Process for producing hydroxylated chalcones and flavanones

Abstract

The purpose of the present invention is to provide an easy method for producing hydroxylated chalcones and flavanones.　The present invention relates to a method for producing hydroxylated chalcones and flavanones, the method being characterized in that bismuth chloride is used.　In a demethoxymethylation step, target chalcones or target flavanones are obtained efficiently as a single product, and thus the present invention can provide an effective method for producing chalcones and flavanones where purification is easily performed.

Description

Technical Field

[0001] The present invention relates to a novel method for producing hydroxylated chalcones and flavanones. The present invention also relates to novel chalcones and flavanones used in the production method, and novel hydroxylated flavanones obtained by the production method.

Background Art

[0002] Chalcones and flavanones are polyphenols belonging to flavonoids widely present in plants (such as vegetables and fruits). In particular, hydroxylated chalcones and flavanones have attracted attention because a number of reports have been made so far that they exhibit various biological function regulating effects (Non-Patent Document 1).

[0003] As a general method for producing hydroxylated flavanones, chalcones obtained by the reaction of acetophenones having a protected hydroxy group (phenolic hydroxy group) and benzaldehydes are subjected to a deprotection and oxy-Michael addition reaction under acidic or basic conditions. Although this method is well known, usually, under any reaction conditions, it is obtained as a mixture of hydroxylated flavanones and hydroxylated chalcones. And such a mixture has a problem that separation and purification are difficult.

[0004] As a protecting group for phenolic hydroxy groups, the methoxymethyl (hereinafter sometimes referred to as "MOM") group is a general-purpose protecting group that can be easily deprotected under acidic conditions (Non-Patent Document 2). However, when chalcones in which the hydroxy group is protected by the MOM group are subjected to deprotection conditions with a normal acid (e.g., hydrogen chloride-methanol), the oxy-Michael addition reaction also proceeds during deprotection. Therefore, although the corresponding flavanones are obtained as the main product, it has been reported that deprotected chalcones are also simultaneously generated and obtained as a mixture of both compounds as in the above-described conventional production method (Non-Patent Document 3).

Prior Art Documents

Non-Patent Literature

[0005]

Non-Patent Literature 1

Non-Patent Literature 2

Non-Patent Literature 3

Summary of the Invention

Problems to be Solved by the Invention

[0006] As described above, in the conventional production method of hydroxylated flavanones from chalcones having a protected hydroxy group (phenolic hydroxyl group), since an equilibrium exists between hydroxylated chalcones and hydroxylated flavanones, a mixture thereof is formed, but this mixture has the problem that separation and purification are difficult. Also, when only hydroxylated chalcones are desired, the oxy-Michael addition reaction, which is a side reaction, also proceeds, so it has been difficult to completely suppress the formation of hydroxylated flavanones. Therefore, it has not been easy to selectively and efficiently obtain only hydroxylated chalcones or only hydroxylated flavanones.

Means for Solving the Problems

[0007] As a result of intensive studies to solve such problems, the present inventors have found that chalcones having a hydroxy group protected with a MOM group can be reacted with bismuth chloride to obtain only hydroxylated chalcones in good yield without proceeding an oxy-Michael addition reaction. Further, the inventors have found that flavanones having a hydroxy group protected with a MOM group can be obtained in good yield by treating chalcones having a hydroxy group protected with a MOM group with an aqueous solution of disodium hydrogen phosphate (Na 2 HPO 4 ) and performing an oxy-Michael addition reaction. In addition, by subjecting the obtained MOM-protected flavanones to a deprotection reaction with bismuth chloride, only hydroxylated flavanones could be successfully obtained in good yield, leading to the completion of the present invention.

[0008] That is, the present invention is as follows. [1] A process for producing a compound represented by the formula (II):

[0009] [Chemical formula]

[0010] [In the formula, R and R' each represent a hydrogen atom, or R and R' together form a single bond; A-B represents a carbon-carbon single bond or a carbon-carbon double bond; m R 1 's each independently represent a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group or a haloalkoxy group; R 2 , R 3 and R 4 each independently represent a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group or a haloalkoxy group; n represents an integer of 0 to 3; m represents an integer of 2 to 5; and n + m is 5.]. The method for producing a compound represented by the following formula (I):

[0011] [Chemical formula]

[0012] [Each symbol in the formula represents the same meaning as described above.] A production method characterized by including a step of reacting a compound represented by the following formula with bismuth chloride (hereinafter, may also be referred to as "the production method of the present invention"). However, when both R and R' in the above formula (I) and formula (II) are hydrogen atoms, A-B represents a carbon-carbon double bond, and when R and R' in the above formula (I) and formula (II) together form a single bond, A-B represents a carbon-carbon single bond. [2] When both R and R' in the above formula (I) and formula (II) are hydrogen atoms, the following formula (III):

[0013] [Chemical formula]

[0014] [Each symbol in the formula represents the same meaning as described above.] A compound represented by the following formula and a compound represented by the following formula (IV):

[0015] [Chemical formula]

[0016] [Each symbol in the formula represents the same meaning as described above.] The production method according to [1] above, further including a step of condensing the compound represented by the following formula and the compound represented by the following formula (IV) to convert them into the compound represented by the above formula (I) (hereinafter, may also be referred to as "the production method (1) of the present invention"). [3] When R and R' in the above formula (I) and formula (II) together form a single bond, the following formula (III):

[0017] [Chemical formula]

[0018] [In the formula, each symbol has the same meaning as described above.] and a compound represented by the following formula (IV):

[0019] [Chemical formula]

[0020] [In the formula, each symbol has the same meaning as described above.] are condensed to obtain a compound represented by the following formula (Ia):

[0021] [Chemical formula]

[0022] [In the formula, each symbol has the same meaning as described above.] and converting to a compound represented by the following formula (Ia), and treating the compound represented by the formula (Ia) with an aqueous solution of disodium hydrogen phosphate to convert it to a compound represented by the formula (I) [wherein R and R' together form a single bond]. The production method according to [1] above (hereinafter, may also be referred to as "the production method (2) of the present invention"). [4] The following formula:

[0023] [Chemical formula]

[0024] A compound represented by the formula. [5] The following formula:

[0025] [Chemical formula]

[0026] A compound represented by the formula. [6] The following formula:

[0027] [Chemical formula]

[0028] The compound represented by [Advantages of the Invention]

[0029] According to the production method of the present invention, only hydroxylated chalcones can be obtained in good yield from chalcones having a hydroxy group protected with a MOM group without proceeding with an oxy-Michael addition reaction. Further, according to the production method of the present invention, chalcones having a hydroxy group protected with a MOM group are treated with an aqueous solution of disodium hydrogen phosphate (Na 2 HPO 4 ) to carry out an oxy-Michael addition reaction, whereby flavanones having a hydroxy group protected with a MOM group can be obtained in good yield, and only hydroxylated flavanones can be obtained in good yield by deprotecting the obtained flavanones protected with a MOM group. Furthermore, according to the present invention, novel MOM-protected chalcones and MOM-protected flavanones used in the production method of the present invention, and novel hydroxylated flavanones obtained by the production method can be provided. [Modes for Carrying Out the Invention]

[0030] The definitions of the terms and symbols used in this specification will be described below.

[0031] In this specification, the "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0032] In this specification, the "alkyl group" means a linear or branched alkyl group having 1 or more carbon atoms. When there is no particular limitation on the carbon number range, it is a C 1-20 alkyl group. Among them, a C 1-6 alkyl group is preferred, and a C 1-4 alkyl group is more preferred.

[0033] In this specification, "C 1-20 alkyl group" means a linear or branched alkyl group having 1 to 20 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, eicosyl, etc. can be mentioned.

[0034] In this specification, "C 1-6 alkyl group" means a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc. can be mentioned.

[0035] In this specification, "C 1-4 alkyl group" means a linear or branched alkyl group having 1 to 4 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. can be mentioned.

[0036] In this specification, "haloalkyl group" means a group in which one or more hydrogen atoms in the alkyl group are substituted with halogen atoms. Specifically, for example, difluoromethyl, trifluoromethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2,3,3-tetrafluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl, etc. can be mentioned. Among them, "halo C" in which one or more hydrogen atoms in the "C 1-6 alkyl group" are substituted with halogen1-6 "Alkyl" is preferred, and the "C" 1-4 "Halo C" in which one or more hydrogen atoms in the "alkyl group" are substituted with halogen atoms 1-4 "alkyl" is more preferred. Further, as the "haloalkyl group", a "fluoroalkyl group" is preferred.

[0037] In this specification, the "fluoroalkyl group" means a group in which the halogen atom in the "haloalkyl" group is a fluorine atom. Specifically, for example, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2,3,3-tetrafluoropropyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl, etc. can be mentioned. Among them, "fluoro C" such as difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2,3,3-tetrafluoropropyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, 4,4,4-trifluorobutyl, etc. 1-4 "alkyl (group)" is preferred, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or pentafluoroethyl is more preferred, and trifluoromethyl is particularly preferred.

[0038] In this specification, the "alkoxy group" means a group in which a linear or branched alkyl group is bonded to an oxygen atom, and the carbon number range is not particularly limited, but C 1-20 is an alkoxy group, and among them, C 1-6 alkoxy group is preferred, and C 1-4 alkoxy group is more preferred.

[0039] In this specification, "C" 1-20"Alkoxy group" means a linear or branched alkoxy group having 1 to 20 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, isohexyloxy, 1,1-dimethylbutoxy, 2,2-dimethylbutoxy, 3,3-dimethylbutoxy, 2-ethylbutoxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, eicosyloxy and the like.

[0040] In this specification, "C 1-6 "Alkoxy group" means a linear or branched alkoxy group having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like.

[0041] In this specification, "C 1-4 "Alkoxy group" means a linear or branched alkoxy group having 1 to 4 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

[0042] In this specification, "haloalkoxy group" means a group in which one or more hydrogen atoms in the alkoxy group are substituted with halogen atoms. Specifically, for example, difluoromethoxy, trifluoromethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, 5,5,5-trifluoropentyloxy, 6,6,6-trifluorohexyloxy and the like. Among them, one or more hydrogen atoms in the "C 1-6 "Alkoxy group" are substituted with halogen atoms to form "halo C1-6 "alkoxy" is preferred, and the "C" 1-4 "haloalkoxy" in which one or more hydrogen atoms in the "alkoxy group" are substituted with halogen is more preferred. Further, as the "haloalkoxy group", a "fluoroalkoxy group" is preferred. 1-4 "fluoroalkoxy" is more preferred. Also, as the "haloalkoxy group", a "fluoroalkoxy group" is preferred.

