KR101157995B1 - Novel bis-3-hydroxy-4-methyl-phenyl Derivatives and Methods for Preparing the Same - Google Patents

Abstract

The present invention relates to a bis- (3-hydroxy-4-methoxy-phenyl) derivative, which is a novel compound, and a preparation method thereof. According to the invention, the derivative is tetraacetyl mannoosyl trichloroacetonitrile and 1,7-bis- (3-hydroxy-4-methoxy-phenyl) hepta-1,6-diene-3,5- In addition to the method of manufacturing using dione, de novo synthesis, which is a synthetic method using these initial compounds ( de novo synthesis) can be used to produce a purity of 99% or more. In addition, the bis- (3-hydroxy-4-methoxy-phenyl) derivative of the present invention is combined with tetraacetyl-mannose or mannose, which are water-soluble substituents, to increase the solubility in polar solvents such as water, and these are alpha forms It is bound to and deglycosylated by a deglycosylation enzyme in the body such as α-Mannosidase, thereby maximizing bioavailability and may act as an important substance in the development of medicines and foods.

Bis- (3-hydroxy-4-methoxy-phenyl) derivative, mannose, de novo synthesis, anomer, glycosylation

Description

Novel bis- (3-hydroxy-4-methyl-phenyl) derivatives and methods for preparing the same

The present invention relates to a water-soluble bis- (3-hydroxy-4-methoxy-phenyl) derivative and a method for preparing the same.

Curcuma longa (L) is a perennial herb belonging to the family Zingiberaceae, and its root stem is called Curcuma Rhizoma , which is cultivated in Asia, including China, mainly in India. Since ancient times, the root has been used for edible, medicinal, and dyeing purposes. In Korea, Eulgeum (Gumgeum), Gulgeum (乞 金), jadeumum (玉 金), Wanggeum (王金), turmeric (深 黄) is also known as the root of the spring turmeric is used as a herbal medicine that shows excellent efficacy have. Curcuminoids, the major component of turmeric, are used as yellow dyes and are the ingredients that make curry yellow. In addition, due to the characteristic that the color changes with pH, it is used as an indicator reagent such as pH paper. In addition, it is attracting attention as the prevention effect for various diseases is reported.

The bioactive substance of turmeric currently used as a herbal medicine in Korea is curcuminoid, a yellow pigment component containing about 3-6%, consisting of curcumin (I) and its derivatives curcumin (II) and (III) Phenolic mixtures (Paolo S. et al . J. Ethnopharm 72: 23-43, 2000; Ammon HP et al . , Planta Med 57: 1-7, 1999). Of these, curcumin (I) has the strongest pharmacological action, and its chemical name is 1,7-bis (4-hydroxy-3-methoxyphenyl) -1,6-heptadiene-3,5-dione. .

The pharmacological action of curcumin is antioxidant (Jitoe VR et. al . , J Agri Food Chem 40: 1337-1340, 1992; Meydani M. et al . , Mech Ageing Dev 111: 123-132, 1999), Antithrombosis (Bukhtiar HS et al . , Biochem Pharm 58: 1167-1172, 1999), lowering cholesterol in the blood (Babu PS et al . , Mol Cell Biochem 166: 169-175, 1997) and overlying triglyceride breakdown in the liver (Akira A et. al . , J Nutr 131: 2932-2935, 2001), and has been reported to inhibit cell growth and metastasis by inducing cell death (Lin JK et. al . , Proc Natl Sci Counc 25 (2): 59-66, 2001). In addition, it is expected to be effective in the treatment and prevention of senile dementia by inhibiting beta amyloid formation in the brain (Giselle PL et. al . , J Neurosci 21 (21): 8370-8377, 2001).

