JPS6075496A - 7alpha-substituted 3-oxo-17alpha-pregn-4- ene-21,17-carbolactone, manufacture and antialdosteronic pharmaceutical medicine - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula: [wherein represents an O-a single bond or an a-O double bond, or represents a group h, R7 is a group EV (R' is hydrogen 000f or C0Fe' (f
is an alkyl group having 1 to 4 carbon L9 atoms) and) C1, C-C single bond I- or group) Σ
Or does it represent 'w゛-2-? 7α-Substituted 6-oxy-17α-zoregun-4-ene-21,17-carbolactone of 7α-substituted 6-oxy-17α-zoregun-4-ene-21,17-carbolactone [1] and a pharmaceutical preparation containing the compound B and having anti-aldosterone activity.

In the general formula ①, R', which is an alkyl group having 1 to 6 carbon atoms and optionally substituted with a hydroxy group or an acyloxy group in the form of a candy or a candy, is, for example, a methyl group, an ethyl group, a propyl group. group, inzolovyl group, butyl group, hydroxy- or acetoxyethyl group, 14 is 2-
Hydroxy- or -acetoxyprobyl group.

Does the new compound in general 2. have the property of inhibiting or reversing the sodium and potassium salt precipitation effects of aldosterone or desoxycorticosterone? have The compounds according to the invention are therefore useful in the treatment of certain types of high pressure, heart failure, edema in cirrhosis and nephrotic syndromes, secondary and secondary hyperaldosteronism and other endocrine disorders induced by aldosterone. suitable for It can also be used as a diuretic.

This new compound has superior activity and longer life compared to commercially available spironolactone and metabolic substrates containing a mercapto group or a methylthio group instead of an acetylthio group at the 7-position [5tero14s', Vol. 20, p. 41 (1972)]. It has the advantage of time action.Furthermore, it exhibits reduced anti-androgenic and r-stagen side effects.

At least one 1α, 2α- or 15α.

Compounds according to the invention containing a 16α-methylene group were tested in Holman's test model [1Jaunyn-8chm-1
edebergs Arch, Exp, Path, P
harmak,” vol. 247, p. 419 (1964)
], the spironolactone which is superior to the known spironolactone in its anti-alcosterone action and which does not contain a 1α, 2α- or 15α, 16α-methylene group and the corresponding compound of West German Patent Publication No. 3111951 It is surprising that it has been found to be superior with lower anti-androgen side effects compared to other drugs.

Anti-androgenic effects are observed in compounds which do not themselves have androgenic effects, but which, by virtue of their high binding affinity, exclude all or part of the native androgens from their receptors; this is the case, for example, to some extent with spironolactone. It has been revealed that a new compound of general formula (2) has a lower compatibility with the androgen receptor than spinolactone.

Is R7 an oxoalkyl group? The represented compounds according to the invention are based on the Holman test model ["" Naunyn-8ch
mieaebergs Arch, Fixp, Path
, Pharmak, ', vol. 247, p. 419 (1964
)] and has an anti-aldosterone effect comparable to that of spironolactone. Unlike sugironolactone, the compounds according to the invention no longer bind to androgen and rstaden receptors. Thus, the new compounds do not have anti-androgenic and gestagen side effects.

This new compound of general formula I is therefore suitable for the treatment of symptoms associated with edema and secondary or secondary hyperaldosteronism, for example in severe heart failure, liver cirrhosis or nephrotic syndrome.

The following compounds have been found to be particularly pharmacologically effective: 1,7α-mercapto-1α,2α-methylene-6-oxo-17α-predan-4-ene-21,17-carbolactone, 2 , 7α-methylthio-1α, 2α-methylene-6-oxo-17α-predan-4-ene-21,17-carbolactone, 6.7α-ethylthio-1α, 2α-methylene-6-oxo-17α-predanone- -Nine-21.17-carboractone, 4.7α-propylthio-1α, 2α-methylene-6-
oxo-17α-zoregn-4-ene-21.17-calactone, 5.7α-(2-propylthio)-1α, 2α-methylene-6-oxo-1phα-pregn-4-ene-21,
17-carbolactone, 6,7α-butylthio-1α,
2α-methylene-6-oxo-17α-predan-4-
En-21,17-cal71glactone, Z7α-(2-hydroxyethylthio)-1α,2α-
Methylene-6-oxo-1ph-alpha-pregn-4-ene-
21,17~carbolactone-8,7α-mercapto-6-oxy-1α-solegner 1,4-diene-21,17-carbolactone, 27α-methylthio-3-oxo-17α-pregna-
1,4-diene-21,17-carboractone, 10.7α-mercapto-15β, 16β-methylene-
3-oxo-1ph α-pregn-4-ene-21,17
-carbolactone, 11.7α-mercapto-15β, 16β-methylene-
6-oxy-1ph α-zoregner 1゜4-diene-21
, 17-carbolactone, 12.7α-mercapto-1
α, 2α; 15β.

16β-dimethylene-6-oxo-17α-predan-
4-ene-21,17-carboractone-16,7α-methylthio-15β,16β-methylene-
6-oxo-17α-zoregun-4-en-21.17
-carbolactone, 14.7α-ethylthio-15β, 16β-methylene-
6-oxo-17α-zoregun-4-en-21.17
-carbolactone, 15.7α-propylthio-15,6', 16β-methylene-6-oxo-17α-predan-4-ene-21
, 1 fucarboractone, 16.7α-butylthio-1
5β,16β-methylene-6-oxo-17α-predan-4-ene-21,17-carboractone, 17,7α-methylthio-1! M', 16β-methylene-6-oxy-17α-pregna~1°4-diene-2
1,17-carboractone, 18.7α-(2-hydroxyethylthio)-15β, 16β-methylene-6-oxo-17α-predan-4-ene-21,17-carboractone, 19,7α-(2 -hydroxyethylthio)-15β,
16β-methylene-3-oxo-17α-pregna-1
, 4-diene-21,17-carboractone, 20.7α-(2-acetoxyethylthio)-15β,
16β-methylene-3-oxo-1ph α-zoregun-4
-ene-21,17-carboractone, 21.7α-(2-hydroxypropylthio)-15β
, 16β-methylene-6-oxo-17α-zoregun-4-ene-21,17-carbolactone, 22.7α-mercapto-15α,16α-methylene-
3-oxo-17α-predan-4-ene-21,1fucarboractone, 23.7α-(2-hydroxyethylthio)-15α,
16α-methylene-6-oxo-17α-predan-4
-ene-21,1fucarboractone, 24.7α-(2-hydroxyethylthio)-1α,2
α; 15β, 16β-dimethylene-3-oxo-1 α
-pregn-4-ene-21゜17-cal-4-glactone, 25.7α-(2-hydroxypropylthio)-1α,
2α; 15β, 16β-dimethylene-3-oxo-1phα-pregn-4-ene-21,17-carbolactone, 26.7α-mercapto-1α, 2α; 15α.

16α-dimethylene-6-oxo-17α to pregun-4-ene-21,17-carbolactone 27,7α-methylthio-1α,2α; 15α.

16α-dimethylene-6-oxo-17α-zoregn-4-ene-21.17-carboractone- 28,7α-methylthio-15α,16α-methylene-
3-oxo-1ph α-zoregun-4-ene-21,17
-carbolactone, 29,7α-(2-hy)70xyethylthio)-1α,
2α; 15α, 16α-dimethylene-6-oxo-17
α-Zolegn-4-ene-21°17-carboractone, 60.7α-methylthio-1α,2α; 15β.

16β-dimethylene-6-oxo-17α-predan-
4-ene-21,1-fucarboractone, 31.7α-ethylthio-1α,2α; 15β.

16β-dimethylene-6-oxo-17α-predan-
4-ene-21,1-fucarboractone-32,7α-(2-hydroxyzolobylthio)-1α,
2α; 15β, 16β-dimethylene-3-oxo-17
α-Zolegn-4-ene-21,17-carbolactone, 36.7α-methoxycardignyl-15α,16α-
Methylene-6-oxo-17α-pregn-4-ene-
21,17-carboractone, 54,7α-methoxycarbonyl-1α, 2α-methylene-3-oxo-17α
-zoregun-4-ene-21.17-carbolactone,
35.7α-ethoxycarbonyl-1α, 2α-methylene-3-oxo-17α-pregn-4-ene-21,
17-carboractone, 36.7α-isopropyloxycarbonyl-1α, 2α-methylene-6-oxo-1
7α-Turequn-4-ene-21,17-carboractone, 37,7α-methoxycarbonyl-1α,2α;15β
, 16β-dimethylene-6-oxo-17α-predan-4-ene-21,1 fucal lactone, 38.7α-ethoxycarbonyl-1α,2α; 15β
, 16β-dimethylene-6-oxo-17α-zoregun-4-ene-21,17-carbolactone, 39, 7α-propoxycarbonyl-1α,2α; 15
β, 16β-dimethylene-6-oxo-17α-zoregun-4-ene-21.17-carbolactone, 40.7α-inpropyloxycarbonyl-1α,2
α; 15β, 16β-dimethylene-3-oxo-17α
-Pregn-4-ene-21゜17-carboractone, 41.7α-methoxycarbonyl-1α, 2α; 15α
, 16α-dimethylene-6-oxo-17α-pregn-4-ene-21,17-carbolactone, 42.7α-methoxycarbonyl-15α, 16α-methylene-6-oxo-17α-pregna-1,4-diene- 21,1 fucarboractone, 43.7α-acetyl-15β, 16β-methylene-6
-oxo-17α-pregun-4-ene-21,17-
Carbolactone, 44.7α-(1-oxopropyl)-15β.

16β-methylene-3-oxo-17α-predan-4
-ene-21,1 fucarboractone, 45,15β,
16β-methylene-6-oxo(25)-17α-(1-oxobutyl)-17α-zoregun-4
-en-21.17-carboractone, 46.7α-acetyl-1α, 2α-methylene-3-oxo-17α-
Predanone--21.17-carbolactone, 47,7α-acetyl-1α, 2α; 15β.

16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-carboractone-48,7α-(1-oxopentyl)-1α.

2α; 15β, 16β-dimethylene-3-oxo-17
α-Lugun-4-ene-21,17-carbolactone.

The following table shows the competition coefficients used in rats as a measure of anti-aldosterone activity and binding to androgen or gestagen receptors.
or:KF).

