KR100966027B1 - The novel preparation method of decursin and decursin analoges - Google Patents

Abstract

The present invention comprises the steps of: a) preparing a compound of Formula 2 by introducing an amine group or a hydroxyl group at the alpha carbon position of the carboxyl group in the compound of Formula 1; And b) reacting the compound of formula 2 obtained in step a) with a compound of formula 3 under a nucleophilic catalyst to produce a compound of formula 4;

 [Formula 1] [Formula 2] [Formula 3] [Formula 4]

,

,

,

,

,

,

Where

X ₁ is a hydroxy group (-OH) or an amine group (-NH ₂ ),

X ₂ is an oxygen atom (-O-) or an amine group (-NH-),

Y is a halogen atom or a hydroxy group (-OH),

R ₁ and R ₂ are each a straight or branched C1-C5 hydrocarbon,

또는

이다.Z is

or

to be.

Deckerin, Deckerin analogs, Deckerin intermediates

Description

The novel preparation method of decursin and decursin analoges

The present invention relates to a process for making decosin and decosin analogs.

Decursin is a coumarin analogue in Angelica gigas, which has the following structural formula:

Deckerin enters the brain and protects brain cells by reducing beta-amiroids, known as toxic substances in the brain, and inhibiting their production, thus preventing and treating dementia. In particular, by activating blood circulation and metabolism has been reported to contribute to the removal of free radicals, as well as antioxidant activity, thereby maintaining the brain function actively. In addition, it has been shown that decusin exhibits anti-cancer activity in vivo and enhances the activity of protein kinase C. The anti-tumor effect and growth of human immune cells, B cells and T cells, and natural killer cells, NK cells It is known to promote. In particular, decusin is effective in treating leukemia, reducing renal toxicity, and treating diabetic hypertension. In addition, it has whitening function and antibacterial function against Helicobacter pylori.

Thus, various methods of making such useful decusins are disclosed. For example, Korean Patent Publication No. 2002-0003940 discloses a step of adding 7-hydroxy-2,2-dimethylchroman-4-one (1) by chemical reaction by adding diphosphorous pentoxide to methanesulfonic acid; Adding LiAlH ₄ to tetrahydrofuran and adding the obtained compound thereto, followed by chemical reaction to prepare 2,2-dimethylchroman-4,7-diol (2); Preparing 2,2-dimethyl-2H-chromen-7-ol (3) by adding p-toluenesulfonic acid and THF to the compound (2) and reacting them chemically; Compound (3), acetic anhydride, pyridine and 4-dimethylaminopyridine were added to methylene chloride, followed by chemical reaction to prepare 7-acetoxy-2,2-dimethyl-2H-chromen (4). ; CH ₂ CN was added with the compound (4) and Na ₂ B ₄ O ₇ 10H ₂ O, n-Bu ₄ NHSO ₄ and 1,1,1-trifluoroacetone, followed by adding NaHCO ₃ aqueous solution and oxone aqueous solution. Reacting to prepare 7-acetoxy-3,4-epoxy-2,2-dimethylchroman (5); Preparing 2,2-dimethylchroman-3,7-diol (6) by chemical reaction by adding LiAlH ₄ and THF to the compound (5); Preparing a decosinol (7) by chemical reaction by adding ZnCl ₂ , ethyl propiolate and aqueous hydrochloric acid to the compound (6); A method for synthesizing the anticancer drug deckercin, which comprises the step of adding 3,3-dimethylacryloyl chloride, the compound (7) and pyridine to methylene chloride, and then chemically reacting to produce deckerin.

In addition, Korean Patent Publication No. 2001-0096074 discloses a physiological activity by reacting an allyl compound represented by Formula A with an aromatic compound of Formula B or D using a renewable metal indium as a catalyst, as shown in Scheme 1. After preparing an allylated aromatic compound represented by the formula (C) or (E), which is a precursor of the compound (F), which is a compound useful for preparing a natural coumarin compound, the coumarin compound represented by the formula (E) is prepared by using an MMPP or H ₂ O ₂ oxidizing agent. Disclosed is a method for preparing a pyranokumarin analogue represented by Formula (F) and reacting with a compound of Formula (F) with sesencioyl chlorid to produce decusin.

