JPH0468296B2 - - Google Patents

Description

Detailed Description of the Invention (Industrial Application Field) The present invention relates to two types of dienes that are glycyrrhetinic acid reduction-modified compounds, namely, olean-9(11),12-diene-3β,30-diol (Homoannular diene )
(hereinafter abbreviated as diene[]), and olean-11,13(18)-diene-3β,30-diol (hereinafter referred to as diene[])
(abbreviated as )).

(Prior art) The diene [] and [] of the present application (in the present application,
These two compounds are collectively referred to as glycyrrhetinic acid reduction-modified compounds) and are known compounds. The present inventors have now discovered that these compounds exhibit excellent anti-allergic effects, and are expected to be useful as anti-allergic agents.

Traditionally, both dienes have been described as “Zh, Org, Klim.3
(1), 64-71 (1967). This method uses 18βH-glycyrrhetinic acid as a starting material, and reduces both of them with methyl ester. Diene [ ] is obtained from the starting material and diene [ ] from the latter.

(Problems to be Solved by the Present Invention) However, the above manufacturing method has the following problems. That is, the α-retinoic acid used in this method is obtained by converting β-retinoic acid by treating it with an acid or alkali, but this reaction is complicated and the yield of the target product is low. Due to these reasons, α-retinoic acid is difficult to obtain today.

Therefore, in order to produce drugs such as antiallergic agents containing both dienes as active ingredients, it has been desired to develop an efficient and practical production method.

The present invention has been made in view of the above circumstances, and it is an object of the present invention to provide a new production method that leads to the target compound in one step from 18βH-glycyrrhetinic acid, which is usually easily available on the market.

(Structure of the invention) The compound of the present application is represented by the following structural formula.

The present inventors disclosed a new method for producing olean-12-ene-3β,30-diol in JP-A-57-73000. When a reaction solution containing a triol (olean-12-ene-3β,11ξ,30-triol) obtained by reduction with sodium bis(2-methoxyethoxy)aluminum, etc. is acidified with hydrochloric acid,
Diene [] and [] which are the target compounds of the present application
It has become clear that approximately the same amount of can be obtained at the same time.

This reaction process is shown by a chemical reaction formula.

To explain the above reaction in more detail, 18βH−
Glycyrrhetinic acid is dissolved in an inactive organic solvent that does not participate in this reaction, such as toluene, dioxane, or tetrahydrofuran, preferably tetrahydrofuran. This solution is added dropwise to a sodium bis(2-methoxyethoxy)aluminum hydride solution under a stream of _N2 gas, and the solution is reduced under reflux for 1 hour at the boiling point of the solvent. Next, water or alcohol and dilute hydrochloric acid are added to the reaction solution to decompose the excess reducing agent and aluminum complex and form a precipitate. After filtering out the precipitate,
A triol solution is obtained.

Add dilute hydrochloric acid to the triol solution obtained here.
Adjust the pH to 1 and perform heat treatment.

The heat treatment can be carried out at a temperature ranging from room temperature to the boiling point of the solvent.

Triol becomes diene [], []. Add chloroform to this solution for extraction, wash with water, and dehydrate. The dehydrating agent is separated and chloroform is distilled off to obtain a mixture of dienes [] and [].

The obtained compound is subjected to silica gel column chromatography, for example, and hexane:ethyl acetate:isopropyl alcohol (69:
30:1) etc., white crystals of diene[]diene[] are obtained.

According to the present method, there is no need to use α-retinoic acid, which is difficult to obtain, unlike the conventional method, and the step of methylating retinoic acid is also omitted, and there is no need to use lithium aluminum hydride, which is troublesome to handle. There is no.

That is, by using hydrogenated sodium bis(2-methoxyethoxy)aluminum, which is easy to treat 18βH-glycyrrhetinic acid as it is, both dienes can be easily obtained in one step. Therefore, its effectiveness as an industrial production method is highly evaluated.

