JPS6111238B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides androsta-1,4-diene-3.
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This invention relates to a method for preparing estrone using 17-dione 17-acetal as a raw material.

More specifically, it describes a method for producing estrone by contacting androsta-1,4-diene-3,17-dione 17-acetal with metallic sodium and an anion derived from a polycyclic aromatic compound in tetrahydrofuran. Regarding improvements.

Estrone is an important female hormone and is extremely important as a pharmaceutical agent for treating prostatic hypertrophy and as an intermediate raw material for various other steroidal medications.

Conventionally, androstar-1,4-diene-3,17
As a method for producing estrone from -dione 17-acetal, for example, the method described in Japanese Patent Publication No. 10226/1983 is known. This is a method for obtaining estrone by contacting androsta-1,4-diene-3,17-dione 17-acetal with an anion derived from a mixture of an alkali metal and a polycyclic aromatic in an ether solvent.

However, according to these methods, the only alkali metal that can be used to produce estrone in good yield is lithium, and as far as the present inventors have investigated, sodium and potassium have extremely low yields. found.

(See Comparative Example) The method using lithium as the alkali metal is as follows:
Although it gives a good yield of estrone, it has disadvantages such as the need to add a methyllithium scavenger. In addition, lithium is expensive and has a high melting point, which causes problems in operability.If lithium could be replaced with sodium, which is inexpensive and industrially easy to handle, the industrial advantage would be enormous.

The present inventors have focused on this point, and as a result of extensive research, they have arrived at the present invention, which makes it possible to obtain a high yield of estrone using metallic sodium.

That is, the gist of the present invention is to
1,4-diene-3,17-dione 17-acetal is produced from metallic sodium and a polycyclic aromatic compound that can act as a radical anion precursor in a mixed solvent containing tetrahydrofuran and polyethers. The present invention relates to a method for producing estrone, which comprises bringing the estrone into contact with a reaction mixture of

For example, the androsta-1,4-diene-3,17-dione 17-acetal used as a raw material in the method of the present invention has the general formula [] (In the formula, R represents a lower alkyl group having 1 to 6 carbon atoms.)
17-dione 17/17-acetal and general formula [] (In the formula, R ¹ represents a lower alkylene group having 2 to 6 carbon atoms.)
Examples include 17-dione 17-alkylene acetal.

These androstar-1・4-diene-3・
As the 17-dione 17-acetal, androsta-1,4-diene-3,17-dione 17,17-dimethyl acetal, androsta-1,4-diene-3,17-dione 17,17-diethyl acetal , androsta-1,4-diene-3,17-dione 17,17-dipropyl acetal, androsta-1,4-diene-3,17-dione 17-ethylene acetal (hereinafter abbreviated as ADDK) and androsta -1,4-diene-3,17-dione 17-propylene acetal and the like.

Tetrohydrofuran is used as a component of the solvent in the method of the invention. Tetrohydrofuran has the industrial advantages of being inexpensive and easy to recover due to its low boiling point.

By adding another polyether to tetrohydrofuran, the present inventors have discovered that estrone
This made it possible to dramatically increase the yield.

Examples of the polyethers used include the following two types of compounds.

1 General formula [] R ² O (CH ₂ CH ₂ O) nR ³ [] (In the formula, R ² and R ³ are methyl group or ethyl group, n
represents an integer greater than or equal to 2. ) Polyethylene glycol dialkyl ether. In the formula, R ² and R ³ may be the same. Examples of polyethylene glycol dialkyl ethers include diclime, triglyme, tetraglyme, and pentaglyme.

2 A cyclic polyether (another name: crown ether) represented by the general formula [ ] (CH ₂ CH ₂ O) m [] (wherein, m represents an integer of 4 to 6).

Examples of cyclic polyethers include, for example, 15-
Crown-5 (m=5) and 18-crown-
6 (m=6).

Of course, two or more types of polyethers may be used in combination.

The metallic sodium used in the method of the present invention is rod-shaped,
It may be used in either bulk or granular form, and may also be used in the form of sodium dispersion. Alternatively, it may be introduced into the reactor in a molten state. Polycyclic aromatic hydrocarbons that can form radical anions with sodium metal include biphenyl, naphthalene, methylnaphthalene (2 isomers), dimethylnaphthalene (10 isomers), ethylbiphenyl (3 isomers), phenanthrene, and terphenyl. (3 isomers), acetracene, acenaphthene, fluoranthene, dibenzofuran, benzophenone, etc. Any of the isomers can be used.

Particularly good among these substances (radical anion precursors) are biphenyl, naphthalene, ethylbiphenyl, methylnaphthalenephenanthrene, and terphenyl.

