparation of compound (E-5) The raw materials (A) (1 mmol) and (B) were reacted and purified in the same manner as in Example 1, according to the charging ratio, reaction temperature, and reaction time shown in Table 1-2, to obtain compound (E-5) in the yield shown in Table 1-2. The identification of E-5 was performed in the same manner as in Example 1. 1This was performed by 1H-NMR analysis.

[0098] Examples 32-40: Preparation of compounds (E-6)-(E-14) Starting material (A) (50 mmol), starting material (B), and basic compound (C) were reacted and purified under the conditions shown in Table 2-1 in the same manner as in Example 1, yielding pale yellow oily products. 1 ¹H-NMR analysis confirmed that the products obtained in Examples 22-36 were the target compounds. 1 The results of the 1H-NMR analysis are shown in Table 3.

[0099] Examples 32-40: Preparation of compounds (E-6)-(E-14) Starting material (A) (50 mmol), starting material (B), and basic compound (C) were reacted and purified under the conditions shown in Table 2-1 in the same manner as in Example 1, yielding pale yellow oily products. 1 ¹H-NMR analysis confirmed that the products obtained in Examples 22-36 were the target compounds. 1 The results of the 1H-NMR analysis are shown in Table 3.

[0100] Examples 41-49: Preparation of compounds (E-15)-(E-23) Starting material (A) (50 mmol), starting material (B), and basic compound (C) were reacted and purified under the conditions shown in Table 2-2, in the same manner as in Example 1, to obtain pale yellow oily products. 1 ¹H-NMR analysis confirmed that the products obtained in Examples 22-36 were the target compounds. 1 The results of the 1H-NMR analysis are shown in Table 3.

[0101] [Table 1-1]

[0102] [Table 1-2]

[0103] [Table 2-1]

[0104] [Table 2-2]

[0105] [Table 3]

[0106] Comparative Example 1 Salicylaldehyde (A-1) (6.14 g, 50 mmol), morpholinamide propionate (35.19 g, 250 mmol), and potassium carbonate (C-3) (6.91 g, 50 mmol) were charged into a 100 mL flask and mixed. Under a nitrogen atmosphere, the mixture was heated to 130 °C with stirring and reacted at 130 °C for 18 hours. The reaction mixture was then cooled to 25 °C, extracted with ethyl acetate, and the water in the organic layer was removed with sodium sulfate. The mixture was concentrated using an evaporator to obtain a pale yellow liquid. The pale yellow liquid was 1 H-NMR analysis identified it as salicylaldehyde (A-1), and compound (E), which has a benzopyran-3-carboxylic acid amide structure, was not produced.

[0107] Comparative Example 2 2H-1-benzopyran-3-carbonitride (7.86 g, 50 mmol), acroylmorpholine (B-1) (35.29 g, 250 mmol), and potassium carbonate (C-3) (6.91 g, 50 mmol) were charged into a 100 mL flask and mixed. Under a nitrogen atmosphere, the mixture was heated to 130°C with stirring and reacted at 130°C for 18 hours. The reaction solution was then cooled to 25°C, extracted with ethyl acetate, and the water in the organic layer was removed with sodium sulfate. The mixture was concentrated using an evaporator to obtain a pale yellow solid. The pale yellow solid was 1¹H-NMR analysis identified the compound as a mixture of 2H-1-benzopyran-3-carbonitride and 2H-1-benzopyran-3-carboxyacid, and compound (E) having a benzopyran-3-carboxylic acid amide structure was not formed.

[0108] Example 50: Preparation of compound (F-1) 2H-1-benzopyran-3-yl-4-morpholinylmethanone (E-1) (4.91 g, 20 mmol) and tetrahydrofuran (D2-1) (50 mL) were added to a 300 mL flask. While stirring, a solution of D2-1 in 1.5 M phenylmagnesium chloride (G1-1) (40 mL, equivalent to 60 mmol of G1-1) was added dropwise to the flask, and the mixture was reacted under a nitrogen atmosphere at 25°C for 2 hours. Then, ammonium chloride (3.21 g, 60 mmol) was added and mixed. After adding 200 mL of ethyl acetate, the mixture was washed with deionized water (200 mL) and saturated saline (200 mL). The organic layer was separated, and the water in the organic layer was removed with Glauber's salt. The mixture was purified by column chromatography. The reaction solvent was removed under reduced pressure to obtain a yellow oily product (0.80 g). 1 ¹H-NMR analysis confirmed the presence of protons derived from benzopyran (position 2: 5.17 ppm, d, 2H; position 4: 7.12 ppm, s, 1H; position 5: 7.10 ppm, dd, 1H; position 6: 6.95 ppm, td, 1H; position 7: 7.28 ppm, td, 1H; position 8: 6.91 ppm, d, 1H) and protons derived from the phenyl group (7.50-7.72 ppm, 5H), confirming that the product was 2H-1-benzopyran-3-ylphenylmethanone (F-1). The yield was 17%.

[0109] Examples 51 and 52: Preparation of compounds (F-2) and (F-3) Using the raw materials (E), (G), and reaction solvent (D2) shown in Table 4, the reactions and purifications of Examples 51 and 52 were carried out in the same manner as in Example 50 under the conditions shown in Table 4, yielding pale yellow oily products. 1¹H-NMR analysis confirmed that Example 51 yielded 2H-1-benzopyran-3-ylethylmethanone (F-2) and Example 52 yielded 2H-1-benzopyran-3-ylallylmethanone (F-3). Table 4 shows the yields for each. F-2: The presence of protons derived from benzopyran (position 2: 5.02 ppm, d, 2H; position 4: 7.32 ppm, s, 1H; position 5: 7.16 ppm, dd, 1H; position 6: 6.94 ppm, td, 1H; position 7: 7.26 ppm, td, 1H; H-8: 6.86 ppm, d, 1H), protons derived from methylene (2.79 ppm, q, 2H) from the ethyl group, and protons derived from methyl (1.17 ppm, t, 3H) was confirmed. F-3: The presence of protons derived from benzopyran (position 2: 5.01 ppm, d, 2H; position 4: 7.35 ppm, s, 1H; position 5: 7.17 ppm, dd, 1H; position 6: 6.95 ppm, td, 1H; position 7: 7.28 ppm, td, 1H; position 8: 6.86 ppm, d, 1H) and protons derived from the allyl group (3.55 ppm, dt, 2H; 6.01 ppm, ddt, 1H; 5.23 ppm, ddd, 2H; 5.20 ppm, ddd, 1H) was confirmed.

[0110] Example 53: Preparation of compound (F-1) Compound (E-1) (4.91 g, 20 mmol) and reaction solvent (D2-1) (50 mL) were added to a 300 mL flask. While stirring, a solution of 1.5 M phenyllithium (G2-1) in D2-1 (26.7 mL, equivalent to 40 mmol of G2-1) was added dropwise to the flask. The reaction was carried out under a nitrogen atmosphere at -78 °C for 2 hours. After the reaction mixture was allowed to return to room temperature, ammonium chloride (3.21 g, 40 mmol) was added and mixed. After adding 200 mL of ethyl acetate, the mixture was washed with deionized water (200 mL) and saturated brine (200 mL), and the organic layer was separated. Then, the water in the organic layer was removed with sodium sulfate, and the mixture was purified by column chromatography. The reaction solvent was then removed under reduced pressure to obtain a yellow oily product. 1 1H-NMR analysis confirmed that the product was compound (F-1). The yield was 68%.

[0111] Examples 54 and 55: Preparation of compounds (F-4) and (F-5) Using raw materials (E), (G), and reaction solvent (D2), the reaction and purification were carried out in the same manner as in Example 53 under the conditions shown in Table 4, and Examples 54 and 55 each yielded a pale yellow oily product. 1 ¹H-NMR analysis confirmed that Example 54 yielded 2H-1-benzopyran-3-yl-methylmethanone (F-4), and Example 55 yielded 2H-1-benzopyran-3-yl-butylmethanone (F-5). Table 4 shows the yields for each. F-4: The presence of protons derived from benzopyran (position 2: 5.01 ppm, d, 2H; position 4: 7.31 ppm, s, 1H; position 5: 7.17 ppm, dd, 1H; position 6: 6.94 ppm, td, 1H; position 7: 7.26 ppm, ddd, 1H; H-8: 6.86 ppm, d, 1H) and protons derived from the methyl group (2.41 ppm, s, 3H) was confirmed. F-5: The presence of protons derived from benzopyran (position 2: 5.01 ppm, d, 2H; position 4: 7.31 ppm, s, 1H; position 5: 7.17 ppm, dd, 1H; position 6: 6.94 ppm, dd, 1H; position 7: 7.26 ppm, ddd, 1H; position 8: 6.86 ppm, d, 1H) and protons derived from the butyl group (2.77 ppm, t, 2H; 1.67 ppm, dd, 2H; 1.38 ppm, dd, 2H; 0.95 ppm, t, 3H) was confirmed.