In this case, the symbol represents the following: (+) Significant adverse effect of the test substance (10) Test substance (8~/animal)/
Significant equivalent effect (10 → ~) of the prototype substance (8 da/mouse) compared to the standard substance
The use of active substances can be carried out in the same way as for spironolactone. The dose of active substance is below spironolactone. Based in part on long-lasting effects,
- It can be administered to sharks once a day. The active substance can be processed into pharmaceutical preparations for enteral administration in the known Gallen formula (1). The excipient contains approximately 50-200 ml of active substance.

According to the invention, the compounds of general formula I according to the invention are prepared by known methods as follows.

When R7 represents a group EIR'(R' is a hydrogen atom), the 7α-thioester of the corresponding general formula When represented by Y (which is an alkyl group optionally substituted by a hydroxyl group), Δ6- of the general formula Adding to the unsaturated compound a thioalcohol of formula ■: [7α-carboxyl compound of] is converted into a C□-C4-alkyl ester, or when R7 represents a group caf (Y′ is an alkyl group having 1 to 4 carbon atoms), A 7α-formyl compound of the general formula (2): 2 and 2' each represent a silyl group] is converted into a metal-organic compound m'-x [where y' represents the above-mentioned compound and X represents lithium or magnesium halide]. ], and the resulting 7α-(1-hydroxyalkyl)-compound of the general formula ■: is treated with an acidic oxidizing agent to eliminate the IJ-1 ether and oxidize it to a hydroxyl group, and optionally Δl. - Introducing double bonds and optionally esterifying free hydroxy groups.

In producing the 7α-mercapto compound (R'2H), the corresponding 7α-thioester (R"-lower alkyl group) of the general formula (2) is saponified by a known method. The formation of lower alkyl radicals R", especially methyl, J-thyl radicals, by using a base in an alcoholic bath such as sodium methylate or -ethylate, is carried out using a base in an alcoholic bath such as sodium methylate or -ethylate. For the preparation of chain-like or branched hook-like alkyl groups with 1 to 6 carbon atoms, optionally substituted by hydroxy groups, Δ6-unsaturated olo compounds of the general formula I are substituted with the formula R"- Add 8H thioalcohol. The reaction is carried out in a basic medium in the presence of a protic solvent, such as methanol or ethanol, at a temperature of 0 to 60°C. The base may be a secondary or tertiary amine such as diethylamine and piperidine.

Esterification of the 7α-carboxyl compound of general formula (1) is carried out by a known method. For example, a 7α-carboxylic acid is reacted with a diazoalkane, such as diazomethane or siadoethane, in a suitable solvent such as diethyl ether, tetrahydrofuran or dioxane or a mixture of these four solvents at a temperature of 0 to 60°C. Subsequently, 1 minute of the diazoalkane is dissolved in an organic acid such as acetic acid or tartaric acid and the solvent is removed from the solution in vacuo.

However, the esterification can be carried out in a known manner using the general formula (A) with a 2'a' chlorosabalic acid alkyl ester, in a suitable solvent such as tetrahydrofuran or dioxane, and in the presence of a tertiary amine such as triethylamine. mixed anhydride (a
oooo-alkyl) and convert this into alcohol R
In other embodiments, for example, dicyclohexylcarboxylate can be directly reacted with the alcohol R'OH by reacting the carboxylic acid with the alcohol R'OH in the presence of a condensing agent such as a diimide. The desired esters of general formula (2) can also be obtained by reacting a carboxylic acid with a halogen alkane such as bromoethane or iodopropane in the presence of silver oxide.

In preparing a compound of formula 1 in which R7 is an oxyalkyl group, the free hydroxy group is silylated to form "C"
Formilization that understands the formula, 4! ! IJ is a metal-organic compound R" to
7α of the general formula ■ was obtained in this way.
The -(1- and 120-xyalkyl)-compounds are silyl ether removed and the hydroxy groups are oxidized using an acidic oxidizing agent.

Silyl groups 2 and 2' can be trialkylsilyl groups, in particular trimethylsilyl or dimethyl-tert-butylsilyl, or triaryl- or triarylalkylsilyl groups, such as triphenyl- and tripentylsilyl groups, furthermore e.g. dimethylsilyl. Also applicable are sialic and kylsilyl groups.

The reaction with the metal-organic compound R"-X is carried out by a known method.

Particularly suitable metal-organic compounds are alkyllithiums such as methyl, ethyl, propyl and butyllithium.

However, metal-organic compounds such as methyl-, ethyl-,
Grignard compounds such as propyl- or zotylmagnesium bromide or -magnesium yoside may also be used.

The reaction is carried out in a solvent such as dialkyl ether, tetrahydrofuran, dioxane, benzene or toluene at room temperature up to the boiling point of the solvent in question.

Silyl ether elimination and hydroxyl group oxidation are carried out with a hostile oxidizing agent. An excellent oxidizing agent is chromium trioxide in acetic acid, such as Jones solution.

The optional subsequent introduction of the Δ1-double bond can be carried out chemically or microbiologically by known methods.
In Example 1, a suitable chemical dehydrogenating agent for dehydrogenating 1,2 is selenium dioxide, 2,6-dichloro-5t6-
Dicyazbenzoquinone, chloranil, thallium triacetate or lead tetraacetate.

For example, suitable microorganisms for 1,2-dehydrogenation are Sahizomyctes, in particular Arthrobacter f4 (Arthrobacter J), for example Arthrobacter simplex
er Simplex) ATOO6946; Bacillus (BaO11uus), such as Bacillus lentus (Bacillus 1entus) ATOo 13
805, Bacillus fistulacus
5phaericus ) ATOo7055; Pseuaomona day, such as Zosoi P% eggplant fist! Luginosa (Pseudomolas a)
erugi-noSa) IFO35Q 5; 7
Flavobacterium
), for example Frapobacterium frappescens (Fl
avobacterium flav-ascens
) It is better to carry out the 1,2-dehydrogenation chemically, such as IPo 5058. At this time, 1,2-dihytalosnaroid is heated to 60-120 degrees OK over a long period of time using a dehydrogenating agent in a suitable solvent. For example, suitable solvents are dioxane, toluene, benzene, tetrahydrofuran, t-butanol and mixtures of these solvents. The reaction was completed after several hours. It may be desirable to follow the reaction by thin layer chromatography; if the starting materials have reacted, work up the reaction mixture.

The optional subsequent esterification of the hydroxy group contained in the substituent P' is carried out by conventional methods of steroid chemistry. The esterification is advantageously carried out using derivatives of lower aliphatic carboxylic acids in the presence of bilicin and/or 4-dimethylaminopyridine. Suitable derivatives in particular are the anhydrides and halides of lower carboxylic acids, especially acetic acid, propionic acid, butyric acid and valeric acid.

The starting compounds necessary to carry out the process of the invention are known (for example from US Pat. No. 4,129,564) or can be prepared by the methods described below.

A, 1α,2α-methylene-3-oxo-17α-pregna-4,6-diene-21,1 In a bath solution of 15.7 g of trimethylsulfoxonium iodide in 1 somg of fucarpolactone dimethyl sulfoxide, under alin. 55% suspension of sodium hydride in mineral oil 2.84,
! Add i' and stir until a clear solution develops.

Subsequently, 6-oxo-17α-zoregnar 1.4.6
-) Liene-21° 10.9 of the 17-carbolactone is added in solid form. Post-treatment is carried out after about 45 minutes by pouring into ice water made weakly acidic with hydrochloric acid. The precipitated product is filtered off, washed with water, dried and then chromatographed using silicic acid gel. 1α,2α-methylene-6-oxo-17 with melting point 25 (69) 6.7 °C after recrystallization from acetone/hexane.
8.73 g of α-pregna-4,6-cyene-21.17-carbolactone are obtained. [α]0=+176°
(in chloroform), TJv: 6 □ 82 = 21100 (
in methanol).

B, 7α-acetylthio-1α,2α-methylene-3-
Oxo-17α-zoregun-4-ene-21.1α12α-methylene-6- in 100 mJ of 17-carbolactone methanol
Oxo-17α-pregna-4,6-ginine-21.1
20.5 mJ of water and 10 ml of thioacetic acid are added to a solution of 5.1 g of 7-carboractone and left at room temperature for 5 hours.

Dilute with ethyl ethyl bicarbonate, wash with IJ solution and water (\sulfuric acid), dry over IJ solution and evaporate in vacuo. The residue is chromatographed on silicic acid gel. 3.28 g were obtained which was recrystallized from dichloromethane/diisozorobyl ether.
7α-acetylthio-1α,2α- with melting point 224.3°C
Methylene-6-oxo-17α(40)-lugun-4-ene-21.17-cal-4-glactone 2
．． 04g is obtained. [α]. -19o0 (in rioo form), Uv: ε235-16000 (in methanol) C,7α-acetylthio-15β,16β-methylene-
6-oxo-17α-pregna-1゜4-diene-21
, 17-cal is the lactone 7α-acetylthio-15β,
16β-methylene-3-oxo-17α-predan-4
1.5 g of -ene-21,1-fucal lactone are boiled for 24 hours with 50 ml of benzene and 1.5 g of 2,6-dicou-5,6-cycyan-1,4-pen-doquinone. The reaction solution is diluted with diethyl ether, washed with sodium bicarbonate solution and water, dried and concentrated by evaporation. The residue is purified by column chromatography using silicic acid gel. 7α-acetylthio-15β, 16β-methylene-6-oxo-17α with melting point 280.6°C
-Pregna-1,4-diene-21,17-carbolactone 820Iv is obtained. [α]o--86° (in chloroform).

D, 7α-acetylthio-1α, 2α; 15α, 16α
-dimethylene-6-oxo-17α-zoregnar-4-ene-21,17-carbolactone 1,15α116α-methylene-3-oxo-17α-
5.0 g of pregna-4,6-diene-21゜17-carbolactone is stirred with 5.0 g of 2,6-dichloro-5,6-dicyan-1,4-benzoquinone in 50 ml of dioxane at 100°C for 6 hours. . After that, the reaction solution is cooled,
The precipitated hydroquinone is filtered off with suction and washed with dioxane. Concentrate most of the filtrate in vacuo.

