JPH04235194A - Coal enrichment reaction - Google Patents

Abstract

PURPOSE:To simply carry out carbon increasing reaction of side chain part of steroid skeleton in high yield by reacting a specific compound derived from cholic acid with an acrylic ester. CONSTITUTION:A compound shown by formula I (R1 is acyl, methoxymethyl, alkyl, alkyl, silyl, methoxyethoxymethyl, H, ethoxyethyl or tetrahydropyranyl) is treated with one reagent selected from an acrylic ester compound, a Grignard reagent (e.g. methylmagnesium iodide), an alkyllithium and a Wittig reagent (e.g. methylenetriphenylphosphorane) to give a compound shown by formula II {R2 is group shown by formula III [R3 is alkyl, aryl, group shown by formula IV (R4 is formyl or alkoxycarbonyl)] or CH=CH-R5 (R5 is H, alkyl or alkoxycarbonyl)}.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention is an important reaction for synthesizing synthetic intermediates for synthesizing various bile alcohols having physiological activities useful as choleretic and other pharmaceuticals. This is about a certain carbonization reaction.

[Prior Art and Problems] It is well known that animal secretions have various medicinal uses. For example, primary bile acids such as cholic acid and deoxycholic acid have been shown to play an important role in promoting the absorption of fat-soluble substances, regulating cholesterol biosynthesis, and bile production and secretion. When these compounds having a steroid skeleton (hereinafter referred to as bile alcohols) are to be used as medicines, they need to be produced at low cost and in large quantities, and therefore it is necessary to chemically synthesize bile alcohols in large quantities. Numerous studies have been conducted to date on the synthesis of bile alcohols, and reports have been made from all angles. Particularly in the series of synthesis processes for bile alcohols, the carbon-enriching reaction of the side chain portion of the steroid skeleton is important, and there has been a desire to develop a simpler carbon-enriching reaction with higher yields.

Furthermore, in the conventional synthesis of cholic acid derivatives and various bile alcohols, the solubility of the reaction intermediate itself is low;
Furthermore, since the usable protecting groups are limited, the synthesis method is limited and the yield is poor.

[Means for Solving the Problems] As a result of intensive research by the present inventors in search of a higher-yield and simpler carbon-enriching reaction of the side chain portion of the steroid skeleton,
The present invention was completed by discovering that a higher yield and simpler carbonization reaction can be carried out by using an acrylic acid ester compound, a Grignard reagent, an alkyl lithium, or a Wittig reagent.

That is, the present invention provides the following formula I (in formula I, R1 represents an acyl group, a methoxymethyl group, an alkyl group, a silyl group, a methoxyethoxymethyl group, a hydrogen atom, an ethoxyethyl group, or a tetrahydropyranyl group). The represented compound is reacted with one reagent selected from an acrylic acid ester compound, a Grignard reagent, an alkyl lithium, and a Wittig reagent to form the following formula II [In formula II, R2 is the following formula III (In formula III, R3 is , an alkyl group, an aryl group, or the following formula V (in the formula V, R4 represents a formyl group or an alkoxycarbonyl group) or the following formula IV-CH=
CH-R5(IV) (In formula IV, R5 represents an alkyl group, a hydrogen atom, or an alkoxycarbonyl group.) This is a carbon enrichment reaction (hereinafter referred to as the method of the present invention) characterized by obtaining a compound represented by the following.

The present invention will be explained in detail below.

First, the compound of formula I can be obtained by, for example, using cholic acid as a raw material, protecting the hydroxyl group with a THP (tetrahydropyranyl) group, reducing the methyl ester to hydroxymethyl, and then oxidizing it. In addition to the THP group, protecting groups such as methoxymethyl group, methoxyethoxymethyl group, and ethoxyethyl group can be used to protect the hydroxyl group, thereby increasing the solubility of the reaction intermediate itself.

A specific example of the preparation of the compound of formula I is as follows.

Specific example 1 R. B. Methy obtained by the method of Moffett et al.
l-3α,7α,12α-Trihydroxy-5β
-cholan-24-oate (10.0 g; 23.7 mM) and a catalytic amount of p-Toluene sul
fonic acid mono-hydrate (4
3 mg) in 10 ml of methylene chloride, 3,4-Dihydro 2H-Pyran was added while stirring under water cooling.
(41.5ml, 45.05g; 535mM) in methylene chloride (100ml) is added dropwise over 30 minutes.