Scheme 1

However, the above production methods only disclose a method of preparing only the decosin itself, which has the disadvantage of hydrolyzing into decursinol, which is relatively inferior in cell membrane or vascular-brain barrier permeability in vivo.
Hereinafter, the research of the present invention was carried out with the support of Seoul-Academic-Industry Cooperation Project, the details are as follows.
-Assignment No.:10524,
-Name of department: Seoul,
-Project name: Seoul-Industry Cooperation Project (Seoul City Support Project),
-Title of research: Natural drug cluster business,
-Host organization: Kyung Hee University
-Research period: 2005.12.01 ~ 2010.11.30

In this regard, the present inventors aim to provide a simpler manufacturing process and a method of obtaining a good yield of decusin and analogues.

The present invention provides methods for making decosin and decosin analogs.

Specifically, the present invention comprises the steps of: a) preparing a compound of Formula 2 by introducing an amine group or a hydroxyl group at the alpha carbon position of the carboxyl group in the compound of Formula 1; And b) reacting the compound of formula 2 obtained in step a) with the compound of formula 3 under a nucleophilic catalyst to prepare a compound of formula 4 which is a deckerin analog. ;

[Formula 1]

(2)

[Formula 3]

[Formula 4]

Where

X ₁ is a hydroxy group (-OH) or an amine group (-NH ₂ ),

X ₂ is an oxygen atom (-O-) or an amine group (-NH-),

Y is a halogen atom or a hydroxy group (-OH),

R ₁ and R ₂ are each a straight or branched C1-C5 hydrocarbon,

또는

이다.Z is

or

to be.

In the production method of the present invention, the introduction of the amine group in step a) is preferably performed using a reaction condition in which a nitro group is introduced and then the nitro group is reduced to convert to an amine group.

Introduction of the nitro group in step a) can be carried out under reaction conditions already known to those skilled in the art of introducing the nitro group to the carboxy group alpha position. For example, it may be performed in the presence of NaNO ₂ , HNO ₃ and an acid.

The introduced nitro group can be converted to an amine by a reaction of reducing the nitro group to an amine, a method already known to those skilled in the art. For example, the reduction reaction may be performed in the presence of a catalyst and hydrogen gas such as palladium (Pd), rhodium (Rh), platinum (Pt), silver (Ag), zinc (Zn) and the like.

The hydroxyl group introduction reaction of step a) in the preparation method of the present invention may be carried out under reaction conditions known to those skilled in the art to introduce the hydroxyl group to the carboxy group alpha position. For example, it may be performed in the presence of iodobenzene diacetate or CAN (ceric ammonium nitrate in acetic acid), Pb (OAc) ₄ , Pb (OCCF ₃ ) ₄ .

In the preparation method of the present invention, the nucleophilic catalyst of step b) is, for example, pyridine, Et ₃ N or dimethylaminepyridine (DMAP).

In addition, the present invention, in addition to the production method of the present invention for preparing the formula (4), by deoxygenation reaction of the compound of formula (4) obtained in step b) of the formula (5) showing another deckerin analogue or deckerin It provides a method for preparing a compound of Formula 5 further comprising the step of preparing a compound;

[Formula 5]

Where

X ₂ , R ₁ , R ₂ and Z are as defined above.

In the present invention, the deoxygenation reaction may be performed under reaction conditions known to those skilled in the art for removing oxygen from the carboxyl group. For example, in the presence of hydrazine (NH ₂ NH ₂ ) and a strong base, the reaction is carried out in the presence of Wolff-Kishner reduction or Zn (Hg) [an alloy of zinc and mercury] and strong acid. There is a Clemmensen reduction reaction. By strong acid is meant ordinary strong acid known to those skilled in the art such as sulfuric acid, hydrochloric acid, bromic acid.

In addition, the present invention provides a compound of formula 2, which is a novel compound prepared as an intermediate in the preparation method of the present invention;

(2)

Where

X ₁ is a hydroxyl group (-OH), a nitro group (-NO ₂ ) or an amine group (-NH ₂ ),

또는

이다.Z is

or

to be.

The preparation method of the present invention is conventional polar or nonpolar organic compounds such as tetrahydrofuran (THF), ether, acetone, hexane, benzene, toluene, methylene chloride (MC), carbon tetrachloride, chloroform, ethyl acetate, dimethyl sulfoxide (DMSO) It may be carried out in a solvent. In some cases, it may also be carried out in water or a mixed solvent of water and an organic solvent.

