JPS5925000B2 - 3-(17 beta-hydroxyandrost-4-ene-3one-17 alpha-yl)propiolactone - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 3-(17β-hydroxyandroslot-4
The present invention relates to a method for producing -en-3-one-17α-yl)propiolactone.

More specifically, 3-(7α-acetylthio-17β-hydroxyandrost-4-en-13-one-17α-yl)propiolactone (hereinafter abbreviated as spironolactone) is useful as an antialdosterone diuretic and antihypertensive agent.
The present invention relates to a novel method for producing 3-(17β-hydroxyandrost-4-ene-1(3-one-17α-yl)propiolactone), which is an intermediate for.

Spironolactone can be produced by the method illustrated below using 3-(17β-hydroxyandrost-4-en-13-one-17α-yl)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 give 3-(3βIl7β-dihydroxyandrost-5-en-17α-yl)acrylolactone, which was hydrogenated to give a saturated lactone, followed by Otzpennauer monoxidation to give 3-(17β- Hydroxyandrost-4-en-3-one-17α-yl)propiolactone.

(J.A. Cella, E.A. BrOwnandR.
R. Burtner: J. Org. Chem. ,24,
743 (1959)) Further obtained 3-(17β-hydroxydiandrost-4-en-3-one-17α-
Propiolactone is dehydrogenated at the 6th and 7th positions and reacted with thioacetic acid to produce spironolactone.

(J.A. Cella and R.C. Tweit: J.
Org. Chem. , 24llO9 (1959)) The disadvantages of the above-mentioned method are that 3β-hydroxyandrost-5-en-17-one is used as the starting material and that the number of steps is extremely large and complicated. 3β-Hydroxyandrost-5-ene-117-one is manufactured through a complicated six-step process using diosgenin extracted from the roots of dioscorea (a type of mountain tuber) that grows wild in the mountains of Mexico. Coupled with the difficulty of cultivating wild potatoes, they are becoming expensive.

On the other hand, androsta-1,4-diene-3,17-
Methods have been developed to produce diones at low cost. The object of the present invention is to use the expensive 3β-hydroxyandrost-5-
Cheaper Androsta-1,4 instead of En-17-on
- A simpler method for producing 3-(17β-hydroxyandrost-4-en-3-one-17α-yl)propiolactone, an important intermediate of spironolactone, using diene-3,17-dione as a raw material. It is about providing.

The gist of the present invention consists essentially of the following steps.
-(17β-hydroxyandrost-4-ene-3-
This is a method for producing on-17α-yl)propiolactone. (4) 17β-hydroxy-17 represented by the following general formula (1) (in the above formula, Z usually represents an alkylene group having 10 or less carbon atoms, such as ethylene, propylene, trimethylene, tetramethylene, etc.)
3- of α-ethynylandrost-5-en-3-one
Acetal and the following general formula ()RM() (In the above formula, R is an alkyl group usually having 20 or less carbon atoms such as methyl, ethyl, butyl, an aralkyl group usually having 20 or less carbon atoms such as benzyl or phenethyl, or phenyl, Usually represents an aryl group having 20 or less carbon atoms such as naphthyl,
A Grignard reagent or an organolithium compound represented by MgX (X represents a halogen atom such as Ct, Br, I, etc.) or Li is reacted with the following general formula () (in the above formula, Z is (6)
The generated acetylides and carbon dioxide are reacted to form the following general formula () (in the above formula, Z is as defined in the above general formula (1), and M is as defined in the above general formula ()). produce propiolic acids represented by
(C) The generated propiolic acids, the hydrolysis product of the propiolic acids, or the amine salt of the hydrolysis product of the following formula (V), () or () (in the above formula, Z is As defined in formula (1), M is as defined in the above general formula (), Rl,
R2 and R3 are represented by an alkyl group usually having 20 or less carbon atoms such as methyl or ethyl, an aralkyl group usually having 20 or less carbon atoms such as benzyl or phenethyl, or an aryl group usually having 20 or less carbon atoms such as phenyl or naphthyl. The propiolic acid derivative obtained is hydrogenated in the presence of a palladium catalyst, and the hydrogenated product is then decomposed under acidic conditions to form a lactone ring, forming 3-(17β-hydroxyandrost-4-ene-3-one). -17α-yl)propiolactone is produced.

Next, the present invention will be explained in detail.

The 3-acetal of 17β-hydroxy-17α-ethynylandrost-5-en-3-one, which is a raw material for the method of the present invention and is represented by the following general formula (1), can be prepared by ,4-diene-3,1
It can be easily produced from 7-dione.