The residue is taken up in diethyl ether, washed with sodium bicarbonate solution and water, dried and concentrated by evaporation. 15α, 16α- after chromatography on silicate
Methylene-6-oxo-17α-pregna-1,4,6
-Doriene-21.17-carboractone 3.46,
! i! is obtained. Uv:ε222=11250.
ε254-9140, ε299-11500 (in methanol)2. Trimethylsulfoxonium iodide 8.8g
of sodium hydride in 99 ml of dimethyl sulfoxide. ! Stir until i+ (55% oily suspension) and hydride are dissolved. 15α, 16α- under althane
Methylene-6-oxo-17α-! Retanner 1.4.6
-) Lien-21° 2.8 g of 17-carbolactone are added and the mixture is stirred for 2 hours at room temperature. The reaction solution was placed in ice water with stirring, made weakly acidic with 2N sulfuric acid, and the precipitate deposited was collected by filtration. After bathlysis in methylene chloride, it is washed with water, dried and concentrated by evaporation. Chromatography of the residue on silicic acid gel yielded 1α.

2α; 15α, 16α-dimethylene-3-oxo-17
2.1 g of α-pregna-4,6-dinine-21°17-carbolactone is obtained. Uv: ε2sx = 19
500 (in methanol) 6.1αI2α; 15α, 1
6α-dimethylene-3-oxo-17α-pregna-4
, 1.0 g of 6-nonine-21,1 fucarboractone (45) 4 m7 of water in methanol 20 proof! &bithioacetic acid 1.5-
and stir at room temperature for 16 hours. The reaction bath is diluted with diethyl ether, washed with hydrogen carbonate and water, dried and concentrated by evaporation.

The residue is chromatographed on silicic acid gel.

Melting point 246°C after recrystallization from diisozorobyl ether
(under decomposition) 7α-acetylthio-1α, 2α:15α
, 16α-dimethylene-6-oxo-17α-predan-4-ene-21°17-carzalactone 460m& is obtained. Uv: ε234-15600 (in methanol) E, 7α-acetylthio-1α, 2α: 15β, 16
β-dimethylene-6-oxo-17α-pregna-4-
En-21,1 fucarboractone 1, 15β, 16β-methylene-6-oxo-17α-pregna-4°6-diene-2 in 100 ml of toluene
2.6-dichloro-5,6-dicyan-1,4-benzoquinone to 5.0 g of d solution of 1,1 fucal lactone 5.
Add Og and heat to 80° C. for 2 (44) hours. The cooled reaction bath liquid is filtered through silicic acid gel. After washing with diethyl ether,
4.54 g of crude product are produced, which is again chromatographed on silicic acid gel.

Amorphous 15β, 16β-methylene-6-oxo-17α-zoregner 1.4.6-driene-21.17-calzelactone 3.88,! elute i'. [α)D-+ 1
[1° (in chloroform), Uv2 ε22a=1
0000. ε255 = 8 2 0 0, ε3o
1 = 1 [1800 (in methanol) 2, in dimethyl sulfoxide 58-] + 1 methyl sulfoquinnium yoshidro, 09 g solution in solution of ammonium 55-1 suspension of sodium hydride in mineral oil 1 Add .1 g and stir at room temperature for 2 hours. Subsequently, 15β, 16β-methylene-3-oxo-17α-zoregnar 1 + 4 +
6-triene-21,17-carbolactone 6.88
Add 9 in solid form. The reaction mixture is stirred for an additional hour and then poured into ice water. The precipitated product is filtered off, washed with water, dried and chromatographed on silicic acid gel. 5
0 to 60 - diethyl ether/dichloromethane 3.
49,! Elute i' and recrystallize it from dichloromethane/diisozorobyl ether v, melting point 232.
1α, 2α; 15β, 16β-dimethylene-6- at 4°C
Oxo-17α-pregna-4,6-ginine-21.1
7-carboractone 2.25,'7 is obtained. [α
'ID = +198° (in chloroform), Uv: ε28
2=206011 (in methanol) 3. Solution of 4.7 g of 1α, 2α; 15β, 16β-dimethylene-3-oxo-17α-pregna-4,6-dinine-21.17-carbolactone in 1 Brnl of methanol Thioacetic acid at 60℃ 21! The Ll is screened off and stirred at this temperature for 5 hours.

After cooling, dilute with chloroform, wash with sodium bicarbonate and water, dry over magnesium sulfate and concentrate in vacuo. The crude product obtained is purified by column chromatography on silicic acid gel. 7α-acetylthio-1
α, 2α; 15β, 16β-dimethylene-6-oxo-
2.84 g of 17α-predan-4-ene-21,1-fucarboractone are obtained. Melting point 257-259°QS
UV: ε235 = 16600 (in methanol) F, 7α-carboxy-15α, 16α-methylene-6
-oxo-1ph α-pregn-4-ene-21,17-
Carbolactone 1, 15α1 in anhydrous tetrahydrofuran 5 [ ] m/i
16α-methylene-3-oxo-17α-pregna-4
, 25 ml of 1.8 mol diethylaluminum cyanide fl solution in toluene was added to a bath solution containing 6.6 g of 6-dinine-21.1 fucal lactone through a sieve [2 and stirred at room temperature for 4 hours]. For work-up, 50 ml of methanol are added, stirred for 1 hour at 5.degree. C. and 1 hour at room temperature, and the precipitated aluminum salt is filtered off with suction through silicic acid gel, washed with methanol and concentrated in vacuo. The resulting residue was taken up in 30ml of methanol and 1g of potassium carbonate and 1.5ml of potassium carbonate were added.
Stir for an hour. After filtering off the potassium carbonate (47) with suction, it is concentrated in vacuo. The obtained crude product was purified by column chromatography.

2.21 g of 7α-cyan-15α,16α-methylene-3-oxo-17α-predan-4-ene-21°17-carbolactone are obtained. One point 260.2°C1
(α: ID-+45° (in chloroform), Uv: ε2
34-16 (] 00 (in methanol) 2.1lI
7α-cyan- in Q water dichloromethane 10[']m/
15α,16α-methylene-6-oxo-17α-delegen-4-ene-21.17-carbolactone 1.94
21.3 m of a 20% solution of diisobutylaluminum in toluene was added to a solution cooled to 40°C.
/ is sieved and stirred for 90 minutes. For post-treatment, the potassium/sodium tartrate solution was stirred and charged for 30 min.
After stirring for a minute, extract with acetic ester and wash with water to neutralize. After drying over magnesium sulfate, concentrate in air. 1.59 g of 3β 5/-dihydroxy-15α,16α-methylene-4-androstene [(17β-1′)-spiro-2′]Berchgeguchi (48) furan-7α-carbaldehyde is obtained.

3. 3β,5′-dihydroxy-15α,16α-methylene-4-androstene [(
17β-1')-spiro-2']perchrroalane-7
A solution of 1.5 g of .alpha.-carbaldehyde at -1000° C. is sieved with 4.7 ml of Jones solution and stirred for 30 minutes at this temperature. For post-treatment, methanol 0.5-
is added, diluted with acetate, the organic phase is extracted with dilute caustic soda, the aqueous phase is washed with acetate, made acidic with sulfuric acid, extracted with acetate and washed with twice diluted saline solution to make it neutral. . After drying over magnesium sulfate, concentrate in vacuo. 7α-cal-hoxy 15α, 16α-methylene-3-oxo-17α-zoregun-4-en-2
1.17-Carpolactone 696In9 is obtained. U
v: ε24□-14500 (in methanol) G, 7α-
Carboxy-1α,2α-methylene-3-oxo-17
α-Zolegn-4-ene-21.17-Carzalactone 1, 55% suspension of sodium hydride in mineral oil under alyne in a solution of 15.7 g of trimethylsulfoxonium iodide in 150 ml of dimethylsulfoxide i 2. 8
4,! Add i' and stir until a clear solution forms. Then, 3-oxo-17α-pregna-1,4
, 6-) IJen-21,17-carbolactone 10
g in solid form. Post-treatment is carried out after 45 minutes by pouring into ice water that has been slightly acidified with hydrochloric acid. The precipitated product is filtered off, washed with water, dried and then chromatographed on silicic acid gel. 1α,2α-methylene-6-oxo-17α-Lugnar 4,6-dinine-21 with melting point 253.7°C after recrystallization from acetone/hexane.
．． 8.73 & of 17-carbolactones are obtained. [α
) D-+176° (in chloroform), UV: ε28
2-21100 (in methanol) 2, 1α in dimethylformamide 20 punishment.

2α-methyV-3-oxo-17α-preguti4.
6-Dinin-21.17-Cal to a solution of 1.0 g of lactone, potassium cyanide 6oo + a ammonium chloride 65
Add Oda and 2 ml of water and heat to 100°C for 2.5 hours. The reaction mixture is stirred into ice water and the precipitated product is filtered off, washed with water and dried. The crude product is chromatographed on silicic acid gel. Elution of 980■ with 12-15% dichloromethane/acetone, which was recrystallized from dichloromethane/diisozorobyl ether, gave 7α·-cyan-1α.

2α-methylene-3-oxo-17α-pregna-4,
6-cyene-21.17-cal lactone 587 da is obtained. Melting point 244.3°c1 [α)D=+210°(
[in chloroform], Uv: ε231-14000 (in methanol) 6.7α-cyan-1α,2α-methylene-3-oxo-17α-pregna-4,6-diene-2
3.40.9 of the 1,1 fucarboractone is dissolved in 200 mJ of anhydrous toluene. Cool the solution to -50°C,
6511L of 20 Qi solution of Shiibutyral (51) miniram hydride under argon! The mixture was sieved and stirred at -40°C for 1 hour. Thereafter, the excess reaction components are decomposed by adding 5 mJ of amyl alcohol and the reaction mixture is stirred into an ice-cooled potassium/tartaric acid bath.

Extract with acetic acid ester, dry the organic phase with sulfuric acid and evaporate the solvent in vacuo.

6β,5′-dihydroxy-1α as crude product.

2α-methylene-4-an-rostene [(17β-1'
)-spiro-2')perhydrofuran-7α-carbaldehye)-”3.41 g are obtained.

4. 6β,5′-dihydroxy-1α,2α-methylene-4-androstene [(17
β-1′)-spiro-2′]perhydrofuran-7α-
Add 10.4 mJ of Jones reagent to a solution of 3.41 ml of carbaldehyde. After 15 minutes, 1 ml of ethanol is added and the mixture is stirred into ice water saturated with sodium chloride. The organic phase is extracted with sodium sulphate and the bath is evaporated in vacuo. 7α-carboxy-1α as a residue.

(52) 2α-methylene-6-oxo-17α-predan-4-
6.18 g of en-21,1-fucal lactone is obtained.

H,7α-carboxy-1α,2α:15β.

