JPS5840560B2 - 3-(17 beta-hydroxyandrost-4-en-3-one-17 alpha-yl)propiolactone - Google Patents

Description

[Detailed description of the invention] The present invention provides 3-(17β To4-en-3-on hydroxyandros 17α-yl)propyl☆ ☆Regarding the production method of oractone.

More specifically, the present invention relates to 3-(7α-acetylthio-17β-hydroxyandrost-4-en-3-one-17α-yl)propiolactone (hereinafter referred to as spironolactone) used as an antialdosterone diuretic and antihypertensive agent. It is abbreviated as

This invention relates to a novel method for producing 3-(17β-hydroxyandrost-4-en-3-one-17α-yl)propiolactone, which is useful as a synthetic intermediate for

Spironolactone can be produced by the method illustrated below using 3-(17β-hydroxyandrost-4-en-3-one-17αyl)propiolactone obtained by the method of the present invention as a raw material.

As a method for producing spironolactone, a method using 3β-hydroxyandrost-5-en-17-one as a starting material is known.

According to this method, 3β-hydroxyandrost-5-
En-17-one is ethynylated, reacted with carbon dioxide to give a propiolic acid derivative, and then hydrogenated to give an acrylic acid derivative.

The acrylic acid derivative was further acid-treated to form 3(3β・17
3-(17
β-Hydroxyandrost-4-en-3-one-1
7α-yl)propiolactone.

(J, A, Ce1la, E, A, Brown and
R, R, Burtner; J, Org.

Chem, 24 743 (1959)) Furthermore, the 6-position of the obtained 3-(17β-hydroxyandrost-4-en-3-one-17α-yl)propiolactone,
The 7-position is dehydrogenated and this is reacted with thioacetic acid to produce spironolactone.

(J, A, Ce1la and R6C, Tweit
: J. Org, Chem, 24 1109 (19
59)) A disadvantage of the process described above is the use of 3β-hydroxyandrost-5-en-17-one as a starting material.

3β-Hydroxyandrost-5-en-17-one is a dioscorea (a type of mountain potato) that grows naturally in the mountains of Mexico.
It is manufactured using diosgenin extracted from the roots of the grosbeak, and is manufactured through a complicated six-step process.Coupled with the difficulty of cultivating wild potatoes, it is becoming extremely expensive.

On the other hand, in recent years, a method has been developed to produce androsta-1,4-diene-3,17-dione at low cost through microbial oxidation of sterols such as cholesterol obtained from wool grease and fish oil, which can be recovered in large quantities from wool washing wastewater. being developed.

The object of the present invention is to use expensive 3β-hydroxyandrost-5-en-17-one dione and cheap naandrostate 4-diene-3,17-dione as raw materials to produce 3-(17β-dione, an important intermediate of spironolactone). -hydroxyandrost-4-en-3-one-17α-yl)
An object of the present invention is to provide a simpler method for producing floviolactone.

The gist of the present invention is 3(17β-
hydroxyandros)-4-ene-3-one-17α-
This is a method for producing propiolactone.

(a) AND represented by the following general formula (I) (in the general formula (I), Y represents an acetal residue, a dithioacetal residue, a monothioacetal residue, an enamine residue or an enol ether residue) The following general formula is obtained by reacting 3-acetal, 3-dithioacetal, 3-monothioacetal, 3-enamine or 3-enol ether of rost-4-ene-3,17-dione with potassium acetylide in the presence of acetylene. (n) (in the above general formula (II), Y is as defined in the above general formula (I)); (b) producing a 17β-hydroxy-17α-ethynyl steroid; Hydroxy-17α-ethynyl steroid (II) is brought into contact with a Grignard reagent to form the following general formula (III) (In the above general formula (m), Y is as defined in the above general formula (I), and X is (c)
Contact the generated Grignard compound with carbon dioxide gas,
It is then decomposed under acidic conditions to produce 3-(17β-hydroxyandrost-4-ene-3-one-17α-yl)propiolic acid, and (d) the produced 3-(17β-hydroxyandrost-4 The carbonyl group at the 3-position of the steroid skeleton of -en-3-one-17α-yl)propiolic acid is acetalized to produce 3-(17β-hydroxyandrost-4-en-3-one 17α-yl)propiolic acid. (e) The produced acetal is hydrogenated in the presence of a palladium catalyst, and then hydrolyzed under acidic conditions to simultaneously form a lactone ring to form 3(17β-hydroxyandrost-4-ene- 3-one-17α-yl)propiolactone is produced.

