Novel synthetic method of decursin derivatives

Abstract

The present invention relates to a novel method for synthesizing decursin derivatives, which can synthesize decursin derivatives (PRG-A-04) represented by compound I in large quantities with high yields through the reaction between decursinol and an intermediate compound in which a Boc protecting group has been introduced into the OH group of 3-(3-methoxy-4-nitrophenyl)prop-2-en-1-ol in the presence of a platinum catalyst and xantphos.

Description

[Technical field]

[0001] The present invention relates to a novel method for synthesizing decurcin derivatives. [Background technology]

[0002] Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease in which cell death in the spinal cord results in the selective loss of motor neurons. Approximately 10-20% of patients show a genetic pattern (familial ALS; fALS), while the rest are classified as sporadic ALS (sALS). Some genes are known to be ALS-associated loci in familial ALS, among which SOD1 is the gene that was first identified in fALS. It is speculated that fALS-associated genes also play a role in the pathogenesis of sALS, but the exact cause of sALS has not been elucidated to date. In addition, ALS is classified into typical ALS, ALS with dementia, and atypical ALS according to clinical symptoms. In fact, SOD1 mutation induces typical ALS, and C9orf72 is associated with ALS with dementia.

[0003] One of the important characteristics of ALS is that it is a progressive disease in which neuronal cell death is propagated through neural connections. In fact, Alzheimer's and Parkinson's diseases also show similar phenotypes. In relation to the above characteristics, a prion-like propagation mechanism has been proposed, which means that misfolded proteins transform normal proteins into abnormal proteins. In fact, mutant amyloid beta (Aβ) can transform normal Aβ into abnormal Aβ. Recently, it has been reported that mutated or misfolded SOD1 can also be secreted and propagated during the progression of the disease. However, there has been little research on SOD1 aggregation and misfolding inhibitors targeted as therapeutic agents for ALS disease.

[0004] Accordingly, in Korean Patent Publication No. 10-2021-0052326, it was proven that the deucrustin derivative compound, a novel compound, is effective for the prevention, improvement, or treatment of amyotrophic lateral sclerosis (ALS). However, the yield of the deucrustin derivative compound was low, and there were limitations in mass production.

[0005] Therefore, there is a need for research on a new synthesis method that can increase the yield of the deucrustin derivative compound and enable mass production.

Summary of the Invention

Problems to be Solved by the Invention

[0006] An object of the present invention is to provide a new synthesis method of a deucrustin derivative that can increase the yield of the deucrustin derivative compound and enable mass production.

Means for Solving the Problems

[0007] To achieve the above object, the present invention provides a method for synthesizing a deucrustin derivative represented by Compound I, including a step of synthesizing a deucrustin derivative represented by Compound I through a reaction between an intermediate compound (Compound 5) in which a Boc protecting group is introduced into the OH group of 3-(3-methoxy-4-nitrophenyl)prop-2-en-1-ol and deucrinosol (Compound 6):

[0008]

Chemical Formula

Effects of the Invention

[0009] The novel synthesis method of the deucrustin derivative compound according to the present invention has the advantage of being able to increase the yield of the obtained deucrustin derivative compound and enable mass production.

Brief Description of the Drawings

[0010]

Figure 1

Figure 2

Figure 3

Mode for Carrying Out the Invention

[0011] Hereinafter, the present invention will be specifically described.

[0012] The present inventors Pd 2 (dba) By developing a new synthetic method for the large-scale synthesis of the decursin derivative [(S,E)-7-((3-(3-methoxy-4-nitrophenyl)allyl)oxy)-8,8-dimethyl-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-2-one [(S,E)-7-((3-(3-methoxy-4-nitrophenyl)allyl)oxy)-8,8-dimethyl-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-2-one]; PRG-A-04] represented by Compound I through the reaction between the intermediate compound in which a Boc protecting group is introduced into the OH group of 3-(3-methoxy-4-nitrophenyl)prop-2-en-1-ol and decursinol in the presence of 3 and xanthophos in high yield, the present invention has been completed.