The effect of curcumin on platelet aggregation and vascular prostacyclin (PGI ₂ ) synthesis was investigated in rat experiments with adenosine diphosphate (ADP), epinephrine (adrenaline) and collagen when treated with curcumin 100-300 mg / kg. It was shown that platelet aggregation induced by (collagen) was strongly suppressed and PGI ₂ was increased (Srivastava R et. al . , Arzneimittelforschung 36: 715-7, 1986). In addition, administration of 0.5% curcumin for 8 weeks in diabetic rats induced by streptozotocin resulted in a decrease in blood cholesterol, and the activity of cholesterol-7α-hydroxylase was greatly increased. (Ramirez-Tortosa MC et al . , Atherosclerosis 147: 371-8, 1999). In addition, curcumin was shown to reduce oxidative stress and inhibit atherosclerosis in rabbits fed a high cholesterol diet (Quiles JL et. al . , Arterioscler Thromb Vasc Biol 22: 1225-1231, 2002), curcumin-induced proliferation inhibition of vascular smooth muscle cells was also observed in cultured cells (Zhang W et. al . , Chin Med J ( Engl ) 112: 308-311, 1999). Based on the above reports, curcumin-derived curcumin shows the effect of lowering cholesterol in blood, inhibiting platelet and blood coagulation activity, and inhibiting proliferation of vascular smooth muscle cells. It can be predicted that the disease can be effectively prevented. In particular, it can be used as a preparation for preventing vascular restenosis by treating the stent used for vascular stenosis.

As such, curcumin is a material that is highly applicable due to various medicinal effects, but due to its insoluble property in water, it has a poor effect on in vivo administration and is difficult to develop as a food and drug, and thus has not been widely used. It is true.

In order to solve these problems, there have been attempts to dissolve curcumin in organic solvents such as ethanol or dissolve it in edible oils and to apply it to food or medicine, but since the use of a solvent is essential, it is not widely available. In this case, fat-soluble physiologically active substances are often precipitated in the form of solids or solution emulsions and have a low bioavailability. When extracting them using natural materials such as turmeric to extract them, There is a fundamental problem that the purity does not exceed 95% because it contains impurities.

Therefore, there is an urgent need for the development of a new compound that can function similar to curcumin, which can solve the problem of insoluble in water, low bioavailability of curcumin, and the problem of containing impurities in natural extraction. In order to mass-produce derivatives, there is an urgent need in the art for a method capable of synthesizing with high purity of 99% or more and a method for synthesizing derivatives to increase efficiency in vivo.

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

The present inventors have tried to find new compounds that can overcome the shortcomings of curcumin while having curcumin-like activity, and to develop a method capable of synthesizing it with high purity and increasing the efficiency in vivo. As a result, tetraacetyl-mannose or bis- (3-hydroxy-4-methoxy-phenyl) derivatives having mannose having the above activity and de novo synthesis for synthesizing the derivative from the beginning ( de novo synthesis), the present invention was completed.

It is therefore an object of the present invention to provide novel bis- (3-hydroxy-4-methoxy-phenyl) derivatives.

Another object of the present invention is to provide a method for preparing the bis- (3-hydroxy-4-methoxy-phenyl) derivative.

Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the present invention, the present invention provides a bis- (3-hydroxy-4-methoxy-phenyl) derivative of the formula:

Formula 1

R ₁ in the formula And R ₂ is hydrogen, Tetraacetyl-mannose or Mannose, respectively; When R ₁ is hydrogen R ₂ is not hydrogen.

The present inventors endeavored to develop a new substance having a high bioavailability by enzymes in the body, which exhibits a decrease in blood cholesterol, inhibition of platelet activity and blood coagulation activity, and inhibition of proliferation of vascular smooth muscle cells. As a result, de novo synthesis to synthesize tetraacetyl-mannose or bis- (3-hydroxy-4-methoxy-phenyl) derivatives having the above activity and the derivatives from the beginning is carried out. The method was confirmed.

According to a preferred embodiment of the present invention, the bis- (3-hydroxy-4-methoxy-phenyl) derivative is water soluble.

The compound of the present invention is characterized in that the water solubility is greatly improved when tetraacetyl-mannose or mannose is covalently bonded to tetraacetyl-mannose or mannose in covalent bond form, compared to other sugars such as riboside and glucoside. .