Although it has been mentioned that the solvent mixture in the method of the present invention includes tetrahydrofuran and polyethers, if desired, a small amount of benzene, toluene or other specific inert solvent may be used to ensure the solubility of the reactants. There is no problem in mixing with similar organic solvents.

Examples of embodiments of the method of the present invention are as follows. Sodium and polyethers are added to tetrahydrofuran, and then a polycyclic aromatic compound is added to generate a radical anion. Androsta-1,4-diene-3,17-dione was added to the solution of radical anions prepared in this way.
Add 17-acetal at such a rate that the dark green color of the radical anion does not disappear.

The reaction temperature can be chosen over a wide range, but is usually between 30 and
The temperature is 150°C, preferably 60° to 120°C.

The reaction time is approximately 5 minutes to 2 hours for dropping androsta-1,4-diene-3,17-dione 17-acetal, and 1 minute to 2 hours for the reaction after dropping.
Approximately 20 minutes is used.

Although the proportions of the raw materials to be used vary widely, the following molar ratios can generally be used.

Androsta-1,4-diene-3,17-dione For 1 mol of 17-acetal, the polycyclic aromatic compound is not consumed in the reaction, but usually 1 to 8 mol,
Preferably it is 1.5 to 6 mol.

The amount of metallic sodium is usually 2 to 8 mol, preferably 3 to 6 mol, per 1 mol of androsta-1,4-diene-3,17-dione 17-acetal.

The amount of tetrahydrofuran is not particularly limited, but androsta-1,4-diene-3,17-dione
It can be conveniently carried out using 5 to 20 ml, preferably 6 to 15 ml, per gram of 17-acetal.

The addition ratio of polyethers to tetrahydrofuran is usually 5 to 50%, and for economic reasons it is better to add as little as possible, and in that sense it is preferably in the range of 5 to 30%.

The reaction between the androsta-1,4-diene-3,17-dione 17-acetal and the radical anion is carried out in an atmosphere of an inert gas (eg, nitrogen, argon).

In this way, androsta-1,4-diene-3,17-dione 17-acetal was prepared in a mixed solvent containing tetrahydrofuran and polyethers.
When contacted with a reaction mixture formed from metallic sodium and a polycyclic aromatic compound that can act as a radical anion precursor, estrone
The sodium salt of 17-acetal is formed.

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As the estrone 17-acetal, androsta-1,4-diene-3,17-dione 17-acetal, when the one represented by the above general formula [] is used, the general formula [] (In the formula, R has the same meaning as above.)
When used as the 1,4-diene-3,17-dione 17-acetal with the one represented by the general formula [], the general formula [] You will get what is shown in .

The sodium salt of estrone 17-acetal produced by the catalytic reaction is prepared by decomposing the radical anion and excess sodium with methanol, ethanol, water, etc., and then adding a suitable mineral acid such as hydrochloric acid or sulfuric acid or an organic acid such as paratoluenesulfone. It can be acidified with an acid to form estrone 17-acetal.

Estrone 17-acetal can be converted into 17-ketone by heating under the above-mentioned acidic conditions to produce estrone.

The present invention will be described in more detail with reference to Examples below, but the present invention is not limited to the following Examples unless it exceeds the gist thereof.

Example 1 0.87 g (37.8 mmol) of sodium and 2.5 ml of mixed xylene were heated to about 110° C. in an argon stream to melt the sodium, and then cooled. To this, 5.55 g (36 mmol) of biphenyl, tetrahydrofuran
20 ml and 5 ml of tetraglyme (tetraethylene glycol dimethyl ether) were added and heated under reflux for 10 minutes. To prevent the dark green color from disappearing,
ADDK1.971g (6mmol) of tetrahydrofuran
10ml solution was added dropwise over 32 minutes. After heating under reflux for an additional 10 minutes, the mixture was cooled, 20 ml of water was gradually added dropwise, and then 8 ml of concentrated hydrochloric acid was added. This was heated under reflux for 1 hour, concentrated under reduced pressure, and mixed with 20 ml of toluene and 40 ml of water.
ml was added and stirred at 80°C for 1 hour. After standing overnight at room temperature, the crystals were collected by filtration, washed with toluene and water, and dried to obtain estrone. After extracting the toluene layer with a 5% aqueous potassium hydroxide solution, more estrone could be recovered by acidifying the toluene layer. Total estrone yield
1.367g (5.06mmol) Yield 84.3mol% Example 2 When the radical anion precursor was changed to α-methylnaphthalene 5.12g (36mmol) and the rest was carried out in the same manner as in Example 1, estrone yield was 78.3mol%. Obtained with.