16β-dimethylene-6-oxo-17α-zolegen-4-ene-21.17-carbolactone 1, 15β, 16β-methylene-6-oxo-17α-pregna-4°6-diene-2 in 100 liters of toluene
2,3-
Dichloro-5*6-dicyan-1,4-benzoquinone 5.0.9 is added and heated to 80°C for 20 hours.

The cooled reaction solution is filtered through silicic acid gel. After washing with diethyl ether, the crude product 4.54.9 is obtained, which is chromatographed again on silicic acid gel.

9-12% - amorphous 15 in acetone/dichloromethane
β,16β-methylene-6-oxo-17α-pregna-1,4,6-)liene-21.17-carbolactone 3.88.9 is eluted.

[α]D=+1[]' (in rioo form), Uv: ε2
5δ = 8200, ε3ol = 108 D D (in methanol) 2, dimethylsulfoxy)' 58 ynl to a solution of trimethylsulfoxonium Yoshi IF 6.099 hydrogenated in mineral oil under alyne) + 55 parts of Jium −
Add 1.1 g of the suspension and stir for 2 hours at room temperature. Subsequently, 15β, 16β-methylene-6-oxo-17α-
3.88.9 of Pregna-1,4,6-Doriene-21.17-carbolactone are added in solid form. The reaction mixture is stirred for an additional hour and poured into ice water. The precipitated product is filtered off, washed with water, dried and chromatographed on silica gel. 3.49 for 50-60% diethyl ether/dichloromethane,! 7 was eluted and recrystallized from dichloromethane/diisopropyl ether to give 1α with a melting point of 232.4°C.

2α; 15β, 16β-dimethylene-3-oxo-17
2.25 g of α-pregna-4,6-cyene-21°17-carbolactone are obtained.

[α], -+198° (in chloroform), UV: ε2
82 = 20600 (in methanol) 3.1α, 2
α; 15β, 16β-dimethylene-6-oxo-1 α
-Zolegna-4,6-nonine-21,1 fucarboractone 4. 09 in 8 Dml of dimethylformamide, 3 tl of water and 4.0 ml of potassium cyanide. The Ig and ammonium chloride precipitated products are chromatographed on isolated silicic acid gel. 7α-cyan-1α, 2α; 15β, 16 with 8-1o% acetone/zochloromethane
β-dimethylene-3-oxo-17α-lugun-4-ene-21.17-calM Lacto73-96 Elka is obtained. The sample recrystallized from dichloromethane/diethyl ether is bath melted at 288.2°C. [α), −
+206° (in chloroform), UV; ε2sz-13
700 (in methanol) 4, m 7α-Cyanide (55) in 315 ml of water toluene - 1α, 2α; 15β, 16β-dimethylene-6-oxo-17α-predan-4-ene-21,17-carbolactone 6. A solution of 7 g of diisodecylaluminum under alin at 4D° C. 1. 20% of I II P
Add 37 ym of solution and stir at this temperature for 1 hour. The reaction mixture is added to 200 ml of sodium/potassium tartrate bath solution with stirring. Subsequently extracted with acetic acid ester,
The extracts are dried over sodium sulfate and concentrated in vacuo. The residue is 3β, 5'-dihydroxy-1α, 2α
; 15β, 16β-dimethylene-4-androstene [
(17β-1′)-spiro-7]perhydrofuran-7
Consisting of 3.67.9 α-carbaldehyde.

5, 3β, 5'-dihydroxy-1α, 2α; 15β,
16β-dimethylene-4-androstene [(17β-
1')-spiro-7] perch10 furan-7α-cal is an aldehyde 3.67,! Bath i' in 150 ml of acetone and add 11.5 ml of Jones reagent to the bath solution. After addition of ethanol 1 (56) me, it is poured into ice water and extracted with dichloromethane. The organic phase is washed with bicarbonate solution and water, dried and concentrated in vacuo.

7α-carboxy-1α, 2α; 15β, 16β-dimethylene-3-oxo-17α-zoregun-4-en-2
6.56 g of 1.17-carzalactone are obtained.

L 7α-carboxy-1α, 2α; 15α.

16α-dimethylene-3-oxo-17α-predan-
4-ene-21,1-fucarboractone 1,15α,16α-methylene-6-oxo-17α-
Pregna-4,6-nonine-2111 fucarvlactone 5.0 g in dioxane 50we 2,6-dichloro-5,6-iocyan-1.4-pen-doquinone 5.09
and stir at 100°C for 3 hours. The reaction solution is cooled, the precipitated hydroquinone is filtered off with suction and washed with dioxane. Concentrate most of the filtrate in vacuo. The residue is taken up in diethyl ether, washed with hydrogen carbonate solution and water, dried and concentrated by evaporation. After chromatography on silicic acid gel, 15α, 16α-methylene-6-
Oxo-17α-zoregnar 1.4.6-) Lien-2
1,17-carbolactone 3.46,! i' is obtained. Uv:8gg2=11250, ε254=914[
1, ε20. -11500 (in methanol) 2. 8.8g of trimethylsulfoxonium yoshi and 99mA of dimethylsulfoxyl! Sodium hydride (
55% - oily suspension) 1.39!9 and stir until the hydride is dissolved. After that, 15α, 16 under Alin
α-methylene-6-oxo-17α-zoregnar 1.4
．． 6-Doriene-21.17-carbolactone 2.8I
and after-stirring for 2 hours at room temperature. The reaction bath liquid was placed in ice water with stirring, made weakly acidic with 2N sulfuric acid, and the precipitate was collected by filtration. After dissolving in methylene chloride, it is washed once with water, dried and concentrated by evaporation. The residue is chromatographed on silicic acid gel. 1αI2α; 15α, 16α-dimethylene-6-oxo-17α-pregna-4,6-zoene-21
2.1 g of 17-carboractone are obtained. Uv:ε
281 = 19500 (in methanol) 6.1α1
2α; 15α, 16α-dimethylene-3-oxo-17
1.5 g of α-pregna-4,6-diene-21,1-fucal lactone in 50 ml of anhydrous tetrahydrofuran!
The mixture is stirred at room temperature under alyne for 17 hours with 8.2 ml of a 1.8 mol diethylaluminium cyanide bath solution in toluene. Subsequently, the reaction bath is introduced into a potassium/sodium tartrate bath. The crude product obtained by extraction with diethyl ether is stirred in 58 ml of methanol with 451 n9 of potassium carbonate at room temperature for 2 hours. The bath solution is diluted with ether, washed with water and dried. The residue is chromatographed on silicic acid gel. After rubbing with diisonorovyl ether, 7α-cyan-
1α, 2α: 600 da of 15α, 16α-dimethylene-6-oxo-17α-zolegun-4-ene-21,17-carbolactone are obtained.

(59) 4.7α-cyan-1α,2α; 15α,16α-dimethylene-6-oxo-17α-predan-4-ene-2
620 m9 of 1,17-carbolactone to 115 m9 of toluene
ml! 6.2 ml of 20%-diisobutylaluminum Healy 1 bath solution in toluene and stirred under alyne for 30 minutes at -40°C. Potassium/sodium tartrate
After addition of 10 Qml of solution, extract with acetic acid ester. The organic phase is dried over sulfuric acid and concentrated in vacuo. The residue is 6β,5'-dihydroxy-1α,2
α; Consists of 15α, 16α-dimethylene-4-androstene [(17β-1′)-spiro-2′) perhydrofuran-7α-carbaldehyde r650 da.

5. 3β,5'-dihydroxy-1α,2α:15α,16α-dimethylene- in acetone'IO,6rnl
4-androstene [(17β-1')-spiro2'
]Perhydrofuran-7α-carbaldehyde 560g
Jones reagent (chromium oxide α11267g)
, from 230 mJ of concentrated acid, (60) charged with water and made to 1000 m/) 1 g and 3 at 0°C
Stir for 0 minutes. The dichloromethane is processed, washed with water, dried over sulfuric acid (IJ) and concentrated in vacuo. 7α-carboxy-1α, 2α; 15α, 16 as a residue
α-dimethylene-3-oxo-17α-zoregun-4-
520 da of en-21°17-carbolactone remains.

J, 3,5'-bis(t-butyl-dimethylsilyloxy)-1α,2α-methylene-4-androstene [(
17β-1′)-spiro-7]perhydrofuran-7α
-carbaldehyde 1, dimethylsulfoxy)'15
To a solution of 15.7 g of trimethylsulfonium iodide in 0 mJ is added 2.849 g of a 55 Q suspension of sodium hydride in mineral oil under alyne and stirred until a clear solution forms. Subsequently, 6-oxo-17α-pregna-1,4,6-driene-21°17-carbolactone 10F is added in solid form. Post-treatment is carried out after about 45 minutes by pouring into ice water slightly acidified with hydrochloric acid.

The precipitated product is filtered off, washed with water, dried and then chromatographed on silicic acid gel. After recrystallization from acetone/hexane, the 1α,2α-methylene-3-oxo-17α-pregna-4,6-dinine-21.1 fucal lactone 8.769 is obtained, melting point 253.7°C. [α”] D = +176° (in chloroform), U
v: ε282 = 21100 (in methanol) 2, dimethylformamide) - 1α in 20 yd.

2α-methylene-6-oxo-17α-pregna-4,
To a solution of 1.0 g of 6-diene-21,1-fucarboractone was added 600 mg of potassium cyanide and 65 ammonium chloride.
Add Oda and 2 ml of water and heat to 100° C. for 2.5 hours. The reaction mixture is stirred into ice water and the precipitated product is filtered off, washed with water and dried. The crude product is chromatographed on silicic acid gel. 980μ was eluted from 12-15% dichloromethane/acetone and recrystallized from dichloromethane/diisopropyl ether to give 7α-cyan-1α, 2α-methylene-6-oxo-1
5871 da of 7α-pregna-4,6-dinine-21.17-carvlactone is obtained. Melting point 244.3℃, [
α〕D−+210° (in chloroform), U■: ε2
31-14000 (in methanol) 3.7α-cyan-1α, 2α-methylene-3-oxo-1 phenol 4,6-diene-21,1 fucal lactone 6.4 g dissolved in 200++ tl of anhydrous toluene do. The solution was cooled to -50°C and 39 m of a 20% solution of butylaluminum hydride was added under argon.
1 and stirred for 1 hour at -40°C. After that, the excess reagent is destroyed by adding 5 ml of amyl alcohol and the reaction mixture is stirred into a water-cooled potassium/sodium tartrate solution. Extract with acetic ester, dry the organic phase over sodium sulfate and evaporate the solvent in vacuo. 6β,5′-dihige waxy 1α as crude product,
2α-methylene-4-androstene [(17β-1′
)-spiro-2') perhydrofuran-7α-cal(6
5) 3.41 g of Poaldehyge is obtained.