According to a preferred embodiment of the present invention, the bis- (3-hydroxy-4-methoxy-phenyl) derivative is tetraacetyl-mannose of formula (2) Binding derivatives or It is a mannose binding derivative of the formula

Formula 2

Formula 3

One of the greatest features of the present invention is a water-soluble substituent on 1,7-bis- (3-hydroxy-4-methoxy-phenyl) hepta-1,6-diene-3,5-dione which is insoluble in water. By combining tetraacetyl-mannose or mannose, it is possible to maximize the bioavailability by increasing the solubility in polar solvents such as water.

According to a preferred embodiment of the present invention, the tetraacetyl-mannose binding derivative is a derivative represented by the following formula (4), the mannose binding derivative is a derivative represented by the following formula (5):

Formula 4

Formula 5

The tetraacetyl-mannose binding derivative or mannose binding derivative of Formula 4 or Formula 5 is a compound in which tetraacetyl-mannose or mannose is bound in the α-anomer form as indicated in the above formula.

As used herein, the term “anomer” in carbon chemistry refers to an isomer that occurs newly according to the stereoconfiguration of a hemiacetal hydroxyl group in a specific form of an epimer, wherein the stereoconfiguration is If the head α- anomer, and the case head isomerase cyano up β- (Francis Carey (2000). Organic Chemistry , McGraw - Hill Higher Education press (4th ed.))

Another feature of the present invention is that since the human digestive system contains a large amount of alpha-sugar hydrolase, but a small amount of beta-sugar hydrolase is present or not found, 1,7-bis- (3- Tetraacetyl-mannose or mannose bound to hydroxy-4-methoxy-phenyl) hepta-1,6-diene-3,5-dione is bound in alpha form to form α-Mannosidase Deglycosylated by the body deglycosylation, such as can maximize the bioavailability.

According to another embodiment of the present invention, the present invention provides 1,7-bis- (3-hydroxy-4-methoxy-phenyl) hepta-1,6-diene-3,5-dione in Formula 6 or Provided is a method for preparing a derivative of Formula 1 comprising the step (a) of reacting with a compound of Formula 7.

6

Formula 7

Formula 1

R ₁ in the formula And ₂ R is independently selected from hydrogen, acetyl tetra-mannose or mannose, and if R ₁ is hydrogen R ₂ is not hydrogen.

The present inventors endeavored to develop a method for preparing a new substance having a high bioavailability by enzymes in the body, which shows a decrease in blood cholesterol, inhibition of platelet activity and blood coagulation activity, inhibition of proliferation of vascular smooth muscle cells, and the like. As a result, 1,7-bis- (3-hydroxy-4-methoxy) was obtained with tetraacetyl-mannose or a bis- (3-hydroxy-4-methoxy-phenyl) derivative which was soluble in mannose. Tetraacetyl-mannose or 1,7-bis- (3-hydroxy-4-methoxy-phenyl) hepta- with method synthesized from -phenyl) hepta-1,6-diene-3,5-dione 1,6-diene-3,5-dione the synthesis de nobeo out by stepwise synthesis from the initial compound (de novo synthesis) method was confirmed.

Three exemplary preferred embodiments are described below:

According to a first embodiment, the bis- (3-hydroxy-4-methoxy-phenyl) derivative of Formula 1 is 1,7-bis- (3-hydroxy-4-methoxy-phenyl of Formula 10 ) Hepta-1,6-diene-3,5-dione may be prepared by reacting the compound of Formula 6 or Formula 7.

Formula 10

According to a preferred embodiment of the present invention, the compound of Formula 6 is tetraacetyl mannosyl trichloroacetonitrile of the formula (8):

Formula 8

According to an embodiment of the present disclosure, tetraacetyl mannoosyl trichloroacetonitrile of formula 8 and 1,7-bis- (3-hydroxy-4-methoxy-phenyl) hepta-1,6- of formula 10 Diene-3,5-dione was reacted in an organic solvent to obtain a bis- (3-hydroxy-4-methoxy-phenyl) derivative of Chemical Formula 1 (see FIGS. 4 and 5). The organic solvent is preferably (a) anhydrous or hydrous lower alcohol having 1 to 4 carbon atoms (e.g. methanol, ethanol, propanol, butanol, normal-propanol, iso-propanol and normal-butanol, etc.), (b) the lower Mixed solvent of alcohol and water, (c) acetone, (d) ethyl acetate, (e) chloroform, (f) 1,3-butylene glycol, (g) hexane, (h) diethyl ether, (i) Butyl acetate, (j) dichloromethane or (k) water can be obtained as an extraction solvent, and most preferably, it can be extracted using dichloromethane.