[0013] Accordingly, the present invention provides a method for synthesizing a decursin derivative represented by Compound I, including the step of synthesizing a decursin derivative represented by Compound I through the reaction between an intermediate compound (Compound 5) in which a Boc protecting group is introduced into the OH group of 3-(3-methoxy-4-nitrophenyl)prop-2-en-1-ol and decursinol (Compound 6):

[0014] [Chemistry]

[0015] The said compound 5 is synthesized through the following steps: i) a first step of reacting 3-hydroxy-4-nitrobenzaldehyde with CH3I to synthesize 3-methoxy-4-nitrobenzaldehyde; ii) a second step of reacting the said 3-methoxy-4-nitrobenzaldehyde with diethoxyphosphoryl acetate to synthesize Ethyl 3-(3-methoxy-4-nitrophenyl)-2-propenoate; iii) a third step of reacting the said Ethyl 3-(3-methoxy-4-nitrophenyl)-2-propenoate with diisobutylaluminium hydride (DIBAL-H) to synthesize 3-(3-methoxy-4-nitrophenyl)prop-2-en-1-ol; and iv) a fourth step of reacting the said 3-(3-methoxy-4-nitrophenyl)prop-2-en-1-ol with di-tert-butyl dicarbonate [(Boc)2O] to synthesize compound 5 with a Boc protecting group introduced.

[0016] The step of synthesizing the said decursin derivative Pd 2 (dba) In the presence of 3 and xanthphos, the decursin derivative represented by compound I can be synthesized through the reaction between compound 5 and compound 6.

[0017] More specifically, the step of synthesizing the decursin derivative may include: i) adding a solution containing compound 6, Pd2(dba)3 and xanthphos to a solution of compound 5 and stirring; ii) adding N-acetylcysteine to the stirred reaction solution and stirring; iii) filtering the stirred reaction solution and concentrating the organic solvent layer; iv) filtering the concentrated reaction solution, concentrating the collected solution, and adding acetone to completely dissolve it; and v) administering isopropyl alcohol to the dissolved reaction solution, washing to obtain a decursin derivative represented by compound I.

[0018] Compound 5 and compound 6 are contained in a weight ratio of 1:(0.1 to 1). Pd 2 (db a) Pd2(dba)3 and xanthphos may be contained in amounts of 3 to 10 parts by weight respectively per 100 parts by weight of compound 6. If the contents of compound 5, compound 6, Pd 2 (dba) Pd2(dba)3 and xanthphos are outside the above ranges, problems such as insufficient economy or difficulty in mass production will be caused.

[0019] In the present invention, the step of recrystallizing the obtained decursin derivative may further be included.

[0020] The recrystallization step may include: i) adding acetone and isopropyl alcohol to the obtained decursin derivative, stirring and then filtering; and ii) washing and drying the filtered reaction product to obtain a decursin derivative.

[0021] Based on an embodiment of the present invention, the present invention will be described in more detail. The present invention includes: a first step of reacting 3-hydroxy-4-nitrobenzaldehyde with methyl iodide (CH3I) to synthesize 3-methoxy-4-nitrobenzaldehyde; a second step of reacting the 3-methoxy-4-nitrobenzaldehyde with diethoxyphosphoryl acetate to synthesize ethyl 3-(3-methoxy-4-nitrophenyl)-2-propenoate; a third step of reacting the ethyl 3-(3-methoxy-4-nitrophenyl)-2-propenoate with diisobutylaluminum hydride (DIBAL-H) to synthesize 3-(3-methoxy-4-nitrophenyl)prop-2-en-1-ol; a fourth step of reacting the 3-(3-methoxy-4-nitrophenyl)prop-2-en-1-ol with di-tert-butyl dicarbonate [(Boc)2O] to synthesize compound 5 into which a Boc protecting group is introduced; and a fifth step of reacting the compound 5 with decursinol (compound 6) to synthesize compound I. A method for synthesizing a decursin derivative represented by compound I according to the present invention is provided:

[0022]

Chemical formula

[0023] The method for synthesizing a decursin derivative (PRG-A-04) represented by compound I according to the present invention is described in more detail by the following Reaction Scheme 2:

[0024]

Chemical formula

[0025] The first stage may include: adding 3-hydroxy-4-nitrobenzaldehyde (Compound 1), K2CO3, and DMF into a reactor, and then adjusting the internal temperature of the reaction solution to 20-30°C; adding MeI and DMF to the reaction solution while maintaining the temperature of the reaction solution at 20-40°C, and stirring for 16-18 hours while maintaining the temperature of the reaction solution at 20-30°C; after lowering the temperature of the reaction solution to -5-10°C, adding purified water while maintaining the temperature of the reaction solution at -5-10°C, and stirring at -5-10°C for 2-6 hours; and filtering the solid generated from the reaction solution and drying under reduced pressure to obtain 3-methoxy-4-nitrobenzaldehyde (Compound 2).

