KR100377327B1 - A method for preparing allylated 7-hydroxycoumarin derivatives - Google Patents

Abstract

The present invention relates to a method for preparing an allylated aromatic compound 3 by reacting an allyl halide represented by Formula 1 with an aromatic compound represented by Formula 2. More specifically, the present invention relates to a precursor of Formula 4, which is a compound useful for preparing a natural coumarin compound having bioactivity by reacting an allyl compound represented by Formula 1 with an aromatic compound of Formula 2 using a renewable metal indium as a catalyst. It relates to a method for producing an allylated aromatic compound represented by the formula (3).

The following scheme 1 schematically illustrates the reaction.

Scheme 1

In preparing the compound of Formula 3 by reacting the compound of Formula 1 with the compound of Formula 2, by using metal indium as a catalyst, it is stable in air, water, etc., is easy to handle, environmentally friendly, and above all, renewable. You can get economic benefits. In addition, the product can be easily obtained without undergoing a difficult reaction process, has the advantage of high yield and efficiency.

Therefore, the present invention can be applied in various ways to organic synthesis industry and pharmaceutical production.

Description

A manufacturing method of allylated 7-hydroxycoumarin derivatives {A METHOD FOR PREPARING ALLYLATED 7-HYDROXYCOUMARIN DERIVATIVES}

The present invention relates to a method of preparing an allylated 7-hydroxycoumarin derivative 3 by reacting an allyl halide represented by the formula (1) with a 7-hydroxycoumarin represented by the formula (2). More specifically, the present invention relates to a precursor of Formula 4, which is a compound useful for preparing a natural coumarin compound having a physiological activity by reacting an allyl compound represented by Formula 1 with a compound of Formula 2 using a renewable metal indium as a catalyst. It relates to a method for producing an allylated aromatic compound represented by the formula (3).

The following scheme 1 schematically illustrates the reaction.

In general, coumarin, chromone and flavone derivatives are pharmaceutically important compounds as natural analogues extracted from plants. Among them, carcinogen polycyclic aromatic hydrocarbons are known to inhibit cancer (Digiovanni, J. In modification of polycyclic aromatic hydrocarbon carcinogenesis, 1981, 259). Of these, coumarin compounds are widely distributed in nature, and many natural products containing these coumarin subunits are known to play the role of antimicrobial agents, anticoagulants, spasms and inhibitors of bile secretion disorders [Ann. Biochem. Exp. Med. 1957, 17, 57; J. Pharmacol. 1963, 20, 29; J. Pharm. Sci. 1962, 51, 149].

Among them, the compound of formula (3) is an important intermediate that can be used in the preparation of natural derivatives and various heterocyclic compounds, from which the production of a pyranokumarin parent nucleus, such as formula (4) and various substituents react with the active natural pyrano It is known to prepare coumarin derivatives [W. Steck, Can. J. Chem . 1971, 49, 2297].

Further, the compound of formula 4, in particular 2,4-dihydroxy-5- (3-methyl-2-butenyl) benzaldehyde (R ₁ = R ₂ = CH ₃ , R ₃ = H) is a natural coumarin (coumarin) derivatives of Decker Shin (decursin) also known to be useful as an intermediate for synthesis of 5 (Scheme 2), obtained Dekker new (decursin) 5 is pyrano coumarin series having a molecular formula of C ₁₉ H ₂₀ O ₅ important medicinal herbs It is known to be one of the main components of Angelica gigas [J. Pharm. Soc. Korea 1967, 11, 22-26 and 1969, 13, 47-50].

Angelica is an important herbal medicine that has been used for abdominal pain, boils, bruises, and gynecological diseases because of its analgesic, drainage, hemostasis, and tonic effects. It is known that it can be used as an anticancer agent because it exhibits a much lower lethal action than those of the medicinal plants [Journal of Pharmacognosy 1970, 1 (1), 25-32 and 1982, 13 (2), 55-61; Planta Medica 1996, 62, 7-9].

Therefore, the development of a method for efficiently synthesizing important intermediates such as Formula 3, which can be used in the production of bioactive active ingredients of pyranocmarin series including dekerin, secures natural raw materials due to depletion of natural resources and environmental pollution. It is very important for the smooth supply of raw materials necessary for the preparation of various active compounds with the solution of the difficulties.

