JPS5844680B2 - 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-hydroxyandrost-4-
The present invention relates to a method for producing en-3-one-17α-yl)propiolactone.

More specifically, the present invention describes 3-(3-oxo-7α-acetylthio-17β-hydroxyandrost-4-en-17α-yl)furohio**lactone (hereinafter referred to as spironolactone) useful as an antialdosterone diuretic and an antihypertensive agent. It is abbreviated as

) The present invention relates to a method for producing 3-(17β-hydroxyandrost-4-en-3-one-1ph-alpha-yl) floviolactone, which is an intermediate for.

Spironolactone can be produced by the method illustrated below using 3-(17β-hydroxyandrost-4-en-3-one-fαyl)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-hydroxyan]
-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 obtain 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- and 7-positions of the obtained 3-(17β-hydroxyandrost-4-en-3-one-17α-yl)propiolactone were dehydrogenated, and this and thio Spironolactone is produced by reacting acetic acid.

) (J, A, Ce1la and R, C, Twei
t;J. Org, Chem, 24 1109 (19
59)) The disadvantages of the process described above are the use of 3β-hydroxyandrost-5-en-17-one as the starting material and the extremely large number of steps.

Tokuni, 3β-hydroxyan]・added 5ene-1
7-one is made from diosgenin extracted from the roots of dioscorea (a type of mountain tuber) that grows wild in the mountains of Mexico.
It is manufactured through a complicated process of 6 steps,
Coupled with the difficulty of growing mountain potatoes, they are becoming extremely expensive.

On the other hand, in recent years, a method has been developed to inexpensively produce androster 14-diene-3,17-thion by microbial oxidation of steroids such as cholesterol obtained from wool grease and fish oil, which can be recovered in large quantities from wool washing wastewater. .

The object of the present invention is to produce an important intermediate of spironolactone by using inexpensive androsta-1,4-diene-3,17-dione as a raw material instead of expensive 3β-hydroxyandrost-5-en-17-one. 3-(1,7β-hydroxyandrost-4-en-3-one-17α-
An object of the present invention is to provide a simpler method for producing floviolactone.

From androsta-1,4-diene-3,17-dione, 3-(17β-hydroxyandrost-4-ene-3
-on=■7α-yl) Methods for producing floviolactone are already known.

Future For example, in the specification of JP-A-50-30861, it is stated that androsta-1,4 diene-3,17-dione (4) is reacted with 2-propyn-1ol to obtain a 17α-(3-hydroxypropynyl)-17β-hydroxyandrosta-1,4-dien-3-one (B) is hydrogenated in the presence of a complex catalyst to produce 17α-(3-hydroxypropyl)-17β- Hydroxyandrost 4-en-3-one (C) was obtained, which was oxidized with chromic acid to give 3-(17β-hydroxyandrost 4-en-3-one-17α-yl)propiolactone (I). ) is described.

In addition, the same specification also states that androst-4-ene-3,17
-Dione to 3-(17β-hydroxyandrost-
A method for the preparation of 4-en-3-one-17α-yl)propiolactone is also described.

According to it, androst-4-ene-3,17-dione was reacted with 2-propyn-1-ol, and 17α-(
3-hydroxypropynyl)-17β-hydroxyandrost-4-en-3-one was obtained, which was further hydrogenated under pressure using tris(triphenylphosphine)rhodium chloride as a catalyst to obtain 17α-(3-hydroxypropyl)-17β. Hydroxyandrost-4-en-3-one was obtained, which was oxidized with Jones reagent to give 3-(17β-
Hydroxyandrost-4-en-3-one-17α
-il)propiolactone is obtained.

The inventors have discovered that androsta-1,4-diene-3,1
7-dione is used as a starting material, and androst-4 is used as an intermediate.
3-(
As a result of intensive research to develop a method for producing 17β-hydroxyandrost-4-en-3-one-17α-yl)propiolactone, androsta-1,4-diene-
Hydrogenation of 3,17-dione using tris(triphenylphosphine)rhodium chloride as a catalyst by a method known per se to produce androst-4-ene-3,17-ion c, DJerassi and J, Gut
zwillerJ,Am,Chem,Soc,,884
537 (1966)), the obtained androst-4-
The carbonyl group at the 3-position of ene-3,17-dione was protected by a method known per se (J, Fr1ed and J, A
, Edwards, “Organic Reactio.
ns in 5teroid Chemistny”V
ol LP, 375 (1972), Van No5
trandReinhold Co, , ) following general formula (I) (in the above formula, X is an acetal residue, a dithioacetal residue, a monothioacecool residue, an enamine residue,
or represents an enol ether residue.

