KR20010028782A - Preparative method of 7-carboxymethyloxy-3',4',5-trimethoxyflavone - Google Patents

Abstract

PURPOSE: Provided is a method for manufacturing 7-carboxymethyloxy-3',4',5-trimethoxyflavone, in a high yield under mild reaction conditions. Also, its pharmaceutically acceptable salts and solvates are provided. CONSTITUTION: 7-carboxymethyloxy-3',4',5-trimethoxyflavone is manufactured by the following steps of: i) reacting 3',5,7-trihydroxy-4'-methoxyflavone-7-rutinoside of the formula (2) with methylation reagent in the presence of base, in a solvent, in which the base is selected from the group consisting of inorganic salts such as K2CO3, NaOH, and KOH, alcoholic metallic salts such as, CH3ONa, and CH3CH2ONa, or alkaline hydride or alkaline earth metal such as NaH; the methylation reagent is selected from the group consisting of CH3I or ((CH3)2SO4); and the solvent is an aprotic solvent selected from the group consisting of DMF, DMSO, acetone; ii) adding acid to the compound from step i) to obtain a compound of the formula (3); iii) reacting the compound (3) with alpha-haloacetate having protected carboxy group in the presence of base to obtain a compound of the formula (4); and iv) removing a protecting group from the compound (4) to form 7-carboxymethyloxy-3',4',5-trimethoxyflavone of the formula (1). In the formula, R' as a protecting group is a t-butyl, benzyl, silyl, trichloroethyl, or p-methoxybenzyl group. In the formulae, R1 is a protection group of t-butyl, benzyl, silyl, trichloroethyl or p-methoxybenzyl.

Description

Preparation method of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone {Preparative method of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone}

The present invention relates to a method for preparing 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone and the pharmaceutically acceptable salts and solvates thereof of Formula 1, specifically Methylation reaction, acid treatment, reaction with carboxyl-protected alpha-haloacetate and deprotection reaction using 3 ', 5,7-trihydroxy-4'-methoxyflavone-7-rutinoside as starting material To prepare 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone.

Gastritis, gastric ulcer or duodenal ulcer is a high incidence in which over 10% of the population experiences at least once in a lifetime, even though the incidence rate has decreased over the last 10 years. It has been described as an imbalance in the process of defending tissue from autodigestion of attacking agents within.

Conventional treatment methods for gastritis and gastric ulcer have been mainly to promote the therapeutic effect by reducing the attack factor using acid secreting inhibitors such as antacids or H ₂ antagonists, proton pump inhibitors. However, prolonged administration of acid secretion inhibitors can cause dysplasia in gastrointestinal mucosal epithelial cells (Ekman, L. et al., Scand. J. Gastroentrol. 1985, 20 suppl. 108: 53), and influence gastric cancer formation. (Garner, A., Advances in Drug Therapy of Gastrointestinal Ulceration; Garner, A. and Whittle, BJR (Eds.), Wiley & Sons, 1989, 275-88). Therefore, in order to be able to treat gastric ulcers without affecting acid secretion, it is necessary to develop a compound having a cytoprotection effect.

On the other hand, among the flavonoid compounds present in nature, hyporetin-8-glucoside, apigenin-7,4'-dimethyl ether, and camphorol kampferol, quercetin, naringenin, hesperidine and the like are known to have anti-ulcer effects (J. Pharm. Pharmacol. 1984, 36: 820; Ind. J. Pharm. Sci. 1981, 43: 159; Ind. J. Exp. Biol. 1988, 26: 121; Phytotherapy Res. 1992, 6: 168; ibid, 1988, 2: 137).

Also non-naturally synthesized flavone derivatives are 4'-fluoro-5-methoxyflavones (Ares et al., USP 5,399,584), 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavones (WO 98 / 04541) has been reported to have a gastric protective action. In particular, 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone represented by the formula (1) has been reported to have a very good protective effect on the gastrointestinal tract including the large intestine.

As a conventional method for preparing 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone, a process such as Scheme 1 below is known from WO 98/04541 (Korean Patent Application No. 96-30494). In this production method, a total skeleton undergoing 9 steps using 2,4,6-trihydroxyacetophenone as a starting material is used as a basic skeleton.

This preparation method is useful for making various kinds of derivatives having different types of substituents. However, the starting material 2,4,6-trihydroxyacetophenone is uneconomical because it is an expensive material, and there are problems in that the industrial value is low and the yield of the overall reaction is low because the reaction step is 9 steps. In addition, the step of performing hydrogen pressurization under a Pd (palladium) catalyst to remove the benzyl group (Bn) used as a protecting group of the hydroxy group includes two or more steps, which require a special device for handling the compressed gas. This complicated and expensive palladium catalyst is uneconomical and has the disadvantage of being involved in industrial use of hydrogen and the catalyst.

Accordingly, the present inventors have studied to solve the above problems, the methylation reaction, acid treatment using 3 ', 5,7-trihydroxy-4'-methoxyflavone-7- lutinoside of the formula (2) as a starting material And reaction with decarboxylation and deprotection with alpha-haloacetate protected with carboxyl group, the reaction conditions are mild, the reaction step is short, and 7-carboxymethyloxy-3 ', 4', 5-tri with high yield and high purity. The present invention was completed by developing a new method of preparing methoxyflavones.

It is an object of the present invention to provide a novel preparation of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone and its pharmaceutically acceptable salts and solvates with mild reaction conditions and short reaction steps. To provide a way.

In order to achieve the above object, in the present invention, 7-carboxymethyl of the following Chemical Formula 1 using 3 ', 5,7-trihydroxy-4'-methoxyflavone-7-rutinoside of Chemical Formula 2 as a starting material Provided are methods for preparing oxy-3 ', 4', 5-trimethoxyflavones.

Formula 1

Formula 2

Specifically, the method for preparing 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone of formula 1 according to the present invention is 3 ', 5,7-trihydroxy-4'-methoxy of formula 2 The flavone-7-rutinosides are methylated, acid treated, reacted with a carboxyl-protected alpha-haloacetate and then deprotected.

The method for preparing 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone of formula (1) according to the present invention is cheap and easy to purchase 3 ', 5,7-trihydroxy- of formula (2). It is very economical to use 4'-methoxyflavone-7-rutinoside as starting material. In addition, 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone can be prepared in high yield and high purity because the reaction conditions are mild, the reaction step is short, and the selectivity of the reaction is high.

The present invention also provides a process for preparing pharmaceutically acceptable salts and solvates of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone of formula (1).

Hereinafter, the present invention will be described in detail.

The present invention provides a method for preparing 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone represented by Scheme 2.

Wherein R 'represents a t-butyl, benzyl, silyl, trichloroethyl or p-methoxybenzyl group as a protecting group.

Specifically, the preparation method of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone of formula 1 according to the present invention

1) reacting 3 ', 5,7-trihydroxy-4'-methoxyflavone-7-rutinoside of Formula 2 with a methylation reagent in the presence of a base in a solvent (step 1);

2) acid treating the compound obtained in step 1 in a solvent to obtain a compound of formula 3 (step 2);

3) reacting a compound of formula 3 with a carboxyl group protected alpha-haloacetate in a solvent in the presence of a base to give a compound of formula 4 (step 3); And

4) deprotecting the compound of formula 4 to obtain a compound of formula 1 (step 4).

In particular, since the yield and purity of the compound produced in the reaction of Step 1 and Step 2 are high, it is very effective for the preparation of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone.

The 3 ', 5,7-trihydroxy-4'-methoxyflavone-7-rutinoside of Formula 2, which is used as a starting material in the present invention, is easily obtained from nature and can be purchased from a general reagent company.

Hereinafter, the preparation method of the present invention will be described in detail for each reaction step.

I. Methylation Reaction (Step 1)

The 3'- and 5-positions of hydroxy groups are methylated by reacting 3 ', 5,7-trihydroxy-4'-methoxyflavone-7-rutinoside of Formula 2 with a methylation reagent in the presence of a suitable base in a suitable solvent. Let's do it.

Although there are many hydroxy groups in 3 ', 5,7-trihydroxy-4'-methoxyflavone-7-rutinoside of the formula (2), 3' by appropriately adjusting the reaction conditions using the reactivity difference of each hydroxy group The hydroxyl group at the-and 5-positions can be methylated to convert into methyl ether. In addition, even though the hydroxyl group of the glycoside moiety is methylated in addition to the 3'- and 5-positions, the hydroxyl groups other than the 3'- and 5-positions are removed because the glycosidic moiety is removed due to the breakage of the glycoside in the subsequent acid treatment. Methylation is not a problem.

In this case, the reaction solvent is preferably a solvent capable of dissociating polar protons, and in particular, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetone, or the like is used. desirable.

The base is an inorganic base such as potassium carbonate (K ₂ CO ₃ ), sodium hydroxide (NaOH), potassium hydroxide (KOH), alcohol such as sodium methoxide (CH ₃ ONa), sodium ethoxide (CH ₃ CH ₂ ONa) Alkali or alkaline earth metal hydrides such as metal salts and sodium hydride (NaH) may be used. Especially, it is preferable to use potassium carbonate, sodium hydroxide, potassium hydroxide, or sodium hydride especially.

The methylation reagent can be any one that can hydroxylate the hydroxy group, and it is particularly preferable to use methane iodide (CH ₃ I) or dimethylsulfuric acid ((CH ₃ ) ₂ SO ₄ ). At this time, the methylation reagent is preferably added in excess to 3 ', 5,7-trihydroxy-4'-methoxyflavone-7-rutinoside. Moreover, it is preferable that reaction temperature is 0-150 degreeC, and it is more preferable that it is 20-80 degreeC.

The compound produced by the reaction of step 1 can be used as it is in the next reaction after only a simple and simple workup process without purification such as recrystallization or silica gel chromatography.

II. Acid Treatment (Step 2)

The compound produced in Step 1 was treated with an appropriate acid in an appropriate solvent to break the bond with glycoside to prepare 7-hydroxy-3 ', 4', 5-trimethoxyflavone, a compound of Formula 3.

In this case, tetrahydrofuran (THF), alcohol, water or an alcoholic aqueous solution may be used as the reaction solvent, and it is particularly preferable to use an alcoholic aqueous solution.

As the acid, inorganic acids such as hydrochloric acid (HCl), bromic acid (HBr), sulfuric acid (H ₂ SO ₄ ), and organic acids such as acetic acid, trifluoroacetic acid, formic acid, and p-toluenesulfonic acid may be used. Preference is given to using.

Moreover, it is preferable that reaction temperature is 0-100 degreeC.

III. Introduction of substituents at the 7-position (step 3)

The compound of formula 3 is prepared by reacting the compound of formula 3 with alpha-haloacetate protected with carboxyl groups in the presence of a suitable base in a suitable solvent.

In this case, it is preferable to use a polar solvent as the reaction solvent, and in particular, dimethylformamide, dimethyl sulfoxide, acetone, or the like is preferably used.

The base is an inorganic base such as potassium carbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, metal salts of alcohols such as sodium methoxide, sodium ethoxide, alkali or alkaline earth metal hydrides such as sodium hydride, especially potassium carbonate, sodium hydroxide Preference is given to using potassium hydroxide or sodium hydride.

The carboxy protecting group in the carboxy-protected alpha-haloacetates is preferably benzyl, t-butyl, trichloroethyl, silyl, p-methoxybenzyl.

Ⅳ. Deprotection Reaction (Step 4)

The deprotection reaction of the compound of formula 4 to prepare 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone of formula (1).

Specific methods of the deprotection reaction and reaction conditions such as a solvent may vary depending on the characteristics of the protecting group. For example, when the deprotecting group is a t-butyl, benzyl, silyl, p-methoxybenzyl group, the protecting group can be removed by reacting at 20 to 120 ° C. in a solvent in the presence of an acid. In addition, when the deprotecting group is a trichloroethyl group, it can be deprotected by treating with zinc in the presence of an acid.