On the other hand, a method for preparing the compound of formula 3 from 7-hydroxycoumarin of formula 2 is unknown.

Accordingly, it is an object of the present invention to provide a method for synthesizing a compound of formula 3, which is an important intermediate for the production of important natural coumarin compounds, including decusin, with higher yield and higher efficiency than previously known methods.

The present inventors earnestly studied for the development of an efficient natural product synthesis method that solves the shortcomings of the prior art. Patent Application Nos. 99-30637 and 99-11595 have been used to establish a method for producing the compound of Formula 3 in high yield and economically and by an advanced method without going through a difficult reaction process to complete the present invention.

The present invention is stable in air, water and the like, is easy to handle, environmentally friendly, and most of all, is renewable and economical. The compound of formula 2 is reacted with the compound of formula 1 using an indium metal as a catalyst to produce an intermediate of coumarin derivatives. It is characterized in that to efficiently prepare the allyl aromatic compound of Formula 3 to be used as, by using the indium metal as a catalyst to minimize the by-products inevitably formed in the reaction process can obtain the compound of Formula 3 in high yield (Scheme 3).

In formula (1), X is a halogen atom, more preferably chlorine or bromine, and R ₁ and R ₂ each represent hydrogen, straight or branched C _1-5 hydrocarbon. R ₁ and R ₂ in Formula 3 are the same as in Formula 1.

Indium, which is used as a catalyst for the allylation reaction of reacting an allyl halogen compound of Formula 1 with a compound of Formula 2 to produce coumarin derivative 3, is usually in an amount of 0.01 to 2 equivalents relative to 7-hydroxycoumarin represented by Formula 2. It is recoverable and can be reused.

The molar ratio of allyl halogen compound and 7-hydroxycoumarin used in the allylation reaction is usually changeable within the range of 10: 1 to 1:10, preferably 1: 2 to 2: 1, most preferably Preferably in the range of 1: 1.5 to 1.5: 1.

Examples of the organic solvent that can be used in the allylation reaction include C _6-7 aromatic hydrocarbons such as benzene and toluene, methylene chloride, chloroform, acetonitrile, dioxene, diethyl ether and tetrahydrofuran, but are not limited thereto. It doesn't happen.

The allylation reaction is conducted in the presence of a base, and examples of bases that can be used in the reaction is OH ^- it can be a metal compound containing a ^-, CO ₃ ^2- or HCO _3. Examples of the metal include Li, Na, K, Cs, Mg, Ca or Ba. The amount of base used for the reaction is usually 2 equivalents or less (but not including 0) relative to 7-hydroxycoumarin represented by the formula (2).

The addition of a molecular sieve to the reaction gives a more desirable result, for example, 4 Å molecular sieve, the amount is added 200% by mass relative to 7- hydroxycoumarin represented by the general formula (2) (However, 0 is not included).

The allylation reaction is carried out in the range of 20 to 150 ° C, preferably 30 to 70 ° C, most preferably 35 to 50 ° C, and the reaction time is within the range of 1 to 48 hours, preferably 3 to 6 hours. It is adjustable.

The allylation reaction is described in more detail as follows. After dissolving 7-hydroxycoumarin represented by the formula (2) in a suitable organic solvent, allyl halide represented by the formula (1) was slowly added dropwise, and 0.01-2 equivalents of an indium metal atom, a suitable base, and a 4 'molecular sieve were added to the mixed solution. After the addition, the reaction may be performed at 20-150 ° C. for 1-48 hours to prepare the main product. The most preferred molar ratio of allyl halide represented by the formula (1), 7-hydroxycoumarin and the indium catalyst represented by the formula (2) is 0.8: 1: 0.01. The organic solvent may be selected from benzene, toluene, dioxene, acetonitrile, diethyl ether or tetrahydrofuran, wherein the substituent X of Formula 1 has a good yield of both bromine and chlorine atoms. Examples of the base to be used in the present invention is a hydroxy (OH ^-), such as Li, Na, K, Cs, Mg, Ca, Ba ^- metal compound, including, carbonate (CO ₃ ^2-), and sodium hydrogen carbonate (HCO ₃₎ When the use of a solid base used in combination with an indium catalyst, but to obtain the desired compound in a high yield, and examples of preferred bases are solid CaCO ₃ / 4Å molecular sieve system. Preferred amounts of base and 4 'molecular sieves are 40 mol% and 5 mass%, respectively, and the desired product is obtained even if the amount of 4' molecular sieve is reduced or absent. As the reaction proceeds, the color of the reaction solution becomes darker. And with the color change of the reaction solution, the reaction termination point can be confirmed by thin film chromatography (TLC). After the reaction, the reaction product is cooled to room temperature, and the obtained product can be separated and purified by evaporation, filtration, extraction, chromatographic separation, combinations thereof, and conventional techniques. For example, the mother liquor is filtered through a thin layer of silica gel and then concentrated or distilled under reduced pressure. The product can be confirmed by conventional methods such as ¹ H-NMR and GC / MSD.

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited to these embodiments. Unless otherwise specified in the present embodiment, percentages or ratios are based on weight.

Example

Example 1

6- (3-methyl-2-butenyl) -7-hydroxycoumarin 3

200 mg (1.234 mmol) of 7-hydroxycoumarin was dissolved in 10 ml of benzene, and 169 mg (1.2 equiv) of indium, 49.4 mg (0.4 equiv) of calcium carbonate, and 10 mg (5 mass%) of 4 ′ molecular sieve were added thereto. Thereafter, 103.2 mg (0.987 mmol) of 1-chloro-3-methyl-2-butene was slowly added dropwise. The reaction temperature was raised to 40 ° C. and stirred for 4 hours. Termination of the reaction was confirmed by thin layer chromatography (TLC), and the reaction was terminated and cooled to room temperature. The reaction mixture was passed through a filter filled with silica gel thinly, and the filtrate was concentrated under reduced pressure, and then purified by column chromatography (developing solvent: ethyl acetate / n-hexane = 1/9) to obtain the title compound (3).

R _f = 0.35 (ethyl acetate: n-hexane = 1: 2)

Yield: 0.248 g, 85%

m. p. 129-133 ℃

¹ H NMR (CDCl ₃ ): δ7.65 (d, J = 9.5 Hz, C H = CH), 7.44 (s, 1H, aromatic H-5), 7.07 (s, 1H, aromatic H-8), 6.23 (d, J = 9.5Hz, CH = C H ), 5.32 (t, J = 7Hz, = CH), 3.38 (d, J = 7Hz, CH ₂ ), 1.75-1.80 (s, 2 vinyl methyls)

Example 2

6- (3-methyl-2-butenyl) -7-hydroxycoumarin 3

200 mg (1.234 mmol) of 7-hydroxycoumarin was dissolved in 10 ml of benzene, and 169 mg (1.2 equiv) of indium, 49.4 mg (0.4 equiv) of calcium carbonate and 10 mg (5 mass%) of 4 ′ molecular sieve were added thereto. Thereafter, 147.1 mg (0.987 mmol) of 4-bromo-2-methyl-2-butene was slowly added dropwise. The reaction temperature was raised to 40 ° C. and stirred for 4 hours. Termination of the reaction was confirmed by thin layer chromatography (TLC), and the reaction was terminated and cooled to room temperature. The reaction mixture was passed through a filter filled with silica gel thinly, and the filtrate was concentrated under reduced pressure, and then purified by column chromatography (developing solvent: ethyl acetate / n-hexane = 1/9) to obtain the title compound (3).

R _f = 0.35 (ethyl acetate: n-hexane = 1: 2)

Yield: 0.248 g, 85%

m. p. 129-133 ℃

¹ H NMR (CDCl ₃ ): δ7.65 (d, J = 9.5 Hz, C H = CH), 7.44 (s, 1H, aromatic H-5), 7.07 (s, 1H, aromatic H-8), 6.23 (d, J = 9.5Hz, CH = C H ), 5.32 (t, J = 7Hz, = CH), 3.38 (d, J = 7Hz, CH ₂ ), 1.75-1.80 (s, 2 vinyl methyls)

Example 3

7-hydroxy-8,8-dimethyl-7,8-dihydro-6H-pyrano [3,2-g] -chromen-2-one (deckerinol 4)

250 mg (1.086 mmol) of 6- (3-methyl-2-butenyl) -7-hydroxycoumarin are dissolved in 20 ml of chloroform, in which 250 mg (0.47 equiv) of parasulfene and 250 mg of magnesium monoperoxyphthalate hexahydrate (MMPP) oxidant are dissolved. 10 mg (0.01 equivalent) of sulfonylic acid was added thereto, followed by stirring at room temperature for 24 hours. The termination of the reaction was confirmed by thin layer chromatography. When the reaction was terminated, the resultant was washed with 0.1 M sodium hydrogen carbonate solution and water, and then filtered with anhydrous magnesium sulfate. The obtained filtrate was concentrated under reduced pressure, and then purified by column chromatography (developing solvent: ethyl acetate / n-hexane = 1/15) to obtain Decusinol 4 as a target compound.

R _f = 0.20 (ethyl acetate: n-hexane = 1: 2)

Yield: 0.237 g, 90%

m. p. 166-168 ℃

¹ H NMR (CDCl ₃ ): δ 7.54 (d, J = 9.5 Hz, C H = CH), 7.15 (s, 1H, aromatic H-5), 6.76 (s, 1H, aromatic H-8), 6.19 (d, J = 9.5 Hz, CH = C H ), 3,86 (dd, J = 5,6 Hz, CH ₂ ), 3.07 (dd, J = 5.16 Hz, C H OH), 2.80 (dd, J = 5.16 Hz, C H OH), 1.37 (s, gem-dimethyls)

Example 4

7-hydroxy-8,8-dimethyl-7,8-dihydro-6H-pyrano [3,2-g] -chromen-2-one (deckerinol 4)

250 mg (1.086 mmol) of 6- (3-methyl-2-butenyl) -7-hydroxycoumarin are dissolved in 20 ml of chloroform, in which 250 mg (0.47 equiv) of pyridium and magnesium monoperoxyphthalate hexahydrate (MMPP) oxidant are dissolved. 15 mg (0.01 equivalent) of paratoluenesulfonate was added thereto, followed by stirring at room temperature for 24 hours. The termination of the reaction was confirmed by thin layer chromatography. When the reaction was terminated, the resultant was washed with 0.1 M sodium hydrogen carbonate solution and water, and then filtered with anhydrous magnesium sulfate. The obtained filtrate was concentrated under reduced pressure, and then purified by column chromatography (developing solvent: ethyl acetate / n-hexane = 1/15) to obtain Decusinol 4 as a target compound.

R _f = 0.20 (ethyl acetate: n-hexane = 1: 2)

Yield: 0.245 g, 92%

m. p. 166-168 ℃

¹ H NMR (CDCl ₃ ): δ 7.54 (d, J = 9.5 Hz, C H = CH), 7.15 (s, 1H, aromatic H-5), 6.76 (s, 1H, aromatic H-8), 6.19 (d, J = 9.5 Hz, CH = C H ), 3,86 (dd, J = 5,6 Hz, CH ₂ ), 3.07 (dd, J = 5.16 Hz, C H OH), 2.80 (dd, J = 5.16 Hz, C H OH), 1.37 (s, gem-di methyls)

Example 5

7-hydroxy-8,8-dimethyl-7,8-dihydro-6H-pyrano [3,2-g] -chromen-2-one (deckerinol 4)

250 mg (1.086 mmol) of 6- (3-methyl-2-butenyl) -7-hydroxycoumarin are dissolved in 20 ml of methylene chloride, where 73.9 mg (2.0 equivalents) of 30% by mass of hydrogen peroxide solution and tetrabutylammonium are added. Sulfate 10 mg (0.01 equiv) was added and stirred at room temperature for 24 hours. The termination of the reaction was confirmed by thin layer chromatography. When the reaction was terminated, the resultant was washed with 0.1 M sodium hydrogen carbonate solution and water, and then filtered with anhydrous magnesium sulfate. The obtained filtrate was concentrated under reduced pressure, and then purified by column chromatography (developing solvent: ethyl acetate / n-hexane = 1/15) to obtain Decusinol 4 as a target compound.

R _f = 0.20 (ethyl acetate: n-hexane = 1: 2)

Yield: 0.158 g, 60%

m. p. 166-168 ℃

¹ H NMR (CDCl ₃ ): δ 7.54 (d, J = 9.5 Hz, C H = CH), 7.15 (s, 1H, aromatic H-5), 6.76 (s, 1H, aromatic H-8), 6.19 (d, J = 9.5 Hz, CH = C H ), 3,86 (dd, J = 5,6 Hz, CH ₂ ), 3.07 (dd, J = 5.16 Hz, C H OH), 2.80 (dd, J = 5.16 Hz, C H OH), 1.37 (s, gem-dimethyls)

Example 6

2,2-dimethyl-8-oxo-3,4-dihydro-2H, 8H-pyrano [3,2-g] -chromen-3-yl 3-methyl-2-butenoic ester (deckerin 5 )

50 mg (0.203 mmol) of decosinol was dissolved in 0.02 g (1.0 equiv) of pyridine, and 24.0 mg (0.203 mmol) of 3-methylcrotonoyl chloride was slowly added dropwise thereto, and the mixture was stirred at 30 DEG C for 1 hour. Was stirred. The reaction mixture was diluted with methylene chloride, washed with 0.1 N aqueous hydrogen chloride solution and water, and the filtrate was concentrated under reduced pressure and recrystallized under ethyl acetate-hexane to obtain the title compound (5).

R _f = 0.18 (ethyl acetate: n-hexane = 1: 3)

Yield: 0.061 g, 92%

m. p. 110-111 ℃

¹ H NMR (CDCl ₃ ): δ 7.54 (d, J = 9.5 Hz, C H = CH), 7.16 (s, 1H, aromatic H-5), 6.73 (s, 1H, aromatic H-8), 6.15 (d, J = 9.5 Hz, CH = C H ), 5.67 (q, J = 1 Hz, = CH), 5.09 (t, 2H, J = 4.8 Hz, -CH ₂ ), 2.14 (d, 3H, (C H ₃ ) ₂ C-), 1.88 (d, 3H, (C H ₃ ) ₂ C-), 1.39 (s, gem-dimethyls, J = 5.16Hz)

In preparing the compound of Formula 3 by reacting the compound of Formula 1 with the compound of Formula 2, it is stable and easy to handle in the air, water, etc. by using metal indium as a catalyst, environmentally friendly, and most of all, renewable and economical. Can benefit. In addition, there is an advantage that the product can be easily obtained without undergoing a difficult reaction process, and is efficient at high yield.

Therefore, the present invention can be applied to various applications such as organic synthesis industry and medicine manufacture.

Claims (13)

A process for preparing a 7-hydroxycoumarin derivative of formula 3 by reacting an allyl halogen compound of formula 1 with 7-hydroxycoumarin of formula 2 in the presence of an organic solvent using a metal indium as a catalyst. [Formula 1] [Formula 2] [Formula 3] In the formula, X in the formula (1) is a halogen atom, R ₁ and R ₂ each represent hydrogen, linear or branched C _1-5 hydrocarbon. R ₁ and R ₂ in Formula 3 are the same as in Formula 1. The method of claim 1 wherein X is a bromine or chlorine atom. The method of claim 1, wherein the organic solvent is selected from the group consisting of benzene, toluene, methylene chloride, chloroform, acetonitrile, dioxene, diethyl ether and tetrahydrofuran. The method of claim 1 wherein the reaction is carried out in the presence of a base. The method of claim 4, wherein the base is an OH ^- characterized in that the metal compound comprising a ^-, CO ₃ ^2- or HCO _3. 6. The method of claim 5 wherein the metal is Li, Na, K, Cs, Mg, Ca or Ba. The method according to claim 6, wherein the amount of base added is 2 equivalents or less (but does not include 0) based on the compound represented by the formula (2). The method of claim 5, wherein a 4 ′ molecular sieve is further added. The method according to claim 8, wherein the amount of the 4 ′ molecular sieve added is 200 mass% or less (but does not include 0) relative to the compound represented by the formula (2). The method of claim 1, wherein the molar ratio of the allyl halogen compound and the compound represented by the formula (2) is 10: 1 to 1:10. The method of claim 1, wherein the amount of indium used is 0.01 to 2 equivalents based on the compound of Formula 2. The method of claim 1, wherein the reaction temperature of the reaction is 20 to 150 ℃. The method of claim 1 wherein the reaction time is 1 to 48 hours.