KR102004245B1 - Preparing method of norathyriol using eco-friendly C-deglycosylation - Google Patents

Abstract

The present invention relates to a method for preparing norartithiol using an environmentally friendly carbon-desorption reaction, comprising the steps of: adding molasses perlein and resorcinol or a derivative thereof to a dilute acid aqueous solution and heating and refluxing; Cooling the refluxed solution to room temperature, and then adding and mixing a basic solution; Stirring the mixed solution, filtering, washing and drying; Adding the dried crude northeriol to an organic solvent, heating and stirring the mixture; And a step of filtering and washing and concentrating the stirred solution, wherein the method comprises the steps of:
The method according to the present invention can be used as a mass production method required for research on the development of raw materials and pharmaceuticals using norartithiol in the case of the present invention, which is an environmentally friendly method that can replace the existing technology for using a toxic substance. have.

Description

Preparation of norathriol using eco-friendly C-deglycosylation using environmentally friendly carbon-

The present invention relates to a process for preparing a mangiferin using an environmentally friendly carbon-decolorization reaction that can replace carbon-decolorization conditions using conventional toxic phenol and hydriodic acid (HI) To a process for preparing norartithiol.

Noratriol, i.e., 1,3,6,7-tetrahydroxyxanthone, a compound as shown below, is a physiologically active substance of the xanthone skeleton.

Noratriol is a metabolite of C-deglycoside of mangiferin, a physiologically active substance isolated from the leaves of Mangifera indica, and exhibits various physiological activities including anticancer, anticoagulant, and anti-diabetic effect. It is widely used in the development of therapeutic substances and pharmaceuticals. In particular, norartiriol and its derivatives have been utilized for the development of a therapeutic agent for diabetes due to their excellent blood glucose lowering effect.

A total synthesis of norartithiol using Friedel-Craft acylation has been known so far (Bioorg. Med. Chem. Lett., 2011, 21, 4013; Res. Chem Intermed., 2014, 40, 1633; J. Chem. Res., 2013, 37, 38).

However, the semi-synthesis method for carrying out the carbon-desorption reaction from cheaper and easier-to-obtain rather than the multistage pre-synthesis method is not only a method for obtaining a less expensive and easy-to-obtain northeryol, but also for mass production This is considered to be a possible method.

It is known that the biological method using some specific intestinal microorganisms also results in the formation of norartithiol from manganese perrin (Phytochemistry, 1989, 28, 1289; Bio. Pharm. Bull., 2005, 28, 1672). However, considering the yield of the biological method, a chemical carbon-decoloring reaction is more effective for producing a large amount of norathiirol.

On the other hand, the carbon-desaturate bond as in the gerbil perlein is a very strong carbon-carbon bond, unlike the O-glycosidic bond widely observed in other natural products, and the acid-labile oxygen- In the mild acid conditions (J. Nat. Prod., 2005, 66, 1180) generally used for cleaving glycosidic bonds, degradation is impossible and no desired aglycone can be obtained.

Thus, the harsh condition of refluxing in a mixed solution of hydriodic acid, which is the strongest acid in hydrohalic acid, and phenol, which is an excessively toxic substance, (Arch Pharm Res., 2015, 38, 598; Biosci. Biothecnol. Biochem., 2004, 68, 1858; Diabetologia, 2014, 57, 2145). Phenol is not only irritating to the eyes, skin and respiratory system, but can also cause dermatitis and burns in severe cases, and inhalation of phenol vapors may cause pulmonary edema. In addition, it is known as a toxic substance that adversely affects major organs of the human body such as the central nervous system, heart, kidney, and liver.

The development of eco-friendly synthetic methods that can replace these potentially toxic substances is required. Resorcinol, known as 1,3-dihydroxybenzene, is structurally similar to phenol and is similar to phenol in that it can participate in various substitution reactions as nucleophiles. However, it has a very high biocompatibility and environmental friendliness compared to phenol, and is widely used as an additive for daily necessities such as cosmetics, shampoo, etc. (J. Appl. Toxicol., 2013, 33, 1222).