In addition, as a reducing agent, the above-mentioned hydrogenated bis(2-
In addition to sodium (methoxyethoxy)aluminum, lithium aluminum hydride, diisobutylaluminum hydride, and the like can also be used.

Manufacturing examples of the present invention are listed below.

[Example] Production of diene [ ] and [ Sodium bis(2-methoxyethoxy)aluminum hydride was placed in a three-necked flask equipped with a sealed stirrer, a reflux condenser with a drying tube, and a dropping funnel with a side tube. Add 30 ml of 70% toluene solution and 50 ml of anhydrous tetrahydrofuran, and reflux on an oil bath. A solution of 9.4 g of 18βH-glycyrrhetinic acid dissolved in 50 ml of anhydrous tetrahydrofuran is added dropwise through a dropping funnel with a side tube while aerating N ₂ gas.
After dropping, the mixture was refluxed for 1 hour and allowed to cool.

After the reaction, methanol and dilute hydrochloric acid are added to adjust the pH to 3, and the excess reducing agent and aluminum complex are decomposed while foaming. Filter the precipitate, add dilute hydrochloric acid to the filtrate to adjust the pH to 1, and heat at 60°C for 1 hour.

After cooling, extract three times with 100 ml of chloroform, wash the combined chloroform solution with water, and dehydrate with anhydrous sodium sulfate.

The dehydrating agent is separated and the solution is concentrated to dryness to obtain 3.5 g of white crystalline powders of diene [] and [], respectively.

The physical properties of the diene are as follows.

Diene [] Melting point: 230-232°C [α] ²³ _D +271°C (dioxane) ¹³ Cnmr spectrum (d ₅ -pyridine) δppm (TMS); 154.5 (s), 115.7 (d, C-11) 78.6 (d, C-3), 65.6 (t, C-30) ¹ Hnmr spectrum ( _CDCl3 ) δppm (TMS); 5.60 (d, d, 2H, _J1 = 4Hz, _J2 = 8Hz, C-
11-H, C-12-H) 3.30 (t, 1H, J = 7Hz, C-3H) 3.66 ((d, d, 2H, J ₁ = 9Hz, J ₂ = 14Hz, C-
30−H ₂ ) Mass spectrum (m/e) M ⁺ Actual value Theoretical value 440.3663 440.3654 C ₃₀ H ₄₈ O ₂ Diene [] Melting point: 267-271℃ [α] ²³ _D +61.5 (dioxane) ¹³ Cnmr spectrum ( d ₅ -pyridine) δppm (TMS); 137.8 (s), 134.2 (d, C-11) 126.0 (d,), 125.9 (d) 78.1 (d, C-30), 73.4 (t, C-30) ¹ Hnmr spectrum ( _CDCl3 ) δppm (TMS); 6.42 (d, d, 1H, _J1 = 4Hz, _J2 = 10Hz, C-
11-H) 5.60 (br, d, 1H, J=10Hz, C-12-H) 3.30 ((m, 1H, C-3-H) Mass spectrum (m/e) M ⁺ Actual value Theoretical value 440.3658 440.3554 _{C30H48O2 _ _}

Claims (1)

[Claims] 1 Glycyrrhetinic acid (3β-hydroxy-11-
The triol (olean-12-ene-3β, 11ξ, 30-triol) was obtained by reducing oxoolean-12-ene-30-oitsucic acid) in an inert solvent, and then the reaction solution was directly acidified with hydrochloric acid. By doing so, Olean-9(11), 12
-Diene-3β,30-diol, and oleane-
1. A method for producing a glycyrrhetinic acid reduction-modified compound, which comprises simultaneously producing 11,13(18)-diene-3β,30-diol and then separating and purifying them. 2 Tetrahydrofuran as an inert solvent and hydrogenated bis(2-methoxyethoxy) as a reducing agent.
A method for producing a glycyrrhetinic acid reduction-modified compound according to claim 1, in which sodium aluminum is used.