KR20210037384A - Dimethylchalcone derivatives and preparation method thereof - Google Patents

Abstract

The present invention relates to a dimethylchalcone (DMC) derivative and a method for preparing the same. A compound according to the present invention is represented by chemical formula I, wherein R1, R2 and R3 are the same or different, R1 represents a hydroxyl group or a methoxy group, each of R2 and R3 is independently selected from the group consisting of H, deuterium, hydroxyl, thiol, amino, substituted or non-substituted (C1-C10 alkyl)amino, substituted or non-substituted C1-C10 alkoxy, substituted or non-substituted C1-C10 alkyl, substituted or non-substituted C2-C10 alkenyl, substituted or non-substituted C2-C10 alkynyl, and substituted or non-substituted C6-C20 aryl groups, and the 'substituted or non-substituted' expression means that the corresponding group is substituted or non-substituted with at least one substituent selected from the group consisting of halogen, nitrile, nitro, hydroxyl, carbonyl, ester, imide, amino, phosphine oxide, alkoxy, aryloxy, alkylthioxy, arylthioxy, alkylsulfoxy, arylsulfoxy, silyl, boron, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, alkylaryl, alkylamine, aralkylamine, heteroarylamine, arylamine, aryl phosphine, and heterocyclic groups.

Description

Dimethylchalcone derivative and its manufacturing method {DIMETHYLCHALCONE DERIVATIVES AND PREPARATION METHOD THEREOF}

The present invention relates to a dimethylchalcone (DMC) derivative and a method for preparing the same, and a high yield through a simple process using inexpensive phloroglucinol derivatives having various substituted chalcone structures as a starting material. It includes a method of making it easy to use.

Various substances extracted from natural plants have had a tremendous effect on the treatment of human diseases. However, in the case of ingestion of natural products, the amount is limited in response to demand, and side effects or effects cannot be changed through control of specific ingredients, so the production of pharmaceuticals that will replace natural products through total synthesis research is essential.

2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone, DMC) It is a chalcone compound and has an aromatic ketone skeleton. It is typically extracted from Cleistocalyx operculatus flower buds, and has been found to have various biological activities such as anti-tumor agents and anti-inflammatory agents.

As such, DMC having a biological value has a lot of interest and various pharmacological studies are being conducted, but only studies of the DMC substance itself exist, and studies on the properties of the DMC derivatives have not been properly conducted yet.

In addition, since the distribution of Cleistocalyx operculatus itself is rare, and the content of DMC extraction from Cleistocalyx operculatus is very low, there is a limitation in conducting in-depth pharmacological research due to insufficient production. In addition, in the case of previous studies on DMC synthesis, which has already been reported, most of the studies that not only require the use of expensive acetophenone-based compounds as starting materials, but also have a total yield of less than 7%.

Therefore, design an economical and efficient synthesis route of DMC and DMC derivatives using inexpensive reactants, produce various derivatives through functional group change, and develop a new manufacturing method that can maximize the efficacy of DMC and its derivatives. Research is needed.

European Patent Publication EP0328669 A1

Although the present invention is industrially useful, various dimethylchalcone derivatives that have not yet been synthesized are prepared, and the derivative is prepared in high yield through a simple process using inexpensive phloroglucinol as a starting material. I want to provide a way.

A compound according to an embodiment of the present invention is represented by the following formula (I).

[Formula I]

In Formula I,

R1, R2, and R3 are the same as or different from each other, R1 is a hydroxy group or a methoxy group, and R2, and R3 are each independently hydrogen, deuterium, a hydroxy group, a thiol group, an amino group, a substituted or unsubstituted (C1-C10 alkyl) amino group, substituted or unsubstituted C1-C10 alkoxy group, substituted or unsubstituted C1-C10 alkyl group, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl , A substituted or unsubstituted C6-C20 aryl group, and the'substituted or unsubstituted' is a halogen group, a nitrile group, a nitro group, a hydroxy group, a carbonyl group, an ester group, an imide group, an amino group, Phosphine oxide group, alkoxy group, aryloxy group, alkylthioxy group, arylthioxy group, alkylsulfoxy group, arylsulfoxy group, silyl group, boron group, alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group , Aralkenyl group, alkylaryl group, alkylamine group. It is unsubstituted or substituted with one or more substituents selected from the group consisting of aralkylamine group, heteroarylamine group, arylamine group, arylphosphine group, and heterocyclic group.

A compound according to an embodiment of the present invention may be represented by the following formula (II).

[Formula II]

In Formula II, R2 and R3 are the same as defined in Formula I.

The compound according to an embodiment of the present invention may be any one of the compounds represented by the following formulas II-1 to II-7.

[Formula II-1]

[Formula II-2]

[Formula II-3]

[Formula II-4]

[Formula II-5]

[Formula II-6]

[Formula II-7]

.

.

A compound according to an embodiment of the present invention may be represented by the following formula (III).

[Formula III]

In Formula III, R2 and R3 are the same as defined in Formula I.

The compound according to an embodiment of the present invention may be any one of the compounds represented by the following formulas III-1 to III-7.

[Formula III-1]

[Formula III-2]

[Formula III-3]

[Formula III-4]

[Formula III-5]

[Formula III-6]

[Formula III-7]

.

.

A method of preparing a compound represented by Formula II according to an embodiment of the present invention includes a reaction 3/4 step of synthesizing a compound represented by Formula E from a compound represented by Formula C below; And a reaction step 5-1 of synthesizing a compound represented by the following formula II from the compound represented by the following formula E; Includes.

[Formula C]

[Formula E]

[Formula II]

In Formula II, R2 and R3 are the same as defined in Formula I.

A method for preparing a compound represented by Formula II according to an embodiment of the present invention may include a first step of synthesizing a compound represented by the following B from a compound represented by the following Formula A before step 3 of the reaction; And it may further include a reaction step 2 of synthesizing the compound represented by the formula (C) from the compound represented by the following B.

[Formula A]

[Formula B]

.

.

In the method for preparing a compound represented by Formula II according to an embodiment of the present invention, step 3/4 of the reaction includes a step 3 of synthesizing a compound represented by Formula D from the compound represented by Formula C; And a reaction step 4 of synthesizing the compound represented by Formula E from the compound represented by Formula D below. It may further include.

[Formula D]

A method of preparing a compound represented by Formula III according to an embodiment of the present invention comprises: 3 steps of synthesizing a compound represented by Formula D from a compound represented by Formula C; Reaction 4/(5-2) step of synthesizing a compound represented by Formula F below from a compound represented by Formula D below; And a reaction step 6 of synthesizing a compound represented by the following formula (III) from the compound represented by the following formula (F).

[Formula C]

[Formula D]

[Formula F]

[Formula III]

In Formula III, R2 and R3 are the same as defined in Formula I.

In a method for preparing a compound represented by Formula III according to an embodiment of the present invention, prior to step 3 of the reaction, a reaction step 1 of synthesizing a compound represented by Formula B from a compound represented by Formula A below; And it may further include a reaction step 2 of synthesizing the compound represented by the formula (C) from the compound represented by the following formula (B).

[Formula A]

[Formula B]

.

.

In the method of preparing a compound represented by Formula III according to an embodiment of the present invention, the reaction step 4/(5-2) is a reaction step 4 of synthesizing a compound represented by Compound E below from the compound represented by Formula D. ; And a reaction step 5-2 of synthesizing the compound represented by compound F from the compound represented by compound E below.

[Formula E]

.

.

The examples of the present invention are industrially useful, but have not yet been reported to be synthesized, and prepare various dimethylchalcone derivatives, and use the derivative as a starting material, such as phloroglucinol, as a starting material, resulting in high yield through a simple process. It provides a method of manufacturing.

Hereinafter, the present invention will be described in more detail through examples. Since these examples are for illustrative purposes only, the scope of the present invention is not to be construed as being limited by these examples.