[0043] In the present specification, the "fluoroalkoxy group" means a group in which the halogen atom in the "haloalkoxy" group is a fluorine atom. Specifically, for example, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 3,3,3-trifluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, 4,4,4-trifluorobutoxy, 5,5,5-trifluoropentyloxy, 6,6,6-trifluorohexyloxy and the like can be mentioned. Among them, "fluoroalkoxy groups" such as difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 3,3,3-trifluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, 4,4,4-trifluorobutoxy are preferred, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy are more preferred, and trifluoromethoxy is particularly preferred. 1-4 "alkoxy group" is preferred, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy are more preferred, and trifluoromethoxy is particularly preferred.

[0044] In the present specification, "bismuth chloride" is bismuth(III) chloride, preferably anhydrous bismuth chloride.

[0045] In the present specification, "disodium hydrogen phosphate" is an inorganic base represented by the chemical formula: Na 2 HPO 4 and any of anhydrous, dihydrate, heptahydrate, octahydrate or dodecahydrate may be used, but preferably anhydrous.

[0046] In this specification, the "aqueous solution of disodium hydrogen phosphate" means an aqueous solution obtained by dissolving the disodium hydrogen phosphate at a specific concentration in water. The aqueous solution of disodium hydrogen phosphate used in the present invention is preferably a 0.5 M aqueous solution of disodium hydrogen phosphate.

[0047] [Manufacturing Method of the Present Invention] Hereinafter, embodiments of the present invention will be described in detail for each step of Scheme 1. In the embodiments of the present invention, each step may be carried out independently, or some or all of the steps may be carried out continuously. When a plurality of steps are carried out continuously, the next step may be carried out after stopping the reaction for each step, or the next step may be carried out without stopping the reaction. Further, the next step may be carried out after purification after the completion of the step, or the next step may be carried out without purification. These steps may be carried out, not carried out, or arbitrarily selected. Further, the reactions of a plurality of steps may be carried out in the same reaction vessel or in different reaction vessels. Hereinafter, "Compound (n)" means a compound represented by formula (n). Compound (III) and Compound (IV) used in Scheme 1 can be synthesized according to a method known per se or a method described in the reference examples described later.

[0048] [Chemical Formula]

[0049] (In the formula, MOM represents a methoxymethyl group, and the other symbols have the same meanings as described above.)

[0050] [Manufacturing Step of Compound (III) → Compound (Ia) (Step 1)] Step 1 is a step of converting Compound (III) into Compound (Ia) by a Claisen-Schmidt condensation reaction between Compound (III) and Compound (IV) in the presence of a base.

[0051] In this step, the normal reaction conditions in the Claisen-Schmidt condensation reaction can be used. The base to be used is not particularly limited, and examples thereof include potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, sodium methoxide, sodium ethoxide, tert-butoxypotassium, etc. Among them, potassium hydroxide is preferred. The amount of compound (IV) used can usually be 1 to 3 moles, preferably 1 to 1.5 moles, per 1 mole of compound (III). The amount of base used can usually be 1 to 10 moles, preferably 2 to 5 moles, per 1 mole of compound (III).

[0052] This reaction can be carried out in a solvent that does not affect the reaction. The reaction solvent is not particularly limited, and examples thereof include alcohols such as methanol and ethanol; aromatic hydrocarbons such as benzene, toluene, and xylene. Among them, ethanol is preferred.

[0053] The reaction temperature is usually 0 to 60°C, preferably 20 to 50°C, and more preferably 40°C. The reaction time is usually about 1 to 30 hours.

[0054] [Production process of compound (Ia) → compound (IIa) (process 2)] Process 2 is a process of converting compound (Ia) into compound (IIa) by deprotecting the MOM group of compound (Ia) in the presence of bismuth chloride.

[0055] The amount of bismuth chloride used can usually be 0.01 to 3 moles, preferably 0.05 to 2 moles, per 1 mole of compound (Ia).

[0056] This reaction can be carried out in a solvent that does not affect the reaction. The reaction solvent is not particularly limited, and examples include alcohols such as methanol, ethanol, and isopropanol; nitriles such as acetonitrile; water; a mixed solvent of alcohols and nitriles; a mixed solvent of water and nitriles, etc. Among them, a mixed solvent of acetonitrile and methanol (more preferably, acetonitrile:methanol = 50:1 (v / v)) is preferred.

[0057] The reaction temperature is usually from room temperature to 100 °C, preferably 60 - 80 °C. The reaction time is usually about 1 - 30 hours.

[0058] [Production process of compound (Ia) → compound (Ib) (Process 3)] Process 3 is a process of converting compound (Ia) into compound (Ib) by treating it with an aqueous solution of disodium hydrogen phosphate (Na 2 HPO 4 ).

[0059] The amount of disodium hydrogen phosphate (Na 2 HPO 4 ) used can usually be 1 - 10 moles, preferably 1 - 3 moles, per 1 mole of compound (Ia). The concentration of the aqueous solution of disodium hydrogen phosphate used is not particularly limited, but is usually 0.1 - 1 M, preferably 0.5 M. Here, M represents moles / liter.

[0060] This reaction can be carried out in a solvent that does not affect the reaction. The reaction solvent is not particularly limited, and examples include water-miscible alcohols such as methanol, ethanol, and isopropanol, and ethanol is preferred.

[0061] The reaction temperature is usually 60 - 100 °C, preferably the reflux temperature of the reaction solvent. The reaction time is usually about 2 - 30 hours.

[0062] [Production Process of Compound (Ib) → Compound (IIb) (Process 4)] Process 4 is a process of converting compound (Ib) into compound (IIb) by deprotecting the MOM group of compound (Ib) in the presence of bismuth chloride.

[0063] The amount of bismuth chloride used can usually be 0.01 - 3 moles, preferably 0.05 - 1.5 moles, per 1 mole of compound (Ib).

[0064] This reaction can be carried out in a solvent that does not affect the reaction. The reaction solvent is not particularly limited. For example, alcohols such as methanol, ethanol, and isopropanol; nitriles such as acetonitrile; aromatic hydrocarbons such as benzene and toluene; water; mixed solvents of alcohols and nitriles; mixed solvents of water and nitriles; mixed solvents of alcohols and aromatic hydrocarbons, etc. Among them, acetonitrile and a mixed solvent of acetonitrile and methanol (more preferably, acetonitrile:methanol = 50:1 (v / v)) are preferred. When acetonitrile is used as the reaction solvent, the addition of sodium iodide promotes the progress of the reaction. The amount of sodium iodide used can usually be 1 - 5 moles, preferably 1.5 - 3 moles, per 1 mole of compound (Ib).

[0065] The reaction temperature is usually from room temperature to 100°C, preferably 50 - 60°C or the reflux temperature of the reaction solvent. The reaction time is usually about 1 - 30 hours.

[0066] The compounds represented by formula (IIa) and formula (IIb) are useful as active ingredients of functional foods and pharmaceuticals because they exhibit various biological function-regulating effects on mammals such as humans. By this production method, the compounds represented by formula (IIa) and formula (IIb) can be selectively produced in good yields from the compounds represented by formula (Ia) and formula (Ib) respectively by simple operations.

[0067] Specific features of this manufacturing method are as follows. (A) By subjecting compound (Ia) to deprotection of the MOM group in the presence of bismuth chloride, only compound (IIa) can be selectively and highly yield-produced without by-production of compound (IIb) due to oxy-Michael addition reaction.

[0068] (B) By subjecting compound (Ib) to deprotection of the MOM group in the presence of bismuth chloride, only compound (IIb) can be selectively and highly yield-produced without by-production of compound (IIa) due to retro-Michael addition reaction.

[0069] When deprotecting the MOM group of compound (Ia) or compound (Ib) under normal acidic conditions, as described in Table 3 of the examples described later, an oxy-Michael addition reaction or a retro-Michael addition reaction also proceeds simultaneously, resulting in a mixture of compound (IIa) and compound (IIb). However, since the mixture of compound (IIa) and compound (IIb) is difficult to separate and purify, there has been a problem in practical applications. According to this manufacturing method, by using bismuth chloride, this problem can be solved.

[0070] (C) By treating compound (Ia) with an aqueous solution of disodium hydrogen phosphate (Na 2 HPO 4 ), the oxy-Michael addition reaction proceeds smoothly, and there is an advantage that compound (Ib) can be obtained in good yield. On the other hand, as described in Table 1 of the examples described later, when other bases are used, the yield of compound (Ib) decreases significantly. Also, as described in Non-Patent Document 3, a method for producing hydroxylated flavanones by subjecting MOM-protected chalcones to acidic conditions to simultaneously perform deprotection and oxy-Michael addition reaction has been reported. Although the corresponding flavanones are obtained as the main product, they are obtained as a mixture with deprotected chalcones, so separation and purification are difficult. As described above, the manufacturing method of the present invention is significantly superior to the conventional method in that it combines the advantages of (A), (B), and (C) above.

[0071] [Compound of the present invention] Hereinafter, the definitions of each symbol in the above formulas (I), (II), (III), (IV), (Ia), (Ib), (IIa) and (IIb) will be described in detail.

[0072] In formulas (I) and (II), both R and R' represent a hydrogen atom, or R and R' together form a single bond.

[0073] When both R and R' in formulas (I) and (II) are hydrogen atoms, A-B represents a carbon-carbon double bond, and when R and R' in formulas (I) and (II) together form a single bond, A-B represents a carbon-carbon single bond.

[0074] m R's 1 each independently represents a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group or a haloalkoxy group, m represents an integer of 2 to 5.

[0075] R 1 is preferably a hydrogen atom, an alkyl group or an alkoxy group, more preferably a hydrogen atom or an alkoxy group (e.g., C 1-4 alkoxy group).

[0076] m is preferably an integer of 3 to 5.

[0077] R 2 , R 3 and R 4 each independently represents a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group or a haloalkoxy group.

[0078] R 2 , R 3 and R 4 are preferably all hydrogen atoms.

[0079] n represents an integer of 0 to 3.

[0080] n is preferably an integer from 0 to 2, more preferably 1 or 2. However, n + m is 5.

[0081] Suitable compounds (I) (i.e., compound (Ia) and compound (Ib)) include the following compounds. [Compound (Ia-1)] Both R and R' are hydrogen atoms; A - B is a carbon-carbon double bond; m R's 1 are hydrogen atoms, alkyl groups or alkoxy groups; R 2 , R 3 and R 4 are all hydrogen atoms; m is an integer from 3 to 5; n is an integer from 0 to 2; and n + m is 5, Compound (I).

[0082] [Compound (Ia-2)] Both R and R' are hydrogen atoms; A - B is a carbon-carbon double bond; m R's 1 are hydrogen atoms or alkoxy groups (e.g., C 1-4 alkoxy groups (preferably methoxy group or ethoxy group)); R 2 , R 3 and R 4 are all hydrogen atoms; m is an integer from 3 to 5; n is 1 or 2; and n + m is 5, Compound (I).

[0083] [Compound (Ib-1)] R and R' together form a single bond; A - B is a carbon-carbon single bond; m R's 1is a hydrogen atom, an alkyl group or an alkoxy group; R 2 、R 3 and R 4 are all hydrogen atoms; m is an integer from 3 to 5; n is an integer from 0 to 2; and n + m is 5, Compound (I).

[0084] [Compound (Ib - 2)] R and R’ together form a single bond; A - B is a carbon - carbon single bond; m R 1 are hydrogen atoms or alkoxy groups (e.g., C 1-4 alkoxy groups (preferably, methoxy group or ethoxy group)); R 2 、R 3 and R 4 are all hydrogen atoms; m is an integer from 3 to 5; n is 1 or 2; and n + m is 5, Compound (I).

[0085] Suitable compounds (II) (i.e., compound (IIa) and compound (IIb)) include the following compounds. [Compound (IIa - 1)] R and R’ are both hydrogen atoms; A - B is a carbon - carbon double bond; m R 1 are hydrogen atoms, alkyl groups or alkoxy groups; R 2 、R 3 and R 4 are all hydrogen atoms; m is an integer from 3 to 5; n is an integer from 0 to 2; and n + m is 5, Compound (II).

[0086] [Compound (IIa-2)] R and R’ are both hydrogen atoms; A-B is a carbon-carbon double bond; m R's 1 are hydrogen atoms or alkoxy groups (e.g., C 1-4 alkoxy group (preferably, methoxy group or ethoxy group)); R 2 , R 3 and R 4 are all hydrogen atoms; m is an integer from 3 to 5; n is 1 or 2; and n + m is 5, Compound (II).

[0087] [Compound (IIb-1)] R and R’ together form a single bond; A-B is a carbon-carbon single bond; m R's 1 are hydrogen atoms, alkyl groups or alkoxy groups; R 2 , R 3 and R 4 are all hydrogen atoms; m is an integer from 3 to 5; n is an integer from 0 to 2; and n + m is 5, Compound (II).

[0088] [Compound (IIb-2)] R and R’ together form a single bond; A-B is a carbon-carbon single bond; m R's 1 are hydrogen atoms or alkoxy groups (e.g., C 1-4 alkoxy group (preferably, methoxy group or ethoxy group)); R 2 , R 3 and R 4 are all hydrogen atoms; m is an integer from 3 to 5; n is 1 or 2; and n + m is 5, Compound (II).

[0089] Preferable examples of Compound (III) include the following compounds.

[0090] [Compound (III-1)] R 2 、R 3 and R 4 are all hydrogen atoms, Compound (III).

[0091] Preferable examples of Compound (IV) include the following compounds.

[0092] [Compound (IV-1)] m R's 1 are hydrogen atoms, alkyl groups or alkoxy groups; m is an integer from 3 to 5; n is an integer from 0 to 2; and n + m is 5, Compound (IV).

[0093] [Compound (IV-2)] m R's 1 are hydrogen atoms or alkoxy groups (e.g., C 1-4 alkoxy groups (preferably, methoxy group or ethoxy group)); m is an integer from 3 to 5; n is 1 or 2; and n + m is 5, Compound (IV).

[0094] Preferable specific examples of Compound (I), Compound (II), Compound (III) and Compound (IV) in the present invention are the compounds exemplified in the reference examples and the examples described later.

[0095] The present invention also relates to a MOM group-protected following formula useful as a precursor for synthesizing Compound (IIa) and Compound (IIb):

[0096] [Chem.]

[0097] A novel compound (Ia) represented by the following formula, and the following formula:

[0098] [Chem.]

[0099] A novel compound (Ib) represented by the following formula can be provided.

[0100] Furthermore, according to the present invention, the following formula:

[0101] [Chem.]

[0102] A novel compound (IIb) represented by the following formula can be provided with high purity. [Examples]

[0103] The present invention will be described in more detail below based on examples. However, the present invention is not limited to the reference examples and examples, and may be changed without departing from the scope of the present invention. In addition, the reagents and raw material compounds used in the present invention are commercially available unless otherwise specified.

[0104] In addition, in each step, the post-reaction treatment may be carried out by a commonly used method. For isolation and purification, if necessary, conventional methods such as crystallization, recrystallization, distillation, liquid separation, silica gel chromatography, preparative HPLC, etc. may be appropriately selected and combined.

[0105] The reagents and starting compounds used in the following examples: 2’,4’-dihydroxyacetophenone (manufactured by Tokyo Chemical Industry Co., Ltd. (TCI)), 2-hydroxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd. (TCI)), 3-hydroxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd. (TCI)), 4-hydroxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd. (TCI)), 3,4-dihydroxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd. (TCI)), 2,3-dihydroxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd. (TCI)), 2,5-dihydroxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd. (TCI)), 3,5-dihydroxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd. (TCI)), 3,4,5-trihydroxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd. (TCI)), 3,4-dimethoxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd. (TCI)), methoxymethyl chloride (MOMCl) (manufactured by Tokyo Chemical Industry Co., Ltd. (TCI)), Na 2 HPO 4 (anhydrous) (manufactured by Fujifilm-Wako), bismuth chloride (BiCl 3 )(manufactured by Fujifilm-Wako), and sodium iodide (manufactured by Nacalai Tesque) were used as commercially available products as they were.

[0106] % indicates mol / mol% for the yield, and weight% for others unless otherwise specified. Also, room temperature indicates a temperature of 15 to 30 °C unless otherwise specified. 1 The 1H-NMR spectra were measured using a JNM ECP500 manufactured by JEOL Ltd., with deuterated chloroform or deuterated methanol as the solvent. 1Data on H-NMR are reported as chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet, dd = double doublet, dt = double triplet, brs = broad singlet), coupling constant (Hz), integration, and assignment. The infrared spectrum was measured using a Horiba Fourier transform infrared spectrometer FT-720. Mass spectrometry (LRMS(EI)) was measured using a JEOL-DX300 manufactured by JEOL Ltd.

[0107] [Reference Example 1] Production of 2'-hydroxy-4'-(methoxymethoxy)acetophenone (3a) 2',4'-Dihydroxyacetophenone (5.00 g, 32.9 mmol) was dissolved in dichloromethane (100 mL). Under ice-cooling, N,N-diisopropylethylamine (DIPEA) (10.6 g, 82.2 mmol) and methoxymethyl chloride (MOMCl) (4.00 g, 49.3 mmol) were added dropwise, and the mixture was stirred at room temperature for 16 hours. The reaction solution was extracted three times with chloroform, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The title compound (6.4 g, 99%) was obtained by purification by silica gel column chromatography [benzene-ethyl acetate (5:1)]. 1 H-NMR (500 MHz, CDCl 3 ): δ 2.56 (3H, s), 3.47 (3H, s), 5.20 (2H, s), 6.54 (1H, dd, J = 2.3, 8.7 Hz), 6.58 (1H, d, J = 2.3 Hz), 7.64 (1H, d, J = 8.7 Hz); 13 C-NMR (125 MHz, CDCl 3 ): δ 26.17 (q), 56.26 (q), 93.89 (t), 103.89 (d), 108.08 (d), 114.64 (s), 132.31 (d), 163.49 (s), 164.73 (s), 202.68 (s); IR (KBr) cm -1 : 3001, 1635.

[0108] [Reference Example 2] Synthesis of 2-(methoxymethoxy)benzaldehyde (4a) 2-Hydroxybenzaldehyde (5.00 g, 40.9 mmol) was dissolved in dichloromethane (150 mL). DIPEA (13.2 g, 102 mmol) was added, and under ice-cooling, MOMCl (4.9 g, 61.4 mmol) was added dropwise, followed by stirring at room temperature for 17 hours. The reaction solution was extracted three times with chloroform, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography [hexane-ethyl acetate (5:1)] gave the title compound (6.5 g, 95%). 1 H-NMR (500 MHz, CDCl 3 ): δ 3.52 (3H, s), 5.30 (2H, s), 7.06 - 7.09 (1H, m), 7.21 (1H, dd, J = 1.8, 8.7 Hz), 7.51 - 7.54 (1H, m), 7.84 (1H, dd, J = 1.8, 8.7 Hz), 10.50 (1H, s); 13 C-NMR (125 MHz, CDCl 3 ): δ 56.47 (q), 94.55 (t), 115.02 (d), 121.86 (d), 125.34 (s), 128.40 (d), 135.99 (d), 159.72 (s), 190.01 (d); IR (KBr) cm -1 : 1685; LRMS (EI) m / z: 166 (M + ).

[0109] [Reference Example 3] Synthesis of 3-(methoxymethoxy)benzaldehyde (4b) The title compound (yield: 84%) was obtained in the same manner as in Reference Example 2, except that 2-hydroxybenzaldehyde was replaced with 3-hydroxybenzaldehyde. 1 H-NMR (500 MHz, CDCl 3): δ 3.48 (3H, s), 5.23 (2H, s), 7.29 - 7.31 (1H, m), 7.44 (1H, t, J = 7.8 Hz), 7.51 - 7.55 (2H, m), 9.96 (1H, s); 13 C-NMR (125 MHz, CDCl 3 ): δ 56.11 (q), 94.38 (t), 115.91 (d), 122.85 (d), 123.84 (d), 130.13 (d), 137.79 (s), 157.76 (s), 192.06 (d); IR (KBr) cm -1 : 1701; LRMS (EI) m / z: 166 (M + ).