The raw material for the method of the present invention has the following general formula (i) (in the above general formula (I), Y represents an acetal residue, a dithioacetal residue, a monothioacetal residue, an enamine residue, or an enol ether residue). 3-acetal, 3-dithioacetal, 3-monothioacetal, 3-enamine or 3-enol ether of the represented androst-4-ene-3.17 dione.

These androst-4-ene-3,17-dione derivatives can be produced by the following method.

Anthrost-4-diene-3,17-dione was hydrogenated by a method known per se using tris(triphenylphosphine)rhodium chloride as a catalyst.
-Producing ene-3,17-dione C, Djeras
si and J.

GutzwillerSJ, Am, Chem, Soc,
, 884537 (1966)), and the carbonyl group at the 3-position of the obtained androst-4-ene-3·17-dione is protected by a method known per se.

(J, Fr1edanb J, A, Ec1wards
J'Organic Reactionsin 5t
eroid Chemistry,”vol 1,P
, 375 (1972), Van No5trand
Re1nhold Ce.

The carbonyl group at position 3 needs to be protected to avoid reaction with the Grignard reagent in the subsequent carbonation step.

As a method for protecting the carbonyl group at the 3-position of androst-4-ene-3,17-dione, known methods such as acetalization, thioacetalization, enamination, and enol etherification are applied.

For acetalization, acetal compounds synthesized from ketones and glycols, such as 2-methyl-2-ethyl-1,3-dioxolane, are generally used.

Ketones include methyl ethyl ketone, diethyl ketone,
Examples of the glycol include cyclohexanone, and examples of the glycol include ethylene glycol, propylene glycol, and trimethylene glycol.

For thioacetalization, dithiols such as ethanedithiol and propanedithiol are used; or thioacetals synthesized from ketones such as acetone, methyl ethyl ketone, diethyl ketone, and cyclohexanone, and dithiols such as ethanedithiol and propanedithiol.

Secondary amines such as dimethylamine, diethylamine, morpholine, piperidine, and pyrrolidine are used for enamination.

Enol etherification includes orthoesters such as orthoacetate, orthoacetate, and orthopropionate; acetals such as dialkoxypropane, dialkoxybutane, and dialkoxycyclohexane; alcohols such as benzyl alcohol; phenylmethanethiol, etc. Thiols and the like are used.

Among the above methods for protecting the carbonyl group at the 3-position, enol etherification is simple and has a high yield.

The thus obtained androst-4-ene-3.17 dione with a protected carbonyl group at the 3-position is ethynylated with potassium acetylide in the presence of acetylene, and the 17β-hydroxy 17α-ethynyl steroid (
The above general formula (■)) is obtained.

The ethynylation is carried out in accordance with the ethynylation method of androst-4-ene-3·7-dione described in West German Patent No. 1096354.

That is, metallic potassium is added to t-butanol to prepare t-butoxypotassium, and dry tetrahydrofuran is added to this and acetylene is blown into it to prepare potassium acetylide.

Ethynylation is performed by adding 17-kedosteroid (the above general formula (I)) to this potassium acetylide.

The reaction temperature is -10°C to 10°C, preferably -5°C to 5°C.
It is.

The amount of potassium t-butoxy to be used is at least 3 times the molar amount, preferably at least 8 times the molar amount of 17-kedosteroid.

17β-hydroxy-17α-ethynyl steroid (the above general formula (■)) is androst-4ene-3,17-
The dione was ethynylated with potassium acetylide (West German Patent No. 1096354), and then the obtained 17α-ethynyl-17β-hydroxyandrost-4-ene-3
It can also be obtained by protecting the carbonyl group at the 3-position of -one by the above method.

However, the above reaction to introduce a protecting group is usually carried out under acidic conditions, but since the ethynyl group is unstable under acidic conditions,
The yield of 17β-hydroxy 17α-ethynyl steroid (general formula (■) above) is low.