The preparation method of the present invention is preferably carried out at room temperature or below the boiling point of the solvent used, but in some cases, it may be heated to the boiling point of the solvent through a reflux apparatus, in order to reduce the reaction rate and reduce the addition reaction, For example, the reaction can be carried out below about 0 ° C. In some cases, the reaction may be performed at cryogenic temperatures such as -78 ° C to -40 ° C.

The present invention has the effect of providing the deckerin or the deckerin analogs in a simpler process and with an improved yield.

Hereinafter, the configuration and operation of the present invention will be described in detail with reference to Examples, but the scope of the present invention is not limited to these Examples.

<Production of Starting Material>

A. Preparation of Starting Material 1 (8,8-dimethyl-7,8-dihydropyrano [3,2-g] chromene-2,6-dione: Compound IV)

2-methyl-3-butene-2-ol (0.70 ml, 6.67 mmol) was dissolved in a 10 ml solution of 95 (v / v)% formic acid dissolved in 2,4-dihydroxybenzaldehyde (1.38 g, 10.00 mmol, compound I ). Added. The mixture was heated to reflux for 4 hours and then cooled. 100 ml of water was poured into the solution and neutralized to pH 7-8 with sodium bicarbonate. The aqueous layer was extracted three times with 50 ml of ethyl acetate. The organic layer was dehydrated with anhydrous magnesium sulfate and the solvent was evaporated in vacuo. The crude product was purified by column chromatography using hexane and ethyl acetate (v: v, 2: 1) to give a white solid compound II (1.07g, 52%).

Compound II (1.07 g, 5.2 mmol) and carbetaxin ethylene triphenyl phosphorolane (27.2 g, 78.0 mmol) compound were heated at 250 for 2 hours. The resulting mixture was heated to silica gel column chromatography using hexane and ethyl acetate (v: v, 8: 1) to give a white solid compound III (886 mg, 3.6 mmol).

Dissolve compound III (886 mg, 3.6 mmol) in ether (20 ml), add water (20 ml) and acetic acid (20 m) to a well mixed solution, and stir CAN (ceric ammonium nitrate, 3.9 g, 7.2 mmol) in small portions. And added. The reaction was frequently stirred and heated in a bath for 20-30 minutes. The reaction mixture was cooled to room temperature and diluted with water. The precipitate was filtered and purified by column chromatography using hexane and ethyl acetate (v: v, 20: 1) developing solvent to give the title compound Compound IV as a colorless solid. ¹ H-NMR (400 MHz, CDCl ₃ ) d 8.03 (s, 1H), 7.67 (d, 1H), 6.84 (s, 1H), 6.30 (d, 1H), 1.50 (s, 6H).

B. Preparation of Starting Material 2 (9,9-dimethyl-8,9-dihydropyrano [2,3-g] chromene-2,6-dione: Compound VII)

To resorcinol (330 mg, 3 mmol, Compound V), 3-methyl-2-butenic acid (300 mg, 3 mmol) was added and stirred rapidly under nitrogen substitution, and 10 ml of methanesulfonic acid and phosphorus pentoxide (240 mg, 1.7 was added at once in a flask containing 70 mmol). The reaction was stirred at 70 for 30 minutes, cooled, and poured into ice water (50 ml). The mixture was extracted three times with 30 ml of ethyl acetate to obtain an organic fraction. The organic layer was washed with water, brine and anhydrous magnesium sulfate. The residue was purified by fresh column chromatography to give compound VI (323 mg, 56%) as a colorless oil.

A mixture of compound VI (3 g, 20.2 mmol) and malic acid (4.2 g, 31.3 mmol) was added well to the hot mixed solution of acetic acid (5 ml) and concentrated sulfuric acid (10 ml). The mixture was kept at 130 for 6 hours with stirring, then cooled to room temperature and slowly added to ice water (50 ml) with rapid stirring for 30 minutes. The aqueous solution was extracted three times with 30 ml of ethyl acetate, and the combined organic fractions were washed with water, saturated aqueous sodium hydrogen carbonate solution and brine, and then water was removed with anhydrous magnesium sulfate. The solvent was removed and the residue was subjected to fresh column chromatography to give 2.42 g (60% yield) of the title compound VII as acicular crystals. ¹ H-NMR (400 MHz, CDCl ₃ ) d 8.07 (d, 1H), 8.01 (d, 1H), 6.93 (s, 1H), 6.39 (d, 1H), 1.53 (s, 6H).

