KR100325268B1 - Process for producing asiatic acid - Google Patents

Abstract

PURPOSE: Provided is an asiatic acid used as an agent for curing trauma, which is produced by using a madecassic acid, obtained from Centella asiatica, as a starting material. CONSTITUTION: The asiatic acid represented by the formula 9 is produced by treating a compound represented by the formula 8 with lithium iodide and hydrolyzing ester at 28-position, wherein the compound represented by the formula 8 is obtained by hydrolyzing a compound represented by the formula 7 under the acidic condition and removing ketal protecting groups at 2- and 3-position. The compound represented by the formula 7 is produced by treating a compound represented by the formula 5 with AIBN and tributyl tin hydride and removing a substituted hydroxy group at 6-position to obtain a compound represented by the formula 6 and then removing an acetyl protecting group at 2-position with potassium carbonate, wherein the compound represented by the formula 5 is produced by using the madecassic acid as a starting material.

Description

How to prepare Asian acid

The present invention relates to a method for producing asiatic acid, and more particularly, to a method for producing asiatic acid using a natural madecassic acid as a starting material.

Asiatic acid represented by the following formula is a substance extracted from Centella asiatica, such as its trisaccharides Asiaticoside and Madecassic acid, and was first isolated by Bontems et al. In 1941 [J.E.Bontems, Bull. Sci. Pharmacol., 49, 186-91 (1941)], Polonsky et al. [J. Polonsky, Compt, Rend., 232, 1878-80 (1951); J. Polonsky, Bull Soc. Chim., 173-80 (1953).

Centella asiatica extracts, including asiatic acid and asiaticosides, have long been used in the treatment of skin wounds and chronic ulcers, and in the treatment of skin transformation caused by tuberculosis or leprosy [P. Boiteau, A. Buzas, E. Lederer and J. Polonsky, Bull. Soc. Chim., 31, 46-51 (1949)], It is reported that the pharmacological mechanism of skin wound healing of these substances is achieved by activating the cells of the Malpighean layer and inducing keratinization [May. Anne, Eur. J. Pharmacol., 4 (3), 331-9 (1968)].

Madecasol, a currently available treatment for skin diseases, is also a mixture of three compounds of asiaticoside (40%) and asiatic acid and madecassic acid (60%). Asian acid itself has been reported to be ineffective, but [Kiesswetter, Wien. Med. Woshschr., 114 (7), 124-6 (1964)], which is due to differences in the absorption process of these substances in the body, and reports that demonstrate that the substance showing the actual efficacy is asiatic acid itself [L.F. Chasseaud, B.J. Fry, D.R. Hawkins, J.D. Lewis, T. Taylor ard D. E. Hathway, Arzneim-Forsch, 21 (9), 179-84 (1971), are also drawing attention to the synthesis of asiatic derivatives and their pharmacological action. However, this Asian acid has been pointed out as a problem because there are so many synthetic steps that it is difficult to presynthesize from a simple starting material.

The present inventors first developed a method for synthesizing asiatic acid through a simple step using madecassic acid obtained with asiatic acid in Centella asiatica to complete the present invention.

The manufacturing method of the present invention will be described below.

Scheme

First, compound (2) was prepared by protecting the 2- and 3-position hydroxy groups with ketal using 2,2-dimethoxypropane, and preparing the compound (2) in ester form. 3) made of The 2-hydroxy free hydroxyl group of this compound (3) is protected by an acetyl group to obtain a compound of formula (4). At this time, the free hydroxy group has two positions, 2-position and 6-position, but compound (4) where only 2-position is protected by acetyl due to the 6-position steric hindrance is obtained. The compound (4) was treated with carbon disulfide and methyl iodide to obtain a compound of formula (5), which was then treated with AIBN and tributyltin hydride to obtain a compound (6) having 6-position removed hydroxy group, followed by carbonic acid. Using potassium to deprotect the 2-position acetyl group to obtain compound (7), and again using hydrochloric acid to deprotect the ketal group at the 3-4 position (compound 8), hydrolyzing the ester group at 28-position to 9) shouts.

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

Example 1 Preparation of 3,23-O-Isopropylidene Madecaic Acid

Madecassic acid (1 g) and p-toluenesulfonic acid (50 mg) were dissolved in 10 ml of dimethylformamide, 0.5 ml of 2,2-dimethoxypropane was added thereto, followed by stirring at room temperature for 12 hours. 5% K ₂ CO ₃ was added to the reaction mixture, neutralized and stirred for 30 minutes.

The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate and purified by column chromatography (dichloromethane / methanol = 30/1) to obtain 0.97 g (90%) of the title compound as a white solid.

Example 2 Preparation of Methyl 3,23-0 Isopropylidene Madecassate

The compound (1 g) obtained in Example 1 was dissolved in ethyl ether and an ether solution of CH ₂ N ₂ was added, but added dropwise until the reaction mixture became light yellow and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and the residue was filtered through a short column to obtain 0.98 g (96%) of a white solid.

Example 3

Compound (3) (1000 mg, 1.792 mmol) prepared in Example 2 was dissolved in anhydrous dichloromethane (10 ml), and pyridine (434 μl, 5.376 mmol) and acetic anhydride (254 μl, 2.688 mmol) were added thereto at 0 ° C. Stir for 48 hours while warming to room temperature. The reaction mixture was treated with 5% potassium carbonate (2 ml), and dichloromethane was removed by concentration under reduced pressure. The obtained residue was extracted with ethyl acetate (50 ml), and the organic layer was washed with water (5 mlx3) and brine (5 mlx3) and dried over anhydrous magnesium sulfate.

The article obtained by concentrating under reduced pressure was purified by column chromatography (ethyl acetate / hexane = 1/3) to obtain 892 mg (83%) of compound (4) as a white solid.

Example 4

Anhydrous tetrahydrofuran (10 ml) was added to Compound 4 (500 mg, 0.833 mmol) and NaH (60% inorganic oil, 166 mg, 4.165 mmol) prepared in Example 3, followed by heating to reflux for 3 hours.

Carbon disulfide (5 ml) was added thereto and heated to reflux for 10 hours. Methyl iodide (0.5 ml) was added to the reaction mixture, and the mixture was heated to reflux for 1 hour.

The reaction mixture was treated with water (1 ml) and THF was concentrated under reduced pressure to remove.

The obtained residue was extracted with ethyl acetate (50 ml) and the organic layer was washed with water (5 ml × 3) and brine (5 ml × 3). The residue obtained by drying over anhydrous magnesium sulfate and concentrated under reduced pressure was purified by column chromatography (ethyl acetate / hexane = 1/6) to obtain 406 mg (71%) of compound (5) as a white solid.

Example 5

Anhydrous benzene (5 ml) was added to Compound 5 (284 mg, 0.41 lmmol) obtained in Example 4 and the catalytic amount of AIBN to dissolve. Tributyltin hydride (228 µl, 0.823 mmol) was added thereto, and the mixture was heated and refluxed for 1 hour.

Benzene was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane = 1/5) to give 222 mg (93%) of the compound (6) as a white solid.

Example 6

To a compound 6 (34 mg, 0.0582 mmol) and potassium carbonate (16 mg, 0.115 mmol) obtained in Example 5, a mixed solvent of methanol and water (methanol: water = 10: 1, 3 ml) was added thereto to dissolve and stirred at room temperature for 2 hours. .

Methanol and water were concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate: hexane = 1: 5) to obtain 25 mg (80%) of the compound (7) as a white solid.

Example 7

To compound 7 (60 mg, 0.110 mmol) prepared in Example 6, THF (3 ml) and IN-HCl (0.3 ml) were added, and the mixture was stirred at room temperature for 2 hours.

The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate = 2: 3) to obtain 53 mg (95%) of the compound (8) as a white solid.

Example 8 Preparation of Asian Acid (9)

2,4,6-collidine (10 ml) was added to a mixture of methyl asiaate (8) (500 mg) and LiI.3H ₂ O (570 mg) and heated to reflux for 10 hours. The reaction mixture was concentrated under reduced pressure to remove collidine, and the residue was purified by column chromatography (dichloromethane / methanol = 20/1) to give 366 mg (75%) of asiatic acid (9).

Claims (3)

The compound of formula 7 was hydrolyzed under acid conditions to remove the ketal protecting groups in 2-position and 3-position to obtain the compound of formula 8, which was treated with lithium iodide to hydrolyze the ester at 28-position. A process for producing the aspartic acid of formula 9 below. According to claim 1, wherein the compound of Formula 7 is treated with AIBN and tributyltin hydride compound of formula 5 to remove the substituted hydroxy group in the 6-position to obtain a compound of formula 6, and then to 2 A process for producing aspartic acid, characterized in that it is prepared by removing the acetyl protecting group in position. According to claim 2, The compound of Formula 5 is a starting material and the free hydroxyl group of the 3-position and 4-position in the ketal form using a madecaic acid of the following formula 1 and 2,2-dimethoxypropane The compound of formula 2 was obtained, an ether solution of CH ₂ N ₂ was added to convert into a compound of formula 3, which is a methyl ester form of formula 2, and acetic anhydride was added to the compound of formula 3 to obtain a free hydroxide in 2-position. It is prepared by converting a compound of formula 4, which is in hydroxy protected form, and then treating the compound of formula 4 with carbon disulfide and methyl iodide to protect the 5-hydroxy free hydroxy group with a (methylthio) thiocarbonyl group. A method for producing asiatic acid.