[0112] Example 56: Preparation of compound (F-6) Compound (E-2) (4.06 g, 20 mmol) and reaction solvent (D2-1) (50 mL) were added to a 300 mL flask. While stirring, a dispersion of 1.5 M sodium hydride (G3-1) in D2-1 (40.0 mL, equivalent to 60 mmol of G3-1) and a dispersion of 1.5 M sodium iodide in D2-1 (13.3 mL, equivalent to 20 mmol of sodium iodide) were added dropwise to the flask, and the reaction was carried out at 40°C for 20 hours under a nitrogen atmosphere. Then, 100 mL of deionized water at 0°C was added. After adding 200 mL of ethyl acetate, the mixture was washed with deionized water (200 mL) and saturated saline (200 mL), and the organic layer was separated. Subsequently, the water in the organic layer was removed with Glauber's salt, and the mixture was purified by column chromatography. After that, the solvent was removed under reduced pressure to obtain a yellow oily product. 1 ¹H-NMR analysis confirmed the presence of protons derived from benzopyran (position 2: 4.90 ppm, s, 2H; position 4: 7.60 ppm, s, 1H; position 5: 7.33 ppm, d, 1H; position 6: 6.95 ppm, t, 1H; position 7: 7.37 ppm, t, 1H; position 8: 6.82 ppm, d, 1H) and protons derived from the aldehyde group (9.55 ppm, s, 1H), confirming that the product was 2H-1-benzopyran-3-carboxyaldehyde (F-6). The yield was 75%.

[0113] [Table 4]

[0114] Example 57: Preparation of compound (H-1) Compound (F-1) (2.36 g, 10 mmol), palladium-activated carbon (containing 10% Pd) (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) (35 mg) as a catalyst, and reaction solvent (D2-1) (35 mL) were added to a 100 mL flask and reacted under a hydrogen atmosphere at 25 °C for 48 hours with stirring. After filtering the reaction mixture to remove the catalyst, the reaction solvent was removed under reduced pressure and the product was purified by column chromatography. The reaction solvent was removed under reduced pressure to obtain a yellow, oily product. 1¹H-NMR analysis confirmed the presence of protons derived from benzopyran (position 2: 3.83-4.19 ppm, ddd, 2H; position 3: 2.26-2.40, m, 1H; position 4: 2.53-2.80 ppm, ddd, 2H; position 5: 7.00 ppm, d, 1H; position 6: 6.84 ppm, dd, 1H; position 7: 7.08 ppm, td, 1H; position 8: 6.80 ppm, dd, 1H) and protons derived from the benzyl group (methylene group: 2.63-2.72 ppm, 2H; phenyl group: 7.17-7.32, 5H), confirming that the product is 3-benzyl-3,4-dihydro-benzopyran (H-1). The yield was 32%. Industrial applicability

[0115] The compounds (E) having a benzopyran-3-carboxylic acid amide structure, (F) having a benzopyran-3-carbonyl structure, and (H) having a dihydrobenzopyran-3-substituted structure of the present invention have potential for use as physiologically active substances and can be suitably used as intermediates for physiologically active substances. These compounds can be produced in a short process. Furthermore, the compounds having a benzopyran-3-carboxylic acid amide structure are novel compounds and can be suitably used as intermediates for pharmaceuticals, agrochemicals, and the like.

