JPH07116219B2 - Method for producing compound having steroid skeleton - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing a compound having a steroid skeleton, and more specifically, it is useful as an intermediate for producing various hormones and vitamins important as pharmaceuticals. And a method for producing a compound having a steroid skeleton.

(Prior Art) As a method for synthesizing a compound having a steroid skeleton, a method utilizing an intramolecular Diels-Alder reaction is generally known (for example, Journal of American Chemical Society, Volume 98). , 3387 pages, 1976).

However, according to this method, at most two rings can be formed at the same time, and the steroid compound to be produced often has a special structure, so that it cannot always be said to be a versatile intermediate.

(Problems to be Solved by the Invention) As a result of intensive research to solve the above-mentioned drawbacks, the present inventors have found that
In recent years, we have found that it is possible to form three rings at the same time by using an intramolecular Diels-Alder reaction inside a macrocyclic compound that has become easily synthesizable. Based on this, the present invention has been completed.

(Means for Solving Problems) Thus, according to the present invention, a steroid precursor having a skeleton represented by the following structural formula [I] is heat-treated to cause an intramolecular Diels-Alder reaction. A method for producing a compound having a steroid skeleton represented by structural formula [II] is provided.

(In the formula [I], the olefin bonded to the hydrogen atom of the wavy line () is an E-form or Z-form, and the other olefins are the E-form. Alternatively, the steroid precursor used in the present invention has a skeleton represented by the structural formula [I]. The hydrogen at the 5-position of the steroid skeleton of the formula [II] produced when the olefin bonded to the hydrogen atom in the formula [I] in the formula is in the E form is in the β form, and in the Z form is in the α form. However, normally, a steroid compound used as a drug has an olefin at the 4-position and a hydrogen at the 5-position disappears, so that it does not matter which one is produced. Therefore, this olefin is
It may be a body or a Z body, or a mixture of E and Z.

On the other hand, the structures of the other two olefins in the formula [I] are important for determining the steric structure at the 8,9,10 position of the steroid skeleton of the formula [II] to be formed, and if not the E form. I won't.

In the present invention, the steroid precursor of the structural formula [I] may have a substituent as long as it does not affect the intramolecular Diels-Alder reaction. For example,
Examples thereof include those having R, R ′ and R ″ as shown by the following structural formula [III].

(In the formula, Represents a single bond or a double bond. ) The structure of R basically has no influence on the intramolecular Diels-Alder reaction in the present invention, and thus is not particularly limited, and the steric configuration may be either an α-form or a β-form. Specific examples of R include an alkyl group, an alkenyl group, an alkynyl group, a hydroxyl group, and an oxygen atom.

The structures of R ′ and R ″ are not particularly limited because the intramolecular Diels-Alder reaction shown in the present invention occurs in the macrocyclic structure having a fixed conformation. Specific examples of R ′ and R ″ Examples thereof include a hydroxyl group, an oxygen atom, a sulfur atom and a nitrogen atom.

The steroid precursor, which is a macrocycle represented by the structural formula [I], can be prepared, for example, by a method of forming a macrocycle with a protected anion of cyanohydrin, which has been shown to be very effective in recent years (eg, tetrahedron letters, 22). roll,
1359 pages, 1981; Tetrahedron Letters, 24, 3
485 pages, 1983; Tetrahedron Letters, Vol. 22, 13
(Page 63, 1981) can be easily synthesized. For example, in the case of a steroid skeleton having an oxygen atom, it can be synthesized by the route shown below.

Cyclopentenone compounds that can be easily synthesized by known methods
A vinyl copper compound 2 is Michael-added to 1, then methylated and treated with an acid to obtain a compound 3 . Then, the phenyl sulfide is oxidatively eliminated, and a terminal olefin is introduced to obtain a compound 4, and then thionyl chloride is converted to a dienyl chloride 5 . After removing the ketal of 5, the ketone and aldehyde are simultaneously protected into cyanohydrin 6 by a conventional method, cyclized with lithium hexamethyldisilazide, etc., and treated with an acid base to obtain a macrocyclic compound [I]. it can.

