Synthesis method for 3-phenyl-2, 3, 4, 8, 9, 10-hexahydropyrano [2, 3-f] chromene derivative

Abstract

The present invention relates to a process for the synthesis of 3-phenyl-2, 3, 4, 8, 9, 10-hexahydropyrano [2, 3-f] chromene derivatives.

Description

Technical Field

[0001] This application claims the benefit of the filing date of Korean Patent Application No. 10-2022-0045022 filed in the Korean Intellectual Property Office on April 12, 2022, the entire contents of which are incorporated herein.

[0002] The present invention relates to a method for synthesizing 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene derivatives. Background Art

[0003] Patent document 1 [Korean Patent No. 10-2015-0075030] discloses that pyranochromenylphenol derivatives are effective in preventing and treating various metabolic syndromes including hyperlipidemia, fatty liver, glucose metabolism disorders, diabetes and obesity. Patent document 2 [Korean Patent No. 10-2019-0116100] is an invention related to a method for synthesizing these pyranochromenylphenol derivatives according to the following reaction scheme for synthesizing pyranochromenylphenol derivatives. That is, Patent document 2 discloses a method for synthesizing formula F by coupling formula A and formula B together to obtain formula C, then cyclizing the formula C to obtain formula D, then reducing the formula D to obtain formula E, and then subjecting the formula E to reductive elimination. Formula F can then be synthesized into various derivatives disclosed in Patent document 1 [Korean Patent No. 10-2015-0075030] by simple hydrogenation.

[0004] Here, since the process of producing Formula F from Formula E uses a McMurry reagent [Ti(0) or Ti(1 + )], so there are difficulties in controlling and refining metal impurities, and commercial mass production involves considerable effort and is difficult. Therefore, a synthetic method that can be mass-produced under simple and mild conditions is required.

[0005] [Reaction scheme]

[0006] Summary of the invention

[0007] Technical issues

[0008] The present invention aims to provide a synthetic method capable of easily preparing 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene derivatives.

[0009] However, problems to be solved by the present invention are not limited to the above problems, and other problems not mentioned above will be clearly understood by those skilled in the art from the following description.

[0010] Technical Solution

[0011] One embodiment of the present invention provides a method for synthesizing 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene derivatives.

[0012] Beneficial Effects

[0013] By the synthesis method according to one embodiment of the present invention, a 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene derivative can be efficiently prepared.

[0014] Furthermore, the synthesis method according to one embodiment of the present invention can efficiently prepare 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene derivatives under simple and mild conditions.

[0015] Furthermore, the synthesis method according to one embodiment of the present invention can commercially produce 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene derivatives in large quantities.

[0016] Furthermore, the synthesis method according to one embodiment of the present invention is advantageous over conventional synthesis methods in that it can overcome the problem of difficulty in controlling and refining metal impurities.

[0017] However, the effects of the present invention are not limited to the above-described effects and can be extended in various ways without departing from the spirit and scope of the present invention. DETAILED DESCRIPTION

[0018] Throughout the present specification, it should be understood that when any part is referred to as “comprising” any component, it does not exclude other components but may further include other components unless otherwise specified.

[0019] Throughout this specification, when any member is referred to as being 'on' another member, it not only refers to a case where any member is in contact with another member but also refers to a case where a third member exists between the two members.

[0020] Hereinafter, the present invention will be described in more detail.

[0021] One embodiment of the present invention provides a method for synthesizing a 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene derivative, the method comprising the steps of: dehydrating a compound represented by the following Formula 1 in the following Reaction Scheme 1 to prepare a compound represented by the following Formula 2; and

[0022] The compound represented by Formula 2 is reduced (hydrogenated) to prepare a compound represented by the following Formula 3:

[0023] [Reaction Scheme 1]

[0024]

[0025] In reaction scheme 1,

[0026] R1 and R2 are each independently a hydrogen atom; a substituted or unsubstituted linear or branched C1-C6 alkyl group; a halogen atom; a substituted or unsubstituted linear or branched C1-C6 alkoxy group; a substituted or unsubstituted linear or branched C1-C4 thioalkyl group; a substituted or unsubstituted C6-C 12 Aryl; substituted or unsubstituted allyloxy; or substituted or unsubstituted C6-C 12 aryloxy;

[0027] R3 is a hydrogen atom, a C1-C2 alkyl group, a C1-C2 alkoxy group, or a halogen atom;

[0028] R4 and R5 are each independently a hydrogen atom or a C1-C6 alkyl group;

