JPS6092300A - Production of soyasapogenol b derivative - Google Patents

Abstract

PURPOSE:To produce the titled substance useful as an intermediate for the synthesis of complement activating agent, from the by-product in the production of fermented soybean product such as MISO (fermented bean paste), by reacting soyasapogenol B with a specific glucopyranuronic acid derivative. CONSTITUTION:The objective 3-O-D-glucuropyranosylsoyasapogenol B of formula IIIis produced by (1) reacting (A) the soyasapogenol B of formula I obtained from the water-soluble waste produced in the production of fermented soybean food such as MISO with (B) the glucopyranuronic acid derivative of formula II(X is reactive group; Y is OH-protecting group; Z is COOH-protecting group) (e.g. methyl 2,3,4-tri-O-acetyl-1-bromo-1-deoxy-alpha-D-glucopyranuronate) preferably in an inert organic solvent in the presence of calcium sulfate and silver carbonate, and (2) removing the protecting groups from the reaction product.

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, and more specifically, to a method for producing soyasapogenol B derivatives, which are useful intermediates in the synthesis of complement activators. -0-D-Glucuronopyranosyl soya savogenol wf manufacturing method. Lower alkyl esters of 3-0-β-D-glucuronobyranocyl soya savogenol B are said to be effective as complement activators for rheumatoid arthritis, nephritis, autoallergic hemolytic anemia, etc. There is. It is known that these esters can be obtained by alcoholysing a mixture of soya saponin LII, (1) with soya saponin B as the aglycone, with a lower alcohol such as methanol or ethanol in the presence of an acid ( Kitayo et al.: Cfk
hem, Pharm, Bull, 22 volumes,
p. 121, 1976).

The mixture of soya saponins ■, ■, ■ used as raw materials here is separated and extracted from soybeans, but the content in soybeans is small ((0.1 to 0.2%)), and the aglycone content of these and aglycones is small. There is a problem that separation from soya saponins AI and A, which have similar structures, is very complicated.
A method for obtaining the ester more simply and inexpensively is desired.

This invention uses Soyasapogenol 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, the soyasapogenol B of formula (I) is reacted with the glucopyranuroic acid derivative of 2...), and then the protecting group in the product is removed, Silsoyasapogenol 1, especially 3-0-β form (
Formula 111 ) is provided, in which X is a reactive group, Y is a hydroxy-protecting group, 2
each means a protecting group for a carboxyl group. ) In the compound of (2...), the reactive group of X is the compound of formula (I)
means a compound that reacts with the hydroxyl group of the compound to form an ether bond. Suitable reactive groups include halogen atoms,
In particular, the protecting group for the hydroxyl group of O Y, of which a bromine atom is preferred, may be any group as long as it protects the hydroxyl group in the compound of formula (I) 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. As an acyl group,
Examples include lower alkanoyl groups such as acetyl group and propionyl group, and aromatic acyl groups such as p-bromophenacyl group and benzyloxycarbonyl group. Examples of the silicon-containing group include trimethylsilyl group, dimethylmethoxysilyl group, tributoxysilyl group, etc.0 Also, the carboxyl group protecting group includes an ester or ti 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.), silicon compounds (trimethylsilyl chloride, dimethylmethoxysilyl chloride, etc.),
Includes esters formed with phosphorus compounds (such as jetoxyphosphonyl chloride). Salts include metal salts (
salts of sodium, potassium, silver, etc.) and amine salts (triethylamine, etc.).

In the compound of formula ff1), the most preferable combination of XSY and Z is that X is a bromine atom, Y is an acetyl group, and 2 is a methyl group. This compound is made from glucuronic acid,
First, the four hydroxyl groups are converted into boron trifluoride ether complex salt,
Acetylation with acetic anhydride in the presence of a catalyst such as perchloric acid. The carboxy group is then methyl esterified with an alkylating agent such as diazomethane in an organic solvent. The resulting methyl 1,2,3.4-tetra-0-acetyl-D-
Glucopyranuronate can be synthesized by bromination with a tetragenating agent such as hydrogen bromide in an organic solvent.

Note that these reactions are generally performed at low temperatures.

The compound 2〇 that can be obtained in this way has the formula (
I) is subjected to a reaction of the compound of
It 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 preferably anhydrous. When the protective groups KY and 2 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 that can accept by-products produced by the reaction, such as hydrogen halide. Silver carbonate is preferred as the hydrogen halide acceptor. It was found that it was necessary to dry this silver carbonate at room temperature under low pressure and use 9 pieces, whereas 9 pieces dried by heating had almost no effect.