[0110] [Reference Example 4] Synthesis of 4-(methoxymethoxy)benzaldehyde (4c) The title compound (yield: 98%) was obtained in the same manner as in Reference Example 2, except that 2-hydroxybenzaldehyde was replaced with 4-hydroxybenzaldehyde. 1 H-NMR (500 MHz, CDCl 3 ): δ 3.49 (3H, s), 5.26 (2H, s), 7.15 (2H, d, J = 8.7 Hz), 7.84 (2H, d, J = 8.7 Hz), 9.88 (1H, s); 13 C-NMR (125 MHz, CDCl 3 ): δ 56.35 (q), 94.05 (t), 116.17 (d), 130.53 (s), 132.05 (d), 162.36 (s), 191.38 (d); IR (KBr) cm -1 : 1685; LRMS (EI) m / z: 166 (M + ).

[0111] [Reference Example 5] Synthesis of 3,4-bis(methoxymethoxy)benzaldehyde (4d) The title compound (yield: 95%) was obtained in the same manner as in Reference Example 2, except that 2-hydroxybenzaldehyde was replaced with 3,4-dihydroxybenzaldehyde. 1 H-NMR (500 MHz, CDCl 3 ): δ 3.47 (3H, s), 3.48 (3H, s), 5.25 (2H, s), 5.28 (2H, s), 7.24 (1H, d, J = 8.3 Hz), 7.46 (1H, dd, J = 1.8, 8.3 Hz), 7.63 (1H, d, J = 1.8 Hz), 9.81 (1H, s); 13 C-NMR (125 MHz, CDCl 3 ): δ 56.28 (q), 56.40 (q), 94.86 (t), 65.25 (t), 115.26 (d), 115.79 (d), 126.25 (d), 131.03 (s), 147.35 (s), 152.51 (s), 190.73 (d); IR (KBr) cm -1 : 1691; LRMS (EI) m / z: 226 (M + ).

[0112] [Reference Example 6] Synthesis of 2,3-bis(methoxymethoxy)benzaldehyde (4e) The title compound (yield: 95%) was obtained in the same manner as in Reference Example 2, except that 2-hydroxybenzaldehyde was replaced with 2,3-dihydroxybenzaldehyde. 1 H-NMR (500 MHz, CDCl 3 ): δ 3.51 (3H, s), 3.57 (3H, s), 5.23 (2H, s), 5.29 (2H, s), 7.14 (1H, t, J = 7.8 Hz), 7.40 (1H, dd, J = 1.8, 7.8 Hz), 7.50 (1H, dd, J = 1.8, 7.8 Hz), 10.46 (1H, s); 13 C-NMR (125 MHz, CDCl 3): δ 56.28 (q), 57.81 (q), 95.16 (t), 99.62 (t), 120.84 (d), 122.18 (d), 124.49 (d), 130.54 (s), 149.84 (s), 150.03 (s), 190.10 (d); LRMS (EI) m / z: 226 (M + ); IR (KBr) cm -1 : 1691.

[0113] [Reference Example 7] Synthesis of 2,5-bis(methoxymethoxy)benzaldehyde (4f) The title compound (yield: 82%) was obtained in the same manner as in Reference Example 2, except that 2-hydroxybenzaldehyde was replaced with 2,5-dihydroxybenzaldehyde. 1 H-NMR (500 MHz, CDCl 3 ): δ 3.47 (3H, s), 3.52 (3H, s), 5.15 (2H, s), 5.25 (2H, s), 7.17 (1H, d, J = 9.2 Hz), 7.22 (1H, dd, J = 3.2, 9.2 Hz), 7.48 (1H, d, J = 3.2 Hz), 10.45 (1H, s); 13 C-NMR (125 MHz, CDCl 3 ): δ 56.02 (q), 56.41 (q), 94.93 (t), 95.23 (t), 114.56 (d), 116.87 (d), 124.75 (d), 126.12 (s), 152.00 (s), 154.97 (s), 189.33 (d); IR (KBr) cm -1 : 1685; LRMS (EI) m / z: 226 (M + ).

[0114] [Reference Example 8] Synthesis of 3,5-bis(methoxymethoxy)benzaldehyde (4g) The title compound (yield: 81%) was obtained in the same manner as in Reference Example 2, except that 2-hydroxybenzaldehyde was replaced with 3,5-dihydroxybenzaldehyde. 1H-NMR (500 MHz, CDCl 3 ): δ 3.94 (6H, s), 5.21(4H, s), 6.98 (1H, t, J = 2.3 Hz), 7.21 (2H, d, J = 2.3 Hz), 9.90 (1H, s); 13 C-NMR (125 MHz, CDCl 3 ): δ 56.09 (q), 94.34 (t), 110.32 (d), 111.03 (d), 138.37 (s), 159.66 (s), 191.51 (d); IR (KBr) cm -1 : 1693; LRMS(EI) m / z: 226 (M + ).

[0115] [Reference Example 9] Synthesis of 3,4,5-tris(methoxymethoxy)benzaldehyde (4h) The title compound (yield: 86%) was obtained in the same manner as in Reference Example 2, except that 2-hydroxybenzaldehyde was replaced with 3,4,5-trihydroxybenzaldehyde. 1 H-NMR (500 MHz, CDCl 3 ): δ 3.52 (6H, s), 3.62 (3H, s), 5.24 (2H, s), 5.27 (4H, s), 7.39 (2H, s), 9.85 (1H, s); 13 C-NMR (125 MHz, CDCl 3 ): δ 56.39 (q), 57.25 (q), 95.20 (t), 98.47 (t), 111.28 (d), 132.37 (s), 141.83 (s), 151.46 (s), 190.85 (d); LRMS(EI) m / z: 286 (M + ); IR (KBr) cm -1 : 1693; LRMS(EI) m / z: 286 (M + ).

[0116] [Example 1] General synthetic method of MOM-protected chalcones (Compound (Ia)) To a solution of acetophenone (3) (10.2 mmol) in ethanol (40 mL) were added benzaldehyde (4) (15.3 mmol) and potassium hydroxide (51.0 mmol), and the mixture was stirred at 40 °C overnight. After neutralization with 10% ethyl acetate-ethanol, the mixture was stirred under ice-cooling for 1 hour, and the precipitated crystals were collected by suction filtration and dried under reduced pressure to obtain Compound (Ia).

[0117] [Example 2] (E)-1-(2-Hydroxy-4-(methoxymethoxy)phenyl)-3-(2-(methoxymethoxy)phenyl)-2-propen-1-one (Ia-1) Using Compound (3a) as acetophenone (3) and Compound (4a) as benzaldehyde (4), the title compound (yield: 85%) was obtained in the same manner as in Example 1. 1 H-NMR (500 MHz, CDCl 3 ): δ 3.49 (3H, s), 3.52 (3H, s), 5.22 (2H, s), 5.29 (2H, s), 6.58 (1H, dd, J = 2.3, 8.7 Hz), 6.64 (1H, d, J = 2.3 Hz), 6.59 (1H, dd, J = 2.3, 8.9 Hz), 7.05 (1H, t, J = 7.8 Hz), 7.18 (1H, d, J = 7.8 Hz), 7.36 (1H, t, J = 7.8 Hz), 7.66 (1H, d, J = 15.6 Hz), 7.67 (1H, dd, J = 2.3, 7.8 Hz), 7.84 (1H, d, J = 8.3 Hz), 8.26 (1H, d, J = 15.6 Hz); 13 C-NMR (125 MHz, CDCl 3 ): δ 56.36 (q), 56.38 (q), 93.99 (t), 64.60 (t), 103.97 (d), 108.13 (d), 114.89 (d), 115.07 (s), 120.85 (d), 121.95 (d), 124.46 (s), 128.64 (d), 131.32 (d), 131.97 (d), 139.85 (d), 156.53 (s), 163.54 (s), 166.21 (s), 192.44 (s); LRMS (EI) m / z: 344 (M + ); IR (KBr) cm -1 : 3074, 1633.

[0118] [Example 3] (E)-1-(2-Hydroxy-4-(methoxymethoxy)phenyl)-3-(3-(methoxymethoxy)phenyl)-2-propen-1-one (Ia-2) Using compound (3a) as acetophenone (3) and compound (4b) as benzaldehyde (4), in the same manner as in Example 1, the title compound (yield: 83%) was obtained. 1 H-NMR (500 MHz, CDCl 3 ): δ 3.49 (3H, s), 3.51 (3H, s), 5.23 (4H, s), 6.59 (1H, dd, J = 2.3, 8.7 Hz), 6.65 (1H, d, J = 2.3 Hz), 7.12 (1H, dd, J = 1.8, 7.3 Hz), 7.29 - 7.36 (3H, m), 7.56 (1H, d, J = 15.6 Hz), 7.85 (1H, d, J = 15.6 Hz) 7.86 (1H, d, J = 8.7 Hz); 13 C-NMR (125 MHz, CDCl 3 ): δ 56.09 (q), 56.39 (q), 94.01 (t), 94.44 (t), 103.96 (d), 108.24 (d), 114.93 (s), 115.85 (d), 118.58 (d), 120.64 (d), 122.39 (d), 130.02 (d), 131.36 (d), 136.21 (s), 144.36 (d), 157.70 (s), 163.69 (s), 166.26 (s), 191.96 (s); LRMS (EI) m / z: 344 (M + ); IR (KBr) cm -1 : 3467, 1641.

[0119] [Example 4] (E)-1-(2-Hydroxy-4-(methoxymethoxy)phenyl)-3-(4-(methoxymethoxy)phenyl)-2-propen-1-one (Ia-3) Using compound (3a) as acetophenone (3) and compound (4c) as benzaldehyde (4), the title compound (yield: 64%) was obtained in the same manner as in Example 1. 1 H-NMR (500 MHz, CDCl 3 ): δ 3.49 (3H, s), 3.50 (3H, s), 5.23 (2H, s), 5.23 (2H, s), 6.59 (1H, dd, J = 2.3, 8.8 Hz), 6.64 (1H, d, J = 2.4 Hz), 7.09 (2H, d, J = 8.8 Hz), 7.48 (1H, d, J = 15.4 Hz), 7.61 (2H, d, J = 8.8 Hz), 7.85 (1H, d, J = 8.8 Hz), 7.87 (1H, d, J = 15.4 Hz); 13 C-NMR (125 MHz, CDCl 3 ): δ 56.20 (q), 56.39 (q), 94.02 (t), 94.18 (t), 103.97 (d), 108.12 (d), 115.00 (s), 116.56 (d), 118.26 (d), 128.51 (s), 130.27 (d), 131.22 (d), 144.33 (d), 159.39 (s), 163.51 (d), 166.17 (s), 192.03 (s); LRMS (EI) m / z: 344 (M + ); IR (KBr) cm -1 : 3435, 1645.