After protecting the carbonyl group at the 3-position in this way, ethynylation reaction is performed to obtain 17β hydroxy-17
One of the characteristics of the method of the present invention is that α-ethynyl steroid (the above general formula (■)) can be obtained in good yield.

17 with protected carbonyl group at position 3 obtained in the previous step
β-Hydroxy-17α-ethynyl steroid (general formula (■) above) is brought into contact with a Grignard reagent and then carbonated by blowing in carbon dioxide gas.

Ethers are generally used as the solvent for this reaction, and tetrahydrofuran is particularly suitable.

First, the steroid (general formula (■) above) is dissolved in tetrahydrofuran, and a Grignard reagent dissolved in tetrahydrofuran is added thereto.

The reaction temperature is 20-80°C, preferably 30-50°C.

Examples of Grignard reagents used include methylmagnesium bromide, methylmagnesium chloride, methylmagnesium iodide, ethylmagnesium bromide, and phenylmagnesium bromide.

The amount used is at least 3 times the molar amount, preferably at least 8 times the molar amount, of the steroid.

Next, carbon dioxide gas is blown into the reactor, but since it generates a lot of heat in the early stages of the reaction, it is desirable to cool the reaction solution to below 5°C.

When the heat generation stops, raise the temperature to room temperature to complete the reaction.

By simply pouring the reaction solution directly into an acid such as ice-sulfuric acid or ice-hydrochloric acid and stirring, the reaction product is decomposed by the acid and 3-
(17β-hydroxyandrost-4-en-3-one-17α-yl)propiolic acid is obtained.

The concentration of acids such as sulfuric acid and hydrochloric acid is usually about 5 to 20% by weight.

The obtained 3-(17β-hydroxyandrost-4-en-3-one-17α-yl)propiolic acid is then hydrogenated and converted into a propionic acid derivative.

However, L, 3-(17β-hydroxyandrost-4-
If the triple bond of en-3-one-17α-yl)propiolic acid is attempted to be hydrogenated, the double bond at the 4-position of the steroid skeleton will also be hydrogenated, which is undesirable.

Therefore, the present inventors focused on the fact that when the carbonyl group at position 3 is acetalized, the double bonds at positions 4 and 5 move to the 5 and 6 positions, and after acetalization, hydrogenation is performed. They found that only the triple bond of propiolic acid was hydrogenated, and the moved double bonds at the 5th and 6th positions were not hydrogenated.

Furthermore, after the reaction, when the product is decomposed under acidic conditions and the protecting group of the carbonyl group at the 3-position is removed, the double bond moves to the 4- and 5-positions, and at the same time, a lactone ring is formed at the 17-position. , the desired 3-(17β hydroxyandrost-4
-en-3-one 17α-yl)propiolactone is obtained.

3-(17β-hydroxyandrost-4-ene-3
A method known per se is usually applied to acetalize the carbonyl group at the 3-position of -one-17α-yl)propiolic acid.

(J, Fr1edand J, Edwards,
”Organic reactions in
S teroid Chem 1st try,”
vol, 1, P.

391-393 (1972), Van No5tra
ndReinhold Co 0,) That is, usually a steroid is dissolved in benzene, p-)luenesulfonic acid is reacted with a catalyst, glycols such as ethylene glycol, trimethylene glycol, and propylene glycol, and the resulting water is azeotroped with benzene. Remove and allow the reaction to proceed.

Other methods use acetal compounds synthesized from ketones and glycols, such as 2-methyl-2-ethyl-1.3 dioxolane.

Ketones include methyl ethyl ketone, diethyl ketone,
Examples include acetone, cyclohexanone, etc. Glycols include ethylene glycol, propylene glycol,
Examples include trimethylene glycol.

According to the above method, acetalization converts steroids into P-)
It is carried out by heating with acetals in the presence of an acid catalyst such as luenesulfonic acid.

The acetalized and protected propiolic acid derivative is then hydrogenated using palladium as a catalyst.

As palladium, palladium supported on activated carbon is suitable.

The supported amount is usually 2 to 10% based on activated carbon, preferably 5°C.
It is preferable that the

The reaction temperature is 5-40°C, preferably 15-25°C.

A propionic acid derivative in which the carbonyl group at the 3-position is protected with an acetal is decomposed under acidic conditions to obtain 3(17β-hydroxyandrost-4-ene-3-one-17α-yl)propiolactone.