Claims

1. A method for producing a compound having a benzopyran-3-carboxylic acid amide structure as shown in general formula (3), by reacting a compound having a salicylaldehyde structure as shown in general formula (1) with a compound having an acrylamide structure as shown in general formula (2). (R １ and R ２ R is attached to any position between positions 3 and 6 of general formula (1) or between positions 5 and 8 of general formula (3). In each formula, R １ and R ２ Each of these independently represents a hydrogen atom, fluorine, chlorine, bromine, iodine, a saturated linear hydrocarbon group having 1 to 36 carbon atoms, an unsaturated linear hydrocarbon group having 2 to 36 carbon atoms, a saturated or unsaturated branched hydrocarbon group having 3 to 36 carbon atoms, an alkylcarboxyl group having 1 to 36 carbon atoms, an alkylcarboxyamide group having 1 to 36 carbon atoms, an alkyl ester group having 1 to 36 carbon atoms, an alkylamide group having 1 to 36 carbon atoms, an alkylthiol group having 1 to 36 carbon atoms, a thioalkoxy group having 1 to 36 carbon atoms, an alkoxy group having 1 to 36 carbon atoms, a carboalkoxy group having 2 to 4 carbon atoms, an alkylene oxide group having 2 to 18 repeating units, or an alkoxy group having 1 to 36 carbon atoms (a polyalkylene oxide having 2 to 18 repeating units of an alkylene oxide group having 2 to 4 carbon atoms). １ and R ２ These may join with one side of the benzene ring supporting them to form a 5-12 member saturated or unsaturated ring, and the carbon atoms other than the one side of the benzene ring of the formed ring may be substituted with heteroatoms, and the hydrogen atoms of the ring may be substituted with a saturated linear hydrocarbon group having 1-6 carbon atoms or an alkoxy group having 1-6 carbon atoms. R ３ and R ４ each independently represents a hydrogen atom, a saturated straight-chain hydrocarbon group having 1 to 18 carbon atoms, an unsaturated straight-chain hydrocarbon group having 2 to 18 carbon atoms, a saturated or unsaturated branched hydrocarbon group having 3 to 18 carbon atoms, a saturated or unsaturated cyclic hydrocarbon group having 6 to 18 carbon atoms, a primary, secondary or tertiary aminoalkyl group having 1 to 18 carbon atoms, a hydroxyalkyl group having 1 to 18 carbon atoms, an alkyl (having 1 to 18 carbon atoms) carbonyl alkylene (having 1 to 8 carbon atoms) group. R ３ and R ４ together with the nitrogen atom carrying them form a 5- to 18-membered saturated or unsaturated ring (the atoms forming the ring may have 1 to 6 heteroatoms, and the hydrogen atoms of the ring may be substituted with a saturated straight-chain hydrocarbon group having 1 to 6 carbon atoms or a saturated alkoxy group having 1 to 6 carbon atoms.) (including).)

2. A method for producing a compound having a benzopyran-3-carboxylic acid amide structure according to claim 1, wherein the reaction is carried out in the presence of a basic compound.

3. A method for producing a compound having a benzopyran-3-carboxylic acid amide structure according to claim 2, wherein the basic compound has a pKa value of 8.0 to 18.0 for its conjugate acid.

4. A method for producing a compound having a benzopyran-3-carboxylic acid amide structure according to claim 2 or 3, wherein the basic compound is an organic basic compound, an inorganic basic compound, an organic-inorganic hybrid basic compound, a basic ion exchange resin, or a mixture thereof.

5. A method for producing a compound having a benzopyran-3-carboxylic acid amide structure according to any one of claims 2 to 4, wherein the basic compound is one or more metal salts selected from alkali metal salts and alkaline earth metal salts.

6. A method for producing a compound having a benzopyran-3-carboxylic acid amide structure according to any one of claims 1 to 5, wherein the reaction temperature is 40 to 150°C.

7. A method for producing a compound having a benzopyran-3-carboxylic acid amide structure according to any one of claims 1 to 6, carried out in the presence of a reaction solvent.