4.6β,5′-dihydroxy-1α,2α-methylene-4-androstene [(17β-1′)-spiro-2
'] Perhydrofuran-7α-carbaldehye I'1.
1. ! 9 in dimethylformamin r12rnl. To this bath solution, 0.6 g of imida-toru and 1.9 g of t-butyl-dimethylsilyl chloride in 4 ml of dimethylformamide are added to the bath solution while cooling on ice, followed by stirring at room temperature for 3 hours. Pour into ice water, filter off the precipitate and take up in diethyl ether. The solution is washed with water, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on silicic acid gel. When removed with 6-10% diethyl ether/pentane, 6°5'-bis(1-butyl-
dimethylsilyloxy)-1α,2α-methylene-4-
Androstene [(17β-1′)-spiro-2′]perhydrofuran-7α-calgialdehy-860In9
is obtained.

K, 3,5'-bis(t-butyl-dimethylcyclo(64)lyloxy)-1α,2α:15β,16β-dimethylene-4-an10stenC(17β-1')-spiro-
7] Perhyrofuran-7α-carbaldehyr 1, 15β,16β-methylene-3-oxo-17α-zoregner 4°6-nonine-2 in toluene 1100F
1,1 Fucarboractone 5. 5. 2.6-dichloro-5,6-cycyan-1,4-benzoquinone in a solution of DI.
Add 0 g and heat to 80° C. for 20 hours. The cooled reaction solution is filtered through silicic acid gel. After washing with diethyl ether, 4.54 g of crude product are obtained, which is again chromatographed using a silicate filter. 9
Amorphous 15β, 16β-methylene-3-oxo-17α-solegner 1,4°6-driene-21.17-cal♂lactone 6°88.9 is stripped using ~12% acetone/dichloromethane. [αTh-+10 (in chloroform), UV2ε2a3-10000, ε285
-8200,'soz -10800 (in methanol)
2. A solution of 6,09 g of trimethyl sulfoxonium yoshi in dimethyl sulfoxide 513 me and 1.1 g of a suspension of 55 Qi of sodium foliate in mineral oil under alyne.
and stirred at room temperature for 2 hours. Subsequently, 15β,
16β-methylene-6-oxo-17α-pregna-1
,4,6-Doriene-21.17-Calzalactone6.
889 is added in solid form. The reaction mixture is stirred for an additional hour and then poured into ice water. The precipitated product is filtered off, washed with water, dried and chromatographed on silicic acid gel. 3.49 g was removed with 50-60% diethyl ether/dichloromethane, and this was added with dichloromethane/dichloromethane.
When recrystallized from diisozorobyl ether, the melting point is 232.
．． 40C 1α, 2α; 15β, 16β-dimethylene-
6-oxo-1ph α-pregna-4,6-nonine-21
, 1 fucarboractone 2.25.9 is produced. [α
)D-+198° (in chloroform), ・U■: ε2
a2 = 20600 (in methanol) 6.1α, 2α
; 15β, 16β-dimethyleneno 3-oxo-1ph α-
Soregner 4.6-diene-21,1-fucal lactone 4.09 was dissolved in 80 ml of dimethylformamide and added with 3 ml of water F and 4.0 ml of potassium cyanide. [] 9g
Then add 2.0 g of ammonium chloride. 7 of the reaction mixture
The temperature is maintained at 80° C. for a period of time, after which precipitation with water is carried out.

The precipitated product is isolated and chromatographed on silicic acid gel. 7α-cyan-1α with 8-10%-acetone/dichloromethane.

2α; 15β, 16β-dimethylene-3-oxo-17
α-zoregun-4-ene-21.17-carbolactone 3.96,! i' is obtained. The sample recrystallized from dichloromethane/diethyl ether melts at 288.2°C. [αID = + 206° (in chloroform), UV: ε232 = 13700 (in methanol) 4, anhydrous) 7α-cyan-1 of cyan 315 mA”F’
α, 2α; 15β, 16β-dimethylene-6-oxo-
To a solution of 6.7 g of 17α-predan-4-ene-21,17-carbolactone, add 37 ml of 20% -m solution of (67) sobutylaluminium chloride.
g of 4,060 g of alin are added and stirred at this temperature for 1 hour. The reaction mixture is added to 200 iJ of sodium/potassium tartrate bath under stirring. Subsequently, it is extracted with acetic ester, the extract is dried over sodium sulfate and concentrated in vacuo. The residue consists of 6.67 g of 3β,5'-dihydroxy-1α,2α;15β,16β-dimethylene-4-androstene [(17β-1')-spiro-2')perhyfuran-7α-carbaldehyde. .

5. 6β in dimethylformamide-25tnl.

5′-dihydroxy-1α, 2α; 15β, 16β-dimethylene-4-androstene [:(17β-1′)-
Spiro-cucoperhydrofuran-7α-carbaldehyde I' 2.26 g of t-butyl-dimethylsilylchloride 1J in 5rnl of dimethylformamide was added to a bath solution of 2.26 g under ice cooling.
Add 3.3 g of F and stir at room temperature for 2 hours. After precipitation with ice water, the product is filtered off and taken up in diethyl ether. The bath liquid is washed with water (68), dried and concentrated in vacuo. 3.5′-bis(t-butyl-dimethylsilyloxy)-1α,2α;15β,16β-dimethylene-4- as crude product
3.04 g of androstene ((17β-1′)-spiro-7]perhydrofuran-7α-carbaldehyde are obtained.

L. 3.5'-His(1-butyl-dimethylsilyloxy)-1α,2α; 15α,16α-dimethylene-4-
Androstene ((17β-1′)-spiro-2′]perhyrofuran-7α-carpaldehyde 1,15α,16α-methylene-6-oxo-17α-
Pregna-4,6-dinine-21゜5.0 g of 17-carzalactone in 50 yxe of dioxane with 5.0 g of 2,3-dichloro-5,6-cycyan-1,4-benzoquinone
I! and stir at 100°C for 6 hours. The reaction bath liquid is then cooled and the precipitated hydroquinone is filtered off with suction and washed with dioxane. The filtrate is reduced to approximately 7 Ik in vacuo.

The residue is taken up in diethyl ether, washed with sodium bicarbonate solution and water, dried and concentrated by evaporation. 15α, 16α-methylene-6 after chromatography on silicic acid gel
-oxo-17α-zoregna-1,4,6-driene-21.17-carboractone 3.46,! i' is obtained. UV: ε222-1125[], ε254 =9
140, ε299-11500 (in methanol) 2. Add 8.8 g of trimethylsulfoxonium iodide to dimethylsulfoxy in 99 ml of sodium hydride (55
% - Oily Suspension) 1.39 g and stir until the phyllophyte is dissolved. After that, 15α, 16α under Aldef
-methylene-6-oxo-17α-zoregner 1.4.
6-) Add 2.81 liters of citric-21,1-fucarboractone and stir for 2 hours at room temperature. The reaction bath liquid was stirred into ice water, made weakly acidic with 2N sulfuric acid, and the precipitate was collected by filtration. After dissolving in methylene chloride, it is washed with water, dried and concentrated by evaporation. 11 pieces of residue! 1α after gel chromatography.

2α: 15α, 16α-dimethylene-6-oxo 17
2.1 g of α-pregna-4,6-diene-21°17-calactone is obtained. U■2ε2F+1-195
00 (in methanol) 6.1α, 2α: 15α, 16α
-dimethylene-3-oxo-17α-pregna-4,6
1.5 g of nonine-21,1 fucarboractone in 5 Q ml of anhydrous tetrahydro7ran with 8.2 ml of a 1.8 mol diethylaluminum cyanide solution in toluene and 1
Stir at room temperature under aldenone for 7 hours. Subsequently, the reaction solution is added to the potassium/sodium tartrate solution. The crude product obtained by extraction with diethyl ether is stirred in 38 d of methanol with 451 ψ of potassium carbonate for 2 hours at room temperature. The clear liquid is diluted with ether, washed with water and dried. The residue is chromatographed on building silicate. Melting point after rubbing with diisozorobyl ether>300
7α-cyan-1α,2α; 15α,16α-dimethylene-6-oxo-17α-zoregun-4-ene-2 at °C
1°17-carbolactone 600 ~ is obtained.

(71) 4.7α-cyan-1α,2α:15α,16α-dimethylene-6-oxo-17α-zoregun-4-ene-2
1. 620 ml of 17-carpolactone are stirred with 6.2 ml of a 20% diisozotylaluminum solution in 115 ml of toluene at -40 DEG C. under argon.

After addition of 100 mA' of potassium/sodium tartrate bath solution, extraction is carried out with acetic acid ester. The organic phase is dried over sodium sulfate and concentrated in vacuo. The residue is 6β, 5
'-dihydroxy-1α.

2.alpha.;15.alpha.116.alpha.-dimethylene-4-androstene [(17.beta.-1')-spiro-7]perhydrofuran-7.alpha.-carbaldehyde 650 ml.

5, 6β in dimethylformamide-10tne.

5'-dihydroxy-1α,2α:15α,16α-dimethylene-4-androstene [(17β-1′)-spiro-2′]perhyrroalane-7α-carbaldehyp1. o, yLf) Add 4 m of dimethylformamide to the s solution.
Add 0.5 g of imidazole and 1.89 g of (72) t-butyldimethylsilyl chloride in e and stir at room temperature for 3 hours. Pour into ice water, filter off the precipitate and take up in diethyl ether. The solution is washed with water, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed. 6.5'-bis(
t-butyl-dimethylsilyloxy)-1α, 2α; 1
5α,16α-dimethylene-4-androstene [(1
7β-1')-spiro-2']-perhydro7lan-7
750m9 of σ-carbaldehyde is obtained. Example 1 7α-acetylthio-1α, 2α in methanol 37d
-methylene-6-oxo-17α-zoregun-4-en-21.17-cal is added to a solution of 1.0 g of lactone in 5.5 ml of a 1 mol potassium methylate solution in methanol under an argon atmosphere. Add and stir. After 10 minutes, add 1 ml of acetic acid and pour into ice water. The precipitated product is extracted with acetic acid ester. The extracts are washed with water, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on building silicate. Crystalline product 450 using 18-20%-1' ethyl ether/dichloromethane Y
2 is eluted and the product is recrystallized from dichloromethane/diisozolobyl ether. Yield near α-mercapto-1α, 2α-methylene-6-oxo-1ph α-zoregn-4-ene-21,17-carbolacto 73401
1'9° Melting point 239.7°C, [α], = +190° (L Uv in chloroform: '232 = 13100 (in methanol) Example 2 1α,2α-methylene-3-oxo-17α-pregna-4,6 -Diene-21,1 Fucalzelactone 4.0
g'& 40 ml of methanol and 4 d of giberidine. Methanethiol is introduced into this solution from a steel container over a period of 60 minutes while cooling with water. Subsequently, it is left in the room for 15 hours and then the mixture Y is poured into ice water. The precipitated product is filtered off, washed with water, dried and chromatographed over silicate. Elute 2.99 g with 8.8-10.3 acetone/dichloromethane Y and recrystallize it from hexane/dichloromethane/diisozolopyl ether.