Expressions such as "comprising" used herein are understood as open-ended terms including the possibility of including other embodiments, unless specifically stated otherwise in the phrase or sentence in which the expression is included. It should be.

As used herein, "preferable" and "preferably" refer to embodiments of the present invention that may provide certain advantages under certain circumstances. However, under the same or different circumstances, other embodiments may also be desirable. Additionally, reference to one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the present invention.

An embodiment of the present invention uses inexpensive phloroglucinol as a starting material to make acetophenone material and uses a Claisen-Schmidt reaction between this compound and various benzaldehydes. To synthesize dimethylchalcone and its derivatives. This provides a much more efficient and economical synthesis method than extracting from the plant itself. In addition, by preparing dimethylchalcone derivatives having various functional groups such as electron donating group (EDG) and electron withdrawing group (EWG), the pharmacological effect is better than the existing DMC or less toxic compounds can be synthesized and applied. I can. This will be described in detail below.

A compound according to an embodiment of the present invention is represented by the following formula (I).

[Formula I]

In Formula I, R1, R2, and R3 are the same as or different from each other, R1 is a hydroxy group or a methoxy group, and R2, and R3 are each independently hydrogen, deuterium, a hydroxy group, a thiol group, an amino group, Substituted or unsubstituted (C1-C10 alkyl) amino group, substituted or unsubstituted C1-C10 alkoxy group, substituted or unsubstituted C1-C10 alkyl group, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, a substituted or unsubstituted C6-C20 aryl group, and the'substituted or unsubstituted' is a halogen group, a nitrile group, a nitro group, a hydroxy group, a carbonyl group, an ester group, Imide group, amino group, phosphine oxide group, alkoxy group, aryloxy group, alkylthioxy group, arylthioxy group, alkylsulfoxy group, arylsulfoxy group, silyl group, boron group, alkyl group, cycloalkyl group, alkenyl group, alkynyl group, Aryl group, aralkyl group, aralkenyl group, alkylaryl group, alkylamine group. It is unsubstituted or substituted with one or more substituents selected from the group consisting of an aralkylamine group, a heteroarylamine group, an arylamine group, an arylphosphine group, and a heterocyclic group.

According to the manufacturing method to be described below, when R1 is a hydroxy group, a compound represented by Formula II is prepared from a compound represented by Formula E, or R1 is a methoxy group, a compound represented by Formula F is used to prepare a compound represented by Formula III. When preparing the compound represented by the Claisen-Schmidt reaction (Claisen-Schmidt Reaction) may be carried out. At this time, the reactant becomes benzaldehyde in which R2 and R3 are substituted or unsubstituted. R2 and R3 are not particularly limited as long as the Klaigen-Schmidt reaction can proceed.

The reactants and products of each reaction step according to an embodiment of the present invention may be the compounds listed below.

[Formula A]

[Formula B]

[Formula C]

[Formula D]

[Formula E]

[Formula F]

[Formula II]

[Formula III]

However, if it is not an essential reaction step, reactants and products other than the above-listed reactants and products may react or be produced. Unless it is an essential reaction step, all reactants of the essential reaction step and reactants capable of producing a product are allowed. In addition, if it is not an essential reaction step, any product that can be produced from the reactant and product of the essential reaction step is acceptable.

In the method of preparing a compound represented by Formula II, an essential reaction step is a reaction step 3/4 of synthesizing the compound represented by Formula E from the compound represented by Formula C, and the Formula E from the compound represented by Formula E. The reaction becomes step 5-1 to synthesize the compound represented by II.

In the method for preparing a compound represented by Formula III, the essential reaction step is a reaction step 3 of synthesizing the compound represented by Formula D from the compound represented by Formula C, and represented by Formula F from the compound represented by Formula D. Step 4/(5-2) of synthesizing the compound to be formed, and step 6 of the reaction of synthesizing the compound represented by Formula III from the compound represented by Formula F.

A reaction route I including essential and non-essential reaction steps in a method for preparing a compound represented by Formula II according to an embodiment of the present invention is as follows.

<Reaction route I>

A reaction route II including essential and non-essential reaction steps in a method for preparing a compound represented by Formula III according to an embodiment of the present invention is as follows.

<Reaction route II>

As an embodiment of the present invention, step 1 of the reaction is a step of synthesizing compound B from compound A, and may proceed as follows. Since the compound A is a compound that can be purchased relatively inexpensively, the desired product of the present invention can be economically prepared by using it.

<Reaction Step 1>

As an example, in the first step of the reaction, diformylation may be performed first in order to substitute dimethyl for phloroglucinol. Conventionally, the formylation reaction was carried out using 2',4',6'-trihydroxyacetophenone as a starting material, but the yield of 2',4',6'-trihydroxy-3',5'-diformylacetophenone was remarkably low. Accordingly, compound B can be synthesized using phloroglucinol, which is cheaper and can obtain a high yield, as a starting material. In this reaction, dimethylformamide and phosphorus(V) oxychloride are first stirred to make a Vilsmeier reaction reagent, which is a chloroiminium ion, and then a reaction reagent made in phloroglucinol dissolved in 1,4-dioxane is added and stirred together to synthesize compound B. After synthesis, it can be precipitated with water and dried without any other purification process. However, since the next process, methylation of the hydroxyl group, is sensitive to moisture, it is more preferable to proceed with the next reaction after removing the fine moisture using _{MgSO 4.}

As an embodiment of the present invention, reactions 2 and 3 are steps of synthesizing compound D from compound B through compound C and may proceed as follows.

<Reaction 2 and 3>

The reduction reaction of converting a diformyl compound to a dimethyl compound _{can be performed by using NaBH 3} CN as a reactant and a method using _{zinc amalgam made by mixing HgCl 2} and Zinc as a reactant. In the former case, the final yield after going through the reaction optimization process was only a maximum of 45%. This is because the generation of a lot of heat in the course of the reaction can affect the yield of the product. In addition, considering mass production, _{since the price of the reactant for NaBH 3} CN is relatively expensive, it is more preferable to use zinc amalgam, which is excellent both in terms of economy and efficiency of reaction. However, there is no particular limitation as long as the reaction can proceed.

The conversion rate of the reduction reaction was measured to reach at least 90-95% through GC and TLC, but the yield did not exceed 70% after separation through column chromatography. The adsorption of the hydroxyl group with the silica gel used as the column filler may be the cause, and more preferably, the reaction can be carried out in a Crude state without any purification or separation process in proceeding the O-methylation reaction, which is the next reaction step 3. As a result, the yield was improved by more than 10% when O-methylation was performed in the Crude state without any separate separation process than when the O-methylation reaction was performed by separating after reduction.

As an embodiment of the present invention, step 4 of the reaction is a step of synthesizing compound E from compound D and may proceed as follows.

<Reaction Step 4>

As a catalyst in the acylation reaction, _{a method using AlCl 3} , which is a Friedel-Craft type catalyst, and a method using a BF ₃ Et ₂ O catalyst, may be performed. Reaction aspect but similar to both the catalyst, in the case of AlCl ₃ catalyst BF ₃ reaction proceeds as it represents a stronger reactivity than Et ₂ O catalyst was a hassle to have to proceed in a vacuum box, BF ₃ to Et ₂ O catalyst It was confirmed that by-products were increased than when used. Therefore, more preferably, a BF ₃ Et ₂ O catalyst having mild reaction conditions and excellent conversion may be used. However, if the reaction can proceed, there is no particular limitation.

The reason why Compound E was synthesized in the course of the reaction is that it is difficult to control the reaction due to the selectivity problem first, and when the next reaction, acylation, is performed, one methoxy group is deprotected into a hydroxyl group. When using the BF ₃ Et ₂ O catalyst, the Acyl group synthesized in the benzene ring, the Boron trifluoride used as the catalyst, and the carbon of the Methoxy group present right next to the Acyl group form a triangular ring, and the BF ₃ Et ₂ O catalyst will fall off. When the methyl group of methoxy is released together, it can be deprotection.