Therefore, it is urgent to research and develop a method for effectively synthesizing norathiirol having an excellent blood glucose lowering effect through an environmentally friendly carbon-desorption reaction.

Chinese Patent Publication No. 101367787 (Published on February 18, 2009)

It is an object of the present invention to provide conditions for the synthesis of Noratriol from manganese perynation in a mild and environmentally friendly condition.

In order to accomplish the above object, the present invention provides a process for producing a zeolite, comprising the steps of: adding mangiferin to an acidic aqueous solution, and adding resorcinol or a derivative thereof represented by the following formula (1) Cooling the refluxed solution to room temperature, and then adding and mixing a basic solution; Stirring the mixed solution, filtering, washing and drying; Adding the dried crude norathiirol to an organic solvent, heating and stirring the mixture; And a step of filtering and washing and concentrating the stirred solution, wherein the method comprises the steps of:

[Chemical Formula 1]

In Formula 1,

R ^1, R ^2, and R ³ are the same or different from each other, hydrogen (H), a nitro (NO _2), nitriles _{(CN), (NH 2)} 1 primary or secondary amine, or a C ₁ to Alkyl of C ₁₀ linear or branched (alkyl), C ₂ to Alkenyl of C ₁₀ to know a straight or branched (alkenyl), C ₂ to Alkynyl group (alkynyl) of a C ₁₀ straight or branched chain, or C ₆ to Substituted or non-substituted aryl of C ₃₀ being (aryl) ring.

The method according to the present invention can be used as a mass production method required for research on the development of raw materials and pharmaceuticals using norartithiol in the case of the present invention, which is an environmentally friendly method that can replace the existing technology for using a toxic substance. have.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a schematic view showing a method for producing norathiirol. Fig.

Hereinafter, a method for preparing norartithiol using the eco-friendly carbon-desorption reaction of the present invention will be described in detail.

The inventors of the present invention have conducted research and development to improve the method for preparing norartithiol using hydriodic acid and phenol which is an excessively toxic substance. Under the mild acid condition, The present invention has been accomplished based on the finding that norbornene can be synthesized by using resorcinol, which is environmentally friendly and highly yieldable.

The present invention relates to a process for preparing a compound of formula (I), which comprises the step of adding mangiferin to an acidic aqueous solution and resorcinol or a derivative thereof represented by the following formula (1) Cooling the refluxed solution to room temperature, and then adding and mixing a basic solution; Stirring the mixed solution, filtering, washing and drying; Adding the dried crude norathiirol to an organic solvent, heating and stirring the mixture; And a step of filtering and washing and concentrating the stirred solution, wherein the method comprises the steps of:

[Chemical Formula 1]

In Formula 1,

R ^1, R ^2, and R ³ are the same or different from each other, hydrogen (H), a nitro (NO _2), nitriles _{(CN), (NH 2)} 1 primary or secondary amine, or a C ₁ to Alkyl of C ₁₀ linear or branched (alkyl), C ₂ to Alkenyl of C ₁₀ to know a straight or branched (alkenyl), C ₂ to Alkynyl group (alkynyl) of a C ₁₀ straight or branched chain, or C ₆ to Substituted or non-substituted aryl of C ₃₀ being (aryl) ring.

The step of heating and refluxing may be a step of adding manganese perlein to the anhydrous acid solution and resorcinol or a derivative thereof represented by the following formula 1 and heating and refluxing at 120 to 180 ° C for 3 to 9 hours, no.

The acidic aqueous solution may be a hydrofluoric acid (HF), hydrochloric acid (HCl), bromate (HBr), hydroiodic acid (HI), hwangsang (H ₂ SO _4), and nitric acid (HNO ₃₎ in any one selected from the group consisting of and , But is not limited thereto.

The basic solution may be any one selected from the group consisting of sodium hydrogencarbonate (NaHCO ₃ ) solution, sodium carbonate (Na ₂ CO ₃ ) solution, and sodium hydroxide (NaOH) solution.