According to a second embodiment, the preparation method further comprises the step of preparing tetraacetyl mannoosyl trichloroacetonite triyl using acetic anhydride and mannose (pre-a-1).

According to one embodiment of the present specification, the step (pre-a-1) may include extracting acetic anhydride and mannose using an organic solvent to obtain pentaacetylmannoside; Dissolving the pentaacetylmannoside in DMF and reacting with hydrazine acetate to obtain monohydroxy tetraacetyl mannoside using an organic solvent; And dissolving the monohydroxy tetraacetyl mannoside in an organic solvent, reacting with trichloroacetonitrile (Cl ₃ CCN), and then separating tetraacetyl mannooxyl trichloroacetonitrile using an organic solvent. Can be. The organic solvent is preferably (a) anhydrous or hydrous lower alcohol having 1 to 4 carbon atoms (e.g. methanol, ethanol, propanol, butanol, normal-propanol, iso-propanol and normal-butanol, etc.), (b) the lower Mixed solvent of alcohol and water, (c) acetone, (d) ethyl acetate, (e) chloroform, (f) 1,3-butylene glycol, (g) hexane, (h) diethyl ether, (i) Butyl acetate, (j) dichloromethane or (k) water can be obtained as an extraction solvent.

According to a third embodiment, the preparation method is 1,7-bis- (3-hydroxy-4 using 3-hydroxy-4-methoxybenzaldehyde of formula 9 Further comprising preparing -methoxy-phenyl) hepta-1,6-diene-3,5-dione (pre-a-2):

Formula 9

According to one embodiment of the present specification, after reacting 3-hydroxy-4-methoxybenzaldehyde of Chemical Formula 9 with tri-t-butylborate, and extracting with an organic solvent, 1,7-bis- (3-hydroxy-4-methoxy-phenyl) hepta-1,6-diene-3,5-dione can be prepared (see Figure 3). The organic solvent is preferably (a) anhydrous or hydrous lower alcohol having 1 to 4 carbon atoms (e.g. methanol, ethanol, propanol, butanol, normal-propanol, iso-propanol and normal-butanol, etc.), (b) the lower Mixed solvent of alcohol and water, (c) acetone, (d) ethyl acetate, (e) chloroform, (f) 1,3-butylene glycol, (g) hexane, (h) diethyl ether, (i) Butyl acetate, (j) dichloromethane or (k) water can be obtained as an extraction solvent.

Another one of the greatest features of the present invention is tetraacetyl mannoosyl trichloroacetonitetriyl and 1, which is a compound used to prepare a bis- (3-hydroxy-4-methoxy-phenyl) derivative of the formula (1) In addition to the method for preparing the derivative by reacting 7-bis- (3-hydroxy-4-methoxy-phenyl) hepta-1,6-diene-3,5-dione itself, the compound to be used is initially prepared. De nouveau synthesis step by step from a compound ( de novo synthesis). Tetraacetyl mannoosyl trichloroacetonitrile and 1,7-bis- (3-hydroxy-4-methoxy-phenyl) hepta-1,6-diene-3,5- Even without dione, tetraacetyl mannooxyl trichloroacetonitrile was prepared using acetic anhydride and mannose as their initial compounds as starting materials, or 1,7 using 3-hydroxy-4-methoxybenzaldehyde as starting material. -Bis- (3-hydroxy-4-methoxy-phenyl) hepta-1,6-diene-3,5-dione was prepared and finally the bis- (3-hydroxy-4- of Formula 1 Methoxy-phenyl) derivatives can be prepared.