Example 1 7-hydroxy-8,8-dimethyl-7,8-dihydropyrano [3,2-g] chromene-2,6-dione {7-hydroxy-8,8-dimethyl- Preparation of 7,8-dihydropyrano [3,2-g] chromene-2,6-dione}

10 ml of anhydrous methanol solution in which starting material 1 (244 mg, 1 mmol) was dissolved was added to a mixed solution of potassium hydroxide (168 mg, 3 mmol) and methanol (5 ml) over 0 to 5 minutes. While stirring the suspension, solid iodobenzene diacetate (387 mg, 1.2 mmol) was added in three portions for 2 minutes. The mixture is stirred at 0-1 h and then at room temperature overnight. Methanol was mostly evaporated under reduced pressure and water (20 ml) was added. Saturated with potassium carbonate and extracted with ethyl acetate (3 x 20ml). The ethyl acetate extract was dried over anhydrous magnesium sulfate and concentrated to give dimethyl acetonitrile of compound 12. The crude material was dissolved in 5 ml of 3N hydrochloric acid and the reaction mixture was stirred at room temperature for 30 minutes, then 20 ml of water was added and stirred for at least 10 minutes. The combined ethyl acetate extracts were dried over magnesium sulfate and concentrated under reduced pressure to obtain a solid material. The crude product was purified by column chromatography using hexane and ethyl acetate (v: v. 5: 1) to give 185 mg (yield: 64%) of the title compound as a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ) d 8.11 (s, 1H), 7.82 (d, 1H), 7.12 (s, 1H), 6.10 (d, 1H), 5.31 (s, 1H), 3.78 (q, 1H), 1.69 (s, 3H), 1.37 (s, 3H)

Example 2 2,2-Dimethyl-4,8-dioxo-2,3,4,8-tetrahydropyrano [3,2-g] chromen-3-yl 3-methylbut-2- Preparation of enoate {2,2-dimethyl-4,8-dioxo-2,3,4,8-tetrahydropyrano [3,2-g] chromen-3-yl 3-methylbut-2-enoate}

Pyridine (0.08 ml, 1 mmol) was added to 10 ml of anhydrous dichloromethane solution in which the compound (260.10 mg, 1 mol) prepared in Example 1 was dissolved at once in an ice bath. After stirring for 10 minutes, sesene chloride (0.12 ml) was slowly added to the reaction mixture. The crystalline mixture was extracted with dichloromethane and the organic layer was washed with water, brine and dried. The solvent was removed under reduced pressure, and the crude product was purified by fresh column chromatography with a mixture of hexane and ethyl acetate (v: v, 10: 1) to give 330 mg (yield 96.5%) of the title compound as a colorless oil. ¹ H-NMR (400 MHz, CDCl ₃ ) d 7.92 (s, 1H), 7.60 (d, 1H), 6.80 (s, 1H), 6.25 (d, 1H), 5.78 (s, 1H), 5.60 (s, 1H), 2,16 (s, 3H), 1.90 (s, 3H), 1.50 (s, 3H), 1.31 (s, 3H)

Example 3 7-nitro-8,8-dimethyl-7,8-dihydropyrano [3,2-g] chromene-2,6-dione {7-nitro-8,8-dimethyl-7 , 8-dihydropyrano [3,2-g] chromene-2,6-dione}

To 10 ml of glacial acetic acid dissolved starting material 1 (1,220 mg, 5 mmol) was added 68% nitric acid (1 ml) and sodium nitrite (690 mg, 10 mmol). The mixture was stirred at room temperature for 10 hours, poured into ice water, and extracted three times with 10 ml of ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was evaporated. The crude product was purified by column chromatography using hexane and ethyl acetate mixture (v: v, 6: 1) to give the title compound as a yellow solid (926 mg, 64.0%). ¹ H-NMR (400 MHz, CDCl ₃ ) d 8.16 (s, 1H), 7.78 (d, 1H), 6.97 (s, 1H), 6.45 (d, 1H), 5.28 (s, 1H), 1.65 (s, 3H), 1.56 (s, 3H)

Example 4 7-amino-8,8-dimethyl-7,8-dihydropyrano [3,2-g] chromene-2,6-dione {7-amino-8,8-dimethyl-7 , 8-dihydropyrano [3,2-g] chromene-2,6-dione}