[0029] P represents a protecting group of a substituted or unsubstituted benzyl group, a substituted or unsubstituted allyl group, a methanesulfonyl group (MeSO 2 ), a p-toluenesulfonyl group (p-TsSO 2 ), or a trimethylphenylsulfonyl group;

[0030] P 1 is a hydrogen atom, a substituted or unsubstituted allyl group, a methanesulfonyl group (MeSO2), a p-toluenesulfonyl group (p-TsSO2), or a trimethylphenylsulfonyl group;

[0031] n is 1 to 3;

[0032] When OP and OP 1 When P and P are plural, 1 are the same or different from each other; and

[0033] The substituent of each of the substituted alkyl group, substituted alkoxy group, substituted thioalkyl group, substituted aryl group, substituted allyloxy group, substituted aryloxy group, substituted benzyl group and substituted allyl group is a benzyloxy group, a halogen atom, a linear or branched C1-C5 alkyl group, a linear or branched C1-C5 alkoxy group, a linear or branched C1-C3 thioalkyl group, or a nitro group.

[0034] When P in the above reaction scheme 1 is a substituted or unsubstituted benzyl group, if Pd / C is used as a catalyst for the hydrogenation reaction, the substituted or unsubstituted benzyl group can be removed, leaving hydrogen. Therefore, in this case, P in Formula 2 can be a substituted or unsubstituted benzyl group, and P in Formula 3 can be 1In addition, since substituted or unsubstituted allyl, MeSO2, p-TsSO2 or trimethylphenylsulfonyl do not react under the hydrogenation reaction conditions, P in Formula 2 and P in Formula 3 are 1 Can be the same.

[0035] In the method for synthesizing 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene derivatives according to one embodiment of the present invention, in the above reaction scheme 1,

[0036] R1 and R2 are each independently a hydrogen atom; a substituted or unsubstituted linear or branched C1-C3 alkyl group; or a linear or branched C1-C3 alkoxy group;

[0037] R3 is a hydrogen atom;

[0038] R4 and R5 are each independently a hydrogen atom or a C1-C3 alkyl group;

[0039] P represents a substituted or unsubstituted benzyl group or p-toluenesulfonyl group (p-TsSO2); and P 1 It is a hydrogen atom or a p-toluenesulfonyl group (p-TsSO2).

[0040] In the method for synthesizing 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene derivatives according to one embodiment of the present invention, in the above reaction scheme 1,

[0041] The compound represented by Formula 1 may be any one compound selected from the following compounds:

[0042] 3-(2-(Benzyloxy)-4-propoxyphenyl)-3-hydroxy-8,8-dimethyl-2,3-dihydropyrano[2,3-f]chromen-4(8H)-one;

[0043] 3-(2-(Benzyloxy)-4-ethoxyphenyl)-3-hydroxy-8,8-dimethyl-2,3-dihydropyrano[2,3-f]chromen-4(8H)-one;

[0044] 3-(2-(Benzyloxy)-4-propylphenyl)-3-hydroxy-8,8-dimethyl-2,3-dihydropyrano[2,3-f]chromen-4(8H)-one; and

[0045] 3-(2-(p-Toluenesulfonyloxy)-4-ethoxyphenyl)-3-hydroxy-8,8-dimethyl-2,3-dihydropyrano[2,3-f]chromen-4(8H)-one.

[0046] In the method for synthesizing 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene derivatives according to one embodiment of the present invention, in the above reaction scheme 1,

[0047] The compound represented by Formula 3 may be any one compound selected from the following compounds:

[0048] 2-(8,8-Dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromen-3-yl)-5-propoxyphenol;

[0049] 2-(8,8-Dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromen-3-yl)-5-ethoxyphenol;

[0050] 2-(8,8-Dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromen-3-yl)-5-propylphenol; and

[0051] 1-(8,8-Dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromen-3-yl)-2-(p-toluenesulfonyloxy)-4-ethoxybenzene.

[0052] When Formula 1 in Reaction Scheme 1 is dehydrated, the hydroxyl group at position 3 of Formula 1 is removed, and double bonds are formed at positions 2 and 3. When Formula 2 in Reaction Scheme 1 is hydrogenated, the double bond of pyran is converted into a single bond, and the ketone is reduced, thereby generating Formula 3.

[0053] The dehydration in Reaction Scheme 1 can be performed under acidic conditions. For example, the dehydration can be performed in an acid solution containing at least one of sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid, and p-toluenesulfonic acid. The dehydration can be performed at a temperature of 40° C. to 60° C. or less.

[0054] By performing dehydration under the above conditions, the compound represented by Formula 2 can be stably prepared from the compound represented by Formula 1 in Reaction Scheme 1, and the yield of the compound of Formula 2 can be increased.