Yield: 1α,2α-methylene-7 with melting point 174.0°C
α-Methylthio-6-oxo-17α-zoregun-4-
en-21.17-carbolactone 1.8CN7. Cα
) D=+137° (in chloroform), "V: '2r5
6=13500 (in methanol) (75) Example 6 1 in 50 rnl methanol and 3 ml piperidine
α,2α-methylene-6-oxo-17α-pregna-
4,6-cyene-21.17-carboractone 3.0g
Add 3 rnl of ethanethiol to the solution. The reaction mixture is stirred at room temperature for 15 hours and then poured into ice water.

The precipitated product is filtered off, washed with water and taken up in dichloromethane. The solution is washed with water, dried over sulfuric acid and concentrated in vacuo. The residue is chromatographed on building silicate. Elution of 3.31 g' with acetate/hexane (1:1) and recrystallization from dichloromethane/diisozolobyl ether yielded 7α-ethylthio-1α, 2α-methylene-6-oxo-1α -zoregun-4-ene-21,17-carbolactone 2.4
5,! i' is obtained. Melting point 205.5℃, [α]D
-+115° (in chloroform), UV: ε236 =
13500 (in methanol) Example 4 (76) 1α,2α-methylene-6-oxo-17α-pregna-4,6-dinine-21.1 Fucalzelactone 3.09 was dissolved in 1-propane under the conditions described in Example 3. React with thiol. The reaction product is worked up and purified accordingly. Yield: 1α, 2α-methylene-6-oxo-7α-propylthio-17α-zoregun-4-ene-21,17
-Cal is a lactone 1.57. ii+. Melting point: 191°2°C
, [C1, = +103° (in chloroform), UV: ε
236 = 13800 (in methanol) Example 5 Under the conditions described in Example 3, 1.5 g of 1α,2α-methylene-3-oxo-17α-pregna-4,6-diene-21,1-fucalzelactone 1α, 2α-methylene-3-oxo-7α- in the presence of panthiol
Converted to (2-7” lopyruthio)-17α-zoregun-4-ene-21,17-carboractone. Yield: 89
1 m? , melting point 239.4-C! (Dichloro A/Methane/
(from diisopropyl ether), [α] - +107°
(in riooform), Uv: 6237-14000 (in methanol) Example 6 Under the conditions described in Example 6, 1α,2α-methylene-6-oxo-17α-pregna-4,6-dinine-21.1 fucal 1.0 g of lactone is converted into 7α-butylthio-1α,2α-methylene-3-oxo-17α-zolegun-4-ene-21.17-carbolactone in the presence of 1-butanethiol. Yield near 62■ (from dichloromethane/diisozorobyl ether), [αID=+99
° (in chloroform), Uv: C235K13900 (
Example 7 Under the conditions described in Example 3, 2.0 g of 1α,2α-methylene-6-oxo-17α-pregna-4,6-diene-21,1fucarboractone was dissolved in 2-mercazotoethanol. In the presence of 7α-(2-hydroxyethylthio)-
It is converted into 1α,2α-methylene-6-oxo-17α-pregn-4-ene-21,17-cal-4glactone. Yield: 1.83 g (from dichloromethane/diisozorogyl ether), [α]D=+106° (in chloroform/mu), Uy: '236 = 13650 (in methanol) Example 8 7α- in methanol'l 5 Q ml Acetylthio-3-oxo-17α-pregna-1,4-diene6.
75,! 56.8 ml of a 1 mol potassium methylate solution in methanol is added to the acid solution in step 9 and stirred for 10 minutes under Aldef atmosphere. After addition of 4 ml of concentrated acetic acid, the mixture is stirred into ice water and extracted with diethyl ether. The organic phase is washed with water, dried and concentrated in vacuo. The residue is chromatographed on silicic acid. 18-66 width - 5.09 g'a? with acetate/diethyl ether
7α-mercapto-6-oxo-17α was obtained by elution and recrystallization from ton/diisozolopyl ether
3.87 g of -pregna-1,4-diene-21,17-carmelactone are obtained (79). Melting point 210.8°C, [α]D=+19° (in chloroform), Uv: 6240 = 19900 (in methanol) Example 9 7α-Methylthio-3-oxo-17α-rugun-4-ene-21 in toluene 40+n/ After addition of 2.0 g of 2,6-dichloro-5,6-cycyan-1,4-benzoquinone, a solution of 2.0 g of 17-calzelactone is heated to 80 DEG C. for 20 hours. Then cool and filter. The filtrate is concentrated in vacuo and the residue is chromatographed on silica. Dilute to 880 μm with acetic acid ester and recrystallize from dichloromethane/diisopropyl ether. Yield near α-methylthio-6-oxo-
17α-pregna-1,4-diene-21,17-cal-4-lactone 465 da, melting point 229.4°C, [α]D=
-56° (in chloroform), Uv: 8242 = 154
00 (in methanol) Example 10 (80) 5 m7 of methanol, cooled to 0°C! and 7α-acetylthio-15β, 1 in 13 ml of tetrahydrofuran.
6β-methylene-6-oxo-17α-zoregun-4-
Potassium methyla) in methanol (ZrrLl) to a suspension of lactone 642
Add wvV dropwise and stir after 1 hour. For post-treatment, dilute with dichloromethane, wash with dilute sulfuric acid and water, and add sulfur + 'f.
! Dry over magnesium and concentrate in vacuo. The resulting crude product is purified by missing column chromatography. 7α-mercapto-15β, 16β-methylene-6
-Oxo 17α-zoregun-4-en-21.17-
Cal-zelactone 644■ is obtained. Melting point 246.4
°C, [α] = +58° (in chloroform), Uv:
g236 = 14400 (in methanol) Example 11 Under the conditions described in Example 10, 7α-acetylthio-15
β,16β-methylene-6-oxo-17α-pregna-1,4-diene-21゜17-carzalactone 640
Starting from rv, 7α-mercapto-15β, 16β-
Methylene-3-oxo-17α-pregna-1,4-diene-21,17-calzelactone 2961ψ is obtained. Example 12 Under the conditions described in Example 10, 7α-acetylthio-1α,
2α; 15β, 16β-dimethylene-rhooxo-17
Starting from α-zoregun-4-ene-21,17-calzelactone 73011147, 7α-mercapto-1α
, 2α; 15β.

16β-dimethylene-6-oxo-17α-zoregun-4-ene-21.17-calzelactone 4601v is obtained. Melting point 259.6'O.

[α]D=+180° (in chloroform) Example 16 15β,16β-methylene-6-
Oxo-17α-pregna-4,6-ginine-21.1
1.29 of 7-carmelactone is converted to 15β,16β-methylene-7α-methylthio-6-oxo-17α-zoregun-4-ene-21.17-carzelactone.

Yield: i, oag, melting point 268.7'0 (diisopropy/L/nee f tv color), UV: '238=1
6000 (in methanol) Example 14 15β,16β-methylene-6- under the conditions described in Example 6
Oxo-17α-pre, Buna-4,6-ginine-21.
1 Fucalzelactone 500 ~ Care α-ethylthio-1
5β,16β-methylene-6-oxo-17α-deregun-4-ene-21.17-calzelactone.

Revenue! : 450 da, melting point 261.2"C (diisopropy/
l/x -te/l/kara), UV: g2,8=
16400 (in methanol) Example 15 15β,16β-methylene-6-
Oxo-17α-Lugnar 4,6-Dinin-21.17
-Carbolactone 500 (83) Converted to 15β, 16β-methylene-6-oxo-7α-propylthio-17α-deregun-4-ene-21.17-cal-4glactone with bamboo 1-propanethiol. Yield: 360~, )^ Key point: 259.6℃ (
from acetone), UV: 6241 = 15300 (
(in methanol) Example 16 15β,16β-methylene-6-
Ogin-17α-zoregna-4,6-nonine-21,1
7α-butylthio-15β, 16β-methylene-6-oxo-17α-zolegne-4-ene-21 in the presence of 1-butanethiol
Convert to ゜17 monocal M lactone. Yield: 690In
9. Melting point 262.7℃ (acetone color), UV: 624
□-15600 (in methanol) Example 17 15β, 16β-methylene- in 12rnl dioxane
7α-methylthio-6-oxo-17α-zoregun-4
-En-21.17-Carpora (84) Add 660 da of 2,6-dichloro-5,6-cycyan-1,4-benzoquinone to 600 da of vinegar and add 17
Stir for hours ioo'c. The reaction mixture is diluted with diethyl ether, washed with sodium bicarbonate acid solution and water, dried and concentrated by evaporation. The residue is chromatographed on silicic acid. After drying the diisozolopyl ether, 15β, 16β-methylene-7α-methylthio-3
-oxo-17α-pregna-1,4-diene-21,
17-Cal, Zelactone 145+Q was obtained. Melting point 2
65.3°C, UV: ε244 = 15400 (in methanol) Example 18 15β, 16β-methylene-6 under the conditions described in Example 6
-oxo-17α-pregna-4゜6-diene-21,
15β, 16β-methylene-6 in the presence of 1fucarboractone 5001#'& 2-mercazotoethanol
-oxo-17α-zoregun-4-en-21.17-
Convert to carbolactone. Yield: 530 m9. Melting point 233.2°C (diisozolopyl ether color), U
V: 6238 = 15400 (in methanol) Example 19 7α-(2-hydroxyethylthio)-15β116β-methylene-6-oxo- in 18.5 ml dioxane
17α-zoregun-4-ene-21,17-kaA/Tl
2,6-dichloro-5, in a vinegar solution containing 920 mP of glactone
Add 920 η of 6-cycyan-1,4-benzoquinone and stir at 80° C. for 16 hours. Work-up and isolation of the reaction product is carried out analogously to Example 17. Yield: Melting point 250”C (
7α-(2-hydroxyethylthio)-15β,16β-methylene-6-oxo-17α-pregna-1,4-diene-21,17- (from diisozolopyl ether)
Carbolactone 185m9, Uv:'243=1490
0 (in methanol) Example 20 7α-(2-hydroxyethylthio)-15β, 16β
-methylene-6-oxo-17α-predan-4-ene-21,1 400 m9 of pyridine
．． 6rnl and 0.8ml of acetic anhydride. The f4iHw was released at room temperature for 2.5 hours, and then poured into ice water. The precipitated product is filtered off with suction, washed with water, dried and chromatographed on silicic acid.

After recrystallization from acetone/diisozorobyl ether, 1
111 points 195□ 9℃ 7α-(2-acetoxyethylthio)-15β, 16β-methylene-6-oxo-17
α-Lugun-4-ene-21,17-cal? Lactone 2
75 In9 is obtained.

Uv:'+3s=16150 (in Meta/-/I') Example 2
1 15β,16β-methylene-6 under the conditions described in Example 6
-oxo-17α-pregna-4゜6-diene-21,
1 Fucal 4 Glactone 500 m9 Y 7α-(2
-hydroxyzolobylthio)-15β, 16β-methylene-6-oxo-17α-zoregn-4-ene-21,
Convert to 1(87) 7-cal-4-lactone. Yield: 419 ■, melting point 250.3'O (acetone/diisozorobyl ether color), Uv: '2ge = 16200 (in methanol) Example 22 7α-acetylthio-15α, 16α-methylene-6-
Oxo-17α-pleccono-4-ene-21,17-
Carbolactone 444 mg k' is oxidized under the conditions of Example 8. After chromatography and recrystallization from diisopropyl ether, 7α-mercapto-15α, 16α-
Methylene-6-oxo-17α-zoregun-4-ene-21.17-calzelactone 220~ is obtained. Melting point 215.3'O, UV: 62rh4=14100
(in methanol) Example 23 15α,16α-methylene-6-
Oxo-17α-pregna-4,6-soen-21.1
Fucal, Zelactone 500m? 'React with f2-mercaptoethanol.

(88) Yield: 7α-(2-hydroxyethylthio)-15α,16α-methylene-6-oxo-1 with melting point 213.8°C
7α-zolegen-4-ene-21, 17-calrK rough) 7365mt; 1, Uv: ε240 = 166
50 (in methanol) Example 24 Under the conditions described in Example 6 1α, 2α; 15β.

16β-dimethylene-3-oxo-17α-pregna
4,6-ginine-21.17-carboractone 5001
11fil [react with 2-mercaptoethanol.

Yield near α-(2-hydroxyethylthio)-1α,2
α; 15β, 16β-dimethylene-3-oxo-17α
-Zolegen-4-ene-21.17-CalM-lactone 6
85■, M1235.2℃ (diisozorobyl ether/
from acetone), ty V; aa40 = 127
00 (in methanol) Example 25 Under the conditions described in Example 6 1α, 2α; 15β.

16β-dimethylene-6-oxo-17α-pregna
4,6-ginine-21.17-carboractone 500I
React v with 1-mercapto-propan-2-ol. Reaction time: 6 days, yield near α-(2-hydroxyzolobylthio)-1α, 2α; 15β, 16β-dimethylene-6-oxo-17α-zolegen-4-ene-21
, 17-Cal is a lactone 3451! , melting point 242°C (
from acetone/diisozorobyl ether), UV: g
z3g=13900 (in methanol) Example 26 7α-acetylthio-1α, 2α; 15α.

16α-dimethylene-6-oxo-17α-zoregun-4-ene-21.17-Calzelactone 780Iv is hydrogenated under the conditions of Example 8. 7α-Mercapto- with melting point 234.1°C (from acetone/diisozorobyl ether)
7250 m9 of 1α, 2α; 15α, 16α-dimethylene-6-oxo-17α-zoregun-4-ene-21.17-calzelact are obtained. [JV: '232
"12750 (in methanol) Example 27 1αI2α; 15α116α-dimethylene-6-oxo-17α-pregna-4,6-nonine-21,1-fucal-7]lactone 750019 Reacted with methanethiol as described in Example 2. 7α-Methylthio-1α,2α;15α,16α-dimethylene-6-oxo-17α-zolegn-4-ene- as a biviscous oil.
21,17-Cal Ij Gracto 1540m9, UV: ε
237 = 12900 (in methanol) Example 28 Under the conditions of Example 2 15α, 16α-methylene-6-oxo-17α-pregna-4,6-dinine-21.1 Fucal 4 Glactone 400 #I & melting point 197.6' O(
7α-methylthio-1 (from diisozolopyl ether)
5α,16α-methylene-6-oxo-17α-predan-4-ene-21,1 fucal d-lactone 1901
You can get da. UV: ε23B= 14800 (in methanol (91)) Example 29 1α, 2α; 15α, 16α-dimethylene-6-oxo-17α-pregna-4,6-dinine-21.1 Fucal Diminutolactone 500/lI&' 2- under the conditions of Example 6.
React with mercaptoetashield. Yield: 7α-(2-hydroxyethylthio)-1α, 2α as an oil;
15α,16α-dimethylene-6-oxo-17α-deregn-4-ene-21.17-carbolactone 440
da, UV: ε234=11800 (in methanol) Example 30 1α, 2α; 15β, 16β-dimethylene-6-oxo-17α-pregna-4,6-nonine-21,1fucal is lactone 1.2g Example 20 conditions 1α, 2α; 1 below
5β,16β-dimethylene-7α-methylthio-6-oxo-17α-predan-4-ene-21,1 is converted to fucal 4-glactone. Yield', 875 m9, melting point 1
(92) 21.7°C (from diethyl ether/diisozolopyl ether), [α]. = +118° (in chloroform/mu), Uv: '2sy = 13000 (in methane 1-l) Example 61 1α, 2α; 15β, 16β-dimethylene-6-oxo-17α-pregna-4,6-diene-21 , 1' fucarboractone 1.2 g Example B Under the conditions of 7α-ethylthio-1α, 2α; 15β, 16β-dimethylene-6-
Convert to oxo-17α-zoregun-4-ene-21.17-calzelactone. Yield: 1.0.1 (from dichloromethane/diisozolopyl ether), [α]ゎ=+
109° (in chloroform), Uv: ε2315 =
13700 (in methanol) Example 62 Under the conditions of Example 6, 1α, 2α; 15β, 16β-dimethylene-6-oxo-17α-pregna-4,6-dinine-21. React with 1-ol. Melting point 241.7
'O7α-(6-hydroxypropylthio)-1α,
2α; 15β, 16β-dimethylene-6-oxo-17
275 m9 of α-zoregn-4-ene-21.17-cal lactone is obtained. Uv:6236=14100
(in methanol) Example 63 Under the conditions described in Example 9, 7α-methylthio-15α,1
6α-methylene-6-oxo-17α-lugun-4-ene-21. Starting from 420 m9 of 17-carzelactone, 7α-methylthio-15α116α-methylene-6
-oxo-17α-solegena 1,4-diene-21,
195m9 of the 17-cal lactone is obtained. UV:
'242 = 14500 (methanol) Example 64 7α-carboxy-1 in 10 ml of tetrahydrofuran
5α,16α-methylene-6-oxo-17α-zolegn-4-ene-21.17-carbolactone 690rv
Add the shea/methane solution to the m solution until a yellow color remains. Excess diazomethane is destroyed with acetic acid and concentrated in vacuo. The crude product obtained is purified by Y column chromatography and recrystallized from methanol. 7α-Methoxylic A-gunyl-15α, 16α-methylene-6-
Oxo-17α-zoregun-4-en-21.17-calactone 661m9 is obtained. Melting point 187.4"
C, (α〕ゎ=+9.1°(in chloroform), Uv:
ε240 = l 5200 (in methanol) Example 35 1.2 g of 7α-calgoxy-1α,2α-methylene-3-,oxy-17α-zolegn-4-en-21.17-carvlactone in 40 ml of tetrahydrofuran
To the solution was added 2Qmly of an ethereal diazomethane solution prepared from 750ml of N-nitrosomethylurea. 6
After 0 minutes add 1wt1'i7 of acetic acid and concentrate in vacuo. The residue is chromatographed on silicic acid gel. 60～
47q6-diethyl ether/dichloromethane 8
(95) Release 1 omgvi@ and recrystallize it from dichloromethane/diisopropyl ether. Aperture α-methoxycargonyl-1α,2α-methylene-6-oxo-
17α-zoregun-4-ene-21.17-CalHlactone 5211 da, melting point 268-274”O, (α),
−+156” (in chloroporum), [J v t, e
2zB = 12300 (in methanol) Example 66 7α-calxy 1α,2 in dichloromethane 5me
α-methylene-6-oxo-17α-deregun-4-ene-21.17-cal was added to a solution of 1.2 g of lactone with 4-
Add 4Qmy of dimethylaminopyridine, 6001ψ of dicyclohexylcalzadiimide and 1mA of ethanol.After 15 minutes, the N,N'-dicyclohexylurea formed is filtered off with suction and the filtrate is concentrated by evaporation in vacuo.Residue 7. Chromatography several times at 20-2
4601119 md with 2-thiacetone/hexane
When this is recrystallized from 7 dichloromethane/di(96) isozologyl ether, the melting point is 244.
．． 7α-ethoxylic)zenyl-1α, 2α of 8′O
-methylene-6-oxo-17α-delegen-4-ene-21.17-cal-4-g-lacto 7322+114 il is obtained. [α], = +138° (in Rio o Ho, +mu), UV: '240 = 13400 (in methanol) Example 37 Under the conditions described in Example 6, but using 2-propanol instead of ethanol 7α-carboxy-1α, 2α- at the bottom
Methylene-6-oxo-17α-predan-4-ene-
From 1.0 g of 21,1 fucarboractone to 7α-isozolobyloxycarzenyl-1α,2α-methylene-6-
295 m9 of oxo-17α-zoregun-4-ene-21.17-carbolactone are obtained. -1 point 240~2
42°C, [α) o = +124° (in chloroform),
Uv: '240 = 13700 (yl methanol solution 8 Under the conditions described in Example 2, 7α-cal→Cxy-1α, 2α
;15β,16β-dimethylene-6-oxo-17α-
Zoregun-4-ene-21゜17-calzelactone 1.
React with 30 g'% didiazomethane. The crude product is chromatographed on silicic acid gel. Recrystallization from dichloromethane/diisopropyl ether at 9609 m using acetic acid ester/hexafluoride yields 7α-methoxycarzenyl-1α, 2α; 15β, 16β-dimethylene with a melting point of 260.9”O. -6
-oxo-17α-predan-4-ene-21.1 in fucarloform), UV:! ,,3B=140001' in ethanol) Example 69 7α-carboxy- in 10 ml of dimethylformamide P
1α, 2α; 15β, 16β-dimethylene-6-oxo-17α-zoregun-4-en-21.17-cal was added to a solution of 500 Jv of lactone with 1.0 g of silver C and 2 ml of bromoethane & processed and stirred for 4.5 hours. .