[0026] The second stage may include: adding diethoxyphosphoryl acetate (DBU) and 2-Me-THF into a reactor and stirring; adding a mixed solution of 3-methoxy-4-nitrobenzaldehyde (Compound 2) and 2-Me THF to the reaction solution, stirring at 20-30°C for 8-12 hours, then adding purified water, and stirring at 20-30°C for 30-60 minutes; and treating the organic solvent layer of the stirred reaction solution with an acetic acid solution and a NaHCO3 solution, and then distilling the obtained organic solvent layer under reduced pressure to obtain 3-(3-methoxyphenyl)-2-propen-1-ol [Compound 3].

[0027] The third stage may include: adding 3-(3-methoxyphenyl)-2-propen-1-ol [Compound 3] and 2-Me-THF into a reactor and stirring; adding DIBAL-H (toluene solution, 96.5 kg, 112.2 moles, 2.5 eq) to the reaction solution and stirring; adding a seignette salt solution to the reaction solution and stirring; and treating the organic solvent layer of the stirred reaction solution with a seignette salt solution, an acetic acid solution, and a NaHCO3 solution, and then distilling the obtained organic solvent layer under reduced pressure and adding 2-Me THF to obtain a solution of 3-(3-methoxyphenyl)-2-propen-1-ol [Compound 4].

[0028] The four steps may include: a step of charging a solution of 3-(3-methoxy-4-nitrophenyl)prop-2-en-1-ol [Compound 4] and dichloromethane (DCM) into a reactor and performing distillation under reduced pressure; a step of charging DCM into the reaction solution after the distillation under reduced pressure; a step of charging tetra-butyl-ammonium-hydrogen-sulfate (TBAHS), di-tert-butyl dicarbonate ((Boc)2O) and DCM into the reaction solution and then stirring; a step of charging an aqueous NaOH solution into the reaction solution and stirring; and a step of treating the organic solvent layer of the stirred reaction solution with an acetic acid solution and a NaHCO3 solution, and then obtaining a solution of Compound 5 which is the obtained organic solvent layer.

[0029] The five steps may include: a step of charging a solution containing Compound 6, Pd2(dba)3 and xanthphos into the solution of Compound 5 and stirring; a step of charging N-acetylcysteine into the stirred reaction solution and stirring; a step of filtering the stirred reaction solution and concentrating the organic solvent layer; a step of concentrating the solution collected by filtering the concentrated reaction solution, adding acetone and completely dissolving it; and a step of administering isopropyl alcohol to the dissolved reaction solution, washing it to obtain a decursin derivative (PRG-A-04) represented by Compound I.

[0030] In addition, according to Korean Patent Publication No. 10-2021-0052326, the decursin derivative (PRG-A-04) represented by Compound I synthesized by the present invention, that is, (S,E)-7-((3-(3-methoxy-4-nitrophenyl)allyl)oxy)-8,8-dimethyl-7,8-dihydro-2H,6H-pyrano[3,2-g]chromen-2-one is an inhibitor of SOD1 aggregation and misfolding, and can be usefully utilized as a therapeutic agent for ALS disease by showing a protective effect against muscle weakness and motor impairment in ALS model mice.

[0031] Hereinafter, the present invention will be described in more detail through examples. These examples are merely for explaining the present invention more specifically, and it is obvious to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention.

[0032] <Example 1> Synthesis method of PRG-A-04 The synthesis method of PRG-A-04 according to the present invention was synthesized according to the following Reaction Formula 2.

[0033]

Chemical formula

[0034] A more detailed synthesis method of PRG-A-04 is as follows.

[0035] 1. Synthesis of Compound 2 Compound 2 was synthesized according to the following Reaction Formula 3.