[0055] The reduction (hydrogenation) in Reaction Scheme 1 can be performed by hydrogenation using Pd / C (palladium on carbon) as a catalyst to perform both reduction of the double bond and removal of the carbonyl group, thereby producing a compound represented by Formula 3. Here, the reduction can be performed at a temperature of 0° C. to 60° C. In addition, the reduction can be performed under a hydrogen pressure of 1 atmosphere to 7 atmospheres.

[0056] By performing the reduction under the above conditions, the compound represented by Formula 3 can be stably prepared from the compound represented by Formula 2 in Reaction Scheme 1, and the yield of the compound of Formula 3 can be increased.

[0057] The object of the present invention is to provide an economical method that fundamentally solves the problem of Patent Document 2 (Korean Patent No. 10-2019-0116100) by directly preparing Formula 3 via dehydration of Formula 1 and hydrogenation of Formula 2 in Reaction Scheme 1.

[0058] Conventional synthesis methods including Korean Patent Publication No. 10-2019-0116100 require three steps (reduction, reductive elimination, and hydrogenation) to synthesize Formula 3 from Formula 1, and encounter difficulties in handling the reagents used (McMurry reagent). The present invention has great advantages in commercialization because Formula 3 can be synthesized by only two steps (dehydration and hydrogenation), and the handling of the reagents used or the reaction conditions are not difficult.

[0059] name:

[0060] Formula 1:

[0061] 3,3-Phenylhydroxy-2,3-dihydropyrano[2,3-f]chromen-4(8H)-one derivatives

[0062] Formula 2:

[0063] 3-Phenyl-pyrano[2,3-f]chromen-4(8H)-one derivatives

[0064] Formula 3:

[0065] 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene derivatives

[0066] One embodiment of the present invention provides a compound represented by the following Formula 2:

[0067] [Formula 2]

[0068]

[0069] In the above Formula 2, R1 to R5 are the same as defined in the above Reaction Scheme 1.

[0070] The compound represented by Formula 3 can be easily prepared using the compound represented by Formula 2. In addition, the compound of Formula 3 can be prepared in a simple manner under milder conditions.

[0071] According to one embodiment of the present invention, the compound represented by Formula 1 in Reaction Scheme 1 can be prepared according to the following Reaction Scheme 2:

[0072] [Reaction Scheme 2]

[0073]

[0074] In the above Reaction Scheme 2, R1 to R5 are the same as defined in the above Reaction Scheme 1, and X may be a halogen. Formula D in the above Reaction Scheme 2 may be Formula 1 in the above Reaction Scheme 1.

[0075] The coupling step in the above reaction scheme 2 can be carried out under alkaline conditions. The alkaline conditions can be formed by adding at least one weakly alkaline compound selected from sodium carbonate (Na2CO3), lithium carbonate (Li2CO3), potassium carbonate (K2CO3), sodium bicarbonate (NaHCO3), potassium bicarbonate (KHCO3), triethylamine and pyridine.

[0076] The cyclization in Reaction Scheme 2 can be carried out by adding a salt to the compound of Formula C via benzoin condensation to obtain a compound of Formula D. Specifically, the salt can be thiazole Salt, triazole Salt or 6,7-dihydro-5h-pyrrolo[2,1-c][1,2,4]triazole Salt.

[0077] Embodiments of the invention

[0078] Hereinafter, the present invention will be described in detail by way of embodiment. However, embodiments according to the present invention may be modified into various forms, and the scope of the present invention is not to be construed as being limited to the embodiments described below. The embodiments of this specification are provided to more fully illustrate the present invention to those skilled in the art.

[0079] Example

[0080] Example 1: Preparation of 2-(8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromen-3-yl)-5-propoxyphenol

[0081] 1-1. Synthesis of 3-(2-(benzyloxy)-4-propoxyphenyl)-8,8-dimethyl-pyrano[2,3-f]chromen-4(8H)-one

[0082]

[0083] 516 g of 95% sulfuric acid was added dropwise to 800 mL of THF at 0° C. to 20° C., and 50 g (0.1028 mol) of 3-(2-(benzyloxy)-4-propoxyphenyl)-3-hydroxy-8,8-dimethyl-2,3-dihydropyrano[2,3-f]chromene-4(8H)-one was added to the solution in batches at 20° C. or lower. The mixture was warmed to 40° C. to 45° C. and stirred for 2 hours. After the reaction was completed, the reaction solution was cooled to 20° C. or lower, 500 mL of purified water was added thereto, and then stirred at 20° C. to 30° C. for 1 hour. The reaction solution was filtered, and the filtrate was washed with 250 mL of purified water at room temperature and then dried. 180 mL of methanol was added to 45.2 g of the dried product, and then stirred at 55° C. for 1 hour. The reaction solution was cooled to 25°C, stirred for 1 hour, filtered and dried to obtain 42.8 g (yield 88.8%) of 3-(2-(benzyloxy)-4-propoxyphenyl)-8,8-dimethyl-pyrano[2,3-f]chromen-4(8H)-one.