) of androst-4-ene-3,17-dione to produce 3-acecool, 3-dithioacecool, 3-monothioacecool, 3-enamine or 3-enol ether of androst-4-ene-3,17-dione, (a) l7 Androst-4-en-3,1
7 dione 3-acecur, 3-dithioacecul, 3-
Monothioacecool, 3-enamine or 3-enol ether and the following general formula (II) L lCH2CH2CH
2OR (It) (In the above formula, R represents an alkyl group.

) is reacted with the following general formula (I) (in the above formula, X is as defined in general formula (1), and R is as defined in general formula (II)).

) is produced, (b) the produced 17β-hydroxysteroid derivative is decomposed under acidic conditions to form the following general formula (-in the above formula, R is defined in the general formula (n)). That's right.

) 17α-(3-alkoxypropyl)-
17β-human xyandros(·-4-en-3-one is produced, (c) the produced 17α-(3-alkoxypropyl)-
17β-hydroxyandrost-4en-3-one is oxidized with chromic acids to form a lactone ring to form 3-(17
β-Hydroxyandrost-4-en-3-one-1
By producing 7α-yl)propiolactone, the above-mentioned objective could be distantly achieved.

In the 17β-hydroxysteroid derivatives represented by the above general formula (■), the position of the double bond (one or more) in these derivatives is, for example, the 5th position in the case of acecur, the 4th position in the case of thioacecul, and the enamine and the 3rd and 5th positions in the case of enol ether.

To explain the present invention in detail, in the method of the present invention, the organolithium derivative is androst-4ene-3,17-
It is necessary to react selectively to the carbonyl group at position 17 of the dione.

For this purpose, the carbonyl group at position 3 is protected.

As a method for protecting the carbonyl group, known methods such as acecoolization, thioacecoylization, enamination, and enol etherification can be applied.

For acecooling, 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 thioacecooling, dithiols such as ethanedithiol and propanedithiol are used; or thioacecools 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 involves orthoesters such as orthoformate, orthoacetate, and orthopropionate, dialkoxypropane, dialkoxybutane,
Acecools such as dialkoxycyclohexane; alcohols such as benzyl alcohol; and thiols such as phenylmethanethiol 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 organolithium derivative that reacts with the 17-keysteroid protected at the 3-position is represented by the above general formula (Il), where R in the general formula (II) usually represents an alkyl group having 10 or less carbon atoms, Specifically, methyl group, ethyl group, propyl group, isopropyl group, isobutyl group, t-butyl group,
t-pentyl group, etc.

Organolithium derivatives are halogenated propyl ethers (0), which are easily synthesized from halogenated propatool (E) and olefins (F), as shown in the reaction formula below, and react with metallic lithium using ethers as a solvent. It can be easily obtained by

In particular, halogenated isopropoxypropane, which is easily synthesized from olefins such as propylene, butene, isobutylene, and 2-methylbutene, and halogenated propatool;
Lithium compounds derived from halogenated isobutoxypropane, halogenated t-butoxypropane, halogenated t-pentyloxypropane are preferably used.

□, + (in the formula, X represents C1 or Br, R1, R2, 11
(,3+R4 represents a hydrogen atom or a hydrocarbon residue.

) The solvent is preferably diethyl ether, and the reaction temperature is 30°C to -30'C, preferably 10°C to -20°C.

In order to react a 17-'7-1-steroid with a protected carbonyl group at the 3-position with an organolithium derivative, 17-
This is carried out by dissolving the keisteroid in a suitable solvent such as tetrahydrofuran and adding an ether solution of an organolithium derivative thereto, or by dropping a solution of 17-kedosteide into an ether solution of an organolithium derivative. .

The reaction temperature is 30°C to -30°C, preferably 10°C to -20°C.

In the above reaction, 3 mol or more, preferably 10 to 15 mol, of the organolithium derivative is used per 11 mol of 17-ketosteroid.

When 3 moles or less of the organolithium derivative is used per 11 moles of 17-ketosteroid, the yield of the 17β-hydroxysteroid derivative is low.

The 17β-hydroxysteroid derivative represented by the general formula (Il) obtained as described above is in a liquid state, but if it is immediately decomposed under acidic conditions without isolation and purification, the 17β-(3- alkoxypropyl)
-17β-hydroxyandrost-4-en-3-one is obtained in high yield.

A high yield is extremely advantageous considering the high cost of raw material steroids.