The organic solvent may be any one selected from the group consisting of ethyl acetate, ethanol, acetonitrile, and acetone, but is not limited thereto.

Hereinafter, a method for preparing norartithiol using the environmentally friendly carbon-desorption reaction according to the present invention will be described in more detail with reference to the following examples. However, the present invention is not limited by these examples.

<Example 1> Synthesis of norathiirol using environmentally-friendly carbon-desorption reaction

(300 mg, 0.71 mmol, Xian Lyphar Biotech) and resorcinol (1.06 mmol, 1.5 eq., TCI) were added to a solution of 3N HCl (10 mL, Respectively. After the refluxed solution was cooled to room temperature (25 ° C), a saturated sodium hydrogencarbonate (NaHCO ₃ ) solution was slowly added to neutralize the mixed solution. The mixed solution was stirred for 30 minutes, then filtered, and the solid was washed with water. The filtered solid was dried in vacuo to give brown crude ornithiolol (yield: 71%, 131 mg).

Crude dinitrilol was added to ethyl acetate (10 ml), and the mixture was heated and stirred for 30 minutes, cooled to room temperature (25 ° C), and filtered. The solid was washed several times with ethyl acetate, and the filtrate was concentrated to obtain norartithiol.

Example 2 Synthesis of Noratriol Using Eco-friendly Carbon-Desorption Reaction

Synthesis of norathiirol was carried out under the same conditions as in Example 1, except that brown crude norbornylthiol (yield: 71%, 132 mg) was obtained using 6N HCl (10 ml, sigma-aldrich) Respectively.

<Example 3> Synthesis of norathiirol using environmentally-friendly carbon-desorption reaction

(yield: 70%, yield: 129 mg) was obtained by using c- HCl (10 ml, sigma-aldrich) in the same manner as in Example 1, except that natrathiol Were synthesized.

Example 4 Synthesis of Noratriol Using Eco-friendly Carbon-Desorption Reaction

(yield: 68%, 126 mg) was obtained by using c- HI (1.5 ml, sigma-aldrich) solution in the same manner as in Example 1, Were synthesized.

COMPARATIVE EXAMPLE 1 Synthesis of Noratriol Using Carbon-Desorption in Harsh Conditions

(300 mg, 0.71 mmol, Xian Lyphar Biotech) and phenol (1.1 g, 16.5 eq.) were added to a solution of c- HI (1.5 ml, sigma-aldrich) (Yield: 70%, 128 mg) was obtained in the same manner as in Example 1, except that thiophenol was used as a starting material.

&Lt; Comparative Example 2 > Synthesis of norathiirol using carbon-desorption reaction under harsh conditions

Except that phenol was not used and c- HI (10 ml, sigma-aldrich) solution was used instead of c- HI (1.5 ml) solution, the synthesis reaction of noratriol was carried out under the same conditions as in Comparative Example 1 But no reaction occurred.

&Lt; Comparative Example 3 > Synthesis of norathiirol using carbon-desorption reaction under harsh conditions

Except that phenol was not used and c- H ₂ SO ₄ (10 ml, sigma-aldrich) solution was used instead of c -HI (1.5 ml) The synthesis reaction was carried out but the reaction did not occur.

&Lt; Comparative Example 4 > Synthesis of norathiirol using carbon-desorption reaction under harsh conditions

Except that phenol was not used and 50% H ₂ SO ₄ (10 ml, sigma-aldrich) solution was used instead of c -HI (1.5 ml) solution, The synthesis reaction was carried out but the reaction did not occur.

&Lt; Comparative Example 5 > Synthesis of norathiirol using carbon-desorption reaction under harsh conditions

Except that phenol was not used and c- HBr (10 ml, sigma-aldrich) solution was used instead of c- HI (1.5 ml) solution, the synthesis reaction of noratriol was carried out under the same conditions as in Comparative Example 1 But no reaction occurred.

&Lt; Comparative Example 6 > Synthesis of norathiirol using carbon-desorption reaction under harsh conditions

Without the use of phenol, a c -HI (1.5 ㎖) Nora tea rheology, the synthesis reaction and is in the same conditions as in Comparative Example 1, except that instead of using c -HCl (10 ㎖, sigma-aldrich) solution solution But no reaction occurred.