As an embodiment of the present invention, step 5-1 of the reaction may proceed to the step of synthesizing the II compound from the E compound.

<Reaction Step 5-1>

In step 5-1 of the reaction, a Claisen-Schmidt reaction of Acetophenone and Benzaldehyde may proceed.

In the case of the acetophenone group, since two are made of methoxy groups, the reaction can proceed without any special protection. As a result, it is possible to synthesize the final product dimethylchalcone derivatives in high yield through relatively few processes. However, in the case of 4-hydroxybenzaldehydem, since the aldol reaction cannot be proceeded immediately, more preferably, the Claisen-Schmidt reaction may be performed after protection using methoxymethyl chloride.

As the protecting group of the hydroxyyl group, methyl group, methoxymethyl group, etc. may be used, but there is no particular limitation as long as the reaction can proceed. More preferably, a methoxymethyl group capable of performing the reaction under relatively mild conditions may be used even in the deprotection process.

Next, in order to optimize the reaction to remove the protecting group, experiments were performed on the reaction temperature and the strength of the acid. As a result, when the reaction was carried out using a strong acid such as an aqueous HCl solution, the starting material disappeared and the reaction was terminated within a short time, but it was confirmed that the retro-aldol reaction occurred as the double bond of the chalcone structure was broken. . Therefore, more preferably, p -TsOH, a weak acid that does not affect the structure of the product chalcone, can be used, and as a result, a result of 94.8%, which is the best yield, can be obtained. The results according to the conditions of each reaction are shown in Table 1 below. However, there is no particular limitation as long as the reaction can proceed.

Entry II, III (g) Reaction reagent Solvent Temp Time II, III yield (%) One One 36% HCl (5mL) MeOH reflux 20min 50.8 2 One 36% HCl (5mL) MeOH 50 °C 2h 51.2 3 One 36% HCl (5mL) MeOH r.t. 3h 52.6 4 One 1% HCl (10mL) MeOH 50 °C overnight 53.4 5 One 1% HCl (10mL) MeOH r.t. overnight 55.9 6 One p -TsOH (2eq) MeOH reflux overnight 78.6 7 One p -TsOH (2eq) MeOH 50 °C overnight 80.4 8 One p -TsOH (2eq) MeOH r.t. 36h 92.6 9 One p -TsOH (1.1eq) MeOH r.t. 36h 94.8

As an embodiment of the present invention, step 5-2 of the reaction may proceed to the step of synthesizing compound F from compound E.

<Reaction Step 5-2>

Step 5-2 of the reaction may be performed by adding potassium carbonate to compound E to proceed with the reaction, and then refluxing dimethyl sulfate. However, as long as the compound F can be synthesized, there is no particular limitation.

As an embodiment of the present invention, step 6 of the reaction may proceed to the step of synthesizing compound III from compound F.

<Reaction step 6>

Step 6 of the reaction may be carried out by a Claisen-Schmidt reaction of Acetophenone and Benzaldehyde. However, if compound III can be synthesized, there is no particular limitation on the reaction.

As described above, according to an embodiment of the present invention, when synthesizing various dimethylchalcone derivatives using fluoroglucinol as a starting material, it can be prepared through a total of 5 to 6 steps. This is fewer steps and much more economical than conventional manufacturing methods. In addition, as described below, the synthesized final composites were separated and purified to complete structural analysis.

In each of the Examples to be described later, the analysis method of each reaction step is as follows.

<Thin Layer Chromatography (TLC)>

The substrate used in the TLC analysis was a product _{of Merck's F 254} with a thickness of 250 μm and a pore size of 60 Å (particle size 5 to 20 μm). Analysis of each sample was performed using a UV lamp of 254 nm and 365 nm, and a developing solvent that satisfies each condition was used, and the substrate was placed in the Iodine TLC Chamber for measurement.

<Gas Chromatography (GC)>

Hewlett Packard's HP 6890 gas chromatography (30m * 0.25 mm cross-linked methyl silicone column, a flame ionization detector) was used to confirm the reaction progress and the purity of the product. The resulting sample was dissolved in a solvent and injected with 2-3 μm GC using a micro syringe. Hydrogen, air, and nitrogen were used as the mobile phase, and the measurement temperature condition was increased to 280°C by setting 60°C as the starting temperature and increasing by 10°C per minute.

<Nuclear Magnetic Resonance (NMR)>

NMR analysis was measured by Verian VNS ( ¹ H-NMR 600 MHz, ¹³ C-NMR 150 MHz), Verian Germini 2000 spectrometer ( ¹ H-NMR 300 MHz). The product was used by selecting dmso-d ₆ as a solvent for the measurement of the hydroxyl group, which appears at 2.50ppm. The chemical shift was expressed in ppm (δ) and the coupling constant (J) in hertz (Hz).

<Melting Point Gauge>

Bamstead Electrothermal Corporation’s 9100 (15V, 45W, 1AMP). It was measured using.

<Example 1> Reaction Step 1

Into a 2-neck round bottom flask, dimethylformamide 59.30 ml (6.34 mol) was added, and phosphorus(V) oxychloride 49.12 ml (6.34 mol) was added dropwise at 0°C using a dropping funnel, and stirred vigorously for 30 minutes. After the reaction was over, a yellow viscous liquid (Vilsmeyer reaction reagent) was formed. In another round-bottom flask, add 1,4-dioxane (200 ml) and compound A, anhydrous phloroglucinol (40 g, 3.17 mol), and strongly stir to completely dissolve it. Then, use a dropping funnel to dissolve the Vilsmeyer reaction reagent at 0 ℃ It was added dropwise and stirred vigorously. After stirring at room temperature for 4 hours or more, a yellow solid was obtained. This compound was transferred to a 2L round bottom flask, and DI water (1.5 L) was added thereto, followed by vigorous stirring for 3 hours. After stirring, the precipitated yellow solid was filtered and dried in a vacuum oven at 30° C. for 12 hours to obtain a pale orange compound B (56.84 g, 98.4%).

mp = 221-224 °C; TLC R _f = 0.208 (n-hexane: acetone = 1:2); IR νmax (cm ⁻¹ ) 2887.88, 1598.70, 1503.24, 1438.64, 1393.32, 1253.50, and 1186.97; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.52 (br s, 2H, -OH), 10.01 (s, 2H, CHO), 5.90 (s, 1H, ArH); and ¹³ C NMR (150 MHz, DMSO- d ₆ ) δ 191.37 (2C), 169.42 (2C), 169.02 (1C), 103.77 (2C) and 94.07 (1C).

<Example 2> Reaction step 2

After activating Zn by adding 300 mL of 1% HCl aqueous solution and 30 g of Zn to a 1000 mL beaker, the activated Zn is transferred to a beaker containing 450 mL of 3% HCl, and mercury(II) chloride (HgCl ₂ 0.9g) and stirred vigorously at room temperature. The mixture was stirred until it became fluffy to prepare zinc amalgam, which was washed with water and 1,4-dioxane, and then filtered using a filter paper. Compound B (3 g, 19.46 mmol) synthesized beforehand in a round bottom flask and 1,4-dioxane (300 mL) were dissolved at room temperature, and then Zinc amalgam, a reaction reagent, was added, stirred for 20 minutes, and cooled to 0°C. A 36% HCl aqueous solution (12 mL) was slowly added and stirred. After confirming that the reactant compound B completely disappeared, the mixture was filtered with 200 mL of water using a filter paper. The mixture was diluted with 300 mL of ethyl acetate, and the organic solvent layer in which the product was dissolved was washed with water and saturated NaCl aqueous solution to remove salt, and then water was removed using _{MgSO 4.} The organic solvent layer containing the mixture was distilled under reduced pressure to remove the solvent, and the product was separated using column chromatography (n- hexane: acetone = 8: 1) to obtain a reddish brown compound C (1.717 g, 67.4%).

mp = 139-140 ° C; TLC R _f = 0.647 (n- hexane: acetone = 3:2); IR ν _max (cm ^-1 ) 2897.52, 1614.13, 1593.88, 1188.90, and 1080.90; ¹ H NMR (300 MHz, CDCl ₃ ) δ 13.64 (s, 1H, -OH), 13.09 (s, 1H, -OH), 10.18 (s, 1H, CHO), 10.05 (s, 1H, CHO), 5.92 (s, 1H, ArH), 3.95 (s, 3H, OCH ₃ ); and ¹³ C NMR (150 MHz, DMSO- d ₆ ) δ 191.85 (1C), 191.48 (1C), 171.21 (1C), 168.89 (1C), 168.87 (1C), 104.60 (1C), 104.53 (1C) 91.96 (1C) 1C), and 57.46 (1C).