In the case of using the above-described synthesis method, bis- (3-hydroxy-4-methoxy-phenyl) derivative can be obtained with high purity, preferably at least 90%, more preferably at least 95%, even more preferred. Preferably bis- (3-hydroxy-4-methoxy-phenyl) derivatives of the compounds of the present invention can be obtained with a purity of at least 98%, most preferably 99% -100% (see Figure 8).

According to a preferred embodiment of the invention, the compound of formula 6 or 7 is the 1,7-bis- (3-hydroxy-4-methoxy-phenyl) hepta-1,6-diene-3,5- Sugar conjugation in the form of alpha in Dion.

When 1,7-bis- (3-hydroxy-4-methoxy-phenyl) hepta-1,6-diene-3,5-dione compound of Formula 6 or 7 is glycosylated in alpha form, α -Deglycosylated by the deglycosylation enzyme in the body, such as mannosidase (α-Mannosidase) can maximize the bioavailability.

According to a preferred embodiment of the present invention, the method for preparing the bis- (3-hydroxy-4-methoxy-phenyl) derivative of Chemical Formula 1 further includes the step (b) of performing a deprotection reaction. do.

According to one embodiment of the present specification, the tetraacetyl-mannose coupling derivative of Chemical Formula 4 may be obtained in the presence of an organic solvent and sodium methoxide (NaOMe) (see FIG. 5). The organic solvent is preferably (a) anhydrous or hydrous lower alcohol having 1 to 4 carbon atoms (e.g. methanol, ethanol, propanol, butanol, normal-propanol, iso-propanol and normal-butanol, etc.), (b) Mixed solvent of the lower alcohol with water, (c) acetone, (d) ethyl acetate, (e) chloroform, (f) 1,3-butylene glycol, (g) hexane, (h) diethyl ether, ( i) Butyl acetate, (j) dichloromethane or (k) water can be obtained as an extraction solvent.

According to another aspect of the present invention, the present invention provides a pharmaceutical composition or a food composition comprising a bis- (3-hydroxy-4-methoxy-phenyl) derivative of the formula (1).

When the composition of the present invention is made into a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers included in the pharmaceutical compositions of the present invention are those commonly used in the preparation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like It doesn't happen. In addition to the above components, the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).

The pharmaceutical composition of the present invention may be administered orally or parenterally, and preferably applied by oral administration.

The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . Preferred dosages of the pharmaceutical compositions of the invention are in the range of 0.001-100 mg / kg on an adult basis.

The pharmaceutical compositions of the present invention may be prepared in unit dose form by formulating with a pharmaceutically acceptable carrier and / or excipient according to methods which can be easily carried out by those skilled in the art. Or may be prepared by incorporation into a multi-dose container. The formulation may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or in the form of extracts, powders, powders, granules, tablets or capsules, and may further comprise dispersants or stabilizers.

When the composition of the present invention is made of a food composition, as an active ingredient, as well as the bis- (3-hydroxy-4-methoxy-phenyl) derivative of the formula (1), and includes components that are commonly added during food production And, for example, proteins, carbohydrates, fats, nutrients, seasonings and flavoring agents. Examples of the above carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose, oligosaccharides and the like; And sugars such as conventional sugars such as polysaccharides such as dextrin, cyclodextrin and the like and xylitol, sorbitol, erythritol. As the flavoring agent, natural flavoring agents [tautin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used.

For example, when the food composition of the present invention is prepared with a drink, citric acid, liquid fructose, sugar, glucose, in addition to the bis- (3-hydroxy-4-methoxy-phenyl) derivative of Formula 1, which is an active ingredient of the present invention Acetic acid, malic acid, fruit juice, tofu extract, jujube extract, licorice extract and the like may be further included.

The features and advantages of the present invention are summarized as follows:

(Iii) The present invention provides a bis- (3-hydroxy-4-methoxy-phenyl) derivative which is a novel compound and a method for producing the same.

(Ii) According to the present invention, the derivative is converted to tetraacetyl mannoosyl trichloroacetonitrile and 1,7-bis- (3-hydroxy-4-methoxy-phenyl) hepta-1,6-diene-3 In addition to the preparation using 5,5-dione, de novo synthesis, which is a synthesis method using these initial compounds ( de novo synthesis) can be used to produce more than 99% purity, this strategy has not been adopted conventionally.