[0120] [Example 5] (E)-1-(2-Hydroxy-4-(methoxymethoxy)phenyl)-3-(3,4-bis(methoxymethoxy)phenyl)-2-propen-1-one (Ia-4) Using compound (3a) as acetophenone (3) and compound (4d) as benzaldehyde (4), the title compound (yield: 91%) was obtained in the same manner as in Example 1. 1H-NMR (500 MHz, CDCl 3 ): δ 3.49 (3H, s), 3.53 (3H, s), 3.56 (3H, s), 5.23 (2H, s), 5.30 (2H, s), 5.30 (2H, s), 6.60 (1H, dd, J = 2.3, 8.7 Hz), 6.65 (1H, d, J = 2.3 Hz), 7.21 (1H, d, J = 8.7 Hz), 7.28 (1H, dd, J = 2.3, 8.7 Hz), 7.45 (1H, d, J = 15.1 Hz), 7.48 (1H, d, J = 2.3 Hz), 7.83 (1H, d, J = 15.1 Hz), 7.85 (1H, d, J = 8.7 Hz); 13 C-NMR (125 MHz, CDCl 3 ): δ 56.34 (q), 56.36 (q), 56.39 (q), 94.02 (t), 95.11 (t), 95.55 (t), 103.94 (d), 108.15 (d), 114.97 (s), 116.09 (d), 116.18 (d), 118.74 (d), 124.15 (d), 129.20 (s), 131.31 (d), 144.38 (d), 147.43 (s), 149.63 (s), 163.54 (s), 166.16 (s), 191.98 (s); LRMS (EI) m / z: 404 (M + ); IR (KBr) cm -1 : 3437, 1635.

[0121] [Example 6] (E)-1-(2-Hydroxy-4-(methoxymethoxy)phenyl)-3-(2,3-bis(methoxymethoxy)phenyl)-2-propen-1-one (Ia-5) Using compound (3a) as acetophenone (3) and compound (4e) as benzaldehyde (4), the title compound (yield: 87%) was obtained in the same manner as in Example 1. 1 H-NMR (500 MHz, CDCl 3): δ 3.49 (3H, s), 3.52 (3H, s), 3.63 (3H, s), 5.21 (2H, s), 5.22 (4H, s), 6.58 (1H, dd, J = 2.3, 8.7 Hz), 6.64 (1H, d, J = 2.3 Hz), 7.10 (1H, dd, J = 7.8, 8.3 Hz), 7.22 (1H, dd, J = 1.4, 8.3 Hz), 7.35 (1H, d, J = 1.4 Hz), 7.64 (1H, d, J = 15.6 Hz), 7.85 (1H, d, J = 8.7 Hz), 8.27 (1H, d, J = 15.6 Hz); 13 C-NMR(125 MHz, CDCl 3 ): δ 56.32 (q), 56.39 (q), 57.99 (q), 94.01 (t), 95.18 (t), 99.50 (t), 103.95 (d), 108.17 (d), 115.02 (s), 118.50 (d), 121.00 (d), 121.64 (d), 124.54 (d), 129.93 (s), 131.37 (d), 139.92 (d), 146.57 (s), 150.38 (s), 163.60 (s), 166.23 (s), 192.15 (s); LRMS (EI) m / z: 404 (M + ); IR (KBr) cm -1 : 3431, 1643.

[0122] [Example 7] (E)-1-(2-Hydroxy-4-(methoxymethoxy)phenyl)-3-(2,5-bis(methoxymethoxy)phenyl)-2-propen-1-one (Ia-6) Using compound (3a) as acetophenone (3) and compound (4f) as benzaldehyde (4), the title compound (yield: 89%) was obtained in the same manner as in Example 1. 1 H-NMR (500 MHz, CDCl 3): δ 3.49 (3H, s), 3.50 (3H, s), 3.51 (3H, s), 5.17 (2H, s), 5.22 (2H, s), 5.23 (2H, s), 6.59 (1H, dd, J = 2.3, 8.7 Hz), 6.64 (1H, d, J = 2.3 Hz), 7.07 (1H, dd, J = 2.8, 8.7 Hz), 7.13 (1H, d, J = 8.7 Hz), 7.34 (1H, d, J = 2.8 Hz), 7.61 (1H, d, J = 15.6 Hz), 7.85 (1H, d, J = 8.7 Hz), 8.21 (1H, d, J = 15.6 Hz); 13 C-NMR (125 MHz, CDCl 3 ): δ 56.00 (q), 56.31 (q), 56.40 (q), 94.02 (t), 95.08 (t), 95.27 (t), 103.97 (d), 108.17 (d), 115.06 (s), 115.77 (d), 116.47 (d), 120.11 (d), 121.20 (d), 125.43 (s), 131.39 (d), 139.48 (d), 151.78 (s), 152.06 (s), 163.60 (s), 166.23 (s), 192.34 (s); IR (KBr) cm -1 : 3589, 1682; LRMS (EI) m / z: 404 (M + ).

[0123] [Example 8] (E)-1-(2-Hydroxy-4-(methoxymethoxy)phenyl)-3-(3,5-bis(methoxymethoxy)phenyl)-2-propen-1-one (Ia-7) Using compound (3a) as acetophenone (3) and compound (4g) as benzaldehyde (4), the title compound (yield: 89%) was obtained in the same manner as in Example 1. 1 H-NMR (500 MHz, CDCl 3): δ 3.49 (3H, s), 3.51 (6H, s), 5.20 (4H, s), 5.23 (2H, s), 6.62 (1H, dd, J = 2.3, 8.7 Hz), 6.64 (1H, d, J = 2.3 Hz), 6.81 (1H, d, J = 2.3 Hz), 6.98 (1H, d, J = 2.3 Hz), 7.51 (1H, d, J = 15.6 Hz), 7.77 (1H, d, J = 15.6 Hz), 7.84 (1H, d, J = 8.7 Hz); 13 C-NMR (125 MHz, CDCl 3 ): δ 56.16 (q), 56.41 (q), 56.40 (q), 94.02 (t), 94.51 (t), 95.27 (t), 103.94 (d), 107.13 (d), 108.26 (d), 109.77 (d), 114.92 (s), 120.93 (d), 131.45 (d), 136.79 (s), 144.31 (d), 158.63 (s), 163.71 (s), 166.23 (s), 191.95 (s); IR (KBr) cm -1 : 3446, 1649; LRMS (EI) m / z: 404 (M + ).

[0124] [Example 9] (E)-1-(2-Hydroxy-4-(methoxymethoxy)phenyl)-3-(3,4,5-tris(methoxymethoxy)phenyl)-2-propen-1-one (Ia-8) Using compound (3a) as acetophenone (3) and compound (4h) as benzaldehyde (4), the title compound (yield: 88%) was obtained in the same manner as in Example 1. 1 H-NMR (500 MHz, CDCl 3): δ 3.49 (3H, s), 3.54 (6H, s), 3.63 (3H, s), 5.20 (2H, s), 5.22 (2H, s), 5.26 (4H, s), 6.59 (1H, dd, J = 2.3, 8.7 Hz), 6.63 (1H, d, J = 2.3 Hz), 7.16 (2H, s), 7.41 (1H, d, J = 15.6 Hz), 7.77 (1H, d, J = 15.6 Hz), 7.84 (1H, d, J = 8.7 Hz); 13 C-NMR (125 MHz, CDCl 3 ): δ 56.34 (q), 56.39 (q), 57.21 (q), 94.01 (t), 95.35 (t), 98.56 (t), 103.90 (d), 108.20 (d), 110.61 (d), 114.91 (s), 119.85 (d), 130.90 (s), 131.43 (d), 138.77 (s), 144.40 (d), 151.35 (s), 163.62 (s), 166.19 (s), 191.87 (s); IR (KBr) cm -1 : 3467, 1633; LRMS (EI) m / z: 464 (M + ).

[0125] [Example 10] (E)-1-(2-Hydroxy-4-(methoxymethoxy)phenyl)-3-(3,4-dimethoxyphenyl)-2-propen-1-one (Ia-9) Using compound (3a) as acetophenone (3) and 3,4-dimethoxybenzaldehyde (4i) as benzaldehyde (4), the title compound (yield: 98%) was obtained in the same manner as in Example 1. 1 H-NMR (500 MHz, CDCl 3): δ 3.49 (3H, s), 3.94 (3H, s), 3.97 (3H, s), 5.23 (2H, s), 6.58 (1H, dd, J = 2.3, 8.7 Hz), 6.64 (1H, d, J = 2.3 Hz), 6.91 (1H, d, J = 8.7 Hz), 7.16 (1H, d, J = 2.3 Hz), 7.26 (1H, dd, J = 2.3, 8.7 Hz), 7.44 (1H, d, J = 15.6 Hz), 7.85 (1H, d, J = 15.6 Hz), 7.86 (1H, d, J = 8.7 Hz); 13 C-NMR (125 MHz, CDCl 3 ): δ 56.01 (q), 56.02 (q), 56.40 (q), 94.02 (t), 103.98 (d), 108.12 (d), 110.27 (d), 111.17 (d), 115.01 (s), 117.97 (d), 123.36 (d), 127.76 (s), 131.21 (d), 144.80 (d), 149.31 (s), 151.64 (s), 163.51 (s), 166.19 (s), 191.96 (s); LRMS (EI) m / z: 344 (M + ); IR (KBr) cm -1 : 3434, 1637.

[0126] [Example 11] General synthetic method of MOM-protected flavanones (Compound (Ib)) To a solution of MOM-protected chalcone (Compound (Ia)) (4.36 mmol) in ethanol (34 mL) was added an aqueous solution of 0.5 M disodium hydrogen phosphate (Na 2 HPO 4 ) (26 mL, 13.0 mmol), and the mixture was refluxed overnight. The reaction solution was extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain MOM-protected flavanone (Compound (Ib)).