[0036]

Chemical formula

[0037] Compound 1 (17.9 kg, 107.1 mol, 1 eq), K2CO3 (20.5 kg, 148.3 moles, 1.4 equivalents), and DMF (80 kg) were charged into a reactor, and then the internal temperature of the reaction solution was adjusted to 25°C. While maintaining the temperature of the reaction solution at 30°C, MeI (33.8 kg, 238.1 moles, 2.2 equivalents) and DMF (11 kg) were added to the reaction solution, and the reaction solution was stirred for 17 hours while maintaining the temperature at 25°C. After lowering the temperature of the reaction solution to 5°C, purified water (180 kg) was charged while maintaining the temperature of the reaction solution at 5°C, and the mixture was stirred for 4 hours (stirring temperature: 5°C).

[0038] The solid generated from the reaction solution prepared as described above was filtered (internal temperature of the filter: 5°C), and the filtered solid was washed with purified water (72 kg x 2 times). The filtered solid was placed in a dryer and dried under reduced pressure for 20 hours to obtain Compound 2 [yield: 17.53 kg (90.4%), purity: 99.9% (HPLC), content: 99.2% (w / w), residual DMF <0.0442% (w / w), residual MeI: 176 ppm] (internal temperature of the dryer: 50°C).

[0039] 2. Synthesis of Compound 3 Compound 3 was synthesized according to the following Reaction Formula 4.

[0040] [Chemical formula]

[0041] 2 - Diethoxyphosphoryl acetate (DBU, 20.5 kg, 91.4 moles, 1.1 eq.) and 2-Me-THF (130 kg) were charged into a reactor, and the reaction solution was adjusted to 0 °C. While maintaining the solution temperature at 0 °C, DBU (15.5 kg, 101.8 moles, 1.2 eq.) was charged and stirred at 0 °C for 2 hours. A mixed solution of Compound 2 (15 kg, 83.0 mol, 1.0 eq) and 2-Me THF (225 kg) was charged into the reaction solution, and the temperature of the reaction solution was maintained at 0 °C. After stirring the reaction solution at 25 °C for 10 hours, purified water (82 kg) was charged and stirred at 25 °C for 45 minutes. The stirring was stopped, and after waiting at 25 °C for 45 minutes until the solution layer was separated, the aqueous layer and the organic solvent layer were separated. The aqueous layer was discarded, and 10% aq. acetic acid solution [(mixed solution of purified water (156 kg) and glacial acetic acid (16.0 kg), 83 kg] was charged into the organic solvent layer and stirred at 25 °C for 45 minutes. The stirring was stopped, and after waiting at 25 °C for 45 minutes until the solution layer was separated, the aqueous layer and the organic solvent layer were separated. The aqueous layer was discarded, and 9.6% aq. NaHCO3 solution [mixed solution of purified water (176 kg, 11.7X) and NaHCO3 (18.1 kg), 84 kg] was charged into the organic solvent layer and stirred at 25 °C for 45 minutes. The stirring was stopped, and after waiting at 25 °C for 45 minutes until the solution layer was separated, the aqueous layer and the organic solvent layer were separated. The aqueous layer was discarded, and the process of charging 9.6% aq. NaHCO3 solution, stirring, and separating the solution layer was repeated. The thus-obtained organic solvent layer was distilled under reduced pressure (the temperature of the reactor was maintained at 50 °C or below), and the distillation was stopped when the solution volume decreased by approximately 60 L. n-Heptane (130 kg) was maintained at 25 °C for 2 hours and charged, and after stirring the reaction solution at 25 °C for 6 hours, the filtered solid was washed with n-heptane (17.0 kg). The filtered solid was placed in a dryer and dried under reduced pressure for 20 hours (the internal temperature of the dryer: 50 °C) to obtain Compound 3 [yield: 18.35 kg (88%), purity: 99.7% (HPLC), content: 99.1% (w / w), residual moisture: 0.1% (KF)].

[0042] 3. Synthesis of Compound 4 Compound 4 was synthesized according to the following Reaction Formula 5.