(Iii) The bis- (3-hydroxy-4-methoxy-phenyl) derivative of the present invention may combine tetraacetyl-mannose or mannose, which is a water-soluble substituent, to increase solubility in polar solvents such as water, It is combined in the form and deglycosylated by a deglycosylation enzyme in the body such as α-Mannosidase to maximize bioavailability and may act as an important substance in the development of medicines and foods.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

Example 1 Preparation of Tetraacetyl Mannoosyl Trichloroacetimidadate

Step 1: Preparation of Pentaacetylmannoside

A mixture of acetic anhydride (500 mL, 5.29 mol) and NaOAc (15 g, 0.183 mol) was heated at 100 ° C. for 15 minutes. D -mannose (50 g, 0.278 mol) was slowly added to this heated solution over a period of 30 minutes by one spoon (about 5 g each). After the addition, the mixture was further heated at 100 ° C. for 20 minutes, and then cooled to room temperature. The reaction was poured into about 300 g of ice and cooled, and the aqueous layer was extracted three times with ethyl acetate (300 mL × 3). The organic layer was dried over anhydrous MgSO ₄ , filtered and the solvent was removed. After complete solvent removal 107.35 g (0.275 mol, yield 99%) of pentaacetylmannoside was obtained.

Step 2: Preparation of Monohydroxy Tetraacetyl Mannoside

Pentaacetylmannoside (200 g, 0.512 mol) obtained in step 1 was dissolved in anhydrous DMF (370 mL). Hydrazine acetate (56.6 g, 0.615 mol, 1.2 equiv) was added at room temperature and stirred for 1 hour. After the reaction, the reaction was poured into a container containing 1 L of water, extracted with ether (ether, 200 mL × 4), and further extracted using CH ₂ Cl ₂ (200 mL × 1). The obtained organic layer was dried over anhydrous MgSO ₄ , filtered and the solvent was removed to obtain 177 g (0.509 mol, yield 99.3%) of monohydroxy tetraacetyl mannoside (the yield is the yield corrected for the amount of DMF).

Step 3: Preparation of Tetraacetylmannoosyl Trichloroacetimidadate

After dissolving the monohydroxy tetraacetyl mannoside (123 g, 0.35 mol) obtained in step 2 in CH ₂ Cl ₂ (450 mL), trichloroacetonitrile (Cl ₃ CCN, 177 mL, 1.76 mol) Slowly put in. DBU (1,8-diazabicyclo [5,4,0] undecene, 10.5 mL, 0.071 mol) was slowly added while stirring the solution at 0 ° C. (exothermic reaction). After stirring for 48 hours, the solvent was removed under reduced pressure. The remaining oil was loaded onto a silica gel column, and then the product imidate was separated using a solvent (hexane: EtOAc = 4: 1) to give 135 g (0.275 mol, yield 78%) of tetraacetylmannooxyl triclo. Loacetimidate was obtained and the reaction remaining without reaction was recovered using a solvent (hexane: EtOAc = 1: 1) (yield 15%). The NMR data of the prepared tetraacetylmannoosyl trichloroacetimidadate are as follows, and the spectra are shown in FIGS. 1 and 2.

¹ H NMR (CDCl ₃ ): 2.0-2.2 (m, 12H), 4.16-4.29 (m, 3H), 5.4 (m, 2H), 5.48 (m, 1H), 6.28 (s, 1H), 8.781 (s , 1H)

Example 2: 1,7-bis- (3-hydroxy-4-methoxy-phenyl) hepta-1,6-diene-3,5-dione (1,7-Bis- (3-hydroxy- Preparation of 4-methoxy-phenyl) hepta-1,6-diene-3,5-dione)

3-hydroxy-4-methoxybenzaldehyde (3.04 g, 20 mmol) and tri-t-butylborate (11.35 mL, 40 mmol) were added to ethyl acetate (10 mL), followed by stirring at room temperature for 10 minutes. After adding 4-pentanedione (1.02 mL, 10 mmol) and boric anhydride (0.5 g, 7 mmol) and stirring at room temperature for 10 minutes, butylamine (0.2 mL) was slowly added dropwise and stirred at room temperature for 4 hours, followed by standing for 12 hours. It was. 0.4 N HCl (30 mL) was added slowly, stirred for 1 hour, extracted with ethyl acetate, and concentrated under reduced pressure to 20 mL. Methanol (20 mL) was added thereto, and the solid formed by standing in the refrigerator for 1 day was filtered and dried under reduced pressure to obtain 0.8 g of the target substance (FIG. 3).