300 mg of Pd / C (10% Pd) was added to 20 ml of anhydrous methanol in which the compound (926 mg, 3.2 mmol) prepared in Example 3 was dissolved, and reacted for 6 hours while stirring at 40 under hydrogen gas. The black solid was removed with a pad of celite and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography using hexane and ethyl acetate mixture (v: v, 3: 1) to afford the title compound as a clear oil (646 mg, 78.0%). ¹ H-NMR (400 MHz, CDCl ₃ ) d 8.15 (s, 1H), 7.65 (d, 1H), 7.20 (s, 1H), 6.16 (d, 1H), 4.23 (s, 1H), 1.64 (s, 3H), 1.32 (s, 3H)

Example 5 N- (2,2-dimethyl-4,8-dioxo-2,3,4,8-tetrahydropyrano [3,2-g] chromen-3-yl) -3- Methylbut-2-eneamide

Preparation of {N- (2,2-dimethyl-4,8-dioxo-2,3,4,8-tetrahydropyrano [3,2-g] chromen-3-yl) -3-methylbut-2-enamide}

Senesinol hydrochloride (0.3 ml, 2.8 mmol) was slowly added to anhydrous dichloromethane, in which the compound (646 mg, 2.5 mmol) and pyridine (0.2 ml, 2.5 mmol) prepared in Example 4 were dissolved in an ice bath. The crystal mixture was extracted with dichloromethane, washed with water and brine and dried. The solvent was removed under reduced pressure and the crude product was purified by column chromatography using hexane and ethyl acetate mixture (v: v, 8: 1) to give the title compound as a colorless oil (802 mg, 94%). ¹ H-NMR (400 MHz, CDCl ₃ ) d 8.07 (d, 1H), 7.56 (d, 1H), 6.83 (d, 1H), 6.30 (d, 1H), 5.30 (s, 1H), 5.12 (s, 1H), 2,12 (s, 3H), 1.86 (s, 3H), 1.43 (s, 3H), 1.32 (s, 3H)

Example 6 8-hydroxy-9,9-dimethyl-8,9-dihydropyrano [2,3-g] chromene-2,6-dione {8-hydroxy-9,9-dimethyl- Preparation of 8,9-dihydropyrano [2,3-g] chromene-2,6-dione}

10 ml of anhydrous methanol containing starting material 2 (244 mg, 1 mmol) was added to a 5 ml solution of potassium hydroxide (168 mg, 3 mmol) for 0 to 5 minutes. Solid iodobenzene diacetate (387 mg, 1.2 mmol) was added three times over 2 minutes with continued stirring of the reaction. The mixture was stirred at 0 for one hour and then allowed to react overnight at room temperature. Most of the methanol was evaporated under reduced pressure, and then water (20 ml) was added. After saturated with potassium carbonate, the mixture was extracted three times with 20 ml of ethyl acetate. The ethyl acetate extract was removed with water, anhydrous magnesium sulfate, and concentrated to give 12 dimethyl acetal. The crude material was dissolved in 3N hydrochloric acid and stirred at room temperature for 30 minutes, 20 ml of water was added and then stirred for at least 10 minutes. The ethyl acetate extract was dried over magnesium sulfate and concentrated under reduced pressure to obtain a solid material. The crude product was purified by column chromatography using hexane and ethyl acetate mixture (v: v, 5: 1) to afford the title compound as a white solid (237 mg, 82%). ¹ H-NMR (200 MHz, CDCl ₃ ) d 8.20 (d, 1H), 8.00 (d, 1H), 7.03 (d, 1H), 6.46 (d, 1H), 4.46 (s, 1H), 1.69 (s, 3H). 1.36 (s, 3 H).

Example 7 2,2-dimethyl-4,9-dioxo-2,3,4,9-tetrahydropyrano [2,3-g] chromen-3-yl 3-methylbut-2- Enoate

Preparation of {2,2-dimethyl-4,9-dioxo-2,3,4,9-tetrahydropyrano [2,3-g] chromen-3-yl 3-methylbut-2-enoate}

Pyridine (0.07 ml, 0.82 mmol) was added to 10 ml of anhydrous dichloromethane in which the compound (237 mg, 0.82 mmol) prepared in Example 6 was dissolved at once in an ice bath. After stirring for 10 minutes, Senesinol hydrochloride (0.10 ml, 0.90 mmol) was slowly added to the reaction mixture. The clear mixture was extracted with dichloromethane and the organic layer was washed with water, brine and water was removed. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography using hexane and ethyl acetate mixture (v: v, 10: 1) to give the title compound as a colorless oil (333 mg, 97%). ¹ H-NMR (500 MHz, CDCl ₃ ) d 8.08 (q, 1H), 7.98 (d, 1H), 6.98 (d, 1H), 5.86 (m, 1H), 5.70 (s, 1H), 2.24 (s, 3H). 1.98 (s, 3H), 1.62 (s, 3H), 1.27 (s, 3H).