[0084] 1 H-NMR (CDCl3): 8.0648 (d, 1H, J = 8.76Hz), 7.9123 (s, 1H), 7.3544~7.2182 (m , 6H), 6.8447 (d, 1H, J = 8.76Hz), 6.7856 (d, 1H, J = 10.0Hz), 6.6035 (s, 1H), 6 .5644 (d, 1H, J = 8.52Hz), 5.6888 (d, 1H, J = 10.00Hz), 5.0573 (s, 2H), 3.9161 (t, 2H, J = 6.52Hz), 1.7967 (m, 2H), 1.4879 (s, 6H), 1.0291 (t, 3H, J = 7.40Hz).

[0085] 13 C-NMR(CDCl3):176.0145,160.6824,157.8164,157.2211,153.5956,152.5656,137.233 3,132.3996,130.2681,128.6029,127.8214,127.3682,126.8727,122.3239,118.6639,1 15.2862, 115.1127, 113.9942, 109.3931, 105.9793, 101.3679, 77.7617, 77.5482, 77.4322, 77.2300, 76.9125, 70.8135, 69.8359, 68.1466, 28.3101, 25.7900, 22.7301, 10.7101.

[0086] 1-2. Synthesis of 2-(8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromen-3-yl)-5-propoxyphenol

[0087]

[0088] 3g (0.0064mol) of 3-(2-(benzyloxy)-4-propoxyphenyl)-8,8-dimethyl-pyrano[2,3-f]chromene-4(8H)-one and 0.3g of Pd / C (50% wet) were added to a mixed solution of 60ml of ethanol / dichloromethane (1 / 1) and stirred for 8 hours at 40°C and 2 atmospheres of hydrogen pressure. The reaction solution was filtered to remove Pd / C, and the filtrate was concentrated under reduced pressure. 31.5mL of methanol was added to the concentrate, which was then dissolved by heating to 60°C. Next, the solution was cooled to 40°C to 50°C, and 9mL of purified water was added thereto. Then, the suspension was heated to 62° C., stirred for 1 hour, cooled to 0° C., filtered and dried to obtain 2.1 g (yield 89.1%) of 2-(8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromen-3-yl)-5-propoxyphenol.

[0089] 1 H-NMR (CDCl3): 6.976 (d, 1H, J = 8.4Hz), 6.817 (d, 1H, J = 8.4Hz), 6.452 (dd, 1H, J = 8.4, 2.0Hz), 6.391 (d, 1H, J=8.4Hz), 6.316 (d, 1H, J=2.0Hz), 5.600 (s, 1H), 4.385 (d, 1H, J=10.0Hz), 4.000 (t, 1H, J=10.0Hz), 3.812(t,2H,J=6.4Hz),3.488(m,1H),2.997(dd,1H,J=15.6,11.2Hz),2.837(dd,1H,J=15.6,4.4Hz),2 .640 (m, 2H), 1.782 (t, 2H, J = 6.8Hz), 1.765 (m, 2H), 1.329 (s, 3H), 1.314 (s, 3H), 0.994 (t, 3H, J = 7.2Hz).

[0090] 13C-NMR(CDCl3):159.25,157.52,153.05,152.46,137.18,128.81,128.06,127.85,127.66,127.37,122.53,113.15,109.48,109.38 ,105.59,100.65,77.55,77.43,77.23,76.91,73.83,70.47,70.29,69.81,32.59,31.62,31.07,27.03,26.73,22.80,17.37,10.75

[0091] Example 2: Preparation of 2-(8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromen-3-yl)-5-ethoxyphenol

[0092] 2-1. Synthesis of 3-(2-(Benzyloxy)-4-ethoxyphenyl)-8,8-dimethyl-pyrano[2,3-f]chromen-4(8H)-one

[0093]

[0094] 103 g of 95% sulfuric acid was added dropwise to 200 mL of THF, and 10 g (0.0212 mol) of 3-(2-(benzyloxy)-4-ethoxyphenyl)-3-hydroxy-8,8-dimethyl-2,3-dihydropyrano[2,3-f]chromene-4(8H)-one was added to the solution at 10° C. or lower. The mixture was warmed to 45° C. and stirred for 1 hour. Next, 100 mL of purified water was added to the reaction solution, and then 150 mL of dichloromethane was added thereto. The mixture was stirred and the organic layer was separated. The separated organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then filtered. After the filtrate was concentrated under reduced pressure, 33 mL of methanol was added to the concentrate, which was then warmed to 50° C. and subsequently stirred for 1 hour. Next, the reaction solution was cooled to 25° C., stirred for another 1 hour, filtered and dried to obtain 8.3 g (yield 86.1%) of 3-(2-(benzyloxy)-4-ethoxyphenyl)-8,8-dimethyl-pyrano[2,3-f]chromen-4(8H)-one.