Androsta-1,4-diene-3,17-dione (formula A above) was converted into C.I. DJerassi and J. Gutzw
iller's method (J. Arn. Chem. SOc.,
8-8, 4537 (1966)) to produce androst-4-ene-3,17-dione (formula B above) by hydrogenation using tris(triphenylphosphine)rhodium chloride as a catalyst, This is H. J. Dauben
, Jr. ,B. Ldken and H. J. RlngOl
d method (J.lkin.Chem.SOc., 76,
1359 (1954)) using o-toluenesulfonic acid as a catalyst, e.g. 2-methyl-2-ethyl-1
, 3-dioxolane to form 3-ethylenedioxyandrost-5-en-17-one (general formula C above)
The resulting 3-acetal is reacted with KC=CH or BrMgC...CH and then hydrolyzed, or androst-14-ene-3,17-dione is prepared as described in German patent 1.
096354, acetylene was introduced in the presence of t-butoxypotassium and hydrolyzed to give 17β-hydroxy-17α-ethynylandrost-4-ene-3.
-one (formula D above), and by acetalizing the carbonyl group at the 31-position by a method known per se, 17
β-Hydroxy-17α-ethynylandrost-5-
3-acetal of en-3-one (general formula (1) above)
is manufactured.

(J. Friedand and J.A. Edwards, tt.
OrganlcReactiOnsinSterOld
Chemistvl, VOll, P. 375 (1972
), VanNOst-RandReinhOldCO.
,) What must be particularly emphasized here is that the raw material must be 3-acetal.

This is because, as explained in the later step, when hydrogenating a propiolic acid group, the A group may be of the 4-ene-3-one type and do not protect the carbonyl group at the 3-position, or the carbonyl group at the 3-position may not be protected. When the group is protected as an enamine or enol ether, the double bond in the steroid nucleus is also hydrogenated at the same time, resulting in the final formation of 3-(17β-hydroxyandrost-3-one-17α-yl)propiolactone. This is because a large amount of is produced as a by-product. 1 represented by the above general formula (1)
7β-hydroxy-17α-ethynylandrost-5
- 3-acetal of en-3-one is dissolved in a solvent such as tetrahydrofuran, and a Grignard reagent such as methylmagnesium bromide, ethylmagnesium bromide, or methylmagnesium iodide represented by the above general formula (H) is added to the solution, When organic lithium compounds such as methyllithium, butyllithium, and phenyllithium are added, the above general formula ([I(l
Acetylides represented by are obtained.

The amount of the Grignard reagent or organic lithium compound to be added is required to be at least twice the mol of the 3-acetal of the general formula (1), and is usually used in a range of 2 to 10 times the mol. The reaction temperature is usually 80°C or lower - 60°C or higher, and 5
0-30°C is suitable. As a reaction solvent, a Grignard reagent or ethers, aliphatics, hydrocarbons, etc. that stably dissolve the organic lithium compound can be used.
Tetrahydrofuran is preferred because it has a high solubility in steroids. Next, carbon dioxide is blown into the resulting solution of acetylides to effect carbonation.

This reaction is an exothermic reaction, and especially in the early stages of the reaction, heat generation is intense, and the reaction temperature rises, causing undesirable reactions to occur. Therefore, the reaction liquid must be cooled to 5°C or less before blowing carbon dioxide gas. Desirable. Once the heat generation has stopped, the temperature is raised to room temperature to complete the reaction. After the reaction is completed, some of the propiolic acids represented by the above general formula () precipitate as crystals.
The precipitated crystals are filtered, dissolved in a solvent such as methanol, and hydrogenated. Further, when an alcohol, particularly preferably methanol, is added to the above reaction solution, the precipitated product is dissolved to form a homogeneous solution. This solution is directly sent to the hydrogenation step. Furthermore, when water or an aqueous ammonium chloride solution is added to a reaction solution containing propiolic acids (the above general formula ()) obtained by carbonation, a partial hydrolysis product of the propiolic acids of the above general formula (V) precipitates out as white crystals. .

This is separated from P and the tetrahydrofuran layer of P solution is separated to recover unreacted 3-acetal represented by general formula (1). The partial hydrolysis product of the general formula (7) above dissolves well in alcohols, especially methanol, so
It is dissolved in methanol and sent to the hydrogenation process. The above general formula (
When the partial hydrolysis product of propiolic acids in 7) is suspended in tetrahydrofuran and hydrochloric acid or sulfuric acid in an amount equivalent to the steroid is carefully added, the salt is decomposed and the propiolic acids represented by the above general formula () are hydrolyzed. The product is liberated and is dissolved in tetrahydrofuran.