<Example 3> Reaction 3rd step

Compound C (1.717g, 11.14mmol) and potassium carbonate (K ₂ CO ₃ 6.1573g, 44.55mmol) were added to a two-necked round bottom flask, dried completely under reduced pressure, and air was removed, and the reaction would proceed in a nitrogen atmosphere. I made it possible. Thereafter, dry actone was added to dissolve the mixture, and then dimethyl sulfate (DMS 4.2154ml, 44.55mmol) was injected using a syringe, and then refluxed until the next day. After confirming that the reactant compound C completely disappeared, the mixture was cooled at room temperature, diluted with 300 mL of ethyl acetate, and the remaining base potassium carbonate was removed through an aqueous 1% HCl solution. The organic solvent layer in which the product is dissolved was washed by removing salts using water and a saturated NaCl aqueous solution, and water was removed using _{MgSO 4.} The organic solvent layer containing the mixture was distilled under reduced pressure to remove the solvent, and the product was separated using column chromatography (n- hexane: acetone = 300: 1) to obtain a white solid compound D (2.1550g, 98.6%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.45 (s, 1H, ArH), 3.81 (s, 6H, -OCH ₃ ), 3.61 (s, 3H, -OCH ₃ ), 2.02 (s, 6H, -CH ₃ )

<Example 4> Reaction Step 4

The resulting compound D (2.1550g, 10.98mmol) was added to a two necked round bottom flask and dried under reduced pressure for at least 1 hour, and then the reaction was allowed to proceed in a nitrogen atmosphere. Thereafter, acetic anhydride (2.07ml, 21.96mmol) was injected using a syringe, and then the temperature of the reactor was lowered to 0°C using an ice-bath. Then, a catalyst, Boron-trifluoride diethyl etherate (BF ₃ Et ₂ O 2.7582ml, 21.96mmol) was added using a syringe. After moving the reactor to an oil-bath and adjusting the temperature to 90° C., after 2-3 hours, it was confirmed by GC that all of the starting materials disappeared, and the reaction was terminated. The reaction mixture was cooled at room temperature, diluted with 300 mL of ethyl acetate, and the organic solvent layer in which the product was dissolved was washed with 1% HCl aqueous solution, water and saturated NaCl aqueous solution to remove salts, and water was removed using _{MgSO 4.} . The organic solvent layer containing the mixture was distilled under reduced pressure to remove the solvent, and the product was separated using column chromatography (only n- hexane) to obtain a yellow solid compound E (1.8812g, 76.4%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.81 (s, 1H, -OH), 3.70 (s, 3H, -OCH ₃ ), 3.68 (s, 3H, -OCH ₃ ), 2.65 (s, 3H , -COCH ₃ ), 2.09 (s, 3H, -CH ₃ ), 2.03 (s, 3H, CH ₃ )

<Example 5> Reaction 5-1 step

<Example 5-1> Synthesis of Compound II-1

After putting the produced compound E (0.5g, 2.2296mmol) in a round bottom flask (50mL), it was dissolved by stirring with 20mL of methanol at room temperature, and then benzaldehyde (0.273mL, 2.6756mmol) was added using a syringe. After adding 10mL methanol to another beaker, potassium hydroxide (KOH 0.3753g, 6.6889mmol) was added. This was dissolved through sonication and placed in a round bottom flask containing Compound E, and the reaction was allowed to proceed for 48 hours. After confirming that Compound E completely disappeared through TLC Check, the reaction was terminated and the reaction product was diluted with 150 mL of ethyl acetate. After neutralizing the potassium hydroxide remaining in the reaction with 100 mL of NH ₄ Cl aqueous solution, the organic solvent layer in which the product was dissolved was removed with water and saturated NaCl aqueous solution. The reaction product from which the salt was removed was dried using _{MgSO 4.} The organic solvent layer containing the mixture was distilled under reduced pressure to remove the solvent, and the product was separated using column chromatography (only n -hexane, n -hexane: acetone = 300: 1) to separate the orange solid compound II-1 ( 0.65g, 93.4%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.05 (s, 1H, OH), 7.777.64 (t, J = 18.18 Hz, J = 18.21 Hz, 1H, C=CH), 7.767.70 (m , 2H, ArH), 7.507.40 (m, 3H, ArH), 3.70 (s, 3H, OCH ₃ ), 3.62 (s, 3H, OCH ₃ ), 2.11 (s, 3H, CH ₃ ), and 2.07 ( s, 3H, CH ₃ ); and ¹³ C NMR (151 MHz, dmso) δ 194.23(1C), 162.64(1C), 158.83(1C), 157.86(1C), 143.96(1C), 135.02(1C), 131.13(1C), 129.55(2C) , 129.00(2C), 127.26(1C), 115.92(1C), 115.13(1C), 113.86(1C), 62.43(1C), 60.36(1C), 9.28(1C), 9.21(1C).

<Example 5-2> Synthesis of Compound II-2

After putting the produced compound E (0.5g, 2.2296mmol) in a round bottom flask (50mL), stirring at room temperature with 20mL of methanol to dissolve, and then adding p -tolubenzaldehyde (0.3155mL, 2.6756mmol) using a syringe I did. After adding 10mL methanol to another beaker, potassium hydroxide (KOH 0.3753g, 6.6889mmol) was added. This was dissolved through sonication and added to the reactant, and the reaction was allowed to proceed for 48 hours. After confirming that the compound E completely disappeared, the reaction was terminated, and the reaction product was diluted with 150 mL of ethyl acetate. After neutralizing the KOH remaining in the reaction with 100 mL of NH ₄ Cl aqueous solution, the organic solvent layer in which the product was dissolved was removed by salt using water and saturated NaCl aqueous solution, and then water was removed using _{MgSO 4.} The organic solvent layer containing the mixture was distilled under reduced pressure to remove the solvent, and the product was separated using column chromatography (after separating aldehyde using only n -hexane, and proceeding to n -hexane: acetone = 300: 1). Next, an orange solid compound II-2 (0.6513g, 89.5%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.12 (s, 1H, OH), 7.737.61 (t, J = 16.97 Hz, J = 16.94 Hz, 1H, C=CH), 7.657.60 (d , J = 7.90 Hz, 2H, ArH), 7.30-7.20 (d, J = 7.89 Hz, 2H, ArH), 3.70 (s, 3H, OCH ₃ ), 3.61 (s, 3H, OCH ₃ ), 2.35 (s , 3H, CH ₃ ), 2.11 (s, 3H, CH ₃ ), and 2.07 (s, 3H, CH ₃ ); and ¹³ C NMR (151 MHz, dmso) δ 194.18(1C), 162.56(1C), 158.90(1C), 157.84(1C), 144.18(1C), 141.28(1C), 132.30(1C), 130.18(1C) , 129.53(1C), 129.05(1C), 126.65(1C), 126.18(1C), 115.85(1C), 115.10(1C), 113.81(1C), 62.39(1C), 60.35(1C), 21.53(1C) , 9.28(1C), 9.20(1C).