The olefin bonded to the hydrogen atom of the wavy line is Z-form or E-form. The Z-form olefin can be obtained by synthesizing according to the above route. In the case of E-form olefin, it can be obtained by reacting compound 3 with p-toluenesulfenyl chloride and then treating with trimethylphosphite.

The intramolecular Diels-Alder reaction shown in the present invention is
Although the heating proceeds in good yields only by heating, it is preferable to use a solvent. The solvent is usually benzene,
Aromatic hydrocarbons such as toluene and xylene, ethers such as tetradrofuran and dioxane, alcohols such as ethanol and butanol, and aprotic polar solvents such as dimethylformamide and dimethylsulfoxide are used. The reaction temperature is 0 to 250 ° C, preferably 100 to 200 ° C.

Further, if a polymerization inhibitor such as methylene blue is added as necessary to carry out the reaction, the reaction time is shortened.

The reaction product can be easily isolated by usual organic chemistry techniques.

The compound having a steroid skeleton thus obtained is useful as an intermediate in the production of various hormones such as testosterone, ethisterone, hydrocortisone and vitamins such as vitamin D.

(Effect of the invention) Thus, according to the present invention, since three rings can be simultaneously formed, a compound having a steroid skeleton can be obtained by a simple method as compared with the prior art.

(Example) Hereinafter, the present invention will be described more specifically with reference to Examples.

Example 1 0.31 mmol and 0.001 mmol of methylene blue of a steroid precursor represented by the following structural formula [I] (however, the olefin bonded to the hydrogen atom in the wavy line is the E form) were taken in a sealed tube, and 5 ml of xylene was taken. It was dissolved in. The solution was heated at 180 ° C for 1 h. After cooling, xylene was distilled off, and the obtained oily substance was purified by column chromatography.
The steroid compound represented by [I] was obtained in a yield of 84%. The physical property values are shown.

mp.149-152 ° C (MeOH recrystallization) IR. (neat) 2930,1735,1705,1380,1220,1175,1100,105
_{^{5,1020cm -1 1 H NMR (CDCl 3}} , 90MHz) 0.95 (s, 3H) 0.99 (s, 3H) 1.0~2.7 (m, 18H) 5.5~5.7 (m, 2H) Reference Example 1 (Starting Material Synthesis) ( 1) 3.8 mmol of vinylcopper compound 2 was cooled to -78 ° C in 20 ml of well dried ether. For this solution,
Cyclopentenone compound 1 1.90 mmol of dry ether 10 ml
The solution dissolved in was added dropwise over 30 minutes. After stirring for 2 hours, 3 ml of hexamethylphosphoric triamide and 0.5 ml of methyl iodide were added at -30 ° C, and the mixture was further stirred for 30 minutes. The reaction mixture was quenched with an aqueous solution of ammonium chloride, extracted with ether, and the solvent was distilled off to obtain an oily substance.

This oily substance was dissolved in 50 ml of tetrahydrofuran, 5 ml of 0.1N hydrochloric acid was added, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was quenched with an aqueous solution of sodium hydrogen carbonate, extracted with ether, the solvent was distilled off, and the residue was purified by column chromatography to obtain Compound 3 in a yield of 64%.

(2) Compound 3 (0.61 mmol) was dissolved in ether (5 ml), and triethylamine (1.83 mmol) was added. This mixture was cooled to 0 ° C. and p-toluenesulfenyl chloride 0.92 mmol
Was dripped. Thereafter, the mixture was stirred at room temperature for 2 hours, quenched with water, extracted with ether, and the solvent was distilled off to obtain an oily substance.

This oily substance was dissolved in 5 ml of methanol, and 9.15 mmol of trimethylphosphite was added at room temperature, followed by stirring for 5 hours.
The reaction mixture was quenched with water, extracted with ether, the solvent was distilled off, and the residue was purified by column chromatography to obtain a compound 3 ′ in which the olefin bonded to the hydrogen atom on the wavy line is the E form in a yield of 85%. Got with.

(3) Compound 3 ′ 13.08 mmol was dissolved in acetic anhydride 39.24 mmol and pyridine 10 ml, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with 1N hydrochloric acid, extracted with ether, and the solvent was evaporated to give an oil.

