TWI637947B - Synthetic method of Melaleuca A - Google Patents

Abstract

A method for synthesizing Oroxylin A, which utilizes Baicalin as a starting material, and can synthesize Melalin A simply and efficiently by chemical synthesis.

Description

Synthetic method of Melaleuca A

The invention relates to a method for synthesizing Oroxylin A, in particular to a method for synthesizing Melaleuca A using Baicalin as a starting material.

Oroxylin A, which has the structure shown in the following formula (I), is a flavonoid compound, also known as quercetin or _xylin , mainly composed of Scutellaria baicalensis G _EORGI and wood butterfly ( Oroxylum indicum ). Melaleuca A has a wide range of physiological activities such as antihypertensive, antitumor, neuroprotective, anti-inflammatory, etc., and is therefore also valued by the Institute of Modern Pharmacology.

Melaleuca A is generally extracted from plants such as Astragalus , Wood Butterfly, Capparis spinosa , Ardisia crispa or Eucommia ulmoie O _LIV . However, the extraction method is not only cumbersome, costly, but also low in yield. Therefore, there are also many publications on the synthesis of Melaleuca A. Melaleuca A is structurally distinguished by the order of C ₅ , C ₆ , and C ₇ functional groups, C ₅ and C ₇ are hydroxyl groups, and C ₆ is a methoxy group.

2002 Huang et.al. (Huang, W.-H.; Chien, P.-Y.; Yang, C.-H.; Lee, A.-R. Chem. Pharm. Bull. 2003 , 51 , 339 -340) A method for synthesizing flavonoids from Astragalus membranaceus using timethoxyphenol as a starting material, and also revealing the synthesis results of Melaleuca A. However, the synthesis result of the Melaleuca A is in 2015 by Deepa Panhekar et.al. (Panhekar, D.; Mahale, GD; Renalson, KS; Satpute, S. J. Chem. Pharm. Res . , 2015 , 7 , 174-180) proved to be the wrong structure. That is, Huang et.al. originally published that the result of the synthesis is that the layer of paper A is not correct, and the synthesis result should be a 7-methyl ether zebrain (Negletein) structure represented by the following formula (II). This result shows that how to obtain the corresponding functional group at the correct position is the biggest challenge in synthesizing the correct synthesis of lamellar A.

In addition, 2007 Kostrzewa-Sus Ow et.al.(Kostrzewa-Sus Owa, E.; Dmochowska-G Adysz, J.; Oszmia ' nski, J. J. of Mol . Catal . B: Enzym. , 2007 , 49 113–117), publicly converts Baicalein and Baicalin using biotransformation methods. Melaleuca A.

In 2008, Chen (Chen-C.-P. Yearbook of Chinese Medicine and Pharmacy , 2008 , 26 , 241-358) revealed that 2,4,6-trinitromethoxybenzene was used as a starting material to synthesize thousands. Layer paper A.

In the Japanese Patent No. CN101508689, a method for synthesizing Melaleuca A from the use of baicalein is disclosed. The main purpose is to use step (a) to protect the hydroxyl group at the C ₇ position of baicalein with a protecting group; then proceed to step (b), methylate the hydroxyl group at the C ₆ position, and finally carry out step (c), C _{The 7-} position protective group is removed to obtain a layer of paper A.

The aforementioned chemical synthesis method steps are cumbersome and the reaction conditions are also severe, and the use of the biological conversion method is time consuming (6 days).

Accordingly, it is an object of the present invention to provide a method for synthesizing Melaleuca A which can simplify the steps, and the reaction conditions are mild and simple.

Thus, the method for synthesizing Melalin A of the present invention comprises a methylation step and a deprotection step.

The methylation step is based on baicalin, the methylation reaction is carried out in a basic first reaction solution, and the 6-hydroxy group of the starting material is subjected to a methylation reaction. An intermediate is obtained, wherein the first reaction solution is composed of an inorganic base and a methylating agent.

The deprotection step is accomplished by removing the glycosyl group of the intermediate and forming a hydroxyl group in an acidic second reaction solution to complete the synthesis of the layer of paper A.

The effect of the present invention is that the effect of the present invention is that the baicalin A can be synthesized simply and efficiently by chemical synthesis using baicalin as a starting material.

Referring to Figures 1 and 2, an embodiment of the method for synthesizing Melaleucaine A of the present invention comprises a methylation step 21 and a deprotection step 22.

The methylation step 21 is based on baicalin, and the starting material is subjected to methylation reaction in a first reaction solution composed of an inorganic base and a methylating agent to make the starting material 6 - The hydroxyl group is methylated to give an intermediate.