It is also possible to send this solution to the next hydrogenation step. Further, when an amine, particularly preferably triethylamine, is added to this tetrahydrofuran solution, a hydrolysis product of propiolic acids (amine salt of the above general formula () (the above general formula ()) is precipitated. It is also possible to separate P, dissolve it in an alcohol, especially ethanol, methanol, etc., and send it to the next hydrogenation step.In this operation, special attention must be paid to the When hydrolysis products of propiolic acids are decomposed with hydrochloric acid or sulfuric acid, if too much of these mineral acids is added, the 3-acetal will be acid-decomposed and the A ring of the steroid will be converted to 4-ene-3.
-Become an on-type person. That is, 3-(17β-hydroxyandrost-4-en-3-one-17α-yl)propiolic acid is produced as a by-product. This is 3-(
17β-hydroxyandrost-3-one-17α-
This is because it is hydrogenated to propionic acid, resulting in unfavorable results.

The propiolic acids represented by the above general formula () or the derivatives thereof represented by the above general formula (V), () or () obtained in the above carbonation step are preferably prepared using a palladium catalyst in an alcohol such as methanol or ethanol. Hydrogenated in the presence of hydrogen atmosphere.

A palladium catalyst is a normal hydrogenation catalyst in which palladium is supported on a carrier such as activated carbon, silica gel, or alumina.
The amount of palladium supported is usually 1 to 10% by weight, preferably 2 to 5 tons (based on the carrier). The amount of catalyst used is 1/100 to 10 times (by weight), preferably 1/10 to 1/2 times the amount of the steroid. The reaction temperature is 0~
The temperature is 100°C, preferably 20-40°C. Hydrogen pressure is 100K from normal pressure? /d, preferably 30K2/d from normal pressure
C! It is 7t.

Further, in order to prevent decomposition of 3-acetal during the reaction, an amine, preferably triethylamine, may be added to maintain the basicity of the reaction solution.

When the catalyst in the reaction solution is separated from P and the solution is made acidic by adding a mineral acid such as hydrochloric acid or sulfuric acid to the P solution, a propionic acid derivative is liberated, and at the same time, a lactone ring is easily formed under acidic conditions.

The acetal at position 31 is also decomposed with acid and decomposed into the 4-ene-3-one type.

At this time, when a ketone, preferably methyl ethyl ketone, acetone, etc. is added, the acid decomposition of the acetal at the 31-position proceeds easily. After acid decomposition, the reaction solution is concentrated, an organic solvent that can be separated from water, such as benzene, is added, and the benzene layer is washed with water and concentrated to produce 3-(17β-hydroxyandrost-4-ene-1) as white crystals. 3-one-17α-yl)
Propiolactone is obtained.

This product has extremely high purity and can be used as a raw material for producing spionolactone without any particular purification.
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 3-ethylenedioxy-17α-ethynyl-17β-humanOxyandost-5-ene 0.29239 (0.
820 mm01e) was dissolved in 10 ml of tetrahydrofuran and cooled to -5°C.

To this, 1.0 ml of a hexane solution of butyl lithium (2.4 mm 01 e of butyl lithium) is added. After 15 minutes, the reaction solution was cooled to -70℃, and then the inside of the reactor was heated to 5m7f.
The pressure is reduced to LH9, and dry carbon dioxide gas is blown in to replace the inside of the reactor with carbon dioxide gas.

The reaction solution is stirred at -10°C for 30 minutes and at room temperature (20°C) for 1 hour. The reaction solution became cloudy and white crystals were observed to precipitate. 10 mt of methanol with 1 drop of triethylamine
When added, a clear solution is obtained.

The above reaction solution was added to a hydrogenation reactor containing 90 m9 of 5% palladium and activated carbon, and the mixture was heated at room temperature (20°C) under a hydrogen atmosphere at normal pressure.
Stir for 5 hours until hydrogen absorption stops.

Filter the catalyst and add hydrochloric acid to the P solution to make it acidic. Acetone 5Tn! , and stir for 2 hours. The reaction solution was concentrated, 20 ml of benzene was added, and the mixture was washed with an aqueous sodium carbonate solution. The benzene layer is dried and concentrated to yield a 0.3129 oil. When 10N of n-hexane is added, the mixture is crystallized to obtain 0.2499 of white crystals of 3-(17β-hydroxyandrost-4-en-3-one-17α-yl)propiolactone. The yield of liquid was 89%, and the infrared absorption spectrum and NMR spectrum of the crystals completely matched those of the standard product. Recrystallization from n-hexane (3>-ethyl acetate (2)) yields crystals with a melting point of 146-148°C. Mixture with the standard product shows a melting point of 147-148.5°C. Example 23-Ethylene dioxy-17α-ethynyl-17
β-Hydroxyandrost-5-ene 337η (0.
95 mmOle) in 10 ml of tetrahydrofuran and cooled to -3 to 0<0>C.

Add 1 ml of a hexane solution of n-butyllithium (2.4 mrr101e of n-butyllithium). After 5 minutes-
Cool to 20°C and blow in carbon dioxide gas.

After 10 minutes, the temperature was raised to room temperature, and the mixture was stirred for 1 hour while blowing carbon dioxide gas.