[0043]

Chemical Formula

[0044] First, after confirming that the residual moisture (KF measurement) in 2-Me-THF used as a solvent was 0.05% or less, the residual moisture in the reactor was completely dried. Compound 3 (11.1 kg, 44.2 moles, 1.0 equivalent) and 2-Me-THF (205 kg) were charged into the reactor, and the reaction solution was adjusted to -5 to 5 °C. 1M DIBAL (toluene solution, 96.5 kg, 112.2 moles, 2.5 eq) was gradually added while maintaining the solution temperature at 0 °C over 2 hours or more, and the temperature of 0 °C was maintained and stirred for 3 hours. After adjusting the temperature of the reaction solution to 25 °C, 38.7% aq. Seniiet salt solution [a mixture of purified water (126 kg) and potassium sodium tartrate tetrahydrate (83.4 kg), 113 kg] was added, maintained at 25 °C, and stirred for 45 minutes. After stopping the stirring, waited at 25 °C for 3 hours to ensure smooth separation of the solution layer, then the aqueous layer was discarded, 38.7% aq. Seniiet salt solution (58 kg) was added to the organic solvent layer, maintained at 25 °C, and stirred for 0.5 - 1 hour. After stopping the stirring, waited at 25 °C for 2.5 hours to ensure smooth separation of the solution layer, then the aqueous layer was discarded, 10% aq. acetic acid solution (60 kg) was added to the organic solvent layer, maintained at 25 °C, and stirred for 45 minutes. After stopping the stirring, waited at 25 °C for 45 minutes to ensure smooth separation of the solution layer, then the aqueous layer was discarded, 9.6% aq. NaHCO3 (60 kg) was added to the organic solvent layer, maintained at 25 °C, and stirred for 45 minutes. After stopping the stirring, waited at 25 °C for 45 minutes until separation of the solution layer occurred, then the aqueous layer was discarded, 9.6% aq. NaHCO3 solution was added, stirred, and the process of separating the solution layer was repeated. The thus-obtained organic solvent layer was distilled under reduced pressure (reactor temperature: maintained at 50 °C or below), and the distillation was stopped when the solution volume decreased by approximately 27 L. Solvent 2-Me THF (54 kg) was added, the organic solvent layer was distilled under reduced pressure (reactor temperature: maintained at 50 °C or below), and when the solution volume decreased by approximately 27 L, the distillation was stopped, and the process of adding solvent 2-Me THF and distilling under reduced pressure was repeated. After the distillation under reduced pressure was completed, 2-Me THF (120 kg) was added, and it was confirmed that the residual moisture in the solution was 1.0% or less [Yield: 150 kg of the solution of Compound 4 (in 2-Me-THF), Purity: 84.5% (HPLC), Content: 4.1% (w / w), Residual Moisture: 0.4% (KF)].

[0045] 4. Synthesis of Compound 5 Compound 5 was synthesized according to the following Reaction Scheme 6.

[0046]

Chemical Formula

[0047] A solution of Compound 4 (in 2-Me-THF, 6.0 kg, 4.1 w / w%) and dichloromethane (DCM, 46 kg) were charged into a reactor and distilled under reduced pressure (the temperature of the reactor was maintained at 50 °C or lower). When the solution volume decreased to approximately 9 L, the distillation was stopped. After adding DCM (46 kg), it was distilled under reduced pressure (the temperature of the reactor was maintained at 50 °C or lower). When the solution volume decreased to approximately 9 L, the distillation was stopped, and such a process was repeated. DCM (80 kg) was added and stirred at 25 °C for 1 hour. TBAHS (0.8 kg, 2.4 moles, 0.1 eq), (Boc)2O (12.5 kg, 57 moles, 2.0 eq) and DCM (14 kg) were added to the reaction solution, and then stirred at 25 °C. A 5.4% aq. NaOH solution [a mixed solution of purified water (108 kg) and NaOH (6.10 kg, 152.5 moles, 5.3 eq), 80.0 kg] was gradually added while maintaining the solution temperature at 25 °C for 1 hour, and stirred at the same temperature for 9 hours. After stopping the stirring, it was waited at 25 °C for 45 minutes until the separation of the solution layer occurred, then the aqueous layer was discarded, and a 10% aqueous acetic acid solution [a mixed solution of purified water (61.4 kg) and glacial acetic acid (12.0 kg), 36.2 kg] was added to the organic solvent layer and stirred at 25 °C for 45 minutes. After stopping the stirring, it was waited at 25 °C for 45 minutes until the separation of the solution layer occurred, then the aqueous layer was discarded, and the process of treating the 10% aqueous acetic acid solution was repeated. A 9.6% NaHCO3 aqueous solution [a mixed solution of purified water (162 kg) and NaHCO3 (16.9 kg), 36.2 kg] was added to the organic solvent layer and stirred at 25 °C for 45 minutes. After stopping the stirring, it was waited at 25 °C for 45 minutes until the separation of the solution layer occurred, then the aqueous layer was discarded. After repeating such a process, an organic solvent layer [solution of Compound 5 (in DCM): 100.45 kg, purity: 88.9% (HPLC), content: 9.3% (w / w)] was obtained.