17α-(3-alkoxypropyl)-17β-hydroxyandrost-4-ene-3 obtained by the above method
-one in a suitable solvent such as glacial acetic acid, dichloromethane,
Carbon tetrachloride, dichloromethane-glacial acetic acid, acetone-water,
Oxidation with chromic acids in pyridine-dichloromethane with lactone ring formation produces 3-(17β-hydroxyandrost-4-en-3-one-17α-yl)propiolactone.

The chromic acids used are generally chromium trioxide,
Esters and acid anhydrides of chromic acid such as t-butyl chromate, chromyl acetate, and chromyl benzoate can also be used.

The amount of chromic acids to be used is 2 to 200 times the molar amount of the steroid.

The reaction temperature is -200C to 100C, preferably o'
c to 80°C.

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 Androst-4-ene-3,17-dione 20.05
g (0,070 mol), ethyl orthoformate 2.5 ml
! , 200 ml of dehydrated ethanol and 0.25 g of p-toluenesulfonic acid were mixed and stirred at room temperature for 15 minutes.

0.5 ml of pyridine! was added, the ethanol was distilled off under reduced pressure, and 50 ml of 99.5% ethanol to which a few drops of pyridine had been added was added to the resulting crystals to recrystallize, yielding 18
．． 72. ! 9' pale yellow 3-ethyloxyandroster
3,5-dien-17-one is obtained.

Yield: 852% After purging a 500 ml four-tube flask with nitrogen, 315 g of small pieces of metallic lithium and 80 cm of dry ether were added, and the mixture was cooled to -15°C.

On the other hand, a solution consisting of 40 g of 3-bromo-1-(1,1-dimethylpropoxy)propane and 50 ml of dry ether was prepared, and the solution was added dropwise into the flask over 3 hours with stirring.

Stirring was continued for 1.5 hours after the completion of the dropwise addition.

Next, the previously synthesized 3-ethoxyandrosta3.5-
Dien-17-one 5.05. ＠ was dissolved in 60 ml of dry tetrahydrofuran, and the solution was added dropwise into the flask over 1 hour while stirring.

After the addition was completed, the reaction temperature was raised from -15°C to 0°C and stirring was continued for 1.5 hours.

Pour the reaction solution into ice water and add tetrahydrofuran to extract the organic matter.

At that time, salt is added to salt out and increase extraction efficiency.

The separated tetrahydrofuran layer is dried and then concentrated to 25 ml.

Then add 6C) ml of water! , 25 ml of a hydrochloric acid solution consisting of 40 rnl of ethanol and 2 ml of concentrated hydrochloric acid are added, and the mixture is stirred at room temperature for 1 hour.

After neutralizing by adding soda carbonate, extract by adding tetrahydrofuran.

Concentrating the tetrahydrofuran solution yields 8.69 g of liquid.

This is subjected to chromatography packed with silica gel.

Separation and purification using tetrahydrofuran (13)-benzene (87) as an eluent yields 5.90 g of a liquid product.

When n-hexane is added, it crystallizes and when recrystallized, it becomes 5.7
0 g of 17α-(3-(LL-dimethylpropoxy)propyl)-17β-hydroxyandrost-4-en-3-one are obtained.

Melting point: 111.06-111.57°C Yield: 85.1% Example 2 After purging a 500 ml four-bottle flask with nitrogen, 3.5 g of metallic lithium and 80 ml of dry ether were added.
Cool to -5°C.

On the other hand, a solution consisting of 24.5 g of 3-4-1-ethoxypropane and 50 ml of dry ether is prepared, and this solution is added dropwise into the flask over 2 hours while stirring.

After the dropwise addition is complete, stirring is continued for 1.5 hours.

Then 3-ethoxyandrosta-35-diene-17
-on 5.10.9 Dry tetrahydrofuran 60ml
and added dropwise to the flask over 1 hour while stirring.

After completion of the dropwise addition, the reaction temperature was raised from -5°C to O'C and stirring was continued for 1.5 hours.

The reactants are treated and acidolyzed according to the method shown in Example 1.

After work-up, 6.90 g of liquid is obtained.

This liquid is subjected to chromatography packed with silica gel.

Separation and purification is performed using tetrahydrofuran (15) and benzene (85) as eluents.

5.2 g of liquid is obtained.

It does not crystallize even when n-hexane is added.

Gas chromatography and thin layer chromatography analysis confirmed that it was a single substance, and NMR analysis revealed that it was 17α-(3-ethoxypropyl)-17β-hydroxyandrost-4-en-3-one. I confirmed that there is.