&Lt; Comparative Example 7 > Synthesis of norathiirol using carbon-desorption reaction under harsh conditions

c but -HI (1.5 ㎖) solution instead of the c -HCl and is performing Nora tea rheology, the synthesis reaction in the same conditions as Comparative Example 1, except that (10 ㎖, sigma-aldrich) using the solution, not become a reaction I did.

<Experimental Example 1> Structural analysis of norathiolol

1. Common Experiment Analysis Method

(1) Analytical instruments

NMR spectroscopy ( ¹ H-NMR and ¹³ C-NMR) (equipment name: Bruker Analytik ADVANCE (trade name)) was used to confirm the structure of norathiirol synthesized according to Examples 1 to 4, III 800, solvent: DMSO-d ₆ ) and expressed in m / z form using mass spectrum (JEOL JMS-AX 505WA).

(2) Thin film chromatography and column chromatography

Silica gel (Merck F254, Merck) was used for thin layer chromatography (TLC) analysis and silica (Merck EM9385, 230-400 mesh) was used for column chromatography analysis Respectively.

It was also confirmed by heating the plate after UV lamp (254 nm) or anisaldehyde color development reagent was used to identify the separated material on TLC.

2. Analysis results

(1) Nuclear magnetic resonance spectrum ( ¹ H-NMR and ¹³ C-NMR) and MS spectrum analysis

Nuclear magnetic resonance spectra ( ¹ H-NMR and ¹³ C-NMR) and MS spectrum analysis were carried out using the above method, and the results are as follows.

mp > 320 [deg.] C (decomp.); ^{1 H-NMR (800 MHz,} DMSO-d6) = δ 13.16 (s, 1H), 10.76 (bs 1H), 7.37 (s, 1H), 6.85 (s, 1H), 6.31 (d, 1H, J = 2.1 Hz), 6.14 (d, 1 H, J = 2.1 Hz); ¹³ C-NMR (800 MHz, DMSO-d ₆ ) = δ 178.9, 164.7, 162.6, 157.3, 154.0, 150.9, 143.7, 111.8, 108.0, 102.6, 101.6, 97.7, 93.6; LR-MS (FAB & lt ^; + &gt;) m / z 261 (M + H &lt; ⁺ & gt ^; ); HR-MS (FAB +) calcd for C 13 H 9 O 6 (M + H +) 261.0394; found: 261.0399.

<Experimental Example 2> Identification of optimal carbon-desorption reaction conditions

[Reaction Scheme 1]

Referring to Reaction Scheme 1, nolatiriol can be synthesized by adding various additives and acids from the starting material, manganese perine, and reacting.

[Table 1]

Referring to Table 1, in order to optimize the reaction conditions for the synthesis of norartithiol, the starting material, manganese perine, various additives (phenol or resorcinol) and various inorganic acid solutions were added and reacted.

As a starting material, crown peryne and phenol (16.5 eq.) Are used, and c -HI (1.5 ml) is used as a mineral acid solution, as a conventionally known method, a brown crotonoratriol can be synthesized with a yield of 70% (entry 1, Comparative Example 1).

However, in the case of the above-mentioned Comparative Example 1 (entry 1), since phenol which is a toxic substance is used and c -HI which is a strong acid is used, the reaction is carried out under harsh conditions to synthesize norathiirol, There is a problem.

H ₂ O (entry 2, Comparative Example 2), H ₂ SO ₄ (entry 3 and entry 4, Comparative Example 3 and Comparative Example 4), HBr (entry 5, Comparative Example 5) ), And c- HCl (entry 6, Comparative Example 6) were added to the reaction mixture in the same manner as in the case of the oxygen-dechloric acid to decompose the carbon-glycosidic bond of the manganese perine. Respectively.

However, when only an aqueous acid solution (10 ml) according to Comparative Example 2 to Comparative Example 6 was added without phenol and reacted with manganese perine, a desired norlatiolol could not be synthesized.