When 2.5 ml of distilled water is added, white crystals are precipitated.

When this crystal is filtered by P, 0.3429 lithium salt of propiolic acids is obtained. Add the above lithium salt of propiolic acids to 2 drops of methanol containing 2 drops of triethylamine.
0.10% palladium-activated carbon catalyst dissolved in 0mZ
9 and hydrogenated in the same manner as in Example 1.

When the lithium salt of propiolic acids was isolated and hydrogenated, the hydrogenation rate was significantly faster than in Example 1, and the reaction was completed in 50 minutes. After the reaction, the reaction mixture was treated in the same manner as in Example 1 to obtain 0.286 m9 of 3-(17β-hydroxyandrost-4-en-3-one-17α-yl)propiolactone. Yield: 88.0% The lactone obtained in this example has a yield of 145.5 to 14% without purification such as recrystallization.
It exhibits a melting point of 7.0°C. Example 3 0.3639 (1.02 mmOle) of 3-ethylenedioxy-17α-ethynyl-17β-hydroxyandrost-5-ene was dissolved in 10 ml of tetrahydrofuran, and a solution of ethylmagnesium bromide in tetrahydrofuran (3.0 ml) was prepared at 23°C.
9.0n1n101e).

Ethane evolution stops after stirring for 1 hour.

Cool to 0°C and blow dry carbon dioxide gas.

After stirring at room temperature for 2 hours, add 10ml of ammonium chloride aqueous solution.
Add. When the crystal is separated by P, a crystal of 0.2319 is obtained. Tetrahydrofuran 10 to 0.1989 of the above crystals
m71, 1 ml of saturated ammonium chloride aqueous solution, and 1N water were added, and at 10°C, 4.5 ml of 0.1N-HCt was added with stirring.

The suspended crystals disappear. Separate the tetrahydrofuran layer and dry. Add to this 0.5 m of triethylamine
Add 1. 0.1079 white crystals are obtained. 0.0829 of the obtained crystals are dissolved in 5a of ethanol, 0.0329 of 5% palladium on activated carbon is added, and hydrogenated in the same manner as in Example 1.

After removing the catalyst, add 1 ml of methyl ethyl ketone to the reaction solution.
711, add 3 drops of concentrated hydrochloric acid and stir at room temperature for 1 hour. Add 20 parts of benzene, wash with water, and then dry. Concentration of benzene yields 0.0529 oil. Add n-hexane but no crystallization. According to analysis using gas chromatography, this oily substance is 3-(17β-
Hydroxyandrost-4-ene-3-one-17α
-yl)propiolactone 81.5%, 3-(17β-
3-(
The consistent yield of 17β-human oxyandrost-4-en-3-one-17α-yl)propiolactone was 18.
5 (L.

Reference example 1 3-(17β-hydroxyandrost-4-nin-3
-one-17α-yl)propiolic acid is directly hydrogenated to yield 3-(17β-hydroxyandrost-13-one-17α-yl)propiolactone.

That is, a mixture consisting of 0.8579 g of the triethylamine salt of 3-(17β-hydroxyandrost-4-en-13-one-17α-yl)propiolic acid, 10 ml of ethanol, and 0.10 g of 5% palladium on activated carbon,
Hydrogenation is carried out at 19° C. under a hydrogen atmosphere at normal pressure.

The reaction product was treated in the same manner as in Example 1 to obtain white crystals of 0.5589.

Claims (1)

[Claims] 1 (A) 17β- represented by the following general formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (In the above formula, Z represents an alkylene group)
3-acetal of hydroxy-17α-ethynylandrost-5-en-3-one and the following general formula (II) RM (
II) (In the above formula, R represents an alkyl group having up to 20 carbon atoms, an aralkyl group having up to 20 carbon atoms, or an aryl group having up to 20 carbon atoms, and M represents MgX (X represents a halogen atom) or Li. By reacting a Grignard reagent or an organolithium compound represented by (M is as defined in general formula (II) above)
(B) The generated acetylides are reacted with carbon dioxide to form the following general formula (
IV) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) (In the above formula, Z is as defined in the above general formula (I), and M is as defined in the above general formula (II). ) is produced, and (C) the following general formula (V), (VI) or (VII) is the produced propiolic acid, a hydrolysis product of the propiolic acid, or an amine salt of the hydrolysis product. ) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (V) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VI) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VII
) (In the above formula, Z is as defined in the above general formula (I), M is as defined in the above general formula (II), and R^1, R^2 and R^3 are alkyl (representing a group, aralkyl or aryl group) is hydrogenated in the presence of a palladium catalyst, and the hydrogenation product is then decomposed under acidic conditions to form a lactone ring, forming a 3-( 3-(17β-
Hydroxyandrost-4-en-3-one-17α
-Production method of propiolactone.