JPH048437B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing soyasapogenol B derivatives, which are useful intermediates in the synthesis of complement activators. Yotsute 3-0-D-
The present invention relates to a method for producing glucuronopyranosyl soyasapogenol B.

Lower alkyl esters of 3-0-β-D-glucuronopyranosyl soyasapogenol B are said to be effective as complement activators for rheumatoid arthritis, nephritis, autoallergic hemolytic anemia, etc. There is. These esters are soyasaponin, which has soyasapogenol B as its aglycone.
It is known that it can be obtained by alcoholyzing a mixture of with lower alcohols such as methanol and ethanol in the presence of an acid (Kitagawa et al.:
chem, Pharm, Bull. vol. 22, p. 121, 1971). Soya saponin used as a raw material here,
The mixture is separated and extracted from soybeans, but the content in soybeans is small (0.1-0.2%), and separation of these and soya saponins A ₁ and A ₂ , which have similar aglycone structures, is extremely difficult. The problem is that it is complicated. Therefore, a method for obtaining the ester more simply and inexpensively is desired.

This invention uses soya savogenol B, which can be obtained relatively easily from water-soluble waste produced during the production of fermented soybean foods such as miso, as a raw material, and selectively injects gluclopyrano into its 3-hydroxyl group by a synthetic method. It was completed after obtaining the knowledge that it was possible to introduce a sil group.

According to this invention, soya savogenol B of the formula () is reacted with a glucopyranuric acid derivative of the formula (), then the protecting group in the product is removed, and 3-
A method for preparing 0-D-glucuronopyranosyl soyasapogenol B, especially the 3-0-β form (formula), is provided.

(In the above, X means a reactive group, Y means a hydroxy group protecting group, and Z means a carboxyl group protecting group.) In the compound of formula (), the reactive group of X means the compound of formula (). refers to a substance that reacts with the hydroxyl group of , producing an ether bond. Suitable reactive groups are halogen atoms, of which bromine atoms are particularly preferred.

The protecting group for the hydroxyl group in Y may be any group as long as it protects the hydroxyl group in the compound of formula () so that it does not participate in the reaction and can be easily removed after the reaction. Such protecting groups include acyl groups and silicon-containing groups. Examples of the acyl group include an acetyl group, a lower alkanoyl group such as a propionyl group, and an aromatic acyl group such as a p-bromophenacyl group and a benzyloxycarbonyl group. Examples of the silicon-containing group include trimethylsilyl group, dimethylmethoxysilyl group, and tributoxysilyl group.

Furthermore, the protecting group for the carboxyl group of Z includes an ester or salt form that can be easily removed after the reaction. Examples of esters include lower alkanols (methanol, t-butyl alcohol, etc.), aromatic alcohols (p-nitrobenzyl alcohol, etc.),
Includes esters formed with silicon compounds (trimethylsilyl chloride, dimethylmethoxysilyl chloride, etc.) and phosphorus compounds (diethoxyphosphonyl chloride, etc.). Salts include metal salts (sodium, potassium, silver, etc.) and amine salts (triethylamine, etc.).

In the compound of formula (), the most preferable combination of X, Y, and Z is that X is a bromine atom, Y is an acetyl group, and Z is a methyl group. This compound uses glucuronic acid as a raw material, and its four hydroxyl groups are first acetylated with acetic anhydride in the presence of a catalyst such as boron trifluoride ether complex salt and perchloric acid. Then,
The carboxy group is methyl esterified with an alkylating agent such as diazomethane in an organic solvent. The resulting methyl 1,2,3,4-tetra-O-acetyl-
D-glucopyranuronate can be synthesized by bromination with a halogenating agent such as hydrogen bromide in an organic solvent. Note that these reactions are generally performed at low temperatures.

The compound of formula () thus obtainable is subjected to a reaction with a compound of formula ().
This reaction is usually carried out in a nonpolar inert organic solvent such as benzene, dioxane, toluene, xylene, chloroform, tetrahydrofuran, methylene chloride, dimethylformamide, etc. at a temperature ranging from room temperature to the boiling point of the solvent. The most preferred solvent is benzene or a combination of benzene and dioxane. The reaction is preferred because it is anhydrous. In particular, when the protective groups for Y and Z are groups that are easily decomposed by moisture, it is necessary to make the reaction system as anhydrous as possible. Although the reaction solvent and the like are used after being dehydrated in advance for this purpose, it is preferable to add a powdered dehydrating agent such as calcium sulfate to the reaction system. It is also preferable to add a compound capable of accepting by-products generated by the reaction, such as hydrogen halide. Silver carbonate is preferred as the hydrogen halide acceptor. It was found that this silver carbonate must be dried at room temperature under low pressure, and that silver carbonate dried under heat has almost no effect.

In this way, the mercury group at the 3-position of Soyasapogenol B is selectively etherified.