The proposed mechanism of aryl carbon-glycosides involves a nucleophilic attack of the activated aromatic ring on the anomeric carbon of the activated sugar.

Considering that the glycosylation and diglycosylation reactions are mutually reversible through nucleophilic substitution at the anomeric center, water is not sufficient for nucleophiles to attack the anomeric carbon of the molar perylene Respectively.

Resorcinol, known as 1,3-dihydroxybenzene, has a nucleophilicity similar to that of phenol and has been used for various nucleophilic substitution reactions.

However, resorcinol exhibits higher nucleophilicity than phenol and has a higher biocompatibility than phenol.

For this reason, assuming the resorcinol is an environmentally friendly additive that can replace phenol in the carbon-decolorization of manganese perrin, we have identified the optimal reaction conditions.

Thus, by adding manganese perrine and resorcinol (1.5 equivalents) to the HI solution and heating, noratiriol was obtained (entry 7, Example 4), and through this, under the condition (entry 1) of the conventionally known Comparative Example 1 It has been confirmed that by adding the resorcinol instead of phenol, it is possible to synthesize norate thiol in high yield by an environmentally friendly method.

In addition, a more mild acid condition c-HCl (entry 8, Example 3) or appropriately diluted 6N HCl (entry 9, Example 2), 3N HCl (entry 10, Example 1 ), It was possible to easily carry out the carbon-elimination reaction of the geranium perle and to synthesize a high yield of crude deanthrylol.

After purification of the crude deanthrylol from the column chromatography and recrystallization from ethanol, yellow northeryol as previously reported was obtained.

In addition, when scaling up to 10 g, no problems were encountered in the reaction with resorcinol (1.5 eq) and 3N HCl.

On the other hand, when phenol and c-HCl were added to reflux the manganese perine, no norithiol was obtained (entry 11, comparative example 7).

These results indicate that the resorcinol acts as a more reactive additive in the carbon-desorption reaction than phenol, and can be used as an additive in the presence of manganese peryne under mild conditions and environmentally friendly reaction conditions by using resorcinol It was confirmed that norathiolol could be synthesized through the carbon-desorption reaction.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed exemplary embodiments. It is to be understood that various modifications and changes may be made without departing from the scope of the appended claims.

Claims (5)

Adding mangiferin to the acidic aqueous solution and resorcinol represented by the following formula (1) and heating and refluxing;
Cooling the refluxed solution to room temperature, and then adding and mixing a basic solution;
Stirring the mixed solution, filtering, washing and drying;
Adding the dried crude norathiirol to an organic solvent, heating and stirring the mixture; And
Filtering and washing the stirred solution and concentrating
A process for preparing norartithiol using an eco-friendly carbon-desorption reaction, comprising:
[Chemical Formula 1]

In Formula 1,
R ¹ , R ² , and R ³ are hydrogen (H). The method according to claim 1,
Wherein the heating and refluxing step comprises:
A process for preparing norartithiol using environmentally friendly carbon-desorption reaction, characterized in that the manganese perlein and the resorcinol represented by the formula (1) are added to the anhydrous acid solution and the reaction is refluxed at 120 to 180 ° C for 3 to 9 hours . The method according to claim 1,
The acidic aqueous solution,
Characterized in that it is any one selected from the group consisting of hydrofluoric acid (HF), hydrochloric acid (HCl), bromic acid (HBr), iodic acid (HI), sulfuric acid (H ₂ SO ₄ ), and nitric acid (HNO ₃ ) A process for the preparation of norartithiol using an affinity carbon-desorption reaction. The method according to claim 1,
The basic solution,
Characterized in that it is any one selected from the group consisting of sodium hydrogen carbonate (NaHCO ₃ ) solution, sodium carbonate (Na ₂ CO ₃ ) solution and sodium hydroxide (NaOH) Gt; The method according to claim 1,
The organic solvent may include,
Wherein the organic solvent is any one selected from the group consisting of methanol, ethanol, ethyl acetate, ethanol, acetonitrile, and acetone.

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