[0095] 1H-NMR(CDCl3):8.0651(d,1H,J=8.72Hz),7.9207(s,1H),7.3550~7.2419 (m, 6H), 6.8477 (d, 1H, J = 8.76Hz), 6.7948 (d, 1H, J = 10.08Hz), 6.5939 (s, 1 H), 6.5632 (dd, 1H, J = 8.32, 2.36Hz), 5.6984 (d, 1H, J = 10.00Hz), 5.0598 (s , 2H), 4.0347 (q, 2H, J = 7.00Hz), 1.4949 (s, 6H), 1.4090 (t, 3H, J = 7.00Hz).

[0096] 13 C-NMR (CDCl3): 176.0099, 160.4870, 157.8353, 157.2428, 153.6205, 152.5834, 1 37.2505,132.4447,130.2857,128.6290,127.8392,127.4578,127.3635,126.898 8,122.3177,118.6943,115.3109,115.1300,114.0880,109.4124,105.9419,101.4197,77.7783,77.5471,77.2300,76.9119,70.8369,63.7899,28.3316,15.0114.

[0097] 2-2. Synthesis of 2-(8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromen-3-yl)-5-ethoxyphenol

[0098]

[0099] 0.5 g (0.0011 mol) of 3-(2-(benzyloxy)-4-ethoxyphenyl)-8,8-dimethyl-pyrano[2,3-f]chromene-4(8H)-one and 0.025 g of Pd / C (50% wet) were added to 20 mL of ethanol and stirred at 0°C to 30°C and 5 atmospheres of hydrogen pressure for 72 hours. The reaction solution was filtered to remove Pd / C, and the filtrate was concentrated under reduced pressure. Methanol was added to the concentrate, and then dissolved by heating to 60°C. Then, the solution was cooled to 40°C to 50°C, and purified water was added thereto. The suspension was dissolved by heating, then cooled to 0°C, and the precipitated solid was filtered and dried to obtain 2-(8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene-3-yl)-5-ethoxyphenol.

[0100] 1 H-NMR (CDCl3): 6.989 (d, 1H, J = 8.4Hz), 6.825 (d, 1H, J = 8.0Hz), 6.458 (dd, 1H, J = 8.0, 2.4Hz), 6.387 (d, 1H, J=8.4Hz), 6.324 (d, 1H, J=2.4Hz), 5.355 (s, 1H), 4.386 (m, 1H, J=10.4, 3.2, 2.0Hz), 4.007 (t, 1H, J= 10.4Hz), 3.954 (q, 2H, J = 7.2Hz), 3.484 (m, 1H), 3.006 (dd, 1H, J = 15.6, 11.2Hz), 2.852 (m, 1H, J = 15.6, 4 .8, 1.6Hz), 2.641 (m, 2H), 1.770 (t, 2H, J = 6.8Hz), 1.378 (t, 2H, J = 6.8Hz), 1.331 (s, 3H), 1.316 (s, 3H).

[0101] 13 C-NMR(CDCl3):158.552,154.340,152.719,152.091,128.075,127.465,119.882,112.909,109.305,109. 248, 106.572, 102.504, 73.798, 70.018, 63.450, 32.311, 31.749, 30.614, 26.776, 26.390, 17.116, 14.781.

[0102] Example 3: Preparation of 2-(8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromen-3-yl)-5-propylphenol

[0103] 3-1. Synthesis of 3-(2-(Benzyloxy)-4-propylphenyl)-8,8-dimethyl-pyrano[2,3-f]chromen-4(8H)-one

[0104]

[0105] 103 g of 95% sulfuric acid was mixed with 150 mL of THF at 0° C. to 20° C., and a solution of 10 g of 3-(2-(benzyloxy)-4-propylphenyl)-3-hydroxy-8,8-dimethyl-2,3-dihydropyrano[2,3-f]chromene-4(8H)-one in 50 mL of THF was added to the mixture at 20° C. or lower. The resulting mixture was warmed to 40° C. to 45° C. and stirred. After the reaction was completed, the reaction solution was cooled to 20° C. or lower, and 100 mL of purified water was added thereto, followed by stirring at 20° C. to 30° C. for 1 hour. The reaction solution was filtered, washed with purified water at room temperature, and dried. The resulting crude solid was separated by column chromatography to obtain 4 g of 3-(2-(benzyloxy)-4-propylphenyl)-8,8-dimethyl-pyrano[2,3-f]chromene-4(8H)-one.

