JPH041750B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing yohimbinones.

Yohimbine is an alkaloid obtained from the West African yohembe tree and is well known as an adrenaline blocker. The total synthesis of yohimbine and related compounds has been attempted since around 1960, and great progress has been made in recent years, but there are still many steps required due to problems with stereoselectivity, and practical improvements are desired. .

The present inventor has previously achieved a total synthesis method for obtaining a yohimbane skeleton relatively easily, but further research has led to a method for stereoselectively introducing a lower alkoxycarbonyl group into the 16-position of dehydroyohimbone. We discovered that yohimbinones could be obtained easily and in good yields.

The present invention is based on the following formula A general formula characterized by reacting a dehydroyohimbone represented by with a lithium di-lower alkylamide and a lower alkyl chlorocarbonate, and reducing the resulting product. This is a method for producing yohimbinones represented by the formula (in which R represents a lower alkyl group).

The total synthesis of yohimbinones (16-methoxycarbonyl-yohimbone) has been studied by many chemists, but no one has been able to stereoselectively introduce an alkoxycarbonyl group into the 16-position of yohimbone. This is what happened. By using the method of the present invention, yohimbinone relatives can be obtained by the following formula: It can be obtained in 6 steps with a high total yield of 34 to 41% from harmalan, an indolopyridine represented by This method is revolutionary compared to the conventional method of ring-closing indoquinolitidines after introducing a nitrile group.
It is known that yohimbine, aroyohimbine, α-yohimbine, etc. can be easily obtained from yohimbinone or its relatives by the sodium borohydride reduction method. This provides an extremely excellent intermediate synthesis method.

Examples of dehydroyohimbones as starting materials include dehydroyohimbone (a) and dehydroaroyohimbone (b) of the following formulas.

Dehydroyohimbone can be obtained, for example, by reacting 19,20-dehydroyohimbanone with an organic acid. Dehydroaroyohimbone, for example
Obtained by treating 19,20-dehydroaroyohimbanone with silica gel.

Examples of the lower alkyl group for the group R of yohimbinones () include methyl, ethyl, propyl, and butyl groups.

Lithium di-lower alkylamide (LDA) includes lithium dimethylamide, lithium diethylamide, lithium dipropylamide, lithium dibutylamide, lithium methylethylamide,
Lithium propylbutyramide is used, preferably lithium diisopropylamide. LDA
can be obtained, for example, by reacting a dialkylamine with n-butyllithium. Further, as the alkyl chlorocarbonate, methyl chlorocarbonate, ethyl chlorocarbonate, propyl chlorocarbonate, butyl chlorocarbonate, etc. are used.

In practicing the invention, a compound of formula is first reacted with LDA. This reaction is preferably carried out in a solvent such as tetrahydrofuran at a low temperature of about -80°C. The reaction time is about 1 hour. Next, lower alkyl chlorocarbonate is added to this and reacted. The amount of lower alkyl chlorocarbonate used is preferably 1 to 3 moles per mole of the compound of the formula. The reaction time is preferably around 0°C, and the reaction is completed in about 1 hour. By performing these reactions in the presence of crown ether, magnesium bromide, etc., the desired product can be obtained in good yield.

The reaction product is then reduced to saturate the double bonds to obtain the product of formula. The reduction is preferably catalytic reduction in the presence of a catalyst such as platinum oxide. Reduction is carried out at room temperature and near normal pressure, and 1
Finishes in ~2 hours.

The target product can be isolated and purified using methods such as thin layer chromatography.

According to the method of the present invention, intermediates for producing yohimbine, etc., which are useful as adrenergic blockers, can be synthesized easily and in good yields.

Example 1 Production of yohimbinone 0.062 ml of diisopropylamine and n-butyllithium in 10 ml of anhydrous tetrahydrofuran at -78°C.
Add 0.190ml to produce lithium diisopropylamide. After standing for 10 minutes, a solution of 50 mg of dehydroyohimbone dissolved in 3 ml of anhydrous tetrahydrofuran was added dropwise at -78°C. After leaving at this temperature for 1 hour, 41mg of anhydrous magnesium bromide
A solution of 5 ml of anhydrous tetrahydrofuran is added and left to stand for 40 minutes to obtain magnesium enolate. Then 0.034ml of methyl chlorocarbonate
Add and leave at 0°C for 1 hour. Add water to the reaction solution and extract with methylene chloride. After washing the extract with water and drying, the solvent is distilled off. The residue was dissolved in 15 ml of anhydrous methanol, 23 mg of platinum oxide was added as a catalyst, and hydrogen gas was passed through at room temperature and pressure for 1 hour for catalytic reduction. The catalyst was separated, the liquid was concentrated, and the residue was purified by thin layer chromatography to obtain 20 mg of white crystals. Yield: 34% (yield: 68 when considering raw material recovery)
%). The obtained yohimbinone was identified by matching various spectral data with yohimbinone obtained by a known method.

Example 2 Production of arroyohimbinone 0.062 ml of diisopropylamine and n-butyllithium in 10 ml of anhydrous tetrahydrofuran at -78°C.
Add 0.190ml to produce lithium diisopropylamide. After standing for 10 minutes, a solution of 50 mg of dehydroaroyohimbone dissolved in 3 ml of anhydrous tetrahydrofuran was added dropwise at -78°C. After standing at this temperature for 1 hour, a solution of 41 mg of anhydrous magnesium bromide dissolved in 5 ml of anhydrous tetrahydrofuran was added and left standing for 40 minutes to obtain magnesium enolate. Add 0.034ml of methyl chlorocarbonate,
Leave at 0°C for 1 hour. Water was added to the reaction solution, extracted with methylene chloride, and the extract was washed with water and dried.
The solvent is distilled off. Dissolve the residue in 15 ml of anhydrous methanol, add 23 mg of platinum oxide as a catalyst, and dissolve at room temperature.
Catalytic reduction is carried out by passing hydrogen gas under normal pressure for 1.5 hours.
Then, the catalyst was separated, the liquid was concentrated, and the residue was purified by thin layer chromatography to obtain 39 mg of aroyohimbinone as a yellow oil. Yield 68.4%. The obtained arroyohimbinone was identified by the agreement of various spectral data with arroyohimbinone obtained by a known method.

Claims (1)

[Claims] Linear formula A general formula characterized by reacting a dehydroyohimbone represented by with a lithium di-lower alkylamide and a lower alkyl chlorocarbonate, and reducing the resulting product. A method for producing yohimbinones represented by the formula (wherein R represents a lower alkyl group).