8. A compound having the benzopyran-3-carboxylic acid amide structure shown in general formula (4). (R ５ and R ６ R is attached to any position between positions 5 and 8 in general formula (4). In the formula, R ５ and R ６ Each of these independently represents a hydrogen atom, fluorine, chlorine, bromine, iodine, a saturated linear hydrocarbon group having 1 to 36 carbon atoms, an unsaturated linear hydrocarbon group having 2 to 36 carbon atoms, a saturated or unsaturated branched hydrocarbon group having 3 to 36 carbon atoms, an alkylcarboxyl group having 1 to 36 carbon atoms, an alkylcarboxyamide group having 1 to 36 carbon atoms, an alkyl ester group having 1 to 36 carbon atoms, an alkylamide group having 1 to 36 carbon atoms, an alkylthiol group having 1 to 36 carbon atoms, a thioalkoxy group having 1 to 36 carbon atoms, an alkoxy group having 1 to 36 carbon atoms, a carboalkoxy group having 2 to 4 carbon atoms, an alkylene oxide group having 2 to 18 repeating units, or an alkoxy group having 1 to 36 carbon atoms (a polyalkylene oxide having 2 to 18 repeating units of an alkylene oxide group having 2 to 4 carbon atoms). ５ and R ６ These may join with one side of the benzene ring supporting them to form a 5-12 member saturated or unsaturated ring, and the carbon atoms other than the one side of the benzene ring of the formed ring may be substituted with heteroatoms, and the hydrogen atoms of the ring may be substituted with a saturated linear hydrocarbon group having 1-6 carbon atoms or an alkoxy group having 1-6 carbon atoms. R ７ and R ８ Each of these independently represents a hydrogen atom, a saturated linear hydrocarbon group having 1 to 18 carbon atoms, an unsaturated linear hydrocarbon group having 2 to 18 carbon atoms, a saturated or unsaturated branched hydrocarbon group having 3 to 18 carbon atoms, a saturated or unsaturated cyclic hydrocarbon group having 6 to 18 carbon atoms, a primary, secondary, or tertiary aminoalkyl group having 1 to 18 carbon atoms, a hydroxyalkyl group having 1 to 18 carbon atoms, or an alkyl (1 to 18 carbon atoms) carbonylalkylene (1 to 8 carbon atoms) group. ７ and R ８ This includes a ring formed by these elements together with supporting nitrogen atoms, creating a saturated or unsaturated ring of 5 to 18 members (the ring-forming atoms may have 1 to 6 heteroatoms, and the hydrogen atoms of the ring may be substituted with saturated linear hydrocarbon groups having 1 to 6 carbon atoms or saturated alkoxy groups having 1 to 6 carbon atoms).

9. A method for producing a compound having a benzopyran-3-carbonyl structure shown in general formula (5), by reacting a compound having a benzopyran-3-carboxylic acid amide structure as described in claim 8 with an organometallic compound. (R ５ and R ６ R is attached to any position between positions 5 and 8 in general formula (5). In the formula, R ５ and R ６ This is the same as above. R ９ (wherein 1 represents a hydrogen atom, a saturated linear hydrocarbon group having 1 to 18 carbon atoms, an unsaturated linear hydrocarbon group having 2 to 18 carbon atoms, a saturated or unsaturated branched hydrocarbon group having 3 to 18 carbon atoms, or a saturated or unsaturated cyclic hydrocarbon group having 6 to 18 carbon atoms.) Furthermore, the linear, branched, or cyclic hydrocarbon group may also contain fluorine, chlorine, bromine, iodine, an alkoxy group having 1 to 18 carbon atoms, a thioalkoxy group having 1 to 18 carbon atoms, an alkylene oxide group having 2 to 4 carbon atoms, or a polyalkylene oxide group having 2 to 18 repeating units of an alkylene oxide group having 2 to 4 carbon atoms.

10. A method for producing a compound having a benzopyran-3-carbonyl structure according to claim 9, wherein the organometallic compound is an organometallic compound containing one or more metals selected from lithium, sodium, magnesium, aluminum, zinc, bismuth, and germanium.

11. A method for producing a compound having a benzopyran-3-carbonyl structure according to claim 9 or 10, comprising reacting a compound having a benzopyran-3-carboxylic acid amide structure with an organomagnesium halide represented by general formula (6). (In the formula, R １０ X represents a saturated linear hydrocarbon group having 1 to 18 carbon atoms, an unsaturated linear hydrocarbon group having 2 to 18 carbon atoms, a saturated or unsaturated branched hydrocarbon group having 3 to 18 carbon atoms, or a saturated or unsaturated cyclic hydrocarbon group having 6 to 18 carbon atoms. Furthermore, the linear, branched, or cyclic hydrocarbon group may further contain fluorine, chlorine, bromine, iodine, an alkoxy group having 1 to 18 carbon atoms, a thioalkoxy group having 1 to 18 carbon atoms, an alkylene oxide group having 2 to 4 carbon atoms, or a polyalkylene oxide group having 2 to 18 repeating units of an alkylene oxide group having 2 to 4 carbon atoms. (X represents a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.)

12. A method for producing a compound having a benzopyran-3-carbonyl structure according to claim 9 or 10, comprising reacting a compound having a benzopyran-3-carboxylic acid amide structure with an organolithium represented by general formula (7). (In the formula, R １１ (wherein represents a saturated linear hydrocarbon group having 1 to 18 carbon atoms, an unsaturated linear hydrocarbon group having 2 to 18 carbon atoms, a saturated or unsaturated branched hydrocarbon group having 3 to 18 carbon atoms, or a saturated or unsaturated cyclic hydrocarbon group having 6 to 18 carbon atoms. The linear, branched, or cyclic hydrocarbon group may further contain an alkoxy group or thioalkoxy group having 1 to 18 carbon atoms, an alkylene oxide group having 2 to 4 carbon atoms, or a polyalkylene oxide group having 2 to 18 repeating units of an alkylene oxide group having 2 to 4 carbon atoms.)

13. A method for producing a compound having a benzopyran-3-carbonyl structure according to any one of claims 9 to 12, characterized in that the method is carried out in an ether-based solvent.

14. A method for producing a compound having a benzopyran-3-carbonyl structure according to any one of claims 13, wherein the ether solvent is a linear ether and / or a cyclic ether.

15. A method for producing a compound having a benzopyran-3-carbonyl structure according to any one of claims 9 to 14, wherein the reaction temperature is -100°C to 60°C.

16. A method for producing a compound having a dihydrobenzopyran-3-substituted structure as described in general formula (8), by reacting a compound having a benzopyran-3-carbonyl structure as described in claim 9 with hydrogen. (R １２ and R １３ R is attached to any position between positions 5 and 8 in general formula (8). In the formula, R １２ and R １３ Each of these independently represents a hydrogen atom, fluorine, chlorine, bromine, iodine, a saturated linear hydrocarbon group having 1 to 36 carbon atoms, an unsaturated linear hydrocarbon group having 2 to 36 carbon atoms, a saturated or unsaturated branched hydrocarbon group having 3 to 36 carbon atoms, an alkylcarboxyl group having 1 to 36 carbon atoms, an alkylcarboxyamide group having 1 to 36 carbon atoms, an alkyl ester group having 1 to 36 carbon atoms, an alkylamide group having 1 to 36 carbon atoms, an alkylthiol group having 1 to 36 carbon atoms, a thioalkoxy group having 1 to 36 carbon atoms, an alkoxy group having 1 to 36 carbon atoms, a carboalkoxy group having 2 to 4 carbon atoms, an alkylene oxide group having 2 to 18 repeating units, or an alkoxy group having 1 to 36 carbon atoms (a polyalkylene oxide having 2 to 18 repeating units of an alkylene oxide group having 2 to 4 carbon atoms). １２ and R １３ These may join with one side of the benzene ring supporting them to form a 5-12 member saturated or unsaturated ring, and the carbon atoms other than the one side of the benzene ring of the formed ring may be substituted with heteroatoms, and the hydrogen atoms of the ring may be substituted with a saturated linear hydrocarbon group having 1-6 carbon atoms or an alkoxy group having 1-6 carbon atoms. R １４ (wherein 1 represents a hydrogen atom, a saturated linear hydrocarbon group having 1 to 18 carbon atoms, a saturated branched hydrocarbon group having 3 to 18 carbon atoms, or a saturated or unsaturated cyclic hydrocarbon group having 6 to 18 carbon atoms.) Furthermore, the linear, branched, or cyclic hydrocarbon group may further contain fluorine, chlorine, bromine, iodine, an alkoxy or thioalkoxy group having 1 to 18 carbon atoms, an alkylene oxide group having 2 to 4 carbon atoms, or a polyalkylene oxide group having 2 to 18 repeating units of an alkylene oxide group having 2 to 18 carbon atoms.

17. A method for producing a compound having a benzopyran-3-carbonyl structure as shown in general formula (12), by reacting a compound having a salicylaldehyde structure as shown in general formula (9) with a compound having an acrylamide structure as shown in general formula (10) to obtain a compound having a benzopyran-3-carboxylic acid amide structure as shown in general formula (11), and then reacting the obtained compound having a benzopyran-3-carboxylic acid amide structure with an organometallic compound. (In each formula, R １５ and R １６ It is attached to any position in positions 3-6 of general formula (9), positions 5-8 of general formula (11), or positions 5-8 of general formula (12). １５ and R １６ Each of these independently represents a hydrogen atom, fluorine, chlorine, bromine, iodine, a saturated linear hydrocarbon group having 1 to 36 carbon atoms, an unsaturated linear hydrocarbon group having 2 to 36 carbon atoms, a saturated or unsaturated branched hydrocarbon group having 3 to 36 carbon atoms, an alkylcarboxyl group having 1 to 36 carbon atoms, an alkylcarboxyamide group having 1 to 36 carbon atoms, an alkyl ester group having 1 to 36 carbon atoms, an alkylamide group having 1 to 36 carbon atoms, an alkylthiol group having 1 to 36 carbon atoms, a thioalkoxy group having 1 to 36 carbon atoms, an alkoxy group having 1 to 36 carbon atoms, a carboalkoxy group having 2 to 4 carbon atoms, an alkylene oxide group having 2 to 18 repeating units, or an alkoxy group having 1 to 36 carbon atoms (a polyalkylene oxide having 2 to 18 repeating units of an alkylene oxide group having 2 to 4 carbon atoms). １５ and R １６ These may join with one side of the benzene ring supporting them to form a 5-12 member saturated or unsaturated ring, and the carbon atoms other than the one side of the benzene ring of the formed ring may be substituted with heteroatoms, and the hydrogen atoms of the ring may be substituted with a saturated linear hydrocarbon group having 1-6 carbon atoms or an alkoxy group having 1-6 carbon atoms. R １７ and R １８ Each of these independently represents a hydrogen atom, a saturated linear hydrocarbon group having 1 to 18 carbon atoms, an unsaturated linear hydrocarbon group having 2 to 18 carbon atoms, a saturated or unsaturated branched hydrocarbon group having 3 to 18 carbon atoms, a saturated or unsaturated cyclic hydrocarbon group having 6 to 18 carbon atoms, a primary, secondary, or tertiary aminoalkyl group having 1 to 18 carbon atoms, a hydroxyalkyl group having 1 to 18 carbon atoms, or an alkyl (1 to 18 carbon atoms) carbonylalkylene (1 to 8 carbon atoms) group. １７ and R １８ These, together with the supporting nitrogen atoms, form a saturated or unsaturated ring of 5 to 18 members (the atoms forming the ring may have 1 to 6 heteroatoms, and the hydrogen atoms of the ring may be substituted with a saturated linear hydrocarbon group having 1 to 6 carbon atoms or a saturated alkoxy group having 1 to 6 carbon atoms). R １９ (wherein 1 represents a hydrogen atom, a saturated linear hydrocarbon group having 1 to 18 carbon atoms, an unsaturated linear hydrocarbon group having 2 to 18 carbon atoms, a saturated or unsaturated branched hydrocarbon group having 3 to 18 carbon atoms, or a saturated or unsaturated cyclic hydrocarbon group having 6 to 18 carbon atoms.) Furthermore, the linear, branched, or cyclic hydrocarbon group may also contain fluorine, chlorine, bromine, iodine, an alkoxy group having 1 to 18 carbon atoms, a thioalkoxy group having 1 to 18 carbon atoms, an alkylene oxide group having 2 to 4 carbon atoms, or a polyalkylene oxide group having 2 to 18 repeating units of an alkylene oxide group having 2 to 4 carbon atoms.

18. A method for producing a compound having a salicylaldehyde structure shown in general formula (13) and an acrylamide structure shown in general formula (14) by reacting them to obtain a compound having a benzopyran-3-carboxylic acid amide structure shown in general formula (15); reacting the obtained compound having a benzopyran-3-carboxylic acid amide structure with an organometallic compound to obtain a compound having a benzopyran-3-carbonyl structure shown in general formula (16); and reacting the obtained compound having a benzopyran-3-carbonyl structure with hydrogen to produce a compound having a dihydrobenzopyran-3-substituted structure shown in general formula (17). (In each formula, R ２０ and R ２１ It is coupled to any position in the 3rd to 6th positions of general formula (13) or in the 5th to 8th positions of general formulas (15) and (16). ２０ and R ２１ Each of the following independently represents a hydrogen atom, fluorine, chlorine, bromine, iodine, a saturated linear hydrocarbon group having 1 to 36 carbon atoms, an unsaturated linear hydrocarbon group having 2 to 36 carbon atoms, a saturated or unsaturated branched hydrocarbon group having 3 to 36 carbon atoms, an alkyl carboxyl group having 1 to 36 carbon atoms, an alkyl carboxyamide group having 1 to 36 carbon atoms, an alkyl ester group having 1 to 36 carbon atoms, an alkylamide group having 1 to 36 carbon atoms, an alkylthiol group having 1 to 36 carbon atoms, a thioalkoxy group having 1 to 36 carbon atoms, an alkoxy group having 1 to 36 carbon atoms, a carboalkoxy group having 2 to 4 carbon atoms, an alkylene oxide group having 2 to 18 repeating units, or an alkoxy group having 1 to 36 carbon atoms (a polyalkylene oxide having 2 to 18 repeating units of an alkylene oxide group having 2 to 4 carbon atoms). ２０ and R ２１ These may join with one side of the benzene ring supporting them to form a 5-12 member saturated or unsaturated ring, and the carbon atoms other than the one side of the benzene ring of the formed ring may be substituted with heteroatoms, and the hydrogen atoms of the ring may be substituted with a saturated linear hydrocarbon group having 1-6 carbon atoms or an alkoxy group having 1-6 carbon atoms. R ２２ and R ２３ Each of these independently represents a hydrogen atom, a saturated linear hydrocarbon group having 1 to 18 carbon atoms, an unsaturated linear hydrocarbon group having 2 to 18 carbon atoms, a saturated or unsaturated branched hydrocarbon group having 3 to 18 carbon atoms, a saturated or unsaturated cyclic hydrocarbon group having 6 to 18 carbon atoms, a primary, secondary, or tertiary aminoalkyl group having 1 to 18 carbon atoms, a hydroxyalkyl group having 1 to 18 carbon atoms, or an alkyl (1 to 18 carbon atoms) carbonylalkylene (1 to 8 carbon atoms) group. ２２ and R ２３ These include a 5-18 member saturated or unsaturated ring formed together with supporting nitrogen atoms (the atoms forming the ring may have 1-6 heteroatoms, and the hydrogen atoms of the ring may be substituted with a saturated linear hydrocarbon group having 1-6 carbon atoms or a saturated alkoxy group having 1-6 carbon atoms). R ２４ The first element represents a hydrogen atom, a saturated linear hydrocarbon group having 1 to 18 carbon atoms, an unsaturated linear hydrocarbon group having 2 to 18 carbon atoms, a saturated or unsaturated branched hydrocarbon group having 3 to 18 carbon atoms, or a saturated or unsaturated cyclic hydrocarbon group having 6 to 18 carbon atoms. Furthermore, the linear, branched, or cyclic hydrocarbon group may further contain fluorine, chlorine, bromine, iodine, an alkoxy group having 1 to 18 carbon atoms, a thioalkoxy group having 1 to 18 carbon atoms, an alkylene oxide group having 2 to 4 carbon atoms, or a polyalkylene oxide group having 2 to 18 repeating units of an alkylene oxide group having 2 to 4 carbon atoms. R ２５ and R ２６ R is attached to any position from the 5th to the 8th position in general formula (17). ２５ and R ２６ Each of these independently represents a hydrogen atom, fluorine, chlorine, bromine, iodine, a saturated linear hydrocarbon group having 1 to 36 carbon atoms, an unsaturated linear hydrocarbon group having 2 to 36 carbon atoms, a saturated or unsaturated branched hydrocarbon group having 3 to 36 carbon atoms, an alkylcarboxyl group having 1 to 36 carbon atoms, an alkylcarboxyamide group having 1 to 36 carbon atoms, an alkyl ester group having 1 to 36 carbon atoms, an alkylamide group having 1 to 36 carbon atoms, an alkylthiol group having 1 to 36 carbon atoms, a thioalkoxy group having 1 to 36 carbon atoms, an alkoxy group having 1 to 36 carbon atoms, a carboalkoxy group having 2 to 4 carbon atoms, an alkylene oxide group having 2 to 18 repeating units, or an alkoxy group having 1 to 36 carbon atoms (a polyalkylene oxide having 2 to 18 repeating units of an alkylene oxide group having 2 to 4 carbon atoms). ２５ and R ２６ These may join with one side of the benzene ring supporting them to form a 5-12 member saturated or unsaturated ring, and the carbon atoms other than the one side of the benzene ring of the formed ring may be substituted with heteroatoms, and the hydrogen atoms of the ring may be substituted with a saturated linear hydrocarbon group having 1-6 carbon atoms or an alkoxy group having 1-6 carbon atoms. R ２７ (wherein 1 represents a hydrogen atom, a saturated linear hydrocarbon group having 1 to 18 carbon atoms, a saturated branched hydrocarbon group having 3 to 18 carbon atoms, or a saturated or unsaturated cyclic hydrocarbon group having 6 to 18 carbon atoms.) Furthermore, the linear, branched, or cyclic hydrocarbon group may further contain fluorine, chlorine, bromine, iodine, an alkoxy or thioalkoxy group having 1 to 18 carbon atoms, an alkylene oxide group having 2 to 4 carbon atoms, or a polyalkylene oxide group having 2 to 18 repeating units of an alkylene oxide group having 2 to 18 carbon atoms.

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