At this time, two types of hydroxyl groups, β-type and α-type, can theoretically be formed at the 3-position of the product. However, in the present invention, it is desired to preferentially generate the β-type. For such purposes,
As the protecting group Y for the hydroxyl group in the compound of formula (),
Most preferably, compounds with lower alkanoyl groups (especially acetyl groups) are used. In addition, there are two free hydroxyl groups (-
CH ₂ OH, -OH) is present, and the purification efficiency is high if this is converted into lower alkanoylation and then once purified (for example, subjected to column chromatography) and the protecting group is removed.

Removal of the protecting group is then suitably carried out by means known per se. For example, it can be carried out using an aqueous solution of sodium hydroxide or potassium hydroxide.

Next, the present invention will be specifically explained with reference to Examples.

Example D-glucuronic acid (Hani Chemicals, 3.0 g) was dissolved in acetic anhydride (200 ml)-boron tritoxide ether complex (4 ml) and stirred at 5°C for 12 hours. Pour into ice water and extract with ethyl acetate. The ethyl acetate extract is washed with saturated sodium bicarbonate solution, water, and dried with magnesium sulfate powder. The desiccant was filtered off, the filtrate was distilled off under reduced pressure, and then dissolved in methanol (30 ml). After methylation by adding an ether solution of diazomethane, the mixture is left at room temperature (15°C) for 5 hours. After removing the solvent under reduced pressure,
Purified by silica gel column chromatography [100 g of silica gel (Merck & Co., 60-120 mesh), elution solvent, chloroform and chloroform-ethyl acetate mixture (50:1)] and methyl 1,2,3,4
-Tetra-O-acetyl-D-glucopyranuronate (4.0 g) was obtained.

The obtained methyl 1,2,3,4-tetra-O-
Acetyl-D-glucopyranuronate (3.0g)
25% hydrogen bromide in a chloroform solution (100ml) of
Add acetic acid solution (150 ml) and stir at room temperature (15°C) for 12 hours. Pour into ice water, extract with chloroform, wash the chloroform extract with saturated sodium bicarbonate solution,
Wash with water and dry with magnesium sulfate powder. The desiccant was removed by filtration, and the filtrate was distilled off under reduced pressure, and purified by silica gel column chromatography [80 g of silica gel (Merck & Co., 60-120 mesh), elution solvent, benzene-acetone mixture (30:1)]. , methyl 2,3,4-tri-O-acetyl-1-bromo-
1-deoxy-α-D-glucopyranuronate (2.3 g) was obtained.

After adding calcium sulfate (5 g) and silver carbonate (1.8 g) to a dry benzene solution (250 ml) of Soyasapogenol B (1.0 g), the obtained methyl 2,
3,4-tri-O-acetyl-1-bromo-1-
Deoxy-α-D-glucopyranuronate (2.5
Add a dry benzene solution (10 ml) of g) and heat under reflux for 5 hours. Inorganics were filtered off, and the filtrate was evaporated under reduced pressure. The obtained residue was diluted with acetic anhydride (5
ml) - dissolved in pyridine (10 ml) at room temperature (15°C)
Stir for 8 hours. The mixture is poured into ice water and extracted with ethyl acetate. The ethyl acetate extract is washed with a 5% aqueous hydrochloric acid solution, then with a saturated sodium bicarbonate solution, then with water, and dried over magnesium sulfate powder. The desiccant was filtered off, the filtrate was distilled off under reduced pressure, and then subjected to silica gel column chromatography [Silica gel (Merck, 60-120 mesh) 100
g, elution solvent, benzene-acetone mixture (50:1
15:1)] to obtain penta-O-acetyl-monomethyl ester of 3-O-β-D-glucuronopyranosyl soyasapogenol B (1.2 g).
I got it. Dissolve in methanol (50 ml), add 10% aqueous potassium hydroxide solution (25 ml), stir at 60°C for 3 hours, and neutralize with Dowex 50W x 8 (H ⁺ type).
The resin was filtered off, and the filtrate was distilled off under reduced pressure to obtain 3-
O-β-D-glucuronopyranosyl soyasapogenol B (0.9 g) was obtained. The physicochemical properties of the product thus obtained were consistent with the standard.

Claims (1)

[Claims] 1 Soyasapogenol B has the formula () (In the formula, X is a reactive group, Y is a hydroxyl protecting group, Z
is a carboxyl group protecting group).
The product was subjected to protection group removal treatment to give 3-0-D-
1. A method for producing a soyasapogenol B derivative, which comprises obtaining glucuronopyranosyl soyasapogenol B. 2. The method according to claim 1, which uses a compound in which the prom atom in formula (), Y is an acetyl group, and Z is a methyl group. 3. The method according to claim 1 or 2, wherein the reaction of Soya Sabogenol B with the compound of formula () is carried out in the presence of calcium sulfate and silver carbonate in an inert organic solvent. 4. Any one of claims 1 to 3, wherein 3-0-D-glucuronopyranosyl soyasapogenol B is 3-0-β-D-glucuronopyranosyl soyasapogenol B. The method described in.