This oily substance was dissolved in a mixed liquid of 130 ml of methanol and 25 ml of water, then 42.1 mmol of sodium periodate was added at room temperature, and the mixture was stirred for 5 hours. The reaction mixture was quenched with water, extracted with ether and the solvent was evaporated to give an oil.

This oily substance was dissolved in 90 ml of xylene to give 25.6 mmol of pyridine.
After adding, the mixture was heated and stirred at 160 ° C. for 5 hours in a sealed tube.
After cooling, the solvent was distilled off to obtain an oily substance.

This oil was dissolved in 30 ml of methanol and potassium carbonate 2
1.7 mmol was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with an aqueous solution of ammonium chloride, extracted with ether, the solvent was distilled off, and the residue was purified by column chromatography to obtain compound 4 in a yield of 61%.

(4) Compound 4 (0.29 mmol) was dissolved in pyridine (1.14 mmol) and methylene chloride (3 ml). Thionyl chloride 0.57m in this solution
mol was added dropwise at -78 ° C. After stirring for 5 minutes, the reaction was quenched with dilute hydrochloric acid, extracted with ether, the solvent was distilled off and the residue was purified by column chromatography to obtain the compound in a yield of 83%.

(5) Compound 5 (0.14 mmol) was dissolved in tetrahydrofuran (2 ml), and 3N hydrochloric acid (1 ml) was added dropwise at room temperature. After stirring for 5 hours, the reaction mixture was quenched with an aqueous sodium hydrogen carbonate solution, extracted with ether, the solvent was distilled off, and the residue was purified by column chromatography to obtain an aldehyde in a yield of 73%. It was

4.27 mmol of this aldehyde compound was added to trimethylsilyl cyanide
The mixture was mixed with 4 ml, a catalytic amount of potassium cyanide-18-crown-6 complex was added, and the mixture was stirred at 0 ° C for 1 hr. The reaction mixture was quenched with water, extracted with ether, and the solvent was evaporated to give an oily substance.

This oily substance was dissolved in 30 ml of tetrahydrofuran and 3N hydrochloric acid was added.
10 ml was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water, extracted with ether, and the solvent was evaporated to give an oily substance.

This oily substance was dissolved in 30 ml of benzene, and after adding a catalytic amount of p-toluenesulfonic acid, 20.9 mmol of ethyl vinyl ether was added dropwise at 0 ° C. The reaction mixture was stirred for 30 minutes, then quenched with an aqueous sodium hydrogen carbonate solution, extracted with ether, the solvent was distilled off, and the residue was purified by column chromatography to obtain Compound 6 in a yield of 90%.

(6) Disilazane 2.149 mmol, dioxane 10 ml, and
n-Butyllithium 1.68M solution, 1.842mmol adjusted to a dioxane solution of lithium disilazide, 80 ℃
Then, a solution of 0.307 mmol of Compound 6 in 10 ml of dioxane was added dropwise over 50 minutes. The reaction mixture was stirred at 80 ° C. for a further 30 minutes, then cooled and quenched with aqueous ammonium chloride solution.
This mixture was extracted with ether and the solvent was distilled off to obtain an oily substance.

This oily substance was dissolved in 5 ml of tetrahydrofuran, and 3N hydrochloric acid 2
ml was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with aqueous sodium hydrogen carbonate solution and extracted with ether. Next, 2% sodium hydroxide was added to this ether solution, and the mixture was stirred for 5 minutes. The ether layer was separated, washed with water, and the solvent was evaporated to give an oily substance. This oily substance was purified by column chromatography to obtain a compound [I] (however, the olefin bonded to the hydrogen atom indicated by the wavy line is the E form).

Claims (1)

[Claims] 1. A steroid precursor having a skeleton represented by the following structural formula [I] is heat-treated to produce an intramolecular Diels
The following structural formula [I
[I] A method for producing a compound having a steroid skeleton. (In the formula [I], the olefin bonded to the hydrogen atom of the wavy line () is an E-form or Z-form, and the other olefins are the E-form. Or β body.)