It is known in the art that flavonoids (such as the structure of the lamellar A in this case) are easily cleaved under alkaline conditions, and therefore, in the process of synthesizing flavonoids, When flavonoids are used for the reaction, they are required to be subjected to more severe conditions (for example, the reagents used are all dehydrated and the reaction is carried out under an inert gas) to avoid the γ-pyrone ring during the reaction. Hydrolysis under alkaline conditions causes problems such as disordered reaction products, low yield, or inability to obtain a product. The inventors of the present invention found that baicalin is the starting material and further cooperates with the methylation reagent to replace the solvent, so that the methylation reaction process under alkaline conditions can avoid the cleavage of the γ-pyrone ring, and the reaction can be simplified. The product is conveniently purified; in addition, the methylation reagent is not required to be dehydrated before the reaction, and the reaction can be carried out under a general atmosphere without using an inert atmosphere, and the reaction conditions can be simplified.

In detail, the methylation reaction is carried out at a temperature from an unheated ambient temperature to not more than 80 ° C, and the 6-hydroxy group (-OH) of the starting material is methylated to form a methoxy group ( -OCH ₃ ). The first reaction solution is composed of an inorganic base and a methylating agent. The inorganic base may be selected, for example, from potassium carbonate (K ₂ CO ₃ ), sodium carbonate (Na ₂ CO ₃ ), cesium carbonate (Cs ₂ CO ₃ ), potassium hydrogencarbonate (KHCO ₃ ), and sodium hydrogencarbonate (NaHCO ₃ ). At least one of them; the methylating agent is selected from the group consisting of dimethyl sulfate (DMS), or iodomethane, and the like.

In addition, it should be noted that the molar number of the methylating agent (DMS) is not Less than 5 times the number of moles of the starting material.

The deprotection step 22 is carried out by removing the glycosyl group of the intermediate in an acidic second reaction solution and forming a hydroxyl group, thereby completing the synthesis of the layer of paper A.

In detail, the deprotecting step 22 is carried out at a reaction temperature of from room temperature to 120 ° C without heating; preferably, the temperature is between 40 and 100 ° C, more preferably between 40 and 40 °. Reaction temperature conditions of 80 ° C. The second reaction solution includes a mineral acid and a polar solvent. The inorganic acid is at least one selected from the group consisting of hydrochloric acid, sulfuric acid, and nitric acid, and the polar solvent is at least one selected from the group consisting of methanol, ethanol, 1-propanol, and isopropanol.

It is to be noted that the steps of this embodiment of the method for synthesizing the lamellar A of the present invention can be carried out under atmospheric conditions, and no inert gas can be introduced during the reaction. In addition, the methylation step 21 may be carried out by preliminary purification after the completion of the reaction to obtain a methylated intermediate, and then the purified intermediate is used to carry out the deprotection step 22; or, the methylation Step 21 and the deprotection step 22 can be carried out continuously, that is, after the completion of the methylation step 21, the second reaction can be carried out to carry out the deprotection step 22 without purifying the intermediate. The liquid is directly added to the first reaction liquid which completes the methylation step 21, and the layer of paper A is synthesized by one pot reaction.

Since baicalin has a glycosyl group (C ₇ -O-glucuronide) at the C ₇ position, although the hydroxyl group (-OH) on the glycosyl group should be a reactive functional group, the inventors unexpectedly It is found that the hydroxyl group (-OH) on the glycosyl group does not affect the methylation reaction of the 6-hydroxy group of the baicalin. Therefore, the present invention utilizes baicalin as a starting material and cooperates with the methylation reagent directly. substituted solvent, when 21 is performed, the sugar baicalin gene does not affect the methylation step methylation reaction, it can be regarded as baicalein protective group of the _C-7 hydroxyl group, and substituted with a methylation agent The organic solvent can also avoid the methylation process of baicalin, and the g-pyrone ring is hydrolyzed under alkaline conditions. In addition, the sugar of the baicalin can be easily removed in the air atmosphere and under acidic conditions after completion of the methylation reaction. Therefore, the present invention can easily synthesize the synthesis of the laminin A by using two steps.

This preferred embodiment of the above-described method for synthesizing the lamellae A is described in detail in the following specific examples.

Specific example

First, baicalin (223 mg, 0.5 mmole), dimethyl sulfate (1.26 g, 10 mmole) and potassium carbonate (345 mg, 2.5 mm loe) were added to the reaction flask, and stirred at room temperature for 24 hours to make the baicalin 6 - The hydroxyl group is subjected to a methylation reaction.