[0048] 5. Synthesis of PRG-A-04 PRG-A-04 was synthesized according to the following Reaction Formula 7.

[0049]

Chemical Formula

[0050] First, the dried reactor was filled with nitrogen, and while continuously blowing nitrogen into the reactor, Compound 6 (3.6 kg, 14.61 moles, 1.0 eq) was charged. For the purpose of removing the air remaining inside the reactor, nitrogen / vacuum was alternately exchanged 3 times, and finally, the inside of the reactor was filled with nitrogen. Pd2(dba)3 [Tris(dibenzylideneacetone)dipalladium(0), 202 g, 0.22 moles, 0.015 eq.] and Xantphos (255 g, 0.44 moles, 0.03 eq.) were charged into the reactor. After alternately exchanging nitrogen / vacuum 3 times, finally, the inside of the reactor was filled with nitrogen.

[0051] Compound 5 (8.1 kg, 26.3 moles, 1.8 eq.) was dissolved in DCM (18 L), and then the gas was removed. The solution was gradually maintained at an internal temperature of 42°C of the solution and charged into the solution consisting of Compound 6, Pd2(dba)3, and Xantphos over 4 hours. After stirring at 42°C for 2 hours, the solution temperature was adjusted to 25°C. N-acetylcysteine (0.9 kg) was charged and stirred at 25°C for 18 hours. The reaction solution was filtered using a filter equipped with a diatomite pad (1.0 kg), and the filtered wet cake was washed with DCM (10 L). The solution obtained by filtration was washed twice with water (18 L x 2), then the aqueous layer was discarded, and the organic solvent layer was concentrated to 10 L at a temperature of 50°C or lower.

[0052] Using a filter with a silica gel pad (10 kg) placed in it, the reaction solution was filtered, and to collect the reactants remaining on the silica gel pad, the silica gel pad was washed with DCM. The solution thus collected was concentrated to 5.4 L, acetone (~14.4 L) was added, the solution was concentrated to 5.4 L, acetone (~7.2 L) was added, the solution was concentrated to 5.4 L, and acetone (~7.2 L) was added. The reaction solution was stirred at 35 °C until all solids were completely dissolved.

[0053] Isopropyl alcohol (IPA, 18 L) was maintained at a solution temperature of 35 °C and stirred for 5 hours. Then, the reaction solution was adjusted to 0 °C over 3 hours, stirred at 0 °C for 18 hours, filtered, and the solid filtered was washed with IPA (7.2 L).

[0054] To recrystallize the obtained solid, the solid, acetone (7.2 L), and IPA (14.4 L) were charged into a clean reactor, stirred at 50 °C for 8 hours, the solution temperature was adjusted to 25 °C over 3 hours, stirred at 25 °C for 8 hours, and then filtered. The solid filtered was washed with IPA (3.6 L) and dried at 52 °C for 18 hours to obtain bright yellow powder of PRG - A - 04 [Yield: 4.03 kg (63%), Purity: 98.8% (HPLC), Chiral purity: 99.6% (HPLC), Residual moisture: 0.02% (KF), Loss on drying: 0.23%, Melting point (DSC): Onset 131.31 °C (peaktemp. 133.08 °C), 277.81 °C (peaktemp. 301.39 °C), Residual Palladium (Pd): 17 ppm, Residual Xantphos: 80 ppm, Residual Pd2(dba)3: 104 ppm].

[0055] 11H NMR (CDCl3, 400 MHz): δ 7.85 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 9.5 Hz, 1H), 7.16 (s, 1H), 7.05 - 6.97 (m, 2H), 6.78 (s, 1H), 6.60 (app.dt, J = 15.9, 1.7 Hz, 1H), 6.40 (app.dt, J = 15.9, 5.5 Hz, 1H), 6.22 (d, J = 9.4 Hz, 1H), 4.39 (ddd, J = 13.6, 5.4, 1.7 Hz, 1H), 4.24 (ddd, J = 13.4, 5.5, 1.6 Hz, 1H), 3.97 (s, 3H), 3.59 (dd, J = 7.1, 4.9 Hz, 1H), 3.11 (dd, J = 16.7, 4.9 Hz, 1H), 2.87 (dd, J = 16.7, 7.2 Hz, 1H), 1.43 (s, 3H), 1.38 (s, 3H).