[0127] [Example 12] 7-Methoxymethoxy-2-(2-(methoxymethoxy)phenyl)chroman-4-one (Ib-1) As the MOM-protected chalcone (Compound (Ia)), Compound (Ia-1) was used, and in the same manner as in Example 11, the title compound (yield: 71%) was obtained. 1 H-NMR (500 MHz, CDCl 3 ): δ 2.85 - 2.94 (2H, m), 3.46 (3H, s), 3.47 (3H, s), 5.21 (2H, s), 5.23 (2H, s), 5.85 (1H, dd, J = 6.0, 10.5 Hz), 6.70 - 6.72 (2H, m), 7.10 (1H, t, J = 7.8 Hz), 7.15 (1H, d, J = 8.3 Hz), 7.26 - 7.34 (1H, m), 7.63 (1H, d, J = 7.8 Hz), 7.89 (1H, d, J = 8.3 Hz); 13 C-NMR (125 MHz, CDCl 3 ): δ 43.58 (t), 56.18 (q), 56.30 (q), 75.00 (d), 94.03 (t), 94.28 (t), 103.59 (d), 111.03 (d), 113.90 (d), 115.70 (s), 122.03 (d), 126.49 (d), 128.06 (s), 128.80 (d), 129.40 (d), 153.47 (s), 163.50 (s), 163.65 (s), 191.22 (s); LRMS (EI) m / z: 344 (M + ); IR (KBr) cm -1 : 1689.

[0128] [Example 13] 7-Methoxymethoxy-2-(3-(methoxymethoxy)phenyl)chroman-4-one (Ib-2) As the MOM-protected chalcone (Compound (Ia)), Compound (Ia-2) was used, and in the same manner as in Example 11, the title compound (yield: 70%) was obtained. 1 H-NMR (500 MHz, CDCl 3): δ 2.83 (1H, dd, J = 2.8 Hz, 16.7 Hz), 3.02 (1H, dd, J = 13.3, 16.7 Hz), 3.48 (3H, s), 3.49 (3H, s), 5.21 (4H, s), 5.43 (1H, dd, J = 2.8, 13.3 Hz), 6.70 (2H, d, J = 9.62 Hz), 7.05 (1H, dd, J = 2.3, 8.7 Hz), 7.10 (1H, d, J = 7.8 Hz), 7.16 (1H, s), 7.34 (1H, t, J = 7.8 Hz), 7.87 (1H, d, J = 8.7 Hz); 13 C-NMR(125 MHz, CDCl 3 ): δ 44.38 (t), 56.05 (q), 56.33 (q), 79.70 (d), 94.05 (t), 94.42 (t), 103.62 (d), 111.21 (d), 114.12 (d), 115.60 (s), 116.34 (d), 119.44 (d), 128.75 (d), 129.92 (d), 140.35 (s), 157.61 (s), 163.17 (s), 163.62 (s), 190.58 (s); LRMS(EI) m / z: 344 (M + ); IR(KBr) cm -1 : 1684.

[0129] [Example 14] 7-Methoxymethoxy-2-(4-(methoxymethoxy)phenyl)chroman-4-one (Ib-3) Using compound (Ia-3) as the MOM-protected chalcone (compound (Ia)), the title compound (yield: 72%) was obtained in the same manner as in Example 11. 1 H-NMR(500 MHz, CDCl 3): δ 2.80 (1H, dd, J = 2.8 Hz, 16.7 Hz), 3.04 (1H, dd, J = 13.3, 16.7 Hz), 3.47 (3H, s), 3.48 (3H, s), 5.19 (2H, s), 5.20 (2H, s), 5.41 (1H, dd, J = 2.8, 13.3 Hz), 6.67 (1H, d, J = 2.1 Hz), 6.70 (1H, dd, J = 2.3, 8.7 Hz), 7.09 (2H, d, J = 8.7 Hz), 7.40 (2H, d, J = 8.7 Hz), 7.87 (1H, d, J = 8.7 Hz); 13 C-NMR(125 MHz, CDCl 3 ): δ 44.18 (t), 56.02 (q), 56.34 (q), 79.61 (d), 94.05 (t), 94.32 (t), 103.60 (d), 111.13 (d), 115.60 (s), 116.45 (d), 127.65 (d), 128.76 (d), 132.02 (s), 157.53 (s), 163.30 (s), 163.62 (s), 190.86 (s); LRMS(EI) m / z: 344 (M + ); IR(KBr) cm -1 : 1687.

[0130] [Example 15] 7-Methoxymethoxy-2-(3,4-bis(methoxymethoxy)phenyl)chroman-4-one (Ib-4) Using compound (Ia-4) as the MOM-protected chalcone (compound (Ia)), the title compound (yield: 51%) was obtained in the same manner as in Example 11. 1 H-NMR(500 MHz, CDCl 3): δ 2.81 (1H, dd, J = 2.3 Hz, 16.7 Hz), 3.04 (1H, dd, J = 13.8, 16.7 Hz), 3.47 (3H, s), 3.52 (3H, s), 3.53 (3H, s), 5.20 (2H, s), 5.26 (2H, s), 5.27 (2H, s), 5.40 (1H, dd, J = 2.3, 13.8 Hz), 6.69 (1H, d, J = 2.3 Hz), 6.71 (1H, dd, J = 2.3, 8.7 Hz), 7.07 (1H, dd, J = 1.8, 8.3 Hz), 7.21 (2H, d, J = 8.3 Hz), 7.29 (1H, d, J = 2.3 Hz), 7.87 (1H, d, J = 8.7 Hz); 13 C-NMR (125 MHz, CDCl 3 ): δ 44.27 (t), 56.20 (q), 56.28 (q), 56.34 (q), 79.65 (d), 94.04 (t), 95.33 (t), 95.51 (t), 103.64 (d), 111.16 (d), 114.87 (s), 115.61 (d), 116.65 (d), 120.38 (d), 128.75 (d), 132.94 (s), 147.46 (s), 147.53 (s), 163.23 (s), 163.59 (s), 190.74 (s); LRMS (EI) m / z: 404 (M + ); IR (KBr) cm -1 : 1639.

[0131] [Example 16] 7-Methoxymethoxy-2-(2,3-bis(methoxymethoxy)phenyl)chroman-4-one (Ib-5) Using compound (Ia-5) as the MOM-protected chalcone (compound (Ia)), the title compound (yield: 74%) was obtained in the same manner as in Example 11. 1 H-NMR (500 MHz, CDCl 3): δ 2.93 - 2.95 (2H, m), 3.48 (3H, s), 3.49 (3H, s), 3.51 (3H, s), 5.15 (2H, s), 5.20 (2H, s), 5.21 (2H, s), 5.91 (1H, dd, J = 5.5, 10.5 Hz), 6.68 (1H, d, J = 2.3 Hz), 6.71 (1H, dd, J = 2.3, 8.7 Hz), 7.13 - 7.19 (2H, m), 7.29 (1H, dd, J = 2.3, 8.7 Hz), 7.89 (1H, d, J = 8.7 Hz); 13 C-NMR(125 MHz, CDCl 3 ): δ 43.75 (t), 56.30 (q), 56.33 (q), 57.56 (q), 75.08 (d), 94.06 (t), 95.15 (t), 99.35 (t), 103.61 (d), 111.05 (d), 115.65 (s), 116.52 (d), 119.84 (d), 124.86 (d), 128.84 (d), 133.44 (s), 143.98 (s), 149.56 (s), 163.52 (s), 163.55 (s), 191.05 (s); LRMS(EI) m / z: 404 (M + ); IR(KBr) cm -1 : 1685.

[0132] [Example 17] 7-Methoxymethoxy-2-(2,5-bis(methoxymethoxy)phenyl)chroman-4-one (Ib-6) Using compound (Ia-6) as the MOM-protected chalcone (compound (Ia)), in the same manner as in Example 11, the title compound (yield: 75%) was obtained. 1 H-NMR(500 MHz, CDCl 3): δ 2.84 - 2.94 (2H, m), 3.45 (3H, s), 3.48 (3H, s), 3.50 (3H, s), 5.15 (2H, s), 5.17 (2H, s), 5.21 (2H, s), 5.81 (1H, dd, J = 4.6, 11.9 Hz), 6.71 (1H, s), 6.72 (1H, d, J = 2.3 Hz), 6.99 (1H, dd, J = 2.3, 8.7 Hz), 7.09 (1H, d, J = 8.7 Hz), 7.32 (1H, d, J = 2.3 Hz), 7.89 (1H, d, J = 8.7 Hz); 13 C-NMR(125 MHz, CDCl 3 ): δ 43.58 (t), 55.96 (q), 56.12 (q), 56.34 (q), 74.95 (d), 94.07 (t), 94.91 (t), 95.08 (t), 103.66 (d), 111.13 (d), 114.94 (d), 115.31 (d), 115.71 (s), 116.83 (d), 128.81 (d), 129.31 (s), 148.47 (s), 152.30 (s), 163.53 (s), 163.57 (s), 191.15 (s); LRMS(EI) m / z: 404 (M + ); IR(KBr) cm -1 : 1684.

[0133] [Example 18] 7 - Methoxymethoxy - 2 - (3,4,5 - tris(methoxymethoxy)phenyl)chroman - 4 - one (Ib - 7) Using compound (Ia - 8) as the MOM - protected chalcone (compound (Ia)), the title compound (yield: 59%) was obtained in the same manner as in Example 11. 1 H - NMR(500 MHz, CDCl 3): δ 2.81 (1H, dd, J = 2.8, 16.7 Hz), 3.02 (1H, dd, J = 13.8, 16.7 Hz), 3.48 (3H, s), 3.51 (3H, s), 3.63 (3H, s), 5.17 (4H, s), 5.19 (4H, m), 5.37 (1H, dd, J = 2.8, 13.8 Hz), 6.70 (1H, dd, J = 2.3, 4.6 Hz), 6.72 (1H, d, J = 2.3 Hz), 6.97 (2H, s), 7.87 (1H, d, J = 8.7 Hz); 13 C-NMR (125 MHz, CDCl 3 ): δ 44.43 (t), 56.31 (q), 56.35 (q), 57.15 (q), 79.82 (d), 94.05 (t), 95.36 (t), 98.50 (t), 103.66 (d), 108.26 (d), 111.24 (d), 115.60 (s), 128.75 (d), 134.88 (s), 136.59 (s), 151.32 (s), 163.15 (s), 163.59 (s), 190.61 (s); IR (KBr) cm -1 : 1684; LRMS (EI) m / z: 464 (M + ).