Then, 10 ml of a mixed solution of HCl-EtOH (1:9) (second reaction liquid) is added to the first reaction liquid for completing the methylation reaction, and then reacted at 80 ° C for 10 to 12 hours to complete the layer. Synthesis of paper A. After the reaction is completed, the temperature is returned to room temperature, water is added and extracted with ethyl acetate. Finally, the organic layer is concentrated, and the crude product is purified by silica gel flash chromatography to give the layer A. Total yield: 56% (80 mg).

The reaction formula of this specific example is as follows:

Referring to Figures 2 and 3, Figures 2 and 3 are ¹ H NMR spectra of Oroxylin A synthesized in this specific example using CDCl ₃ and DMSO-d ₆ as solvents.

Figure 2: ¹ H NMR (700 MHz, CDCl ₃ ): δ 13.00 (s, 1H), 7.89-7.88 (m, 2H), 7.56-7.52 (m, 3H), 6.67 (s, 1H), 6.63 (s , 1H), 6.62(s, 1H), 4.05(s, 3H).

Figure 3: ¹ H NMR (700 MHz, DMSO-d ₆ ): δ 12.93 (s, 1H), 10.82 (s, 1H), 8.08-8.06 (m, 2H), 7.62-7.56 (m, 3H), 6.98 (s, 1H), 6.64(s, 1H), 3.76(s, 3H).

The spectral ratio of the spectral results of Figures 2 and 3 to the texture of the layer A paper A synthesized by Chen in 2008, and the synthesis of the layer A paper A obtained by Deepa Panhekar et. After confirming the structure, it was confirmed that the synthesis method of the present invention can be used to accurately and simply synthesize Melaleuca A.

In summary, the present invention utilizes as a starting material baicalin, since the baicalin glycosylation inventors have surprisingly found that without affecting the methylation reaction, it can be regarded as a protecting group baicalein (Baicalein on) to the _C-7 hydroxyl group of And the sugar can be easily removed under the air atmosphere and under acidic conditions after the completion of the methylation reaction. Therefore, the present invention can easily complete the synthesis of the layer of paper A by using two steps, so that the present invention can be achieved. purpose.

However, the above is only the embodiment of the present invention, and the scope of the invention is not limited thereto, and all the simple equivalent changes and modifications according to the scope of the patent application and the patent specification of the present invention are still Within the scope of the invention patent.

<TABLE border="1" borderColor="#000000" width="85%"><TBODY><tr><td> 21 </td><td> methylation step</td><td> </ Td></tr><tr><td> 22 </td><td> Deprotection step </td><td> </td></tr></TBODY></TABLE>

Other features and advantages of the present invention will be apparent from the embodiments of the present invention, wherein: Figure 1 is a text flow diagram illustrating a preferred embodiment of the invention; oroxylin a CDCl ₃ as the solvent measured in ¹ H NMR spectra; and 3, this specific embodiment of the present invention obtained in synthesis oroxylin a in DMSO-d ₆ as solvent ¹ H NMR spectrum measured .

Claims (4)

A method for synthesizing Melaleuca A, comprising: a methylation step, starting from baicalin, and subjecting the starting material to a methylation reaction in a basic first reaction solution to make the starting The 6-hydroxy group of the product is methylated to obtain an intermediate, wherein the first reaction liquid is composed of an inorganic base and a methylating agent selected from the group consisting of potassium carbonate, sodium carbonate, potassium carbonate, and carbonic acid. At least one of hydrazine, potassium hydrogencarbonate, and sodium hydrogencarbonate, the methylating agent is selected from dimethyl sulfate or methyl iodide; and a deprotecting step, the intermediate is in an acidic second reaction solution The synthesis of the millilayer paper A is completed by removing a sugar group and forming a hydroxyl group, and the second reaction liquid includes a mineral acid and a polar solvent, and the inorganic acid is at least one selected from the group consisting of hydrochloric acid, sulfuric acid, and nitric acid. The polar solvent is selected from at least one of methanol, ethanol, 1-propanol, and isopropanol. The method for synthesizing lamelin A according to claim 1, wherein the methylation step is carried out at an unheated ambient temperature to 80 ° C, and the deprotection step is at an unheated ambient temperature to 120 ° C Under temperature conditions. The method for synthesizing laverin A according to claim 1, wherein the methylation step is carried out at an unheated ambient temperature, and the deprotecting step is carried out at a temperature of from 40 ° C to 80 ° C. The method for synthesizing lamelin A according to claim 1, wherein the second reaction liquid is directly added to the first reaction liquid having the intermediate after completion of the methylation step.