[0056] 13 13C NMR (CDCl3, 151 MHz): δ 161.4, 156.8, 154.4, 153.7, 143.2, 143.1, 138.5, 130.7, 130.0, 128.8, 126.5, 118.2, 116.9, 113.4, 112.9, 111.4, 104.9, 78.0, 76.7, 70.1, 56.6, 27.6, 26.0, 21.8;

[0057] IR (film): 2921, 2851, 1722, 1625, 1603, 1585, 1561, 1511, 1132 cm -1 ;

[0058] HRMS: m / z calcd for C 24 H 24 NO7 + [M + H] + : 438.1547, found: 438.1550.

[0059] As described in detail above for specific parts of the content of the present invention, it is clear to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the present invention thereby. That is, the substantial scope of the present invention is defined by the claims and their equivalents.

Claims

1. A method for synthesizing a decursin derivative represented by Compound I, comprising a step of synthesizing a decursin derivative represented by Compound I through a reaction between an intermediate compound (Compound 5) in which a Boc protecting group is introduced into the OH group of 3-(3-methoxy-4-nitrophenyl)prop-2-en-1-ol and decursinol (Compound 6), 【Chemical 1】 wherein the step of synthesizing the decursin derivative comprises synthesizing the decursin derivative represented by Compound I through a reaction between Compound 5 and Compound 6 in the presence of Pd2(dba)3 and xanthphos.

2. Compound 5 is synthesized through: ii) a second step of reacting the 3-methoxy-4-nitrobenzaldehyde with diethoxyphosphoryl acetate to synthesize ethyl 3-(3-methoxy-4-nitrophenyl)-2-propenoate; and i) A first step of reacting 3-hydroxy-4-nitrobenzaldehyde with methyl iodide (CH ３ I) to synthesize 3-methoxy-4-nitrobenzaldehyde, and iii) a third step of reacting the ethyl 3-(3-methoxy-4-nitrophenyl)-2-propenoate with diisobutylaluminum hydride (DIBAL-H) to synthesize 3-(3-methoxy-4-nitrophenyl)prop-2-en-1-ol. The synthesis method according to Claim 1, wherein Compound 5 is synthesized through the above steps. iv) A fourth step of reacting the 3-(3-methoxy-4-nitrophenyl)prop-2-en-1-ol with di-tert-butyl dicarbonate [(Boc) ２ O] to synthesize Compound 5 into which a Boc protecting group is introduced,

3. The step of synthesizing the decursin derivative comprises: ii) adding N-acetylcysteine to the stirred reaction solution and stirring; i) A solution of compound 6 and Pd is added to the solution of compound 5 and stirred ２ (dba) ３ and a solution containing xanthophosphine is added and stirred iii) filtering the stirred reaction solution and concentrating the organic solvent layer; iv) filtering the concentrated reaction solution, concentrating the collected solution, adding acetone, and completely dissolving it; and v) adding isopropyl alcohol to the dissolved reaction solution, washing, and obtaining the decursin derivative represented by Compound I. The synthesis method according to Claim 1, wherein the step of synthesizing the decursin derivative comprises the above steps.

4. Compound 5 and Compound 6 are included in a weight ratio of 1:(0.1-1). The synthesis method according to Claim 3, wherein Compound 5 and Compound 6 are included in the above weight ratio.

5. Pd2(dba)3 and xanthphos are each included in an amount of 3-10 parts by weight per 100 parts by weight of Compound 6. The synthesis method according to Claim 3, wherein Pd2(dba)3 and xanthphos are included in the above amounts.

6. The synthesis method according to Claim 3, further comprising a step of recrystallizing the obtained decursin derivative.

7. The recrystallization step comprises: i) A step of adding acetone and isopropyl alcohol to the obtained depside derivative, stirring, and then filtering; ii) A step of washing the filtered reaction product and drying it to obtain a depside derivative; The synthesis method according to claim 6, characterized by comprising the above steps.

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