Examples of the acid used in the deprotection reaction include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid and p-toluenesulfonic acid.

In addition, when the deprotection group is a benzyl or p-methoxybenzyl group, it may be deprotected through a reduction reaction using palladium, Raney-nickel, or platinum as a catalyst at 5 to 100 ° C. and hydrogen pressure.

The present invention also provides a process for preparing pharmaceutically acceptable salts and solvates of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone of formula (1).

7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone of Formula 1 may be prepared with pharmaceutically acceptable salts and solvates according to methods conventional in the art.

Bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is, for example, dissolved in 1 equivalent of an alkali metal hydroxide or alkaline earth metal hydroxide solution of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone of formula (1) The 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone salt is filtered off and the filtrate is obtained by evaporation and drying. In this case, as the metal salt, it is particularly suitable to manufacture sodium and potassium salts in a pharmaceutically manner.

In the present invention, the molecular structure was confirmed by comparing infrared spectroscopy, ultraviolet visible light spectroscopy, nuclear magnetic resonance spectra, mass spectroscopy and elemental analysis calculated values and representative values of representative compounds.

Hereinafter, the present invention will be described in more detail with reference to Examples.

However, the following examples are merely to illustrate the content of the present invention is not limited to the scope of the present invention.

<Example> Preparation of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone (compound of Formula 1)

(Step 1) Preparation of 7-hydroxy-3 ', 4', 5-trimethoxyflavone (compound of formula 3)

3.1 g of 3 ', 5,7-trihydroxy-4'-methoxyflavone-7-rutinoside (Aldrich) was added to 60 ml of dimethylformamide, where 4.9 g of potassium carbonate and 6.3 ml of iodide methane were added. The reaction was carried out in a closed vessel at 60 ° C. for 48 hours with addition and stirring. 50 ml of a 3: 1 mixed solution of ethyl acetate and n-hexane was added thereto, and the mixture was left to stand for 30 minutes and then filtered.

25 mL of methanol was added to the filtered solid and 25 mL of 35% aqueous hydrochloric acid solution was added thereto while stirring. The reaction mixture was reacted for 24 hours while heating to 70 deg. After cooling the reaction solution to room temperature and left for 1 hour to produce a solid. The solid was filtered and washed with a small amount of cold methanol to obtain 1.27 g (yield: 76%) of the title compound as a yellow solid.

NMR (DMSO-d ₆ ): δ 3.72 (s, 3H), 3.83 (s, 3H), 3.86 (s, 3H), 6.38 (d, 1H), 6.57 (d, 1H), 6.69 (s, 1H) , 7.08 (d, 1H), 7.48 (d, 1H), 7.58 (dd, 1H)

IR (KBr): 1636, 1590 cm^-One

(Step 2) Preparation of 7-t-butyloxycarboxymethyloxy-3 ', 4', 5-trimethoxyflavone (compound of formula 4)

After dissolving 3.9 g of the compound prepared in Step 1 in 20 ml of dimethylformamide, 3.28 g of potassium carbonate and 1.93 ml of t-butylbromoacetate were added thereto, followed by stirring at room temperature for 24 hours. After the reaction, water was added to the reaction solution, and the mixture was extracted twice with chloroform. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The reaction residue was separated and purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain 5.2 g (yield: 99%) of the title compound.

NMR (CDCl ₃ ): δ 1.49 (s, 9H), 3.93 (s, 3H), 3.94 (s, 6H), 4.59 (s, 2H), 6.44 (d, 1H), 6.47 (d, 1H), 6.58 (s, 1H), 6.94 (d, 1H), 7.28 (d, 1H), 7.44 (dd, 1H)

(Step 3) Preparation of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone (compound of formula 1)

5.2 g of the compound prepared in Step 2 was dissolved in 40 ml of benzene, and 1 g of paratoluenesulfonic acid monohydrate was added thereto to reflux for 3 hours. This reaction gave the reaction product directly as a solid. The solid was filtered under reduced pressure, washed with benzene and water, and dried to obtain 4.13 g (yield: 92%) of the title compound.