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

At this time, β-type and α-type in the 3-position hydroxyl group of the product
- Two types of generation are theoretically possible. However, in the present invention, it is desired to preferentially generate the β-type. For this purpose, it is most preferable to use a compound having a lower alkanoyl group (particularly an acetyl group) as the protecting group Y for the hydroxyl group in the compound 2Φ). In addition, the product before removal of the protecting group contains two free hydroxyl groups (−−娨, −
4) exists, and after converting it into lower alkanoylation, once it is purified (e.g., subjected to column chromatography) and the protecting group is removed, the purification efficiency is high. It is suitably prepared by means known per se. For example, it can be carried out using an aqueous solution of potassium hydroxide or potassium oxide.

Next, the present invention will be specifically explained with reference to examples.
Dissolve K and stir at 5'C for 12 hours.

The mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate extract was washed with saturated water, water, and dried over magnesium sulfate powder. After removing the desiccant by filtration and distilling the solvent off of the filtrate under reduced pressure, K was dissolved in methanol (3 otnl).

After methylation by adding an ether solution of diazomethane, room temperature (
Leave at 15°C for 5 hours. After distilling off the solvent under reduced pressure, silica gel column chromatography [silica gel (Merck & Co., 60-120 mesh) 100 f 1 elution solvent,
Chloroform and chloroform-ethyl acetate mixture (50:
1): Purified with 1 to obtain methyl 1,8°3.4-tetra-0-7cetyl-D-glu, co-vilanuronate□ (4,O1p-8-).

A chloroform solution (100wti) of the obtained methyl 1,2,3,4-tetra-〇-acetyl-D-glucobylanurone) (3,Of) was added [25% hydrogen bromide-acetic acid solution (150wt) was added, Stir at room temperature (1!L"c) for 12 hours. Pour into ice water and extract with chloroform. The chloroform extract is washed with saturated 11 water, then water, and dried with magnesium sulfate powder. The desiccant is filtered off, After removing the solvent from the filtrate under reduced pressure, silica gel column chromatography [
Silica gel (Merck, 60-1Jao mesh) a
of + elution solvent, benzene-acetone mixture (so
: l)) and purified with methyl g, 3.4-)
-Acetyl-1-bromo-1-deoxy-α-n-glucopyranurone (2,3F) was obtained.

Dry benzene solution of Sawyer Sapogenol B (1,0y) (250vtl) Calcium K&L acid (15F),
After adding silver carbonate (18f), the obtained methyl j
! , 3.4-) di-0-acetyl-1-p-U-deoxy-α-D-glucobylanuronate (2, fl f
Add a dry benzene solution (10ml) of ) and heat to reflux for 5 hours. Inorganics were filtered off, and the filtrate was evaporated under reduced pressure. The resulting anhydrous tyl acetate extract was washed with a 5% aqueous hydrochloric acid solution and then with saturated water, washed 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 & Co., Ltd., 6
0 to 1 JaO mesh) 10 (lPt elution solvent, benzene-acetone mixture (50:1 to 16:1)) to purify the penta-0 -Acetyl-monomethyl ester (1,1)t- was obtained.Dissolve K in methanol (AOD), add 10% aqueous potassium hydroxide solution (gay/), and 60°C
After stirring for 3 hours, DOWEX 50wX8 (11+ type)
Neutralize with. The resin was filtered off, and the solvent of the filtrate was distilled off under reduced pressure to obtain 3-0-β-D-glucuronopyranosylsoyasubogenol:s(o,9y). The physicochemical properties of the product thus obtained were consistent with the standard.

Claims (1)

[Claims] L Soyasapogenol 1 is reacted with a glucopyranuric acid derivative represented by the formula ■ υ (where X is a reactive group, Y is a hydroxyl group-protecting group, and 2 is a carboxyl group-protecting group). A method for producing a Soyasapogenol B derivative, which comprises subjecting the product to a protective group removal treatment to obtain 3-0-D-glucuronopyranosyl Soyasapogenol B. 2. Claim #I using a compound in which X in formula ([I) is a bromine atom, Y is an acetyl group, and 2 is a methyl group
The method described in Section 1. 3. The method according to claim 1 or 2, wherein the reaction between Soyasapogenol B and the compound of formula (II) 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 the 3-0-D-glucuronopyranosyl soyasapogenol B is 3-0-β-D-glucuronopyranosyl soyasapogenol B. The method described in.