¹ H-NMR (DMSO-d ₆ ): 9.17 (s, 2H) 7.50 (d, 2H) 7.15-7.13 (m, 4H) 6.98 (d, 2H) 6.63 (d, 2H) 3.30 (br s, 2H)

Example 3: Preparation of 1,7-bis- (3-hydroxy-4-methoxy-phenyl) hepta-1,6-diene-3,5-dione-bis (tetraacetylmannoside)

Tetraacetylmannoosyl trichloroacetimidadate (5.33 g, 15.2 mmol) and 1,7-bis- (3-hydroxy-4-methoxy-phenyl) hepta-1,6-diene obtained in step 3 above. -3,5-dione (0.8 g, 2.17 mol) was dissolved in CH ₂ Cl ₂ (10 mL), and 1 g of molecular sieve (4 mm 3) was added thereto. After cooling this solution in an ice-water bath, BF ₃ .OEt ₂ (0.4 mL) was added dropwise. After the addition was completed, while stirring, the mixture was allowed to slowly rise to room temperature on an ice-water bath and stirred for 12 hours. After confirming that the reaction was completed by TLC, 5 mL of saturated NaHCO ₃ solution was added thereto, and 50 mL of water was added thereto. The water layer was extracted with CH ₂ Cl ₂ (50 mL × 3). The obtained organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure to obtain 2.22 g of the target product (FIG. 4).

Example  4: 1,7- Vis - (3- Hydroxy -4- Methoxy - Phenyl ) Hepta -1,6- Diene -3,5- Dion - Dimannoside  Produce

1,7-bis- (3-hydroxy-4-methoxy-phenyl) hepta-1,6-diene-3,5-dione-bis (tetraacetylmannoside) prepared in Example 3 (2.22 g) was dissolved in 60 ml of dry methanol, and 28% sodium methoxide (28% NaOMe) (4.3 mL.) Was slowly dropped at room temperature. After stirring the reaction for 12 hours, the mixture was neutralized with a small amount of DOWEX 50W X8 resin, and the resin was filtered off with methanol, and the methanol layer was concentrated. The concentrated layer was dissolved in 3 mL of water, and purified by iatropide (MeOH: Methylene chloride = 1: 9) to 0.3 g of 1,7-bis- (3-hydroxy-4-methoxy-phenyl) Hepta-1,6-diene-3,5-dione-dimannoside was obtained (FIG. 5).

¹ H-NMR (DMSO-d ₆ ): 7.59-7.54 (m, 4H) 7.40-7.36 (m, 2H) 7.07 (d, 2H) 6.76 (d, 2H) 5.40-5.33 (m, 2H) 4.98 (d , 2H) 4.83 (d, 2H) 4.73 (d, 2H) 4.54 (t, 2H) 4.02 (s, 6H) 3.88-3.82 (m, 8H) 3.77-3.16 (m, 6H)

LC-Mass Spectrum data: (n + 2) 694, (n + 3) 695

¹ H-NMR spectrum and LC-meth spectrum data of 1,7-bis- (3-hydroxy-4-methoxy-phenyl) hepta-1,6-diene-3,5-dione-dimannoside 6 and 7 are shown.