Example 8 8-nitro-9,9-dimethyl-8,9-dihydropyrano [2,3-g] chromene-2,6-dione {8-nitro-9,9-dimethyl-8 , 9-dihydropyrano [2,3-g] chromene-2,6-dione}

68% nitric acid (1ml) and sodium nitrite (690mg, 10mmol) were added to a solution of glacial acetic acid (10ml) in which starting material 2 ((1,220mg, 5mmol) was dissolved.The mixture was stirred at room temperature for 10 hours, poured into ice water, ethyl The organic layer was extracted three times with 10 ml of acetate, the organic layer was dried over magnesium sulfate, and the solvent was evaporated off. The crude product was purified by column chromatography using a mixture of hexane and ethyl acetate (v: v, 6: 1). The compound of was obtained as a yellow solid (1,056 mg, 73.0%). ¹ H-NMR (400 MHz, CDCl ₃ ) d 8.00 (q, 2H), 7.00 (d, 1H), 6.39 (d, 1H), 1.65 ( s, 3H) 1.55 (s, 3H).

Example 9 8-amino-9,9-dimethyl-8,9-dihydropyrano [2,3-g] chromene-2,6-dione {8-amino-9,9-dimethyl-8 , 9-dihydropyrano [2,3-g] chromene-2,6-dione}

300 mg of Pd / C (10% Pd) was added to 20 ml of anhydrous methanol obtained by dissolving the compound (1,056 mg, 3.65 mmol) prepared in Example 8, and the mixture was reacted for 6 hours while stirring at 40 under hydrogen gas. The black solid was removed with a pad of celite and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography using hexane and ethyl acetate mixture (v: v, 2: 1) to afford the title compound as a clear oil (580 mg, 70.0%). ¹ H-NMR (400 MHz, CDCl ₃ ) d 8.10 (d, 1H), 8.03 (d, 1H), 6.95 (s, 1H), 6.40 (d, 1H), 3.99 (s, 1H), 1.71 (s, 3H), 1.47 (s, 3H)

Example 10 N- (2,2-dimethyl-4,9-dioxo-2,3,4,9-tetrahydropyrano [2,3-g] chromen-3-yl) -3 Methylbut-2-enamide

Preparation of {N- (2,2-dimethyl-4,9-dioxo-2,3,4,9-tetrahydropyrano [2,3-g] chromen-3-yl) -3-methylbut-2-enamide}

Senesinol hydrochloride (0.3 ml, 2.8 mmol) was slowly added to anhydrous dichloromethane in which the compound (580 mg, 2.56 mmol) and pyridine (0.2 ml, 2.5 mmol) prepared in Example 9 were dissolved in an ice bath. The crystal mixture was extracted with dichloromethane and washed with water and brine to remove moisture. The solvent was removed under reduced pressure and the crude product was purified by column chromatography using hexane and ethyl acetate mixture (v: v, 7: 1) to give the title compound as a clear oil (800 mg, 92%). ¹ H-NMR (400 MHz, CDCl ₃ ) d 8.01 (q, 2H), 7.00 (d, 1H), 6.43 (d, 1H), 5.87 (s. 1H), 5.71 (s, 1H), 2.25 (d, 3H), 1.99 (s, 3H), 1.64 (s, 3H), 1.30 (s, 3H).

Example 11 2,2-Dimethyl-8-oxo-2,3,4,8-tetrahydropyrano [3,2-g] chromen-3-yl3-methylbut-2-enoate { Preparation of 2,2-dimethyl-8-oxo-2,3,4,8-tetrahydropyrano [3,2-g] chromen-3-yl 3-methylbut-2-enoate}