<Example 5-3> Synthesis of Compound II-3

Compound E (0.5g, 2.2296mmol) was added to a round bottom flask (50mL), stirred at room temperature with 20mL of methanol to dissolve, and then 4-isopropylbenzaldehyde (0.405mL, 2.6756mmol) was added using a syringe. I did. After adding 10mL methanol to another beaker, potassium hydroxide (KOH 0.3753g, 6.6889mmol) was added. This was dissolved through sonication and added to the reactant, and the reaction was allowed to proceed for 48 hours. After confirming that the compound E completely disappeared, the reaction was terminated, and the reaction product was diluted with 150 mL of ethyl acetate. After neutralizing the reaction with 100 mL of NH ₄ Cl aqueous solution, the organic solvent layer in which the product was dissolved was removed by salt using water and saturated NaCl aqueous solution, and water was removed using _{MgSO 4.} The organic solvent layer containing the mixture was distilled under reduced pressure to remove the solvent, and the product was separated using column chromatography (after separating aldehyde using only n -hexane, and proceeding to n -hexane: acetone = 300: 1). Next, an orange solid compound II-3 (0.73g, 92.4%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ δ 12.14 (s, 1H, OH), 7.757.62 (t, J = 18.32 Hz, J = 18.49 Hz, 1H, C=CH), 7.687.63 ( d, J = 8.17 Hz, 2H, ArH), 7.36-7.30 (d, J = 8.24 Hz, 2H, ArH), 3.70 (s, 3H, OCH ₃ ), 3.61 (s, 3H, OCH ₃ ), 2.992. 87 (septet, J = 6.90 Hz, 1H, CH), 2.11 (s, 3H, CH ₃ ), 2.06 (s, 3H, CH ₃ ), 1.23 (s, 3H, CH ₃ ), and 1.21 (s, 3H , CH ₃ ); and ¹³ C NMR (151 MHz, dmso) δ 194.16(1C), 163.00(1C), 152.02(1C), 144.14(1C), 132.71(1C), 129.18(2C), 127.55(2C), 126.91(1C) , 126.72(1C), 126.22(1C), 115.10(1C), 113.76(1C), 62.41(1C), 60.35(1C), 33.86(1C), 24.04(2C), 9.28(1C), 9.20(1C) .

<Example 5-4> Synthesis of Compound II-4

Compound E (0.5g, 2.2296mmol) was added to a round bottom flask (50mL), dissolved by stirring with 20 mL of methanol at room temperature, and then added 4-methoxymethoxy benzaldehyde (0.4445g, 2.6756mmol) using a syringe. I did. After adding 10mL methanol to another beaker, potassium hydroxide (KOH 0.3753g, 6.6889mmol) was added. This was dissolved through sonication and added to the reactant, followed by reaction for 48 hours. After confirming that the compound E completely disappeared, the reaction was terminated, and the reaction product was diluted with 150 mL of ethyl acetate. After neutralizing the reaction with 100 mL of NH ₄ Cl aqueous solution, the organic solvent layer in which the product was dissolved was removed by salt using water and saturated NaCl aqueous solution, and then water was removed using _{MgSO 4.} The organic solvent layer containing the mixture was distilled under reduced pressure to remove the solvent, and the product was separated using column chromatography (only n -hexane, n -hexane: acetone = 300: 1) to separate the orange solid compound II-4 ( 0.7705g, 92.8%) was obtained.

¹ H NMR (600 MHz, DMSO-d ₆ ) δ 12.17 (s, 1H, OH), 7.687.58 (t, J = 15.88 Hz, J = 15.75 Hz, 1H, C=CH), 7.737.66 (d) , J = 8.7 Hz, 2H, ArH), 7.117.06 (d, J = 8.75 Hz, 2H, ArH), 5.26 (s, 2H, -CH ₂ -O-), 3.70 (s, 3H, OCH ₃ ) , 3.61 (s, 3H, OCH ₃ ), 3.38 (s, 3H, OCH ₃ ), 2.11 (s, 3H, CH ₃ ), and 2.06 (s, 3H, CH ₃ ); and ¹³ C NMR (151 MHz, dmso) δ 194.04(1C), 162.49(1C), 159.32(1C), 158.93(1C), 157.82(1C), 144.06(1C), 130.83(1C), 128.57(1C) , 128.19(1C), 125.12(1C), 116.98(1C), 116.58(1C), 115.81(1C), 115.07(1C), 113.78(1C), 94.14(1C), 62.38(1C), 60.34(1C) , 56.19(1C), 9.28(1C), 9.20(1C).

<Example 5-5> Synthesis of Compound II-5

Compound E (0.5g, 2.2296mmol) was added to a round bottom flask (50mL), and then dissolved by stirring with 20mL of methanol at room temperature, and then 4-methoxybenzaldehyde (0.3244mL, 2.6756mmol) was added using a syringe. I did. After adding 10mL methanol to another beaker, potassium hydroxide (KOH 0.3753g, 6.6889mmol) was added. This was dissolved through sonication, placed in a round bottom flask containing compound E, and reacted for 48 hours. It was confirmed that compound E completely disappeared, the reaction was terminated, and the reaction product was diluted with 150 mL of ethyl acetate. After neutralizing the potassium hydroxide remaining in the reaction with 100 mL of NH ₄ Cl aqueous solution, the organic solvent layer in which the product was dissolved was removed with water and saturated NaCl aqueous solution. The reaction product from which the salt was removed was dried using _{MgSO 4.} The organic solvent layer containing the mixture was distilled under reduced pressure to remove the solvent, and the product was separated using column chromatography (only n -hexane, n -hexane: acetone = 300: 1) to separate the orange solid compound II-5 ( 0.694g, 90.9%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.19 (s, 1H, OH), 7.747.67 (d, J = 15.77 Hz, 1H, C=CH), 7.627.56 (d, J = 15.73 Hz) , 1H, C=CH), 7.737.68 (d, J = 8.82 Hz, 2H, ArH), 7.056.97 (d, J = 8.79 Hz, 2H, ArH), 3.82 (3H, -OCH ₃ ), 3.69 (s, 3H, OCH ₃ ), 3.61 (s, 3H, OCH ₃ ), 2.11 (s, 3H, CH ₃ ), and 2.06 (s, 3H, CH ₃ ); and ¹³ C NMR (151 MHz, dmso) δ 194.01(1C), 162.43(1C), 161.93(1C), 158.93(1C), 157.80(1C), 144.33(1C), 130.96(2C), 128.24(1C) , 127.61(1C), 124.62(1C), 115.08(2C), 115.06(1C), 113.80(1C), 62.37(1C), 60.34(1C), 55.86(1C), 9.28(1C), 9.21(1C) .

<Example 5-6> Synthesis of Compound II-6

After putting the resulting compound II-4 (1g, 2.6852mmol) in a round bottom flask (50mL), stirring at room temperature with 300mL of methanol to dissolve it, and then adding p -toluenesulfonic acid (0.5619g, 2.9537mmol) for 36 hours. The reaction proceeded during. After confirming that the compound II-4 completely disappeared through TLC Check, the reaction was terminated and the reaction product was diluted with 150 mL of ethyl acetate. The organic solvent layer in which the product was dissolved was removed using water and saturated NaCl aqueous solution. Moisture was removed from the reaction product from which the salt was removed _{using MgSO 4.} The organic solvent layer containing the mixture was distilled under reduced pressure to remove the solvent, and the product was separated using column chromatography (n -hexane: acetone = 30: 1) to separate the orange solid compound II-6 (0.8359 g, 94.8%). ).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.31 (s, 1H, OH), 10.16 (s, 1H, OH), 7.727.64 (d, J = 15.64 Hz, 1H, C=CH), 7.607 .52 (d, J = 15.60 Hz, 1H, C=CH), 7.877.79 (d, J = 8.61 Hz, 2H, ArH), 7.627.55 (d, J = 8.65 Hz, 2H, ArH), 3.69 (s, 3H, OCH ₃ ), 3.61 (s, 3H, OCH ₃ ), 2.10 (s, 3H, CH ₃ ), and 2.06 (s, 3H, CH ₃ ); and ¹³ C NMR (151 MHz, dmso) δ 193.91(1C), 162.39(1C), 160.79(1C), 159.05(1C), 157.82(1C), 145.04(1C), 131.23(2C), 126.05(1C) , 123.41(1C), 116.49(2C), 115.75(1C), 115.02(1C), 113.65(1C), 62.35(1C), 60.33(1C), 9.27(1C), 9.19(1C).