[0106] 1 H-NMR (CDCl3): 8.0692 (d, 1H, J = 8.75Hz), 7.9285 (s, 1H), 7.3560~7.2367 (m, 6H), 6.8713~6.7856 (m, 4H), 5.6991 (d, 1H, J =10.0Hz), 5.0787 (s, 2H), 2.5891 (t, 2H, J = 7.675Hz), 1.6717~1.6265 (m, 2H), 1.4955 (s, 6H), 0.9530 (t, 3H, J = 7.325Hz).

[0107] 13 C-NMR (CDCl3): 175.6677, 157.0656, 156.5540, 153.4361, 152.3918, 144. 6465, 137.3012, 131.4782, 130.1042, 128.3884, 127.5824, 127.2342, 126. 7165,122.4005,121.1285,118.8690,118.5204,115.1211,114.9583,113 .5411, 109.2258, 77.5909, 70.7133, 38.2456, 28.1388, 24.4552, 13.9173.

[0108] 3-2. Synthesis of 2-(8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromen-3-yl)-5-propylphenol

[0109]

[0110] 2 g of 3-(2-(benzyloxy)-4-propylphenyl)-8,8-dimethyl-pyrano[2,3-f]chromene-4(8H)-one and 0.2 g of 10% Pd / C (50% wet) were added to a 40 ml ethanol / dichloromethane (1 / 1) mixture and stirred at 40° C. and 2 atmospheres of hydrogen pressure for 12 hours. The reaction solution was filtered to remove Pd / C, and the filtrate was concentrated under reduced pressure. The concentrate was recrystallized from a n-hexane / dichloromethane solution to obtain 1.3 g of 2-(8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene-3-yl)-5-propylphenol.

[0111] 1 H-NMR (CDCl3): 7.0347 (d, 1H, J = 7.8Hz), 6.8501 (d, 1H, J = 8.4Hz), 6.7590 (d, 1H, J = 7.8Hz), 6.5937 (s, 1H ), 6.4051 (d, 1H, J = 8.3Hz), 4.9625 (s, 1H), 4.4338 (d, 1H, J = 10.4Hz), 4.0558 (t, 1H, J = 10.3Hz), 3.5504 ( m, 1H), 3.0494 (dd, 1H, J = 15.5, 11.3Hz), 2.8927 (dd, 1H, J = 15.6, 4.4Hz), 2.6648 (m, 2H), 2.5208 (t, 2H, J =7.7Hz), 1.7910 (t, 2H, J = 6.8), 1.6263 (m, 2H), 1.3496 (s, 3H), 1.3346 (s, 3H), 0.9544 (t, 3H, J = 7.3Hz).

[0112] 13 C-NMR(CDCl3):153.2733,152.8039,152.1448,142.7151,127.4789,127.3474,124.8105,121.2198,115.5646,112.8768,1 09.3281,109.2797,73.7602,69.9349,37.5153,32.3508,32.1225,30.6003,26.8295,26.4155,24.3254,17.1536,13.8854.

[0113] Example 4: Preparation of 1-(8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromen-3-yl)-2-(p-toluenesulfonyloxy)-4-ethoxybenzene

[0114] 4-1. Synthesis of 3-(2-(p-toluenesulfonyloxy)-4-ethoxyphenyl)-8,8-dimethyl-pyrano[2,3-f]chromen-4(8H)-one

[0115]

[0116] 82.5 g of 95% sulfuric acid was mixed with 100 mL of THF at 0° C. to 20° C., and a solution of 8 g of 3-(2-(p-toluenesulfonyloxy)-4-ethoxyphenyl)-3-hydroxy-8,8-dimethyl-2,3-dihydropyrano[2,3-f]chromene-4(8H)-one in 40 mL of THF was added to the mixture at 20° C. or lower. The resulting mixture was warmed to 40° C. to 45° C. and stirred. After the reaction was completed, the reaction solution was cooled to 20° C. or lower, and 100 mL of purified water was added thereto, followed by stirring at 20° C. to 30° C. for 1 hour. The reaction solution was filtered, washed with 250 mL of purified water at room temperature, and then dried to obtain 5 g of 3-(2-(p-toluenesulfonyloxy)-4-ethoxyphenyl)-8,8-dimethyl-pyrano[2,3-f]chromene-4(8H)-one.