This reaction is usually carried out by heating using ketones such as acetone, methyl ethyl ketone, cyclohexane, etc. as a solvent and P-4 luenesulfonic acid as a catalyst.

Next, the present invention will be specifically explained using the following examples.
The present invention is not limited to these Examples unless it exceeds the gist thereof.

Example 1 77.39 t-butanol was added to a 11-four-hole flask,
Metallic potassium 13.6 in this? is added, and after potassium is dissolved, t-butanol is distilled off to prepare t-butoxypotassium.

Next, 150 rrLl of dry tetrahydrofuran was added and stirred to dissolve potassium t-butoxy.

After cooling to 0° C., acetylene was blown into the solution to achieve saturation.

3-Ethoxyandrosta-3,5-diene 17-one 12.10f at 100mA! of tetrahydrofuran and added dropwise to the flask under stirring for 30 minutes.

After completing the dropwise addition, acetylene is allowed to flow for 1 hour.

Pour the reaction solution into ice water and add 300WL of 10% NH4Cl solution.
1 and separate the tetrahydrofuran layer.

At this time, salt is added to perform salting out to increase extraction efficiency.

The tetrahydrofuran layer is washed with saturated brine and dried over anhydrous sodium sulfate.

When tetrahydrofuran is concentrated using an evaporator, 1
2.46P 17α-ethynyl-3-ethoxy-17β
-Crystals of hydroxyandrosta-3,5-diene are obtained.

Crude fraction: 95.1% Melting point: 132-137.5°C This product is used as a raw material for the next carbonation step without being particularly purified.

Example 2 Metallic magnesium 1 was placed in a nitrogen-substituted 11 four-bottle flask.
3. Add 15' and 260 ml of tetrahydrofuran, and add 182 ml of methyl bromide tetrahydrofuran solution at room temperature.
1 (51 ml of methyl bromide) was added dropwise to prepare methylmagnesium bromide.

17α-ethynyl-3-ethoxy-1 synthesized in the previous step
7β-Hydroxyandrosta-3,5-diene 12.
Dissolve 11fI in lOml of tetrahydrofuran,
Cool at 40°C for 1 hour and drop into the flask.

After the completion of the dropwise addition, the mixture was stirred for 3.5 hours.

Methane generation stops.

Immerse the flask in an ice-water bath to cool it to 0°C, and slowly blow in carbon dioxide gas.

When the heat generation decreases, the temperature is raised to room temperature, and stirring is continued for 1.5 hours while blowing carbon dioxide gas.

Thereafter, it is left under a carbon dioxide atmosphere overnight.

The reaction solution is poured into a mixture of 300 S' of ice and 31 ml of sulfuric acid, and the organic matter is extracted with tetrahydrofuran.

The tetrahydrofuran layer was dried over anhydrous magnesium sulfate and concentrated to 5Qml.

Adding 20 ml of triethylamine to this results in 16 crystals.
262 is precipitated.

When the above crystals are dissolved in 300 ml of water and 10 ml of concentrated hydrochloric acid is added, white crystals are precipitated.

When the crystals are washed with water, filtered and dried, 7.85 f3
-(17β-hydroxyandrost-4-ene-3-
17α-yl)propiolic acid is obtained.

Yield: 62% Melting point: The crystal form changes at 173°C.
Decomposes at 5-256°C.

Example 3 To 3-(17β-hydroxyandrost-4-en-3-one-17α-yl)propiolic acid obtained in the previous step 7.599%, dry benzene 1000M, p-)luenesulfone e1.2? Add 20 parts of ethylene glycol and heat in a 90'c oil bath.

The distilled benzene is dehydrated through a drying molecular sieve tower and then refluxed into the flask.

After 3 hours, pyridine is added to neutralize the P-)luenesulfonic acid and cooled.

After washing the reaction solution with saturated saline, the separated benzene layer is dried.

When benzene is concentrated using an evaporator, white crystals of 6.479 are obtained.

Add an ethanol solution of triethylamine to the above crystals (triethylamine 16vLl, ethanol ioo).

Addition of m02001nl dissolves the crystals.

Add 5% Pd/C catalyst i and o to this, and heat at 19.5°C.
Hydrogen is introduced at normal pressure.