<Example 6> Reaction 5-2 step

Compound E (1.8812g, 8.389mmol) and potassium carbonate (K ₂ CO ₃ 1.3913g, 10.06mmol) were added to a two-necked round bottom flask, dried completely under reduced pressure, and air was removed, and the reaction could proceed in a nitrogen atmosphere. I made it possible. Thereafter, dry actone was added to dissolve the mixture, and then dimethyl sulfate (DMS 0.9519ml, 10.06mmol) was injected using a syringe and refluxed until the next day. After confirming that the reactant compound E completely disappeared, the mixture was cooled at room temperature, diluted with 300 mL of ethyl acetate, and the remaining base potassium carbonate was removed through a 1% HCl aqueous solution. The organic solvent layer in which the product is dissolved was washed by removing salts using water and a saturated NaCl aqueous solution, and water was removed using _{MgSO 4.} The organic solvent layer containing the mixture was distilled under reduced pressure to remove the solvent, and the product was separated using column chromatography (n- hexane: acetone = 300: 1) to obtain a white solid compound F (1.933g, 96.7%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.71 (s, 3H, -OCH ₃ ), 3.69 (s, 6H, -OCH ₃ ), 2.66 (s, 3H, -COCH ₃ ), 2.10 (s, 3H, -CH ₃ ), 2.04 (s, 3H, CH ₃ )

<Example 7> Reaction step 6

<Example 7-1> Synthesis of Compound III-1

After putting the produced compound F (0.5g, 2.0984mmol) in a round bottom flask (50mL), it was dissolved by stirring with 20mL of methanol at room temperature, and then benzaldehyde (0.1284mL, 2.518mmol) was added using a syringe. After adding 10 mL methanol to another beaker, potassium hydroxide (KOH 0.1761 g, 3.1471 mmol) was added. This was dissolved through sonication and added to the reactant, and the reaction was allowed to proceed for 48 hours. After confirming that the compound F completely disappeared, the reaction was terminated, and the reaction product was diluted with 150 mL of ethyl acetate. After neutralizing the potassium hydroxide remaining in the reaction with 100 mL of NH ₄ Cl aqueous solution, the organic solvent layer in which the product was dissolved was removed with water and saturated NaCl aqueous solution. The reaction product from which the salt was removed was dried using _{MgSO 4.} The organic solvent layer containing the mixture was distilled under reduced pressure to remove the solvent, and the product was separated using column chromatography (only n -hexane, n -hexane: acetone = 300: 1) to separate the orange solid compound III-1 ( 0.6595g, 96.3%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.327.24 (d, J = 16.17 Hz, 1H, C=CH), 7.147.05 (d, J = 16.11 Hz, 1H, C=CH), 7.747 .67 (m, 2H, ArH), 7.467.35 (m, 3H, ArH), 3.70 (s, 3H, OCH ₃ ), 3.58 (s, 6H, OCH ₃ ), and 2.13 (s, 6H, CH ₃ ); and ¹³ C NMR (151 MHz, dmso) δ 194.45(1C), 159.08(1C), 154.25(1C), 145.46(1C), 134.50(1C), 131.20(1C), 129.42(2C), 129.14(2C) , 128.85 (1C), 125.02 (1C), 120.52 (2C), 70.22 (1C), 62.02 (2C), 60.20 (1C), 9.61 (2C).

<Example 7-2> Synthesis of Compound III-2

Compound F (0.25g, 1.0492mmol) was added to a round bottom flask (50mL), and then dissolved by stirring with 20mL of methanol at room temperature, and then p -tolubenzaldehyde (0.2969mL, 1.259mmol) was added using a syringe. . After adding 10 mL methanol to another beaker, potassium hydroxide (KOH 0.3532 g, 6.2952 mmol) was added. This was dissolved through sonication and added to the reactant, and the reaction was allowed to proceed for 48 hours. After confirming that Compound F completely disappeared through TLC Check, the reaction was terminated and the reaction product was diluted with 150 mL of ethyl acetate. After neutralizing the potassium hydroxide remaining in the reaction with 100 mL of NH ₄ Cl aqueous solution, the organic solvent layer in which the product was dissolved was removed with water and saturated NaCl aqueous solution. Moisture was removed from the reaction product from which the salt was removed _{using MgSO 4.} The organic solvent layer containing the mixture was distilled under reduced pressure to remove the solvent, and the product was separated using column chromatography (only n -hexane, n -hexane: acetone = 300: 1) to separate the orange solid compound III-2 ( 0.3289g, 92.1%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.287.21 (d, J = 16.19 Hz, 1H, C=CH), 7.077.00 (d, J = 16.12 Hz, 1H, C=CH), 7.617 .55 (d, J = 8.23 Hz, 2H, ArH), 7.247.17 (d, J = 8.00 Hz, 2H, ArH), 3.70 (s, 3H, OCH ₃ ), 3.58 (s, 6H, OCH ₃ ) , 2.32 (s, 3H, CH ₃ ), and 2.13 (s, 6H, CH ₃ ); and ¹³ C NMR (151 MHz, dmso) δ 194.45 (1C), 159.00 (1C), 154.19 (2C), 145.62 (1C), 141.31 (1C), 131.77 (1C) 130.05 (2C), 129.15 (2C), 127.95 (1C), 125.11 (1C), 120.49 (2C), 61.99 (2C), 60.18 (1C), 21.48 (1C), 9.6 (2C).

<Example 7-3> Synthesis of Compound III-3

Compound F (0.5g, 2.0984mmol) was added to a round bottom flask (50mL), stirred at room temperature with 20mL of methanol to dissolve, and then 4-isopropylbenzaldehyde (0.3812mL, 2.518mmol) was added using a syringe. . After adding 10 mL methanol to another beaker, potassium hydroxide (KOH 0.3532 g, 6.2952 mmol) was added. This was dissolved through sonication and added to the reactant, and the reaction was allowed to proceed for 48 hours. After confirming that Compound F completely disappeared through TLC Check, the reaction was terminated and the reaction product was diluted with 150 mL of ethyl acetate. After neutralizing the potassium hydroxide remaining in the reaction with 100 mL of NH ₄ Cl aqueous solution, the organic solvent layer in which the product was dissolved was removed with water and saturated NaCl aqueous solution. The reaction product from which the salt was removed was dried using _{MgSO 4.} The organic solvent layer containing the mixture was distilled under reduced pressure to remove the solvent, and the product was separated using column chromatography (only n -hexane, n -hexane: acetone = 300: 1) to separate the orange solid compound III-3 ( 0.7291g, 94.3%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.297.22 (d, J = 16.17 Hz, 1H, C=CH), 7.106.95 (d, J = 16.12 Hz, 1H, C=CH), 7.657 .58 (d, J = 8.20 Hz, 2H, ArH), 7.297.25 (d, J = 8.10 Hz, 2H, ArH), 3.70 (s, 3H, OCH ₃ ), 3.58 (s, 6H, OCH ₃ ) , 3.002.80 (septet, J = 6.96 Hz, 1H, CH), 2.13 (s, 3H, CH ₃ ), 1.20 (s, 3H, CH ₃ ), and 1.18 (s, 3H, CH ₃ ); and ¹³ C NMR (151 MHz, dmso) δ 194.40(1C), 159.01(1C), 154.22(2C), 152.04(1C), 145.53(1C), 132.19(1C), 129.28(2C), 128.04(1C) , 127.41 (2C), 125.10 (1C), 120.48 (2C), 61.98 (2C), 60.19 (1C), 33.82 (1C), 24.00 (2C), 9.61 (2C).