[0117] 1 H-NMR (CDCl3): 7.854 (d, 1H, J = 8.7Hz), 7.7135 (s, 1H), 7.4272 (d, 2H, J = 8.6Hz), 7.3062 (d, 1H, J = 8.65Hz), 6.9555 (d, 1H, J = 2.1Hz), 6.8944~6.8625 (m, 3H), 6.834 9(d,1H,J=8.7),6.7729(d,1H,J=10.0Hz),5.7603(d,1H,J=10.0Hz),4.4109(dd , 2H, J=13.9Hz, 6.95Hz), 2.1531 (s, 3H), 1.5308 (s, 6H), 1.4310 (t, 3H, J=6.9Hz).

[0118] 13C-NMR(CDCl3):174.3457,159.5630,157.2083,153.8837,151.7906,14 7.8032, 145.0867, 132.7554, 132.6659, 130.5258, 129.5232, 127.8644, 126.4008, 119.3712, 118.1595, 116.8792, 115.0336, 114.8265, 113.90 47,110.0778,109.1336,77.7865,63.9780,28.1497,21.5455,14.6532.

[0119] 4-2. Synthesis of 1-(8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromen-3-yl)-2-(p-toluenesulfonyloxy)-4-ethoxybenzene

[0120]

[0121] 2.5 g of 3-(2-(p-toluenesulfonyloxy)-4-ethoxyphenyl)-8,8-dimethyl-pyrano[2,3-f]chromene-4(8H)-one and 0.25 g of 10% Pd / C (50% wet) were added to a 50 ml ethanol / dichloromethane (1 / 1) mixture and stirred at 40° C. and 2 atmospheres of hydrogen pressure for 9 hours. The reaction solution was filtered to remove Pd / C, and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography and recrystallized from a n-hexane / dichloromethane solution to obtain 1.9 g of 1-(8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene-3-yl)-2-(p-toluenesulfonyloxy)-4-ethoxybenzene.

[0122] 1H-NMR (CDCl3): 7.7452 (d, 2H, J = 8.25Hz), 7.2901 (d, 2h, J = 8.25), 6.9814 (d, 1H, J = 8.6Hz), 6.791 (dd, 1H, J = 8. 65, 2.45), 6.7515 (d, 1H, J = 2.5Hz), 6.6930 (d, 1H, J = 8.35), 6.3636 (d, 1H, J = 8.35Hz), 4.0019~3.9307 (m, 3H), 3 .7789 (t, 1H, J = 10.375), 3.2182 (m, 1H), 2.6853 (dd, 1H, J = 15.6, 11.25Hz), 2.6214 (t, 2H, J = 6.75Hz), 2.4459 ( s, 3H), 2.3825 (dd, 1H, J = 15.6, 3.6), 1.7884 (m, 2H), 1.3874 (t, 3H, J = 6.975Hz), 1.3474 (s, 3H), 1.3280 (s, 3H).

[0123] 13 C-NMR(CDCl3):158.1649,152.9039,151.8663,148.0588,145.4641,132 .7353,129.9057,128.4824,128.1478,127.2391,126.4626,114.2589,1 12.2769,109.3156,109.2591,108.8719,73.7020,69.8093,63.8097,32 .3222,31.4477,30.9064,26.6849,26.6268,21.7116,17.0980,14.6538.

[0124] The above detailed description illustrates and describes the present invention. In addition, the above description only shows and describes the preferred embodiments of the present invention, but as mentioned above, it should be understood that the present invention can be used in various other combinations, modifications and environments, and can be changed or modified within the scope of the inventive concept as expressed herein, commensurate with the above teachings and / or the skills or knowledge in the art. Therefore, the above detailed description of the present invention is not intended to limit the present invention to the embodiments disclosed herein. In addition, the appended claims are intended to be interpreted as including alternative embodiments.