After the dropwise addition, the mixture was stirred at room temperature for 5 hours, and the reaction solution was diluted with 400 ml of diethyl ether. The extract is washed with 150 ml of 5% aqueous sodium bicarbonate solution, 100 ml of purified water, and 100 ml of saturated saline, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the product was purified by silica gel column chromatography using n-hexane-ethyl acetate (3:1) as an eluent. Product, Methyl 3α,7α,12α-Tritet
rahydropyranoxy-5β-cholan-24-oate is a pale yellow oily substance.

(Yield 15.03 g, yield 94.13%) Next, lithium aluminum hydride (6.
0g; 158mM) of anhydrous tetrahydrofuran (250
ml) of the compound Methy.
l 3α, 7α, 12α-Tritetrahydro
pyranoxy-5β-cholan-24-oate (16.2g; 2
A solution of 3.3 mM) in anhydrous tetrahydrofuran (50 ml) was added dropwise over 30 minutes. After the reaction solution is gradually returned to room temperature, it is heated under reflux for 5 hours.

After cooling, the reaction solution was carefully poured into 300 ml of 0.7N hydrochloric acid, and the product was extracted with 600 ml of ethyl acetate. The obtained organic layer is washed with 100 ml of 1N hydrochloric acid, 100 ml of saturated aqueous sodium bicarbonate solution, 100 ml of purified water, and 100 ml of saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography using n-hexane-ethyl acetate (4:1) as an eluent. product, 3
Obtained as an α,7α,12α-based oil.

A solution of 100 ml of anhydrous methylene chloride containing ol (6.47 g; 10.0 mmol) and pyridinium dichloromate (5.20 g; 15 mmol) is stirred at room temperature for 12 hours. The reaction solution was diluted with 50 ml of methylene chloride, and then filtered with suction. Concentrate the filter under reduced pressure at 25°C. The residue was purified by silica gel column chromatography using n-hexane-ethyl acetate (7:3) as an eluent to obtain a colorless oil.Furthermore, the compound of formula I was obtained by changing the substituents as appropriate depending on the target compound. Obtainable.

Next, specific examples of the acrylic ester compound used in the present invention include methyl acrylate, ethyl acrylate, and isopropyl acrylate. Diazabicyclooctane (DABCO) can be used as a solvent during the reaction, and the reaction is carried out for 1 to 4 weeks at a temperature of 0° C. to room temperature.

Specific examples of Grignard reagents include methylmagnesium iodide, ethylmagnesium bromide, propylmagnesium bromide, phenylmagnesium bromide, and the like. Ether, tetrahydrofuran, etc. can be used as a solvent during the reaction, and the reaction is carried out at a temperature below room temperature for 0.5 to 30 hours.

Specific examples of alkyllithium include methyllithium,
Phenyllithium, ethyllithium, butyllithium,
Examples include pentyllithium, cyclohexyllithium, 2-lithium-3,3-diethoxypropene, and the like. Ether, tetrahydrofuran, etc. can be used as a solvent during the reaction, and 0.5 to 5
React for 0 hours.

Specific examples of the Wittig reagent include methylenetriphenylphosphorane, ethylidenetriphenylphosphorane, propylidenetriphenylphosphorane, methoxycarbonylmethylenetriphenylphosphorane, ethoxycarbonylmethylenetriphenylphosphorane, and the like. As a solvent for the reaction, ether, tetrahydrofuran, benzene, toluene, alcohols, etc. can be used, and the
．． Allow to react for 5 to 30 hours.

The compounds obtained as described above are very important intermediates in the synthesis of various bile alcohols that have physiological activities useful as pharmaceuticals.
It can be purified using purification means such as column chromatography using silica gel or the like.

[Effects of the Invention] According to the present invention, a series of synthetic processes for bile alcohols useful as pharmaceuticals, particularly the carbon enrichment reaction of the side chain portion of the steroid skeleton, can be carried out in a higher yield and more easily. In addition, from the viewpoint of drug development, it is effective in promoting development. Furthermore, the compound obtained by the method of the present invention has good solubility during reaction, which is a great advantage in providing cholic acid derivatives having physiological activity as pharmaceuticals at low cost.

The present invention will be explained in more detail with reference to Examples below.
The present invention is not limited to this in any way.