<Example 7-4> Synthesis of Compound III-4

The resulting compound F (0.5g, 2.0984mmol) was put in a round bottom flask (50mL), stirred at room temperature with 20mL of methanol to dissolve, and then 4-methoxymethoxy benzaldehyde (0.4183g, 2.518mmol) was added. After adding 10 mL methanol to another beaker, potassium hydroxide (KOH 0.3532 g, 6.2952 mmol) was added. This was dissolved through sonication, placed in a round bottom flask containing Compound F, and reacted for 48 hours. It was confirmed that compound F completely disappeared, the reaction was terminated, and the reaction product was diluted with 150 mL of ethyl acetate. After neutralizing the potassium hydroxide remaining in the reaction with 100 mL of NH ₄ Cl aqueous solution, the organic solvent layer in which the product was dissolved was removed with water and saturated NaCl aqueous solution to remove the salt, and then water was removed using _{MgSO 4.} The organic solvent layer containing the mixture was distilled under reduced pressure to remove the solvent, and the product was separated using column chromatography (only n -hexane, n -hexane: acetone = 300: 1) to separate the orange solid compound III-4 ( 7.44g, 91.8%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.277.17 (d, J = 16.11 Hz, 1H, C=CH), 7.026.93 (d, J = 16.23 Hz, 1H, C=CH), 7.707 .62 (d, J = 8.79 Hz, 2H, ArH), 7.067.0 (d, J = 8.74 Hz, 2H, ArH), 5.23 (2H, -CH2-O-), 3.70 (s, 3H, OCH ₃ ), 3.58 (s, 6H, OCH ₃ ), 3.37 (s, 3H, OCH ₃ ), and 2.13 (s, 6H, CH ₃ ); and ¹³ C NMR (151 MHz, dmso) δ 194.33(1C), 159.29(1C), 158.92(1C), 154.16(2C), 145.35(1C), 130.92(2C), 128.03(1C), 127.09(1C) , 125.21 (1C), 120.46 (2C), 116.83 (2C), 94.12 (1C), 61.97 (2C), 60.18 (1C), 56.18 (1C), 9.61 (2C).

<Example 7-5> Synthesis of Compound III-5

Compound F (0.5g, 2.0984mmol) was added to a round bottom flask (50mL), stirred at room temperature with 20mL of methanol to dissolve, and then 4-methoxybenzaldehyde (0.3053mL, 2.518mmol) was added using a syringe. . After adding 10 mL methanol to another beaker, potassium hydroxide (KOH 0.3532 g, 6.2952 mmol) was added. This was dissolved through sonication and added to the reactant, and the reaction was allowed to proceed for 48 hours. After confirming that Compound F completely disappeared through TLC Check, the reaction was terminated and the reaction product was diluted with 150 mL of ethyl acetate. After neutralizing the potassium hydroxide remaining in the reaction with 100 mL of NH ₄ Cl aqueous solution, the organic solvent layer in which the product was dissolved was removed by salt using water and saturated NaCl aqueous solution, and water was removed using _{MgSO 4.} The organic solvent layer containing the mixture was distilled under reduced pressure to remove the solvent, and the product was separated using column chromatography (only n -hexane, n -hexane: acetone = 300: 1) to separate the orange solid compound III-5 ( 0.6948 g, 92.9%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.277.13 (d, J = 16.10 Hz, 1H, C=CH), 7.026.88 (d, J = 15.90 Hz, 1H, C=CH), 7.707 .60 (d, J = 8.70 Hz, 2H, ArH), 7.006.93 (d, J = 8.79 Hz, 2H, ArH), 3.79 (s, 3H, OCH ₃ ), 3.69 (s, 3H, OCH ₃ ) , 3.58 (s, 6H, OCH ₃ ), and 2.13 (s, 6H, CH ₃ ); and ¹³ C NMR (151 MHz, dmso) δ 194.33(1C), 161.88(1C), 158.88(1C), 154.14(2C), 145.58(1C), 131.03(2C), 127.05(1C), 126.66(1C) , 125.27 (1C), 120.45 (2C), 114.92 (2C), 61.96 (2C), 60.18 (1C), 55.81 (1C), 9.61 (2C).

<Example 7-6> Synthesis of Compound III-6

After putting the resulting compound III-4 (1g, 2.5877mmol) in a round bottom flask (50mL), stirring at room temperature with 300mL of methanol to dissolve it, and then adding p -toluenesulfonic acid (0.5415g, 2.8465mmol) for 36 hours. The reaction proceeded during. After confirming that Compound III-4 completely disappeared through TLC Check, the reaction was terminated and the reaction product was diluted with 150 mL of ethyl acetate. The salt was removed from the organic solvent layer in which the product was dissolved using water and a saturated NaCl aqueous solution. Moisture was removed from the reaction product from which the salt was removed _{using MgSO 4.} The organic solvent layer containing the mixture was distilled under reduced pressure to remove the solvent, and the product was separated using column chromatography (n- hexane: acetone = 30: 1), and the orange solid compound III-6 (0.8293g, 93.6%). ).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.09 (s, 1H, OH), 7.207.10 (d, J = 16.07 Hz, 1H, C=CH), 6.916.83 (d, J = 16.01 Hz) , 1H, C=CH), 7.567.48 (d, J = 8.69 Hz, 2H, ArH), 6.806.74 (d, J = 8.62 Hz, 2H, ArH), 3.69 (s, 3H, OCH ₃ ), 3.57 (s, 6H, OCH ₃ ), and 2.12 (s, 6H, CH ₃ ); and ¹³ C NMR (151 MHz, dmso) δ 194.26(1C), 160.65(2C), 158.81(1C), 154.12(2C), 146.14(1C), 131.22(2C), 125.71(1C), 125.34(1C) , 120.41 (2C), 116.32 (2C), 61.93 (2C), 60.17 (1C), 9.59 (2C).

<Example 7-7> Synthesis of Compound III-7

Compound F (0.5g, 2.0984mmol) was added to a round bottom flask (50mL), stirred at room temperature with 20mL of methanol to dissolve, and then 4-dimethylamino benzaldehyde (0.3754g, 2.518mmol) was added using a syringe. I did. After adding 10 mL methanol to another beaker, potassium hydroxide (KOH 0.3532 g, 6.2952 mmol) was added. This was dissolved through sonication and placed in a round bottom flask containing Compound F, and the reaction was allowed to proceed for 48 hours. After confirming that the compound F disappeared, the reaction was terminated, and the reaction product was diluted with 150 mL of ethyl acetate. After neutralizing the potassium hydroxide remaining in the reaction with 100 mL of NH ₄ Cl aqueous solution, the organic solvent layer in which the product was dissolved was removed by salt using water and saturated NaCl aqueous solution, and then water was removed using _{MgSO 4.} The organic solvent layer containing the mixture was distilled under reduced pressure to remove the solvent, and the product was separated using column chromatography (only n -hexane, n -hexane: acetone = 300: 1) to separate the orange solid compound III-7 ( 0.607g, 78.3%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.167.06 (d, J = 15.94 Hz, 1H, C=CH), 6.836.75 (d, J = 15.90 Hz, 1H, C=CH), 7.527 .43 (d, J = 8.90 Hz, 2H, ArH), 6.716.63 (d, J = 8.94 Hz, 2H, ArH), 3.69 (s, 3H, OCH ₃ ), 3.57 (s, 6H, OCH ₃ ) , 2.98 (s, 6H, NCH ₃ ), and 2.12 (s, 6H, CH ₃ ); and ¹³ C NMR (151 MHz, dmso) δ 193.91(1C), 158.60(1C), 154.04(2C), 152.44(1C), 146.83(1C), 130.91(2C), 125.69(1C), 123.61(2C) , 121.58 (1C), 120.34 (2C), 112.20 (2C), 111.31 (1C), 61.89 (2C), 60.17 (1C), 9.61 (2C).

<Experimental Example 1>

The yield of each step product according to an embodiment of the present invention is shown in Table 2.

Compd. Product Yield (%) Compd. Product Yield (%) B

98.4 F

96.7 C

67.4 II

- D

98.6 III

- E

76.4

<Experimental Example 2>

The yield of each product in the preparation method of compound II according to the embodiment of the present invention is shown in Table 3.

Compd. Product Yield (%) II-1

93.4 II-2

89.5 II-3

92.4 II-4

90.9 II-5

92.8 II-6

86.2

<Experimental Example 3>

The yield of each product in the preparation method of compound III according to an embodiment of the present invention is shown in Table 4.

Compd. Product Yield (%) III-1

96.3 III-2

92.1 III-3

94.3 III-4

92.9 III-5

91.8 III-6

88.1 III-7

78.3

Claims (11)

Compounds represented by the following formula (I):
[Formula I]

In Formula I,
R1, R2, and R3 are the same as or different from each other,
R1 is a hydroxy group or a methoxy group,
R2, and R3 are each independently hydrogen, deuterium, hydroxy group, thiol group, amino group, substituted or unsubstituted (C1-C10 alkyl) amino group, substituted or unsubstituted C1-C10 alkoxy group, substituted or unsubstituted It is selected from the group consisting of a C1-C10 alkyl group, a substituted or unsubstituted C2-C10 alkenyl, a substituted or unsubstituted C2-C10 alkynyl, and a substituted or unsubstituted C6-C20 aryl group,
The'substituted or unsubstituted' is a halogen group, nitrile group, nitro group, hydroxy group, carbonyl group, ester group, imide group, amino group, phosphine oxide group, alkoxy group, aryloxy group, alkyl thioxy group, aryl Thioxy group, alkylsulfoxy group, arylsulfoxy group, silyl group, boron group, alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, aralkenyl group, alkylaryl group, alkylamine group. It is unsubstituted or substituted with one or more substituents selected from the group consisting of an aralkylamine group, a heteroarylamine group, an arylamine group, an arylphosphine group, and a heterocyclic group.
The method of claim 1,
Formula I is a compound represented by the following formula II:
[Formula II]

In Formula II, R2 and R3 are the same as defined in Formula I.
The method of claim 1,
Formula I is any one of the compounds represented by the following formulas II-1 to II-7:
[Formula II-1]

[Formula II-2]

[Formula II-3]

[Formula II-4]

[Formula II-5]

[Formula II-6]

[Formula II-7]

.
The method of claim 1,
Formula I is a compound represented by the following formula III:
[Formula III]

In Formula III, R2 and R3 are the same as defined in Formula I.
The method of claim 1,
Formula I is any one of the compounds represented by the following formulas III-1 to III-7:
[Formula III-1]

[Formula III-2]

[Formula III-3]

[Formula III-4]

[Formula III-5]

[Formula III-6]

[Formula III-7]

.
3/4 step of synthesizing a compound represented by the following formula (E) from a compound represented by the following formula (C); And
5-1 step of synthesizing a compound represented by the following formula (II) from a compound represented by the following formula (E); Containing,
Method for preparing a compound represented by Formula II:
[Formula C]

[Formula E]

[Formula II]

In Formula II,
R2, and R3 are the same as or different from each other,
R2, and R3 are each independently hydrogen, deuterium, hydroxy group, thiol group, amino group, substituted or unsubstituted (C1-C10 alkyl) amino group, substituted or unsubstituted C1-C10 alkoxy group, substituted or unsubstituted It is selected from the group consisting of a C1-C10 alkyl group, a substituted or unsubstituted C2-C10 alkenyl, a substituted or unsubstituted C2-C10 alkynyl, and a substituted or unsubstituted C6-C20 aryl group,
The'substituted or unsubstituted' is a halogen group, nitrile group, nitro group, hydroxy group, carbonyl group, ester group, imide group, amino group, phosphine oxide group, alkoxy group, aryloxy group, alkyl thioxy group, aryl Thioxy group, alkylsulfoxy group, arylsulfoxy group, silyl group, boron group, alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, aralkenyl group, alkylaryl group, alkylamine group. It is unsubstituted or substituted with one or more substituents selected from the group consisting of an aralkylamine group, a heteroarylamine group, an arylamine group, an arylphosphine group, and a heterocyclic group.
The method of claim 6,
Prior to the reaction step 3, a reaction step 1 of synthesizing a compound represented by the following B from the compound represented by the following formula A; And
Further comprising a reaction step 2 of synthesizing the compound represented by Formula C from the compound represented by the following B,
Method for preparing a compound represented by Formula II:
[Formula A]

[Formula B]

.
The method of claim 6,
The reaction step 3/4 is a reaction step 3 of synthesizing a compound represented by the following formula (D) from the compound represented by the formula (C); And
A reaction step 4 of synthesizing the compound represented by Formula E from the compound represented by Formula D below; Further comprising,
Method for preparing a compound represented by Formula II:
[Formula D]

3 step of synthesizing a compound represented by the following formula (D) from the compound represented by the following formula (C);
Reaction 4/(5-2) step of synthesizing a compound represented by Formula F below from a compound represented by Formula D below; And
Including a reaction step 6 of synthesizing a compound represented by the following formula (III) from the compound represented by the following formula F;
Method for preparing a compound represented by Formula III:
[Formula C]

[Formula D]

[Formula F]

[Formula III]

In Formula III,
R2, and R3 are the same as or different from each other,
R2, and R3 are each independently hydrogen, deuterium, hydroxy group, thiol group, amino group, substituted or unsubstituted (C1-C10 alkyl) amino group, substituted or unsubstituted C1-C10 alkoxy group, substituted or unsubstituted It is selected from the group consisting of a C1-C10 alkyl group, a substituted or unsubstituted C2-C10 alkenyl, a substituted or unsubstituted C2-C10 alkynyl, and a substituted or unsubstituted C6-C20 aryl group,
The'substituted or unsubstituted' is a halogen group, nitrile group, nitro group, hydroxy group, carbonyl group, ester group, imide group, amino group, phosphine oxide group, alkoxy group, aryloxy group, alkyl thioxy group, aryl Thioxy group, alkylsulfoxy group, arylsulfoxy group, silyl group, boron group, alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, aralkenyl group, alkylaryl group, alkylamine group. It is unsubstituted or substituted with one or more substituents selected from the group consisting of an aralkylamine group, a heteroarylamine group, an arylamine group, an arylphosphine group, and a heterocyclic group.
The method of claim 9,
Prior to the reaction step 3, a reaction step 1 of synthesizing a compound represented by the following formula B from the compound represented by the following formula A; And
Further comprising a reaction step 2 of synthesizing the compound represented by the formula C from the compound represented by the following formula (B),
Method for preparing a compound represented by Formula III:
[Formula A]

[Formula B]

.
The method of claim 9,
The reaction step 4/(5-2) is a reaction step 4 of synthesizing a compound represented by the following compound E from the compound represented by the formula (D); And
5-2 step of synthesizing the compound represented by the compound F from the compound represented by the following compound E; further comprising,
Method for preparing a compound represented by Formula III:
[Formula E]

.