Claims

1. A method for synthesizing 3-phenyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene derivatives, comprising the following steps: Dehydrating a compound represented by the following Formula 1 to prepare a compound represented by the following Formula 2; as well as The compound represented by Formula 2 is reduced to prepare a compound represented by the following Formula 3: [Reaction Scheme 1] In the reaction scheme 1, R1 and R2 are each independently a hydrogen atom; a substituted or unsubstituted linear or branched C1-C2 alkyl group; a halogen atom; a substituted or unsubstituted linear or branched C1-C6 alkoxy group; a substituted or unsubstituted linear or branched C1-C4 thioalkyl group; a substituted or unsubstituted C6-C 12 Aryl; substituted or unsubstituted allyloxy; or substituted or unsubstituted C6-C 12 aryloxy; R3 is a hydrogen atom, a C1-C2 alkyl group, a C1-C2 alkoxy group, or a halogen atom; R4 and R5 are each independently a hydrogen atom or a C1-C6 alkyl group; P represents a substituted or unsubstituted benzyl group, a substituted or unsubstituted allyl group, a methanesulfonyl group (MeSO2), a p-toluenesulfonyl group (p-TsSO2), or a trimethylphenylsulfonyl group; P 1 is a hydrogen atom, a substituted or unsubstituted allyl group, a methanesulfonyl group (MeSO2), a p-toluenesulfonyl group (p-TsSO2), or a trimethylphenylsulfonyl group; n is 1 to 3; When OP and OP 1 When P and P are plural, 1 each the same or different; as well as The substituent of each of the substituted alkyl group, substituted alkoxy group, substituted thioalkyl group, substituted aryl group, substituted allyloxy group, substituted aryloxy group, substituted benzyl group and substituted allyl group is a benzyloxy group, a halogen atom, a linear or branched C1-C5 alkyl group, a linear or branched C1-C5 alkoxy group, a linear or branched C1-C3 thioalkyl group, or a nitro group.

2. The method according to claim 1, wherein R1 and R2 are each independently a hydrogen atom; a substituted or unsubstituted linear or branched C1-C3 alkyl group; a linear or branched C1-C3 alkoxy group; R3 is a hydrogen atom; R4 and R5 are each independently a hydrogen atom or a C1-C3 alkyl group; P represents a substituted or unsubstituted benzyl or p-toluenesulfonyl (p-TsSO2) protecting group; and P 1 It is a hydrogen atom or a p-toluenesulfonyl group (p-TsSO2).

3. The method according to claim 1, wherein the formula 1 is any one compound selected from the following compounds: 3-(2-(Benzyloxy)-4-propoxyphenyl)-3-hydroxy-8,8-dimethyl-2,3-dihydropyrano[2,3-f]chromen-4(8H)-one; 3-(2-(Benzyloxy)-4-ethoxyphenyl)-3-hydroxy-8,8-dimethyl-2,3-dihydropyrano[2,3-f]chromen-4(8H)-one; 3-(2-(Benzyloxy)-4-propylphenyl)-3-hydroxy-8,8-dimethyl-2,3-dihydropyrano[2,3-f]chromen-4(8H)-one; and 3-(2-(p-Toluenesulfonyloxy)-4-ethoxyphenyl)-3-hydroxy-8,8-dimethyl-2,3-dihydropyrano[2,3-f]chromen-4(8H)-one.

4. The method according to claim 1, wherein the formula 3 is any one compound selected from the following compounds: 2-(8,8-Dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromen-3-yl)-5-propoxyphenol; 2-(8,8-Dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromen-3-yl)-5-ethoxyphenol; 2-(8,8-Dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromen-3-yl)-5-propylphenol; and 1-(8,8-Dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromen-3-yl)-2-(p-toluenesulfonyloxy)-4-ethoxybenzene.

5. A 3-phenyl-pyrano[2,3-f]chromene-4(8H)-one derivative compound represented by the following formula 2: [Formula 2] In Formula 2, R1 and R2 are each independently a hydrogen atom; a substituted or unsubstituted linear or branched C1-C6 alkyl group; a halogen atom; a substituted or unsubstituted linear or branched C1-C6 alkoxy group; a substituted or unsubstituted linear or branched C1-C4 thioalkyl group; a substituted or unsubstituted C6-C 12 Aryl; substituted or unsubstituted allyloxy; or substituted or unsubstituted C6-C 12 aryloxy; R3 is a hydrogen atom, a C1-C2 alkyl group, a C1-C2 alkoxy group, or a halogen atom; R4 and R5 are each independently a hydrogen atom or a C1-C6 alkyl group; P is substituted or unsubstituted benzyl, allyl, methanesulfonyl (MeSO2), p-toluenesulfonyl (p-TsSO2), or trimethylphenylsulfonyl; n is 1 to 3; When OP is plural, P may be the same or different; and The substituent of each of the substituted alkyl group, substituted alkoxy group, substituted thioalkyl group, substituted aryl group, substituted allyloxy group, substituted aryloxy group, substituted benzyl group and substituted allyl group is a benzyloxy group, a halogen atom, a linear or branched C1-C5 alkyl group, a linear or branched C1-C5 alkoxy group, a linear or branched C1-C3 thioalkyl group, or a nitro group.

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