12 g of zinc is added to 40 ml of a 0.6 M hydrochloric acid solution of mercury chloride (2 grams) and stirred. It was confirmed that a silvery white droplet was produced and the liquid was filtered. 330 mg (0.96 mmol) of 2,2-dimethyl-4,8-dioxo-2,3,4,8-tetrahydropyrano [3,2-g] chromen-3- in 40 ml of hydrochloric acid (8M) 3-methylbut-2-enoate {2,2-dimethyl-4,8-dioxo-2,3,4,8-tetrahydropyrano [3,2-g] chromen-3-yl 3-methylbut-2- enoate} was added to 20 ml of dissolved toluene solution and stirred. This mixture was added to the silvery white drops and stirred for 3 hours. Then, 40 ml of water was added to stop the reaction, and the organic layer was collected by extraction with ether. The organic layer was dried over saturated brine and magnesium sulfate to remove ether. The obtained material was separated by column chromatography using a mixture of hexane and ethyl acetate (20: 1) to obtain 102 mg (33%) of the title compound as a white solid. ¹ H-NMR (500 MHz, CDCl ₃ ) d 7.58 (d, 1H), 7.16 (s, 1H), 6.80 (s, 1H), 6.25 (d, 1H), 5.68 (s, 1H), 5.10 (t, 1H), 3.19 (dd, 1H), 2,87 (dd, 1H), 2.16 (s, 3H), 1.90 (s, 3H), 1.40 (s, 3H), 1.37 (s, 3H)

Example 12 N- (2,2-dimethyl-8-oxo-2,3,4,8-tetrahydropyrano [3,2-g] chromen-3-yl) -3-methylbutt 2-enamide

Method for preparing {N- (2,2-dimethyl-8-oxo-2,3,4,8-tetrahydropyrano [3,2-g] chromen-3-yl) -3-methylbut-2-enamide}

13 g of zinc was added to 40 ml of a 0.6 M hydrochloric acid solution of mercury chloride (2 grams) and stirred. It was confirmed that a silvery white droplet was produced and the liquid was filtered. 340 mg (1.0 mmol) of N- (2,2-dimethyl-4,8-dioxo-2,3,4,8-tetrahydropyrano [3,2-g] chromen in 40 ml of hydrochloric acid (8M) -3-yl) -3-methylbut-2-enamide {N- (2,2-dimethyl-4,8-dioxo-2,3,4,8-tetrahydropyrano [3,2-g] chromen-3 -yl) -3-methylbut-2-enamide} was added to 20 ml of toluene solution dissolved therein and stirred. The mixture was poured into the silvery white drops and stirred for 3 hours. Thereafter, 40 ml of water was added to the reaction solution to stop the reaction, and the organic layer was collected by extraction with ether. The organic layer was dried over saturated brine and magnesium sulfate, and ether was removed. The obtained material was separated by column chromatography using a mixture of hexane and ethyl acetate (20: 1) to obtain 86 mg (27%) of the title compound as a white solid. ¹ H-NMR (500 MHz, CDCl ₃ ) d 8.10 (d, 1H), 7.60 (s, 1H), 6.97 (s, 1H), 6.54 (d, 1H), 5.72 (s, 1H), 5.03 (t, 1H), 3.24 (dd, 1H), 2,99 (dd, 1H), 2.17 (s, 3H), 1.87 (s, 3H), 1.45 (s, 3H), 1.31 (s, 3H)

Example 13 2,2-Dimethyl-9-oxo-2,3,4,9-tetrapyrano [2,3-g] chromeme-3-yl 3-methylbut-2-enoate Preparation of, 2-dimethyl-9-oxo-2,3,4,9-tetrahydropyrano [2,3-g] chromen-3-yl 3-methylbut-2-enoate}

13 g of zinc was added to 40 ml of a 0.6 M hydrochloric acid solution of mercury chloride (2 grams) and stirred. It was confirmed that a silvery white droplet was produced and the liquid was filtered. 333 mg (0.97 mmol) of 2,2-dimethyl-4,8-dioxo-2,3,4,8-tetrahydropyrano [3,2-g] chromen-3- in 40 ml of hydrochloric acid (8M) Yl3-methylbut-2-enoate {2,2-dimethyl-4,8-dioxo-2,3,4,8-tetrahydropyrano [3,2-g] chromen-3-yl 3-methylbut-2- enoate} was added to 20 ml of dissolved toluene solution and stirred. The mixture was poured into the silvery white drops and stirred for 3 hours. Then, 40 ml of water was added to stop the reaction, and the organic layer was collected by extraction with ether. The organic layer was dried over saturated brine and magnesium sulfate, and ether was removed. The obtained material is separated by column chromatography separation method with a mixture of hexane and ethyl acetate (20: 1) to obtain 143 mg (45%) of the title compound as a white solid. ¹ H-NMR (500 MHz, CDCl ₃ ) d 8.10 (d, 1H), 7.83 (s, 1H), 6.75 (s, 1H), 6.13 (d, 1H), 5.79 (s, 1H), 5.23 (t, 1H), 3.17 (dd, 1H), 2,85 (dd, 1H), 2.15 (s, 3H), 1.87 (s, 3H), 1.46 (s, 3H), 1.32 (s, 3H)