NMR (DMSO-d ₆ ): δ 3.83 (s, 6H), 3.87 (s, 3H), 4.85 (s, 2H), 6.52 (d, 1H), 6.74 (s, 1H), 6.83 (d, 1H) , 7.09 (d, 1H), 7.50 (d, 1H), 7.62 (dd, 1H), 13.5 (br s, 1H)

Elemental Analysis: Found (%): C; 62.08 H; 4.73

Theoretical (%): C; 62.17 H; 4.70

As described above, methylation reaction, acid treatment, carboxyl group using 3 ', 5,7-trihydroxy-4'-methoxyflavone-7-rutinoside of Formula 2 as a starting material by the method of the present invention. The 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone of Formula 1 was subjected to high yield and high purity under mild reaction conditions and short reaction steps through reaction with a protected alpha-haloacetate and deprotection reaction. It can be prepared as.

Claims (9)

1) reacting 3 ', 5,7-trihydroxy-4'-methoxyflavone-7-rutinoside of Formula 2 with a methylation reagent in the presence of a base in a solvent (step 1); 2) acid treating the compound obtained in step 1 in a solvent to obtain a compound of formula 3 (step 2); 3) reacting a compound of formula 3 with a carboxyl group protected alpha-haloacetate in a solvent in the presence of a base to give a compound of formula 4 (step 3); And 4) Deprotection reaction of the compound of Formula 4 to obtain 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone of Formula 1 (Step 4) Method for preparing 3 ', 4', 5-trimethoxyflavone. Scheme 2 Wherein R 'represents a t-butyl, benzyl, silyl, trichloroethyl or p-methoxybenzyl group as a protecting group. The method of claim 1, wherein the solvent of step 1 is selected from the group consisting of dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetone as an aprotic solvent that cannot dissociate protons. -Production method of carboxymethyloxy-3 ', 4', 5-trimethoxyflavone. The method of claim 1, wherein the base of step 1 is an inorganic base such as potassium carbonate (K ₂ CO ₃ ), sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium methoxide (CH ₃ ONa), sodium ethoxide ( 7-carboxymethyloxy-3 ', 4', characterized in that it is selected from the group comprising an alcoholic metal salt such as CH ₃ CH ₂ ONa) or an alkali or alkaline earth metal hydride such as sodium hydride (NaH), Method for preparing 5-trimethoxyflavone. The 7-carboxymethyloxy- ₃ according to claim 1, wherein the methylation reagent of step 1 is selected from the group comprising methane iodide (CH ₃ I) or dimethylsulfuric acid ((CH ₃ ) ₂ SO ₄ ). Method for preparing ', 4', 5-trimethoxyflavone. The process for producing 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavones according to claim 1, wherein the reaction temperature in step 1 is 0 to 150 캜. The 7-carboxymethyloxy-3 ', 4', 5-tree of claim 1, wherein the solvent of step 2 is selected from the group comprising tetrahydrofuran (THF), alcohol, water or alcoholic aqueous solution. Method for preparing methoxyflavones. The acid used in step 2 is an inorganic acid such as hydrochloric acid (HCl), sulfuric acid (H ₂ SO ₄ ), bromic acid (HBr), organic acids such as trifluoroacetic acid, p-toluenesulfonic acid, acetic acid, formic acid, and the like. Method for producing 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone, characterized in that selected from the group containing. The process for producing 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone according to claim 1, wherein the reaction temperature in step 2 is 0 to 100 ° C. The method of claim 1, wherein the solvent of step 3 is a polar solvent and the base is an inorganic base such as potassium carbonate, sodium hydroxide, potassium hydroxide, metal salt of alcohol such as sodium methoxide, sodium ethoxide, alkali or alkali such as sodium hydride A process for producing 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone, which is selected from the group comprising earth metal hydrides.