Example 1 3α,7α,12α- (2.0mM) obtained in Example 1 was mixed with methyl acrylate (1.86g; 20
．． After dissolving the mixture to 0mM), the reaction vessel was tightly closed with a glass stopper, and the mixture was stirred at room temperature for 3 weeks while shielding from light. The reaction solution is washed with 150 ml of ethyl acetate and 150 ml of saturated brine, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was diluted with n-hexane and ethyl acetate (5:2).
) was purified by silica gel column chromatography using an eluent of
ethyl 3α,7α,12α-Example 2 Under conditions of -70°C, 2-Bromo-3,3-die
To a solution of thoxy-propene (4.2g; 20mM) in anhydrous tetrahydrofuran (160ml) was carefully added dropwise 22ml of a 1M solution of n-butyllithium (22mM), and the mixture was stirred for 1 hour.

Add 3α, 7α, 12α-al obtained in Example 1 to this solution (
160 ml of anhydrous tetrahydrofuran solution containing 12.9 g (20 mM) was added and reacted. After the reaction, the temperature was returned to room temperature, the mixture was carefully poured into a 0.25 N sulfuric acid aqueous solution, and further extracted with 200 ml of ethyl acetate to obtain 3α, 7α, 12α-
13.8g (98.5%) was obtained.

The compound represented by the formula (II) obtained by the present invention is optionally deprotected, hydroborated or epoxidized, and then reduced to produce 3α, 7α, 12α, 24, 26, It can be converted to 27-hexahydroxy-5β-cholestane. Hydroboration and reduction can be carried out in the same manner as described above, and epoxidation can be carried out by conventional methods of treatment with peracids.

A specific example of a method for synthesizing a triol form from the compound represented by formula (II) is shown below as a reference example.

Reference Example 1 13.8 g (19
．． 8mM) was dissolved in methanol and activated Dowe
x50W-X8 and stirred for 24 hours to perform deprotection. Next, Dowex 50W-X8 was removed, 200 ml of tetrahydrofuran was added to the residue after removing the solvent, and 200 ml of 1M borine-tetrahydrofuran solution (2
00mM) was added dropwise and stirred for 6 hours. After the reaction is complete,
Add 60 ml of purified water, then add 40 ml of 3M sodium hydroxide aqueous solution and stir, then add 4 ml of 30% hydrogen peroxide solution.
8 ml was added and further reacted. After the reaction, the product was extracted with ethyl acetate-n-butanol (1:1) and purified by silica gel column chromatography using the lower layer of chloroform-methanol and water (60:20:8) as the solvent. , 5.6g (60.4%) was obtained.

Reference Example 2 m-chloroperbenzoic acid 1.0 dissolved in methylene chloride was added to the 3α, 7α, 12α-solution obtained in Example 1.
9g (5mM) was added slowly. Next, the reaction solution was poured into a 5% sodium hydrogen carbonate solution, and a product was obtained from the organic solvent layer. This product was dissolved in 20 ml of tetrahydrofuran, and a tetrahydrofuran suspension containing 935 mg (25 mM) of lithium aluminum hydride was added dropwise to the solution under ice-cooling under a nitrogen stream. After that, heating under reflux for 5 hours, 0.7
Pour into normal hydrochloric acid solution, extract the product with ethyl acetate, and add to activated Dowex 50W-
X8, then chloroform-methanol-water (
The lower layer (60:20:5) was purified by silica gel column chromatography using a solvent, and 1.68 g
(71.8%).

Claims (1)

[Claims] The following formula I (In formula I, R1 represents an acyl group, a methoxymethyl group, an alkyl group, a silyl group, a methoxyethoxymethyl group, a hydrogen atom, an ethoxyethyl group, or a tetrahydropyranyl group.) The compound represented by is reacted with one reagent selected from an acrylic acid ester compound, a Grignard reagent, an alkyl lithium, and a Wittig reagent to form the following formula II [In formula II, R2 is the following formula III (In formula III, R3 represents an alkyl group, an aryl group, or the following formula V (in formula V, R4 represents a formyl group or an alkoxycarbonyl group) or the following formula IV-CH=
CH-R5(IV) (In formula IV, R5 represents an alkyl group, a hydrogen atom, or an alkoxycarbonyl group.) ] A carbon enrichment reaction characterized by obtaining a compound represented by: