JPS5813515A - Antialdosterone active steroid derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formulaI(X and Y<2> are H or halogen; Y<1> is acetylthio, carboxy or ester thereof, lower alkyl or haogen; Z<1> is OH; Z<2> is K or Na salt of carboxyethyl; Z<1> and Z<2> together with the adjacent C form formula II; the broken lines between the carbon atoms at the 1- and 2-positions and the carbon atoms at the 6- and 7-positions represent the presence or absence of double bond). EXAMPLE:3-(7alpha-Acetylthio-17beta-hydroxy-3-oxo-11beta,18-oxido-4-an drosten-17alpha-yl)propionic acid-gamma-lactone. USE:An antiandrosteron agent having a low affinity for androgen receptors to be side effects. PROCESS:The addition reaction is initiated in the double bond in the ring B of a compound expressed by formula IV obtained from a compound expressed by formula III in five steps to introduce Y<1> into the 7alpha-position and give a compound expressed by formula V (Y<2> is H).

Description

DETAILED DESCRIPTION OF THE INVENTION Outline and Objectives of the Invention The present invention is directed to a steroid derivative having antiarthrotherone activity represented by the following general formula (A).

In the formula, X is hydrogen or halogen, y/ is acetylthio,
Carphoki V or its ester, lower alkyl, or halogen yJ is hydrogen or halogen 2/ is hydroxyl group zJ represents potassium salt or sodium salt of carboxyethyl, respectively. Alternatively, a γ-lactone ring represented by the above formula (,) may be formed together with 2' and 2% (adjacent carbon atoms).

Further, the broken lines of C, -CJ and C, -C represent the presence or absence of a double bond.

The steroid derivatives provided by the present invention have structurally a /β, /l-oxide functional group introduced by microbial oxidation, and have been clinically improved in terms of main action and more particularly side effects. It is a useful compound that can be used as an anti-aldosterone agent.

B. Prior art anti-aldosterone agents antagonize aldosterone in the distal tubule and inhibit sodium reabsorption and potassium excretion;
As a result, it has a diuretic effect without causing potassium loss, so it can be used alone to diagnose and improve symptoms of primary hyperaldosteronism, and can also be used in combination with other drugs to treat essential and renal hypertension and cardiac and renal edema. It is widely used for the treatment of

Conventionally used anti-aldosterone agents include spironolactone (The Mark Index, Vol. 1, #37"J and potassium canrenoate [Monthly Yakuji Vol. 22./J, #; (15'J)
'θ)].

The respective chemical names and structural formulas are shown below.

Spironolactone 3-(7α-acetylthio-/7β-hydroxyV 3-
Potassium 3-C/7β-hydroxy-3-oxo-pseudo-6-androstadiene-/7(1-yl)propionate Other similar developed products include potassium mexlenoate (mexr
enoate potassium) (J, Ph
arm, Exp.

Ther, 209. /'I'lC/979)]
The chemical name and structural formula are shown below.

3-(/7β-hydroxy-7α-methoxycarbonyl-3-oxo-l-androsten-/7tl-yl
) Potassium propionate The above-mentioned known anti-aldosterone agents have the disadvantage of exhibiting high affinity for androdiene receptors and having anti-androdiene-like side effects, as is known for spironolactone. In other words, in men, symptoms include decreased libido, impotence, and development of female-shaped breasts, while in women, symptoms include irregular menstruation and enlarged breasts.

In the above definition regarding C0 general formula (A), halogen means fluoro, chloro, bromo, iodo, etc., and fluoro is more preferable. Carboxy or its ester means carboxy or lower alkyl ester, and lower alkyl in this definition is straight chain or branched, all having carbon number/-j. means alkyl, even dimethyl, ethyl, propyl, isopropyl,
Chill.

Includes isobutyl, tertiary butyl, pentyl, isopentyl, and the like.

The compound of the present invention represented by the above general formula (A) has a 3°3-
Ethylenedioxy-/lβ,/I-oxido! - Androstene-7-phoon or its 9°α-halide is used as a raw material, and in the manufacturing process A, , A, , ~
, ~ are manufactured as follows for each type.

(The following is a margin) (In the formula, X, Y', and Y-" have the same meanings as above.)
(First step) This step is a step in which the carbonyl group at position 17 of compound (1) is subjected to acetylene condensation using a nucleophilic reagent, and an alkali metal acetylide is used as the nucleophilic reagent or Grignard reagent is used. Ashityrene may be used. As the solvent, an aprotic solvent such as ether, tetrahydrofuran, glyme, diglyme, benzene, toluene, etc. may be used, and the reaction can be completed in several minutes to several hours if the reaction is carried out under cooling to room temperature or, if necessary, heating.

(Second step) This step is a step of introducing a carboxyl group into the compound (If), and converts it into an alkali metal acetylide such as lithium acetylide using n-butyllithium.Next, carbon dioxide is added and the reaction is carried out at room temperature. It will be achieved if you do this.

Ether as a solvent.

Aprotic solvents such as tetrahydrofuran, glyme, diglyme, and benzene may be used.

(Third Step) This step is a step of catalytically reducing the triple bond of the compound ([1) to form a lactone ring at the same time, and the catalyst used is a Lindlar catalyst or a palladium-carbon catalyst.

Although it is possible to reduce the triple bond to a saturated bond at once using a rhodium catalyst or the like, it is preferable to catalytically reduce the triple bond to an -H cis-type double bond using a Lindlar catalyst or the like to first obtain an unsaturated lactone, and then to obtain an unsaturated lactone. It may be converted into a saturated lactone by reduction. As the solvent, ether solvents such as ether, tetrahydrofuran, and dioxane, alcohol-based solvents such as methanol and ethanol, and ester solvents such as ethyl acetate may be used.9 The reaction is carried out at room temperature under a hydrogen atmosphere for several minutes to several minutes. Complete in time. (Fourth step) This step is a step in which ketal is hydrolyzed into ketone in the presence of an acid catalyst, and inorganic acids such as perchloric acid, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid are used as the acid catalyst. good. As the solvent, a water-miscible solvent such as aqueous methanol, aqueous ethanol, aqueous tetrahydrofuran, aqueous dioxane, and aqueous acetone may be used (one reaction is completed in several minutes to several hours at room temperature or under heating).

In this step, a compound A is obtained in which y'==y'=n, which is a part of the object compound of the present invention in the general formula (A), and the broken line indicates the absence of a double bond.

(Fifth Step) This step is a step of forming a double bond within the steroid ring or B ring using a dehydrogenating agent under strongly acidic conditions. As a dehydrogenating agent, quinones such as chloranil and λ3-dichloro-wet 6-dicyazbenzoquinone (DDQ') may be used; if chloranil is used, A is produced, and DD
If Q is used, ~ will be generated under kinetically-governed conditions, and ~ will be generated under thermodynamics-governed conditions. As an acid catalyst, use hydrochloric acid or concentrated sulfuric acid under anhydrous conditions. good. As a solvent, alcoholic solvents such as methanol, ethanol, and JR lobanol, etheric solvents such as dioxane, ether, and tetrahydrofuran, and aromatic solvents such as benzene and toluene may be used. 1. The reaction is carried out under cooling to room temperature. It can be completed in a few minutes to a few hours.

This step is a step in which an addition reaction is carried out on the double bond in the B ring of the compound ~ to introduce an acetylthio, carboxy or haso ester, lower alkyl or halogen into the 7a position.

In the case of acetylthio, it is sufficient to heat and reflux the material in thioacetic acid for several minutes to several hours.

In the case of galboxyl or its ester, react an alkali metal cyanide such as potassium anhydride or sodium ananide in an alcohol such as ethanol or methanol, or react a dialkyl aluminum cyanide with benzene or toluene.

A cyanide compound obtained by reacting in an aprotic solvent such as tetrahydrofuran.

Water or methanol or elastomer with acid or alkali catalyst. This is achieved by reaction under heating in an alcoholic solvent such as alcohol. Lower alkyl・1.1・1. In the case of , the reaction may be carried out using a Grignanill reagent, more preferably Tsuru-probylmagnesium bromide, in an ether solvent such as tetrohydrofuran or ether.

(Seventh step) This step is a step of introducing a halogen into the 6a position of the compound, and after converting the compound into a dinole ether or enol acetate according to a conventional method, the compound is converted into a dinolyl ether or enol acetate using a dichloromethane such as perchloryl fluoride in a heliline solvent. When the fluorinating agent is allowed to react for several minutes under cooling to room temperature, the fluorine is added and the reaction is completed.

Compounds obtained by the above method 1. ~． A.

~ all have a lactone ring, but the corresponding sodium salt is the lactone ring cleaved by contact with an alkaline aqueous solution,
It can be a salt of hydroxy-V acid, such as a potassium salt.

The raw material '(1) in the above production process is a known substance Hiro-pregnene/lβ, 2-no-diol-42.
A can be obtained from 0-dione 21 acetate or its 9a-fluoro form. In other words, after removing the 21-acetyl group from the hydroxyl group by alkaline ice-lysis, Kondo, Miki et al.
J, Ame, Ch*m, Bog, 17 #116
6jc/963>'') according to the method of microbial oxidation.

The methyl group at the 11β position is oxidized to form /lβ, /l-oxide group. Subsequently, periodic acid oxidation is performed and esterification with diazomethane is performed to obtain a 17β-methoxycarbonyl derivative. Further, according to a conventional method, the carbonyl group at the 3-position was changed to a kecur, the methoxycarbonyl group at the 1-position was changed to an aldehyde group, and the corresponding enamine derivative was oxidized with sodium dichromate to obtain a 7-fluorine-one keto derivative (1).
get.

These reaction process diagrams are shown below.

(The following is a blank space) The compound provided by the present invention is characterized by having excellent anti-aldosterone activity and low affinity for androgien receptors, which can be a side effect.

As a representative compound, 3-C9a-fluoro-17β-
Hydroxy-3-oxo-/, 1β,/1-oxidoderandrosten-17α-yl)propanoic acid-γ-
Select lactone as the sample.

Comparative experiments with spironolactone conducted regarding anti-7JlzF sterone activity and affinity for aldosterone receptors and androgien receptors are listed below.

(1) Anti-aldosterone activity 〔experimental method〕,.

Bilateral adrenal glands were removed from male 8LC-Wistar rats weighing 1♂0-2001, and on the first day they were given the normal amount and Qhij% saline, and on the second day they were given sugar cubes instead of the normal amount, and their urine was collected. 04It% of 6d/1001 body weight 72 hours before the start of
Inject saline intraperitoneally. On the third day, intraperitoneal injection of 6% Qdaj% saline per 1000 body weight is administered, and the test compound or spironolactone is administered together with aldosterone, or aldosphone alone is administered subcutaneously using sesame oil as a vehicle. Urine collection began 2 hours after administration1.
The urine volume for each hour is measured, and the concentrations of sodium and potassium are determined by atomic absorption spectrometry and the ratio of the two is calculated.

(Left below) (2) Affinity for androsterone receptors [Experimental method] Rat kidney side cells were treated with various concentrations of analyte or spironolactone together with approximately/nM JH-aldosterone at o@c/If- 6 at 2'1 hour or 2j℃
Incubate for 0-100 minutes. Next, bound and unbound JH-aldosterone was separated into charcoal powder (Dex
tran coated ehaeoal method
After separation according to d), the bound type is determined. Relative affinity for receptors with aldosterone at 10O
eBinding Affinities, hereinafter referred to as R
BA value) is determined for the specimen and spironolactone.

〔Experimental result〕

The average RBA value was 9 for spironolactone under conditions of 0°C shaking temperature, whereas the sample showed t7, and 2j
``Under the conditions of Cj, the amount of spironolactone is 1, while the amount of sample is left over.

(3) 6 affinity for androgien receptor [experimental method]
゛The ventral prostatic lobe of a 72-week-old castrated male rat was used in experiments a and b, and Cydsil, IInM in experiment a, and sage hydrotestosterone (androgien) in experiment b, and Q n M in experiment b. Incubate overnight at 0°C with co-specimen or spironolactone. Next, bound and unbound JH-dihydrotestosterone were separated by a charcoal separation method.

The binding type is determined and the relative affinity to the receptor, with androdiene as 100, is determined for the analyte and spironolactone.

〔Experimental result〕

In experiment a, the RBA value of spironolactone was 16, whereas the sample was 227 or less, and in experiment b, spironolactone was 002 relative to ZO.

In the above, the results of the experiment (1) conducted as an in-vivo experiment are in good agreement with the results of the experiment (2), which is an in-vivo Ill experiment.1 The compound of the present invention has higher anti-aldosterone activity than spironolactone. It shows.

The above experiment (3) shows that the compound of the present invention has a lower affinity for the androgien receptor than spironolactone.

The compounds of the present invention that have anti-aldosterone activity and have low affinity for androgien receptors are as follows:
It can be used as an anti-alosterone diuretic antihypertensive agent with fewer side effects in place of conventional anti-aldosterone agents.
1 The compound of the present invention can be administered orally or parenterally, and can be formulated into various dosage forms depending on the method of administration. For example, 9 tablets.

It can be made into capsules, gunpowder, granules, fine granules, solutions, emulsions, etc. Carriers or excipients that are not normally used in formulation 9 For example, lactose, sucrose, starch, cellulose,
Talc, magnesium stearate, magnesium oxide, calcium sulfate, gum arabic powder, gelatin, sodium alginate.

Sodium benzoate, stearic acid, etc. are used for injection. Injections are prepared using distilled water, physiological saline, Ringer's solution, etc. When administered orally, the compound of the present invention is administered to an adult for about 7 sips IO to 2,001 sips.
1. Approximately as-s when administered intravenously.

, the cape is administered.

The present invention will be explained below with reference to Examples and Reference Examples.

Example 1 3-C/7β-hydroxy-3-oxo-//β,/l
r-oxide τ-derandrosten-/7a-yl)propionic acid-γ-lactone 6l-(a) 3.3-ethylenedioxy-/7(1-ethynyl->7
β-Hydroquine-/lβ,/1-Okindo! -Androstene 2 Tetrahydrofuran 20fd and ethyl ether/θ
The mixture in step d was cooled to 10°C and acetylene gas was introduced to saturate it. Into this solution, iz.

A hexane solution of Mn-butyllithium (3j3d (3 mmol)) was added dropwise over 70 minutes. 3.3-Ethylenedioxy-7/β,/♂-OkiVdo! was added to the resulting suspension of milk bark. -androstene-/7-one//13*C0
9 mol of Df trahydrofuran♂1 solution was slowly added dropwise.
After reacting for 30 minutes at °C, it is poured into a saturated aqueous ammonium chloride solution and the product is extracted with ethyl acetate. The ethyl acetate layer was further washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off. The obtained product was purified by silica gel chromatography using a mixture of ethyl acetate and benzene (l:2) as an eluent, and reconstituted with dichloromethane-ethyl ether to give the desired product.

The title compound 2Ijlr is obtained at 220-22°C.

Yield 1r/%.

l-←) 3-<33-ethylenedioxy-17β-hydroxy-
//β, /I-Oki V Do! A solution of 3 ml of tetrahydrofuran containing 2200 mmol of the compound obtained from -andro l-〇) was cooled to -7J°C,
X\\n-Butyllithium hexane solution QI'7mC
130Z remol) was added dropwise. The reaction solution was heated to -71°C for 30
After reacting at −6θ0C for 1j minutes, 7 blocks of dry ice were added all at once, and the temperature of the reaction solution was further raised to room temperature to carry out 9 reactions. Then add excess ammonium chloride water.

Extract with ethyl acetate. The ethyl acetate layer was washed twice with water, dried over magnesium sulfate, and the solvent was distilled off. The obtained product is recrystallized from ethyl acetate to obtain the title compound 3/611111, which exhibits a melting point of 3/611111 and decomposes as follows: yield: 72%.

1) 3-<3.3-ethylenedioxy-17β-hydroquine-/, /β, it-oxido-3-androstene-1
7α-yl)propenoic acid-γ-lactone! In a reaction vessel purged with nitrogen, 5% palladium-barium sulfate SOW, 16ml of dioxane, and 16θI of pyridine were added.
and continue to replace hydrogen gas. In this suspension/
-fcl) Compound (N) obtained from 60 Misaki (039
2 ml of a dioxane solution of 1 mmol) was added, the reaction vessel was replaced with hydrogen gas again, and the mixture was stirred for 1 hour and θ minutes under a hydrogen gas flow. The catalyst was removed from the furnace and the furnace solution was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using an ethyl acetate-benzene (2S/) mixture as an eluent, and recrystallized from dichloromethane-ethyl ether to yield the desired product.

211-. 29/”0 of the title compound Da91 Da is obtained.

Yield j91%.

l-) 3-C33-ethylenedioquine-7riβ-hydroxy-
//β,lt-oxido! = Androstene-17a
-yl) propionic acid-r-lactone! Compound II obtained from l-(c) 300 * (0
73; 3 mmol) in dioxane 20 and ethanol 1
5% palladium-carbon t.

Add the cape and stir for 20 minutes under a hydrogen stream. When the title compound 2 obtained by removing the catalyst with F and concentrating under reduced pressure is recrystallized from crude crystal ether, it shows '/', 2rj ~216°C.

l-(e) 3-C17β-hydroxyy3-oxo)°-llβ, /
lr-OkiVDogue-androsten-17a-yl)
Crude product obtained from propionic acid-γ-lactone strain l-! is dissolved in a mixture of dioxane 3jd and water/lid, 1/2d of 60% perchloric acid water is added, and the mixture is allowed to react at room temperature for tS.

° Pour the reaction solution into ice-cold water and extract with mintyl acetate. The ethyl acetate layer was washed with water and then dried with sodium sulfate.

The product obtained by concentration under reduced pressure was purified by silica gel chromatography using a benzene-ethyl acetate ($:/) mixture as an eluent, and recrystallized from dichloromethane-ethyl ether to yield ramie.

The title compound 6233Q is obtained with a temperature of /lr4 to /17°C.

Yield 733%.

Example 2 3-C7α-acylthio17β-hydroxyy3-oxo-/ , /β,ir-oxidoq-androsten-/7a-yl)propionic acid-γ-lactone 1 2-0) j-(/ 7β-hydroxyy3-oxo//β,ll-
Okindo Falls 6-androstadien-l-alpha-il)
\Propionic acid-r-lactone? The compound obtained in Example 1 (6stowtt<at cu mmol) was dissolved in a mixture of acetic acid and toluene 2fId,
'lo92At227WICQ9/Z9%ik>' and heating under reflux for 1.5 hours. The reaction solution was cooled and extracted with loloform. Extract the liquid twice with water.

1 time with saturated saline - 2 times with 096NaOH, 2 times with water
After washing twice, the chloroform layer was dried using mathanesium sulfate, and then concentrated under reduced pressure. The resulting residue was recrystallized from dichloromethane-ether; 'IP, 20!
The title compound 720-da of N20t''C is obtained. Yield 6
6%.

2-←) 3-C7tx-acetylthio-17β-hydroxy V-3
-1-'/-//β, /lr-, oxidoderandrostene/7(1-yl)propionic acid-r-lactone t 72j0 (071 mmol) obtained from thioacetic acid Heating is carried out under reflux for 1 hour in /d (/l mm). The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography using benzene-ethyl acetate (l:/) as an eluent.
The title compound 111011M is obtained at 2°C. Yield j9%.

Example 3 3-C9a-fluoro-17β-hydroquine-3-oxo-//β,l♂-oxidoderandrostene-/
7(1-yl)propionic acid-r-“ah>/IA
-, , , 8, The title compound lda is obtained.

The physical constants of the reaction intermediates and products in Examples 1 to 3 are shown in Table 2.

(Left below) Reference example/43-ethylenedioxyv-9a-fluoro-//β,l
r-oxidation! - Androsden - 77 one on! l-0) 9a-fluoroader pregnene-/'/β, 2/-
Diol-320-Dione 16 J, kn, Ch ez 8 o a, Vol. 77 (7
933) P.

9a-fluoro-goopregnene-l described in 1o6t
lβ, 2/-diol-320-dione 2-acetate/322B39 (j θ mmol) methanol 4
430sl and dioxane/! Cool the solution of Od on ice,
To this, potassium hydroxide 1391 < 33 mmol) methanol! 6- Add the solution dropwise and react for 10 minutes while cooling with water. After neutralizing the reaction solution with 10% aqueous hydrochloric acid, the product was extracted with dichloromethane. The dichloromethane layer was washed with water, sodium bicarbonate water, and saturated saline, and the dichloromethane layer was washed with G74. Drying over magnesium sulfate and evaporation of the solvent gives a crystalline residue. When the residue was recrystallized from dichloroethane-ethyl ether, 'IP, /♂λ! The title compound/6/l♂Hirof is obtained at ~l♂da°C. Yield 91%.

l-←) 9a-Fluoro-//β, l♂-oxidohiro-pregnen-21-ol-320-dione 177- Compound obtained from 7-(a)/6ZO93f as follows
.

Apply biological oxidation as shown below. Namely, Corynespora casii
cola (IMI!60θ7) was grown at 2#”O in a slant medium consisting of 20% potato juice, 1% sucrose, and 20% agar medium.

Glucose 3!
%, polypeptone 2θ%, corn steep liquor (3% CpH'ZO) into a 300 sl slope flask containing 100 ml of liquid medium, and cultured with shaking at 2E°C for q days. After culturing, the bacterial cells are removed using F cloth, washed with deionized water, and used for the reaction. 10 per 100m of culture medium
-/iθf wet bacterial cells are obtained. The wet microbial cell log was suspended in a 300 g/Low flask containing 100 d of deionized water, and a fine powder of the compound lt (lθO<=7ON
, using a total of 299 Sakaro frass,
The reaction solution was shaken and reacted at 2E℃ for 2 days.The reaction solution was separated in a furnace with a cloth, separated into bacterial cells and F solution, and each was extracted with ethyl acetate.The extracts were combined and concentrated under reduced pressure at 10℃ to obtain 2 yg of a residue. obtain. This residue is suspended in an appropriate amount of ethyl acetate-acetone mixture, and the insoluble portion is removed to give 16fl of crude 11-hydroquine.

When suspended in a mixture of 300 d of water and heated under reflux for 1 hour, the crystalline substance is completely dissolved. Acetic acid and water were distilled off under reduced pressure, acetone was added to the residue, acetone-insoluble materials were removed, and the acetone-soluble product 9 was purified from silica gel using a benzene-ethyl acetate (2:l) mixture as an eluent. Separate by chromatography. When the polar parts obtained here are recrystallized from dichloromethane-ethyl ether, the compound 17 with the symbol /lO~/I/''C
Get xtiytt. Yield 102%.

/ -G'1 9α-fluoro-1-β-methoxycarbonyl-7lβ
, lt-Oki V Dohiro-Androstene-3ion l
Compound obtained from tl-(b)/71/θflc3.0
mmol) was dissolved in tetrahydrofuran 12-.

A 3-proof solution of periodic acid dihydrate 1410fcd-2E (Limol) in water is added, and the mixture is stirred at room temperature for 73 hours. The reaction solution was diluted with ethyl acetate, washed three times with saturated brine, and the organic layer was separated, dried over magnesium sulfate, and filtered. After adding an ether solution of diazomethane to the filtrate and esterifying it, the solvent was distilled off and the residue was recrystallized from dichloromethane-ditino J ether to give IIIP, /91~/'#
Title compound/lr? Get 96 Da. Yield 9θt%.

l-) 43-ethylenedioxy-9a-fluoro-17β-methoxycarbonyl-7lβ, “lt-oxide-!-androstene 19 l-(c) Compound l♂965 #066 mmol), ethylene glycol 07jd!, Balator style sulfonic acid-hydrate 20111 and anhydrous benzene/j
ag was added to a reaction vessel equipped with a Dean-Stark type dehydrator containing Molecular Thieves 4IA, and 1
Heat to reflux for 3 hours. 1001 in the reaction mixture after water cooling.
After adding 111 of anhydrous sodium carbonate and thoroughly stirring for S minutes, the product is extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off.

When the residue is recrystallized from dichloromethane-methanol, 5
The title compound 19 of ooIII is obtained. The title compound 19 of Dasew is further obtained by separating the mother liquor by silica gel chromatography using a mixture of ethyl acetate and benzene (/: /) as an eluent. Total 93-11
111. 'IP, /j/N/33℃.

Yield ttS%.

l-(e) 43ethylenedioxy-9a-fluoro-17β-formyl-llβ,/1-oxide-! -Androstene 2
0-HD l-)/9117I%F (U31
mmol) in 10 sl of anhydrous toluene and cooled to -7t''C in a dry ice-acetone bath.
A toluene solution of 13M diisobutylaluminum hydride (A/dc 3 mmol) was added dropwise over 13 minutes.
The reaction mixture was allowed to react for an additional 43 minutes at -7♂°C. 9. Saturated ammonium chloride aqueous solution and ethyl acetate were added to the reaction mixture, and the mixture was stirred.

P is removed from the insoluble substances generated in ξξ through the celite layer,
The ethyl acetate layer of solution F was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off. The resulting product was then separated by silica gel chromatography using an ethyl acetate-benzene C/:41') mixture as the eluent, and recrystallized from 6/9'll of the title compound 20, 'P,/ 33-/39°C crystals are obtained. Yield 7
03%.

l-(to) 43-ethylenedioxy-9a-fluoro-//β,
/r-oxido! -Androsten-17-one?゛.

・In a reaction vessel equipped with a Stark type dehydration device, the compound 206/9111C/6 dammole obtained from l-(e) and molsiphori>(2Z9dC321 mmol) were added.
Add anhydrous Tornidi jIId solution and heat under reflux for 33 hours. The solvent and excess morpholine were removed under reduced pressure,
Residue i Sodium dichromate dihydrate 976111IC3, dissolved in anhydrous benzene and cooled to 0°C.
21r mmol) in a 1 m solution of anhydrous acetic acid (commercially available acetic acid jd + acetic anhydride θOjd) and allowed to react for an additional 2 hours under water cooling. Add 2 ml of methanol to this and add Q.
Let it react for j hours.

The product is extracted with ethyl acetate. The ethyl acetate layer was washed with 20 d of 7% aqueous sodium hydroxide solution and saturated brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography using ethyl acetate-benzene (/l) solution as the eluent.
The title compound 93/jflll of ~23/''C is obtained. Yield j29%.

The title compound 2 is used as a starting material in Example 3.

Reference example 2 43-ethylenedioxyV-1,/β,l♂-oxide-
! -Androstene-17-one (hereinafter in the margin) Helv, Chiac Aota, No. 20
(1937) P, 933. The above compound dapregnene-//β,
2/-diol-420-dione-21-acetate 2
When 1 is used as a raw material and reacted with C in the same manner as in Reference Example 1, the title compound 1 is obtained through the above process formula.

The title compound 1 is used as a starting material in Example 1.

Table 3 shows the physical constants of the main reaction intermediates in Reference Example/2.

(Margin below)

Claims (1)

[Scope of Claims] An anti-aldosterone active steroid derivative represented by the following general formula (A). yJ In the formula, X is hydrogen or halogen, y/ is acetylthio,
Carboxy or its ester, lower alkyl, or halogen yJ is hydrogen or halogen 2/ is hydroxyl group zJ represents potassium salt or sodium salt of carboxyethyl, respectively. Alternatively, 2' and zl may form a γ-lactone ring represented by the above formula (a) together with adjacent carbon atoms. Further, the broken lines C, -C and C, -C represent the presence or absence of a double bond.