Example 14 N- (2,2-dimethyl-9-oxo-2,3,4,9-tetrahydropyrano [2,3-g] chromen-3-yl) -3-methylbut- Of 2-enamide {N- (2,2-dimethyl-9-oxo-2,3,4,9-tetrahydropyrano [2,3-g] chromen-3-yl) -3-methylbut-2-enamide} Produce

10 g of zinc was added to 31 ml of a 0.6 M hydrochloric acid solution of mercuric chloride (1.56 grams) and stirred. It was confirmed that a silvery white droplet was produced and the liquid was filtered. 31 ml of hydrochloric acid (8M) was added to 264 mg (0.76 mmol) of N- (2,2-dimethyl-4,9-dioxo-2,3,4,9-tetrahydropyranot [2,3-g] Men-3-yl) -3-methylbut-2-eneamide {N- (2,2-dimethyl-4,9-dioxo-2,3,4,9-tetrahydropyrano [2,3-g] chromen-3-yl) -3-methylbut-2-enamide} was added to 15 ml of dissolved toluene solution and stirred. This mixture was added to the silvery white drops and stirred for 3 hours. Then, 30 ml of water was added thereto, the reaction was stopped, and the organic layer was collected by extraction with ether. The organic layer was dried over saturated brine and magnesium sulfate, and ether was removed. The obtained material was separated by column chromatography using a mixture of hexane and ethyl acetate (20: 1) to obtain 75 mg (30%) of the title compound as a white solid. ¹ H-NMR (500 MHz, CDCl ₃ ) d 7.97 (d, 1H), 7.02 (s, 1H), 6.97 (s, 1H), 6.29 (d, 1H), 5.50 (s, 1H), 5.21 (t, 1H), 3.17 (dd, 1H), 2,78 (dd, 1H), 2.15 (s, 3H), 1.91 (s, 3H), 1.44 (s, 3H), 1.33 (s, 3H)

Claims (9)

a) preparing a compound of Formula 2 by introducing an amine group or a hydroxyl group at the alpha carbon position of the carboxyl group in the compound of Formula 1; And b) a process for preparing the compound of formula 4 comprising the step of preparing a compound of formula 4 by reacting the compound of formula 2 obtained in step a) with a compound of formula 3 under a nucleophilic catalyst; [Formula 1]

(2)

[Formula 3]

[Formula 4]

Where X ₁ is a hydroxy group (-OH) or an amine group (-NH ₂ ), X ₂ is an oxygen atom (-O-) or an amine group (-NH-), Y is a halogen atom or a hydroxy group (-OH), R ₁ and R ₂ are each a straight or branched C 1 to C 5 hydrocarbon, Z is

or

to be. The method according to claim 1, wherein the amine group introduction reaction of step a) is a reaction in which a nitro group is converted to an amine group by reduction after nitro group introduction reaction. The process according to claim 2, wherein the nitro group introduction reaction is carried out in the presence of NaNO ₂ , HNO ₃ and acid. The method according to claim 2, wherein the reduction is carried out in the presence of a catalyst and hydrogen gas such as palladium (Pd), rhodium (Rh), platinum (Pt), silver (Ag), zinc (Zn) and the like. The hydroxy group introduction reaction of step a) is performed in the presence of iodobenzene diacetate or CAN (ceric ammonium nitrate in acetic acid), Pb (OAc) ₄ , Pb (OCCF ₃ ) _4. Manufacturing method. The method of claim 1, wherein the nucleophilic catalyst of step b) is pyridine, Et ₃ N or dimethylaminepyridine (DMAP). The method according to any one of claims 1 to 6, further comprising the step of deoxygenation reaction of the compound of formula (4) obtained in step b) to produce a compound of formula (5) Compound preparation methods; [Formula 5]

Where X ₂ , R ₁ , R ₂ and Z are as defined in claim 1. 8. A process according to claim 7, wherein the deoxygenation reaction is carried out in hydrazone and strong base conditions or in the presence of Zn (Hg) / HgCl and strong acid. A compound of formula 2 of claim 1; (2)

Where X ₁ is a hydroxyl group (-OH), a nitro group (-NO ₂ ) or an amine group (-NH ₂ ), Z is

or

to be.