Yield 85.8% Example 3 Chromium trioxide 1.53g1 in a 50ml fourth flask
Add 10 ml of dichloromethane and 10 rnl of acetic acid and stir at a reaction temperature of 20'C.

On the other hand, 0.496 g of 17α(3-(1,1-dimethylpropoxy)propyl)=17β-hydroxyandrost-4-ene 3-one was prepared by dissolving it in 5 m, l of dichloromethane and 5 ml of acetic acid. Add dropwise to the reactor over 15 minutes.

Stirring was continued for 2 hours after the completion of the dropwise addition. Pour the reaction solution into ice water and separate the dichloromethane layer.

The dichloromethane layer is washed with water, dried over anhydrous magnesium sulfate, and concentrated.

0.300g of pale yellow liquid can be replaced.

This is subjected to column chromatography packed with silica gel.

Separation and purification using ethyl acetate (28)-benzene (72) as an eluent yielded 169.9 Tnl of white crystals 3-(17
β-Hydroxyandrost-4-en-3-one-1
7α-yl)propiolactone is obtained.

Melting point 149-149.5°C (literature value, melting point 148-1
50°CJ, A, Ce1la and C,M.

Kagawa, J. Am. Chem. Soc.
19 4808 (1957)) Yield 42. O% Example 4 17 α-(3-(1,1
Add 0.500.9 of dimethylpropoxy)-17β-hydroxyandrost-4-en-3-one and 35 ml of acetone and stir at 2-5°C.

Meanwhile, a chromium trioxide solution is prepared by mixing 11.05 g of chromium trioxide, 9.5 ml of concentrated acid, and 41 ml of distilled water.

40 ml of the prepared chromium trioxide solution was dropped into the reactor, and stirring was continued for 4 hours after the dropwise addition was completed.

Pour the reaction solution into ice water and add dichloromethane to extract the organic matter.

The extract is treated in the same manner as in Example 3 to obtain 3-(17β-hydroxyandrost-4-en-3-one-17α-yl)propiolactone 17 Bnrg.

Yield 43.3% Example 5 17 α-(3-(11-
Add 0.500 g of dimethylpropoquine)-17β-hydroxyandrost-4-en-3-one and 10 ml of carbon tetrachloride and bring to 50°C.

To this, 5 ml of t-butyl ester of chromic acid, 11 acetic acid, 2
ml and 1 ml of acetic anhydride are added dropwise.

After completion of the dropwise addition, stir for 4 hours. Cool the reaction solution and add a saturated aqueous oxalic acid solution.

Dichloromethane is added to extract the organic matter, and the mixture is treated in the same manner as in Example 3 to obtain 3-(17β-hydroxyandrost-4-en-3-one-17α-yl)propiolactone 1621119.

Yield 39.4% Example 6 Chromium trioxide 1.53g1 in a 50ml fourth flask
Add 10 ml of dichloromethane and 10 ml of acetic acid and
Stir at °C.

On the other hand, 17α-(3-ethoxypropyl)-17β-hydroxyandrost-4-en-3-one 0.500
Dissolve g in 5 ml of dichloromethane and 5 ml of acetic acid,
This was added dropwise to the reactor over a period of 10 minutes.

After completion of the dropwise addition, stir for 2 hours.

The reaction was worked up according to the method of Example 3 to give 3 of 152
-(17β-hydroxyantrost-4-ene-3-
On-17α-yl)propiolactone is obtained.

Yield 32.8%

Claims (1)

[Scope of Claims] 1(a) The following general formula (I) (In the above formula, X represents an acecous residue, a dithioacetal residue, a monothioacecous residue, an enamine residue, or an enol ether residue) ) and 3-acetal, 3-dithioacecul, 3-monothioacecul, 3-enamine or 3-enol ether of androst-4-ene 3.17-dione and the following general formula (II) Li -CHCHCH-0-R・・・・・・・・・(II
)2 2 2 (in the above formula, R represents an alkyl group) is reacted with an organolithium derivative represented by the following general formula (Il[) (in the above formula, X is as defined in general formula (I)) (b) The generated 17β-hydroxysteroid derivative is decomposed under acidic conditions to produce the following general formula. 17α-(3-alkoxypropyl)- represented by the formula (in the above formula, R is as defined in general formula (II))
(c) The generated 17α-(3-alkoxypropyl)17β-hydroxyandrost-4-en-3-one is oxidized with chromic acids to form a lactone ring. to form 3-(1
7β-hydroxyandrost-4-en-3-one-
3-(17β-hydroxyandrost-4-, which is characterized by producing 17α-yl)propiolactone.
A method for producing en-3-one-17α-yl)proviolactone.