After hydrogen absorption has stopped, the catalyst is separated and the solvent is distilled off.

A liquid containing 11.69 crystals is obtained.

Add 200 ml of methyl ethyl ketone and P to the above product.
- Add 1.02 ml of toluenesulfonic acid and reflux for 1 hour.

After adding pyridine to neutralize p-)luenesulfonic acid, the mixture is washed with water.

The methyl ethyl ketone layer is dried and concentrated.

A liquid of 6.32 f is obtained.

This liquid substance is passed through column chromatography packed with silica gel.

Separation using tetrahydrofuran (30)-benzene (70) as an eluent yields a 3.89P liquid.

When n-hexane is added, it crystallizes and forms 3.72f-3-(
17β-hydroxyandrost-4-en-3-one-17α-yl)propiolactone is obtained.

Yield 50.9% Melting point 149-149.5°C Reference example 1 3-Ethoxyandrost-3,5-diene 17-one is synthesized from androst-4-ene-3,17-dione by the following procedure. be done.

Androst-4-ene-3,17-dione 20.05
f (0,070 mol), ethyl orthoformate 25 ml. 200 ml of dehydrated ethanol and 0.21 ml of P-toluenesulfonic acid are mixed and stirred at room temperature for 15 minutes.

After adding 0.5 ml of pyridine, ethanol was distilled off under reduced pressure, and several drops of pyridine were added to the resulting crystals.
．． Add 50 ml of 5% ethanol and recrystallize.

18.72P pale yellow 3-ethoxyandrosta-3
- 5-dien-17-one is obtained.

Yield 85.2% Reference Example 2 3-(17β-hydroxyandrost-4-ene-3
Hydrogenation of -one-17α-yl)propiolic acid without acetalization yields 3-(17β-hydroxyantrostan-3-one-17α-yl)propiolactone.

3-(17β-hydroxyandrost-4-ene-3
-one-17α-yl)propiolic acid triethylamine salt 0.857? , 10 ml of ethanol and 5% P
d/CO, 10? and hydrogenate at 19°C.

After hydrogen absorption has stopped, the P is separated from the catalyst and the P liquid is concentrated.

Add 7rrLl of ethanol and 1ml of hydrochloric acid to this.
Let stand for a minute, then pour into ice water.

White crystals precipitate.

0.558 P of 3-(17β-hydroxyantrostan-3-one-17α-yl)propiolactone is obtained.

Yield: 86.2 mol% In the infrared absorption spectrum of this crystal, absorption of the carbonyl group at the 3-position at 1710n-1 was observed, and 3-(17β-hydroxyandrost-4-ene-
No absorption of the carbonyl group at the 3-position of 3-one-17α-yl)propiolactone (16706IIL-1) was observed.

Claims (1)

[Claims] 1(a) The following general formula (I) (In the above general formula (I), Y is an acetal residue, a dithioacetal residue, a monothioacetal residue, an enamine residue, or an enol ether residue. 3-acetal, 3-dithioacetal, 3-monothioacetal, 3-enamine or 3-enol ether of androst-4-ene-3,17-dione represented by ) and potassium acetylide are reacted in the presence of acetylene. to produce a 17β-hydroxy-17α-ethynyl steroid represented by the following general formula (■) (in the above general formula (II), Y is as defined in the above general formula (I)), b) The generated 17β-hydroxy-17α-ethynyl steroid is brought into contact with a Grignard reagent to obtain the following general formula (III) (in the above general formula (III), Y is as defined in the above general formula (I)). (c) The generated Grignard compound is brought into contact with carbon dioxide gas, and then decomposed under acidic conditions to produce 3(17β-hydroxyandrost-4- (d) producing 3-(17β-hydroxyandrost-4-en-3-one-17α-yl)propiolic acid at the 3-position of the steroid skeleton; The carbonyl group of 3-(17β-hydroxyandrost-4-
producing an acetal of en-3-one-17α-yl)propiolic acid, (e) hydrogenating the produced acetal in the presence of a palladium catalyst, and then hydrolyzing it under acidic conditions to simultaneously form a lactone ring 3-(17) characterized by
β-Hydroxyandrost-4-en-3-one-1
Method for producing 7α-yl)propiolactone.