Example  5: 1,7- Vis - (3- Hydroxy -4- Methoxy - Phenyl ) Hepta -1,6- Diene -3,5- Dion - Dimannoside  Solubility in water

1,7-bis- (3-hydroxy-4-methoxy-phenyl) hepta-1,6-diene-3,5-dione-dimannoside prepared in Example 4 was added to 1 ml of distilled water. After supersaturation, shaking at room temperature for 1 hour, and then using a centrifugal method insoluble water-soluble 1,7-bis- (3-hydroxy-4-methoxy-phenyl) hepta-1,6-diene-3,5 Water-soluble 1,7-bis- (3-hydroxy-4-methoxy-phenyl) hepta-1,6- synthesized in the present invention by quantitative determination using an absorbance system after removal of -dione-dimannoside As a result of measuring the solubility of diene-3,5-dione-dimannoside in water, it showed a solubility of 40 mg / ml, indicating a high level of solubility in water.

Example  6: 1,7- Vis - (3- Hydroxy -4- Methoxy - Phenyl ) Hepta -1,6- Diene -3,5- Dion - Dimannoside  water

Purity was measured using reverse phase HPLC with a C18 column and the 1,7-bis- (3-hydroxy-4-methoxy-phenyl) hepta-1,6-diene prepared in Example 4 above. -3,5-dione-dimannoside was measured using a 9: 1 H ₂ O: acetonitrile mixture as a developing solvent. Purity was close to about 100% as a result (Fig. 8).

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

1 is a diagram showing an H ¹ -NMR spectrum of a compound of Formula 8. FIG.

2 is an enlarged H ¹ -NMR spectrum of the compound of Formula 8. FIG.

3 is 1,7-bis- (3-hydroxy-4-methoxy-) using 3-hydroxy-4-methoxybenzaldehyde according to one embodiment of the present invention. A diagram illustrating a process of preparing phenyl) hepta-1,6-diene-3,5-dione.

4 is a compound of Formula 6 and 1,7-bis- (3-hydroxy-4-methoxy-phenyl) hepta-1,6-diene-3,5-dione according to one embodiment of the present invention. Is a diagram illustrating a process of preparing a bis- (3-hydroxy-4-methoxy-phenyl) derivative of Chemical Formula 1 by reacting.

5 is a view showing a process of preparing a compound of Formula 5 using the compound of Formula 4 according to an embodiment of the present invention.

6 is a diagram showing an H ¹ -NMR spectrum of a compound of Formula 5. FIG.

7 is a diagram showing LC-Mass spectral data of a compound of Formula 5. FIG.

8 is a diagram showing a reversed phase HPLC result of the compound of formula 5.

Claims (11)

Bis- (3-hydroxy-4-methoxy-phenyl) derivative of the formula Formula 1

R ₁ and R ₂ in the formula are each independently hydrogen, tetraacetylmannose or mannose; When R ₁ is hydrogen, R ₂ is not hydrogen, and when R ₁ and R ₂ are tetraacetyl-mannose or mannose, they are bonded in α-anomer form. delete The derivative of claim 1, wherein the derivative of Formula 1 is represented by Formula 4 below: Formula 4

The derivative of claim 1, wherein the derivative of Formula 1 is represented by Formula 5 below: Formula 5

The derivative of claim 1 wherein the derivative is water soluble. (a) reacting 1,7-bis- (3-hydroxy-4-methoxy-phenyl) hepta-1,6-diene-3,5-dione with a compound of formula Method for preparing a derivative of formula 1 comprising: 6

In the above formula, R ₃ is hydrogen or acetyl (-C (O) CH ₃ ). Formula 7

In the above formula, R ₃ is hydrogen or acetyl (-C (O) CH ₃ ). Formula 1

R ₁ and R ₂ in the formula are each independently hydrogen, tetraacetylmannose or mannose; When R ₁ is hydrogen, R ₂ is not hydrogen, and when R ₁ and R ₂ are tetraacetyl-mannose or mannose, they are bonded in α-anomer form. delete delete According to claim 6, The preparation method is 1,7-bis- (3-hydroxy-4- using 3-hydroxy-4-methoxybenzaldehyde of the formula (9) Method for producing a methoxy-phenyl) hepta-1,6-diene-3,5-dione (pre-a-1) further comprises: Formula 9

The method of claim 6, wherein the reaction is sugar conjugation in alpha form. delete

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