Example 3 4.97g of naphthalene as radical anion precursor
(36 mmol) and carrying out the same procedure as in Example 1 except that estrone was obtained in a yield of 79.5 mol%.

Example 4 The same procedure as in Example 1 was carried out except that the polyether added was changed to 5 ml of pentaglime (pentaethylene glycol dimethyl ether), and estrone was obtained in a yield of 78.5 mol%.

Example 5 Sodium 0.92g (40mmol), mixed xylene
2.5 ml, 3 drops of oleic acid in an argon stream at approximately 110℃
A sodium dispersion was prepared by heating the solution to a temperature of 50% and stirring vigorously. After cooling, α-methylnaphthalene 5.12 g (36 mmol), tetrahydrofuran 20
ml and 5 ml of tetraglyme were added and heated under reflux for 10 minutes. To prevent the dark green color from disappearing, add ADDK1・
A solution of 971 g (6 mmol) in 10 ml of tetrahydrofuran was added dropwise over 35 minutes. After heating under reflux for an additional 10 minutes, the mixture was cooled and subjected to the same post-treatment as in Example 1 to obtain 1.329 g (4.92 mmol) of estrone. Yield 81.9 mol% Example 6 Biphenyl 5.55 as radical anion precursor
g (36 mmol), and otherwise carried out in the same manner as in Example 5 to obtain estrone in a yield of 78.4 mol%.

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Example 7 Biphenyl 1.85 as radical anion precursor
g (12 mmol), the polyether to be added was changed to 5 ml of triglyme (triethylene glycol dimethyl ether), and otherwise the same procedure as in Example 5 was conducted to obtain estrone in a yield of 77.6 mol%.

Example 8 Sodium 0.88g (38mmol), xylene 2.5ml
was heated to about 110°C in an argon stream to melt the sodium, and then cooled. To this, 20 ml of tetrahydrofuran, 15-crown-55.29 (24 mmol),
When 5.55 g (36 mmol) of biphenyl was added and heated under reflux, the reaction mixture turned dark green. To prevent the dark green color from disappearing, a solution of 1.971 g (6 mmol) of ADDK in 10 ml of tetrahydrofuran was added dropwise over a period of 40 minutes. After further heating under reflux for 10 minutes, cooling, and performing the same post-treatment as in Example 1, estrone
1.291g was obtained. Yield 79.6 mol% Example 9 Sodium 0.92 in a solution of 20 ml of tetrahydrofuran and 5 ml of diethylene glycol dimethyl ether
g (40 mmol) and biphenyl 5.55 g (36 mmol) were added and heated under reflux in an argon stream, and the reaction mixture turned dark green. While heating under reflux, a solution of 1.971 g (6 mmol) of ADDK in 10 ml of tetrahydrofuran was added dropwise over 50 minutes to prevent the dark green color from disappearing. After the dropwise addition was completed, the mixture was further heated under reflux for 10 minutes, cooled, and the remaining sodium lumps were removed. After that, the same post-treatment as in Example 1 was carried out to obtain 1.396 g of estrone.
Yield: 86.1% Comparative Example 1 2.56 g of α-methylnaphthalene (18
The procedure was repeated in the same manner as in Example 5 except that estrone was obtained in a yield of 37 mol%.

Comparative Example 2 Estrone was obtained in a yield of 40% in the same manner as in Example 5, except that 5.55 g (36 mmol) of biphenyl was used as the radical anion precursor without adding polyethers.

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Claims (1)

[Claims] 1. Androsta-1,4-diene-3,17-dione 17-acetal acts as a radical anion precursor with metallic sodium in a mixed solvent containing tetrahydrofuran and polyethers. 1. A method for producing estrone, which comprises contacting the estrone with a reaction mixture produced from a polycyclic aromatic compound capable of producing estrone. 2. In the method for producing estrone according to claim 1, androsta-1,4-diene-3,17-dione 17-acetal has the general formula [] (In the formula, R represents a lower alkyl group having 1 to 6 carbon atoms.) 3. In the method for producing estrone according to claim 1, androsta-1,4-diene-3,17-dione 17-acetal has the general formula [] (In the formula, R ¹ represents a lower alkylene group having 2 to 6 carbon atoms.) 4. In the method for producing estrone according to any one of claims 1 to 3, the polyether has the general formula [] R ² O (CH ₂ CH ₂ O) nR ³ [] (in the formula , R ² and R ³ are methyl or ethyl groups,
n represents an integer of 2 or more. ) A method characterized in that the polyethylene glycol dialkyl ether is a polyethylene glycol dialkyl ether represented by 5. In the method for producing estrone according to any one of claims 1 to 3, the polyethers have the general formula [] (CH ₂ CH ₂ O) m [] (where m is 4 to (representing an integer of 6).