[0134] Comparative study of reaction conditions in the conversion reaction from MOM-protected chalcone (Compound (Ia)) to MOM-protected flavanones (Compound (Ib)) Using the MOM-protected chalcone (Compound (Ia)), Compound (Ia-4), the yields of Compound (Ib-4) under various reaction conditions were compared and studied. The results are shown in Table 1 below.

[0135]

Table 1

[0136] According to the results in Table 1, it was confirmed that Compound (Ib-4) can be obtained with the highest yield by performing the oxy-Michael reaction under the reaction conditions of Example 11.

[0137] [Example 19] General synthetic method of hydroxylated flavanones (Compound (IIb)) To a solution of MOM-protected flavanone (Compound (Ib)) (1.00 mmol) in acetonitrile-methanol (50:1, 1 mL), bismuth chloride (28 mg, 0.089 mmol) was added, and the mixture was stirred at 50 - 60 °C for 1 hour to overnight. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain hydroxylated flavanone (Compound (IIb)).

[0138] [Example 20] 7-Hydroxy-2-(2-hydroxyphenyl)chroman-4-one (IIb-1) Using Compound (Ib-1) as the MOM-protected flavanone (Compound (Ib)), the title compound (yield: 49%) was obtained in the same manner as in Example 19. 1 H-NMR (500 MHz, CD 3 OD): δ 2.80 - 2.93 (2H, m), 5.75 (1H, dd, J = 3.2 Hz, 12.7 Hz), 6.41 (1H, d, J = 2.3 Hz), 6.51 (1H, dd, J = 2.3, 8.7 Hz), 6.82 (1H, d, J = 8.7 Hz), 6.89 (1H, t, J = 7.5 Hz), 7.16 (1H, dt, J = 1.7 Hz, 7.5 Hz), 7.49 (1H, d, J = 7.5 Hz), 7.74 (1H, d, J = 8.7 Hz); 13 C-NMR (125 MHz, CD 3 OD): δ 43.97 (t), 76.50 (d), 103.85 (d), 111.77 (d), 114.99 (s), 116.16 (d), 120.66 (d), 127.04 (s), 127.54 (d), 129.93 (d), 130.19 (d), 155.20 (s), 165.88 (s), 166.75 (s), 193.81 (s); IR (KBr) cm -1 : 3400, 1658; LRMS (EI) m / z: 256 (M + ).

[0139] [Example 21] 7-Hydroxy-2-(3-hydroxyphenyl)chroman-4-one (IIb-2) Using the MOM-protected flavanone (Compound (Ib)), Compound (Ib-2), in the same manner as in Example 19, the title compound (yield: 82%) was obtained. 1 H-NMR (500 MHz, CD 3 OD): δ 2.73 (1H, dd, J = 3.2, 16.7 Hz), 2.97 (1H, dd, J = 12.8, 16.7 Hz), 5.39 (1H, dd, J = 3.2, 12.8 Hz), 6.38 (1H, d, J = 2.3 Hz), 6.50 (1H, dd, J = 2.3, 8.7 Hz), 6.77 (1H, d, J = 7.3 Hz), 6.92 (1H, d, J = 6.4 Hz), 7.20 (1H, t, J = 7.3 Hz, 8.7 Hz), 7.72 (1H, d, J = 8.7 Hz); 13 C-NMR (125 MHz, CD 3 OD): δ 45.06 (t), 80.77 (d), 103.80 (d), 111.78 (d), 113.98 (d), 114.91 (s), 116.32 (d), 118.21 (d), 129.81 (d), 130.68 (d), 141.98 (s), 158.71 (s), 165.25 (s), 166.72 (s), 192.97 (s); IR (KBr) cm -1 : 3410, 1651; LRMS (EI) m / z: 256 (M + ).

[0140] [Example 22] 7-Hydroxy-2-(4-hydroxyphenyl)chroman-4-one (IIb-3) Using the MOM-protected flavanone (Compound (Ib)), Compound (Ib-3), in the same manner as in Example 19, the title compound (yield: 69%) was obtained. 1 H-NMR (500 MHz, CD 31H-NMR (500 MHz, CD3OD): δ 2.67 (1H, dd, J = 2.8, 16.7 Hz), 3.02 (1H, dd, J = 13.3, 16.7 Hz), 5.34 (1H, dd, J = 2.8, 13.3 Hz), 6.34 (1H, d, J = 2.3 Hz), 6.49 (1H, dd, J = 2.3, 8.7 Hz), 6.81 (1H, d, J = 8.7 Hz), 7.30 (1H, d, J = 8.7 Hz), 7.71 (1H, d, J = 8.7 Hz); 13 13C-NMR (125 MHz, CD 3 3OD): δ 43.53 (t), 79.59 (d), 102.45 (d), 110.37 (d), 113.56 (s), 114.92 (d), 127.63 (d), 128.50 (d), 129.90 (s), 157.53 (s), 164.15 (s), 165.35 (s), 192.15 (s); IR (KBr) cm -1 -1: 3242, 1655; LRMS (EI) m / z: 256 (M + +).

[0141] [Example 23] 7-Hydroxy-2-(3,4-dihydroxyphenyl)chroman-4-one (IIb-4) Using the MOM-protected flavanone (Compound (Ib)), Compound (Ib-4), in the same manner as in Example 19, the title compound (yield: 71%) was obtained. 1 1H-NMR (500 MHz, CD 3 3OD): δ 2.69 (1H, dd, J = 2.8, 16.7 Hz), 3.00 (1H, dd, J = 13.3, 16.7 Hz), 5.31 (1H, dd, J = 2.8, 13.3 Hz), 6.35 (1H, d, J = 2.3 Hz), 6.49 (1H, dd, J = 2.3, 8.7 Hz), 6.79 (2H, d, J = 1.5 Hz), 6.92 (1H, d, J = 1.5 Hz), 7.72 (1H, d, J = 8.7 Hz); 13 13C-NMR (125 MHz, CD 3OD): δ 44.94 (t), 80.97 (d), 103.78 (d), 111.69 (d), 114.63 (d), 114.89 (s), 116.19 (d), 119.16 (d), 129.79 (d), 131.89 (s), 146.39 (s), 146.72 (s), 165.44 (s), 166.68 (s), 193.48 (s); IR (KBr) cm -1 : 3435, 1658; LRMS (EI) m / z: 272 (M + ).

[0142] [Example 24] 7-Hydroxy-2-(2,3-dihydroxyphenyl)chroman-4-one (IIb-5) As the MOM-protected flavanone (Compound (Ib)), using Compound (Ib-5), in the same manner as in Example 19, the title compound (yield: 70%) was obtained. 1 H-NMR (500 MHz, CD 3 OD): δ 2.80 (1H, dd, J = 2.8, 16.7 Hz), 2.93 (1H, dd, J = 13.3, 16.7 Hz), 5.76 (1H, dd, J = 2.8, 13.3 Hz), 6.39 (1H, d, J = 1.8 Hz), 6.50 (1H, dd, J = 1.8, 8.7 Hz), 6.73 (1H, t, J = 8.0 Hz), 6.78 (1H, dd, J = 1.8, 8.0 Hz), 6.98 (1H, dd, J = 1.8, 8.0 Hz), 7.74 (1H, d, J = 8.7 Hz); 13 C-NMR (125 MHz, CD 3 OD): δ 43.92 (t), 76.46 (d), 103.79 (d), 110.70 (d), 114.93 (s), 115.75 (d), 118.09 (d), 120.53 (d), 127.26 (s), 129.87 (d), 143.55 (s), 146.09 (s), 165.81 (s), 166.65 (s), 193.77 (s); IR (KBr) cm -1 : 3367, 1662; LRMS (EI) m / z: 272 (M +).

[0143] [Example 25] 7-Hydroxy-2-(2,5-dihydroxyphenyl)chroman-4-one (IIb-6) To a solution of compound (Ib-6) (311 mg, 0.769 mmol) in acetonitrile (6 mL) were added bismuth chloride (315 mg, 1.00 mmol) and sodium iodide (346 mg, 2.31 mmol), and the mixture was refluxed for 4.5 hours. Acetonitrile was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [benzene-ethyl acetate (4:1)] to obtain the title compound (152 mg, 73%). 1 H-NMR (500 MHz, CD 3 OD): δ 2.81 - 2.89 (2H, m), 5.70 (1H, dd, J = 5.0, 11.0 Hz), 6.41 (1H, d, J = 2.3 Hz), 6.51 (1H, dd, J = 2.3, 8.7 Hz), 6.62 (1H, dd, J = 3.2, 8.7 Hz), 6.67 (1H, d, J = 8.7 Hz), 6.96 (1H, d, J = 3.2 Hz), 7.74 (1H, d, J = 8.7 Hz); 13 C-NMR (125 MHz, CD 3 OD): δ 43.99 (t), 76.44 (d), 103.85 (d), 111.78 (d), 113.99 (d), 114.97 (s), 116.60 (d), 117.07 (d), 127.81 (s), 129.94 (d), 147.92 (s), 151.33 (s), 165.78 (s), 166.73 (s), 193.77 (s); IR (KBr) cm -1 : 3400, 1664; LRMS (EI) m / z: 272 (M + ).

[0144] Comparative study of deprotection conditions of MOM-protected flavanone (Compound (Ib)) As the MOM-protected flavanone (compound (Ib)), compound (Ib-4) was used, and the yield of compound (IIb-4) and the presence or absence of by-production of compound (IIa-4) under various reaction conditions, including the reaction conditions of Example 19, were compared and studied. The results are shown in Table 2 below.

[0145] [Table 2]

[0146] According to the results in Table 2, when bismuth chloride was used, only compound (IIb-4) was obtained without by-production of compound (IIa-4), whereas when hydrochloric acid or p-toluenesulfonic acid was used, compound (IIb-4) was obtained in a high yield, but it was also found that compound (IIa-4), which was difficult to separate, was by-produced. Further, when trifluoroacetic acid was used, the yield of compound (IIb-4) was significantly reduced. From the above, according to the production method of the present invention using bismuth chloride, since compound (IIb-4) can be obtained in high purity and high yield, the isolation and purification operation can be easily performed.

[0147] [Example 26] General synthesis method of hydroxylated chalcones (compound (IIa)) To a solution of MOM-protected chalcone (compound (Ia)) (1.00 mmol) in acetonitrile-methanol (50:1, 1 mL), bismuth chloride (2.0 mmol) was added, and the mixture was stirred at 60 - 80 °C for 1 hour to overnight. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain hydroxylated chalcone (compound (IIa)).

[0148] [Example 27] (E)-1-(2,4-Dihydroxyphenyl)-3-(2-hydroxyphenyl)-2-propen-1-one (IIa-1) Using compound (Ia-1) as the MOM-protected chalcone (compound (Ia)), the title compound (yield: 57%) was obtained in the same manner as in Example 26. 1 H-NMR (500 MHz, CD 3 OD): δ 6.30 (1H, d, J = 2.3 Hz), 6.41 (1H, dd, J = 2.3, 8.7 Hz), 6.78 - 6.90 (2H, m), 7.23 (1H, dd, J = 1.4, 7.8 Hz), 7.66 (1H, d, J = 7.3), 7.87 (1H, d, J = 15.6 Hz), 7.92 (1H, d, J = 8.7 Hz), 8.14 (1H, d, J = 15.6 Hz); 13 C-NMR (125 MHz, CD 3 OD): δ 103.85 (d), 109.14 (d), 114.80 (s), 117.11 (d), 120.85 (d), 121.41 (d), 123.27 (s), 130.68 (d), 132.83 (d), 133.33 (d), 141.43 (d), 158.81 (s), 166.37 (s), 167.54 (s), 194.00 (s); IR (KBr) cm -1 : 1627, 3338.

[0149] [Example 28] (E)-1-(2,4-Dihydroxyphenyl)-3-(3-hydroxyphenyl)-2-propen-1-one (IIa-2) Using the MOM-protected chalcone (compound (Ia)), compound (Ia-2), in the same manner as in Example 26, the title compound (yield: 61%) was obtained. 1 H-NMR (500 MHz, CD 3 OD): δ 6.31 (1H, d, J = 1.9 Hz), 6.43 (1H, dd, J = 2.3, 9.2 Hz), 6.87 (1H, d, J = 8.7 Hz), 7.12 (1H, s), 7.19 - 7.26 (2H, m), 7.69 (1H, d, J = 15.6 Hz), 7.75 (1H, d, J = 15.6 Hz), 7.94 (1H, d, J = 8.7 Hz); 13 C-NMR (125 MHz, CD 3 OD): δ 103.84 (d), 109.26 (d), 114.64 (s), 115.84 (d), 118.79 (d), 121.23 (d), 121.67 (d), 131.00 (d), 133.45 (d), 137.58 (s), 145.30 (d), 158.99 (s), 166.57 (s), 167.57 (s), 193.28 (s); IR (KBr) cm -1 : 1643, 3298.

[0150] [Example 29] (E)-1-(2,4-Dihydroxyphenyl)-3-(4-hydroxyphenyl)-2-propen-1-one (IIa-3) Using the MOM-protected chalcone (Compound (Ia)), Compound (Ia-3), in the same manner as in Example 26, the title compound (yield: 52%) was obtained. 1 H-NMR (500 MHz, CD 3 OD): δ 6.29 (1H, d, J = 2.3 Hz), 6.41 (1H, dd, J = 2.3, 8.7 Hz), 6.84 (2H, d, J = 8.7 Hz), 7.61 (1H, d, J = 15.1 Hz), 7.61 (2H, d, J = 8.7 Hz), 7.79 (1H, d, J = 15.1 Hz), 7.96 (1H, d, J = 8.7 Hz); 13 C-NMR (125 MHz, CD 3 OD): δ 103.81 (d), 109.10 (d), 114.70 (s), 116.89 (d), 118.32 (d), 127.81 (s), 131.77 (d), 133.31 (d), 145.62 (d), 161.51 (s), 166.30 (S), 167.47 (s), 193.47 (s); IR (KBr) cm -1: 1626, 3390.

[0151] [Example 30] (E)-1-(2,4-Dihydroxyphenyl)-3-(3,4-dihydroxyphenyl)-2-propen-1-one (IIa-4) Using compound (Ia-4) as the MOM-protected chalcone (compound (Ia)), the title compound (yield: 32%) was obtained in the same manner as in Example 26. 1 H-NMR (500 MHz, CD 3 OD): δ 6.29 (1H, d, J = 2.3 Hz), 6.41 (1H, dd, J = 2.3, 8.7 Hz), 6.81 (1H, d, J = 8.2 Hz), 7.09 (1H, dd, J = 1.4, 8.2 Hz), 7.17 (1H, d, J = 1.4 Hz), 7.52 (1H, d, J = 15.6 Hz), 7.72 (1H, d, J = 15.6 Hz), 7.92 (1H, d, J = 9.2 Hz); 13 C-NMR (125 MHz, CD 3 OD): δ 103.81 (d), 109.05 (d), 114.64 (s), 115.69 (d), 116.51 (d), 118.20 (d), 123.53 (d), 128.30 (s), 133.12 (d), 146.02 (d), 146.71 (s), 149.78 (s), 166.19 (s), 167.38 (s), 193.31 (s); IR (KBr) cm -1 : 1633, 3238.

[0152] [Example 31] (E)-1-(2,4-Dihydroxyphenyl)-3-(3,4-dimethoxyphenyl)-2-propen-1-one (IIa-5) Using compound (Ia-9) as the MOM-protected chalcone (compound (Ia)), the title compound (yield: 95%) was obtained in the same manner as in Example 26. 1H-NMR (500 MHz, CD 3 OD): δ 6.28 (1H, d, J = 2.3 Hz), 6.40 (1H, dd, J = 2.3, 8.7 Hz), 6.98 (1H, d, J = 8.2 Hz), 7.28 (1H, d, J = 8.2 Hz), 7.36 (1H, s), 7.65 (1H, d, J = 15.6 Hz), 7.78 (1H, d, J = 15.6 Hz), 8.00 (1H, d, J = 8.7 Hz); 13 C-NMR (125 MHz, CD 3 OD): δ 56.27 (q), 56.43 (q), 103.68 (d), 108.97 (d), 111.71 (d), 112.42 (d), 114.52 (s), 119.37 (d), 124.65 (d), 129.25 (s), 133.26 (d), 145.27 (d), 150.57 (s), 152.81 (s), 166.17 (s), 167.33 (s), 193.09 (s); IR (KBr) cm -1 : 1629, 3188.

[0153] Comparative study of deprotection conditions of MOM-protected chalcone (Compound (Ia)) As the MOM-protected chalcone (compound (Ia)), compound (Ia-4) was used, and the yield of compound (IIa-4) and the presence or absence of by-production of compound (IIb-4) under various reaction conditions, including the reaction conditions of Example 26, were comparatively examined. The results are shown in Table 3 below.

[0154]

Table 3

[0155] According to the results in Table 3, when bismuth chloride was used, no by-production of compound (IIb-4) was observed. However, when other acids were used, a considerable amount of compound (IIb-4) in which the oxy-Michael addition reaction proceeded in addition to the deprotection reaction was by-produced, or decomposition products were obtained. From the above, it was found that only compound (IIa-4) can be obtained without by-producing compound (IIb-4) which is difficult to separate and purify by using the production method of the present invention.

Industrial Applicability

[0156] According to the production method of the present invention, only hydroxylated chalcones can be obtained in good yield from chalcones having a hydroxy group protected with a MOM group without proceeding an oxy-Michael addition reaction. Further, according to the production method of the present invention, chalcones having a hydroxy group protected with a MOM group are treated with an aqueous solution of disodium hydrogen phosphate (Na 2 HPO 4 ) to carry out an oxy-Michael addition reaction, whereby flavanones having a hydroxy group protected with a MOM group can be obtained in good yield, and only hydroxylated flavanones can be selectively obtained in good yield by deprotecting the obtained flavanones having a MOM group. Furthermore, according to the present invention, novel MOM-protected chalcones and MOM-protected flavanones used in the production method of the present invention, and novel hydroxylated flavanones obtained by the production method can be provided.

[0157] This application is based on Japanese Patent Application No. 2020-043830 filed on Mar. 13, 2020 in Japan, the contents of which are incorporated herein in their entirety.

Claims

1. Formula (II): 【Chemical 1】 〔Wherein, R and R' each represent a hydrogen atom, or R and R' together form a single bond; A−B represents a carbon-carbon single bond or a carbon-carbon double bond; m Rs １ each independently represents a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, or a haloalkoxy group; R ２ , R ３ and R ４ each independently represents a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group or a haloalkoxy group; n represents an integer from 0 to 3; m represents an integer from 2 to 5; and n + m is 5.〕 A method for producing a compound represented by the following formula (I): 【Chemical 2】 〔Each symbol in the formula has the same meaning as described above.〕 The method is characterized by including a step of reacting a compound represented by the formula with bismuth chloride in a mixed solvent of acetonitrile and methanol at 50 - 60 °C or 60 - 80 °C. However, when R and R' in the formula (I) and formula (II) are both hydrogen atoms, A−B represents a carbon-carbon double bond, and when R and R' in the formula (I) and formula (II) together form a single bond, A−B represents a carbon-carbon single bond.

2. When R and R' in the formula (I) and formula (II) are both hydrogen atoms, the following formula (III): 【Chemical Formula 3】 〔Each symbol in the formula has the same meaning as described above.〕 A compound represented by the formula is condensed with a compound represented by the following formula (IV): [Chemical Formula 4] 〔Each symbol in the formula has the same meaning as described above.〕 The production method according to claim 1, further including a step of converting the compound represented by the formula (I).

3. When R and R' in the formula (I) and formula (II) together form a single bond, the following formula (III): [Chemical Formula 5] 〔Each symbol in the formula has the same meaning as described above.〕 A compound represented by the formula is condensed with a compound represented by the following formula (IV): [Chemical Formula 6] 〔Each symbol in the formula has the same meaning as described above.〕 To convert to a compound represented by the following formula (Ia): 【Chemical Formula 7】 〔Each symbol in the formula has the same meaning as described above.〕 And a step of converting the compound represented by the formula (Ia) into a compound represented by the formula (I) [wherein R and R' in the formula together form a single bond] by treating the compound with an aqueous solution of disodium hydrogen phosphate The production method according to claim 1, further including

4. A compound represented by the following formula: [Chemical Formula 8]

5. A compound represented by the following formula: 【Chemical Formula 9】

6. A compound represented by the following formula: 【Chemical Formula 10】 ​

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