The reaction mixture is filtered and the product in the filtrate is precipitated with ice water. After extraction with dichloromethane, the organic phase was washed with water,
Dry with sodium sulfate and evaporate to dryness in vacuo. The residue is chromatographed on silicic acid gel. 10-12
364 my was obtained with 4-acetone/dichloromethane, and this? Recrystallize from dichloromethane/diisopropyl ether.

Yield near α-ethoxylic, 1 gynyl-1α, 2α; 1
5β,16β-dimethylene-3-oxo-17α-zolegun-4-ene-21.17-cal,zelactone 274
ml, melting point 233.3° C., [α]D=+146° (in chloroform), UV: ε 238-13600 (in methanol) Example 40 Under the conditions described in Example 6, 7α-cal, 1α, 2
α; 15β, 16β-dimethylene-6-oxo-17α
-Predan-4-ene-21゜17 monocal M lactone 7
001 Dana 1-yotono (99) React with lopane. After 60 minutes, it is worked up and chromatographed on silicic acid. Section 61-62 - 520m with acetone/hexane? '／Is this this? 7α-probogicalzenyl-1, recrystallized from dichloromethane/diisopropyl ether, melting point 180.9'C.
α, 2α; 15β, 16β-dimethylene-6-oxo-
17α-predan-4-ene-21,1 fucalzelactone 357111' is produced.

Example 41 7α-carboxy-1α,2α under the conditions described in Example 6;
15β,16β-dimethylene-6-oxo-17α-zolegun-4-ene-21゜17-calzelactone 700
ln is reacted with 2-iodopropane 2.9ral. Work-up and chromatography after 60 minutes.

60-62% - 510+lf with acetone/hexane
Y elution and recrystallization from dichloromethane/diisopropyl ether yielded 7α-isogropyloxycarzanyl-1α,2α:15β,16β(100)-dimethylene-3-oxo-17α-zoregun-4-ene-21.17 -Cal4glactone 428fv is obtained. Melting point: 214.0°C, [α]9=+129° (in chloroform), ” ■: '239 = 15500 (in methanol) Example 42 7α-Calunlgoxy-1α, 2α; 15α, 16α-
Dimethylene-6-oxo-17α-zolegen-4-ene-21.17-cal le lactone 52011Q in Example 2
React with shea and methane under the conditions described in . The crude product is chromatographed and recrystallized from diisopropyl ether. Yield: α-methoxycarzenyl-1α,2α; 15α,16α-dimethylene-6-oxo-17α-zoregun-4-dyne-21.17-carbolactone 272++v, melting point 237.3'0, UV: ε
pr5e = 13400 (in methanol) Example 43 Dioxane 1 (7α-methoxycarza-15α116α-methylene-3-, d-quin-1 phα-
Deregen-4-en-21,17-cal]+? 500 ml of 2,6-dichloro-5,6-cycyan-1,4-benzoquinone is added to a solution of 500 da of lactone and heated to boiling for 16 hours.

After cooling, filter and concentrate in vacuo. The crude product is chromatographed on silicic acid gel with dichloromethane/acetone. 7α-methoxycarbonyl-15α,16
α-methylene-6-oxo-17α-pregna-1,4
-Diene-21,17-calzalactone 220719 is obtained. UV: g24. = 16700 (in methanol) Example 44 7α-Methoxycarzenyl-15α, 16α-methylene-6-oxo 17α-zoregun-4-ene-21.1
7-Carboractone 205 is suspended in chemethanol 2- and stirred with 28 m9 of potassium hydroxide in 0.5 ml of water for 16 hours at room temperature and 1 hour at 60 DEG C. and concentrated in vacuo. The oily mixture obtained is dissolved in a small amount of ethanol and precipitated with diethyl ether. 17β-hyVroxy7α-methoxycarzenyl-15α,16α-methylene-6-oxo-17α-solegun-4-ene-2
120 Iv of 1-cal-4-gonic acid potassium salt are obtained.

Example 45 A, 3°5'-bis(tert-butyl-dimethylsilyloxy)-15 in 30 ml of anhydrous tetrahydrofuran.
β, 16β-methylene-4-angelosten [(17β
-1')-spiro-2]Perpi10Furan-7α-Cal2Zealdehyl'72Q rn9 in a solution of 1.4 mol of methyllithium in diethyl ether l&i4.5
Add 7 drops of ml and stir for 2 hours in a room temperature. For work-up, add saturated ammonium chloride solution, extract with ether and wash with water to neutralize. After drying over magnesium sulfate, Concentrate in vacuo. 6.5'-bis(t
art-dityl-dimethylsilyloxy)-7α-(1
-hydroxyethyl)-15β, 16β-methylene-4
-androstene ((17β-1')-spiro-2')
50 μm of perhydrofuranf were obtained, which was further reacted without purification.
(tart-butyl-dimethylsilyloxy)-7α
-(1-hydroxyethyl)-15β,16β-methylene-4-androstene [(17β-1′)-spiro-
Add 17 drops of 2.5 ml of Jones's solution to a solution of 50 ml of Cucoperhydrofuranf at o'c and stir after stirring. During post-treatment, methanol/I/Q, 5
Add ml Y, dilute with 200rnl of acetic ester, wash with water and make neutral. After drying over magnesium sulphate, it is concentrated in vacuo and the crude product obtained is purified by column chromatography. Melting point 255.7'O7α
-Acetyl-15β, 16β-methylene-3-oxo-
269 m9 of 17α-predan-4-ene-21,1 fucarboractone are obtained. [α]ゎ-+76°(in chloroform), Uv: ε241 = 14175(
Example 46 A, magnesium 36 in 30 ml of tetrahydrofuran
6.5' in Tetrahydrofuran 5d to a Grignard solution prepared from 5 89 and 1.15 ml of ethyl bromide
-bis(tert-butyl-dimethylsilyloxy)-
15β, 16β-methylene-4-an-rostene [(1
7β-1')-spiro-2') perhydrofuran-7
α-Cal? Add 97 drops of aldehy K 620 m and heat under reflux for 2 hours. Saturated ammonium chloride m for post-treatment
Add liquid, dilute with diethyl ether and wash with water to neutralize. After drying over magnesium sulfate, concentrate in vacuo. 6.57-bis(tert-dithyl-dimethylsilyloxy)-7α-(1-hyroxyzotopyr)-15
β, 16β-methylene-4-androstene [(17β
-1')-spiro-2'] Perch P Lofuran 635Iv
4 was added, and this 7 was further reacted without purification.

30 Under the conditions of Example 45B, 3.5'-bis(tart-
(zotyrusomethylsilyloxy)-7α-(1-hydroxypropyl)-15β,16β-methylene-4-androstene ((17β-1′)-spiro-2-perhydrofuran starting from 620 Da, melting point 266 .15 at 9℃
β,16β-methylene-6-oxo-7α-(1-oxozolopyl)-17α-zoregun-4-21.1
270 da of 7-cal lactone is obtained. [α]. =+
65° (in chloroform), UV'', t2t2
= 14700 (in methanol) Example 47 A0 3.5'-bis(ter) under the conditions described in Example 46A
t--1” thyl-dimethylsilyloxy)-15β,
16β-methylene-4-androstene [(17β-1
')-subiroku] perhydrofuran-7α-cal, 720m9 of zelaldehyde and probylmagnesiumderomiP to 6,5'-bis(tart-butyl-dimethylsilyloxy)-7α-(1-hydroxyethyl)-15
β.

16β-methylene-4-androstene ((17β-1
')-spiro-2'] Perch Plofuran 786 da is obtained.

B, 3,5'-bis(tar) under the conditions described in Example 45B.
t-Butyl-dimethylsilyloxy)-7α-(1-hydroxyethyl)-15β, 16β-methylene-4-angerostene ((17β-1′)-spiro-2′) starting from Berg P Lofuran 780Iv, Melting point 258.7
15β of °C.

16β-methylene-6-oxo-7α-(1-oxodetyl)-17α-zolegn-4-en-21.17-calactone 309Iv is obtained. [α]. =54°
(in chloroform), UV: 6241-14500 (
(in methanol) Example 48 A0 6,5'-bis(ter) under the conditions described in Example 45A
t-butyl-dimethylsilyloxy)-1α,2α-methylene-4-androstene [(17β-1′)-spiro-2]perhydrofuran-7α-carzaldehima 7
60 da to 6°5'-his(tert-tethyldimethylsilyloxy)-7α-(1-hydroxyethyl)-
1α, 2α-methylene-4-androstene [(17β
850 mg of -17-spiro-2']perchrofuran are obtained.

81 Under the conditions of Example 45B, 6.57-bis(tert-butyl-dimethylsilyloxy)-7α-(1-hydroxyethyl)-1α,2α-methylene-4-androstene ] Perhydrofuran 840 ln9 to 7α- with melting point 183.7'C (from dichloromethane/diisopropyl ether/hexane)
Acetyl-1α, 2α-methylene-6-oxo-17α
-zoregun-4-ene-21,17-cal is a lactone 2
1 (My is obtained. [α]9=+167° (in chloroform), Uv: '+a1=13000 (in methanol) Example 49 "3+5'-bis(tert-butyl-dimethylsilyloxy)-1α, 2α; 15β, 16β-dimethylene-
4-androstene [:(17β-1')-spiro-7
]Perhylofuran-7α-carbaldehyde 1.5g
6,5'-bis(tart-butyl-dimethylsilyloxy)-7α-(1-hydroxyethyl)-1α,2α;15β,16β-dimethylene- under the conditions of Example Y 45A.
4-Androstene [(17β-1')-Sugirou 2]
Convert to Perch V Lofran. Yield: 1.57g.

81 under the conditions described in Example 45B.
t-butyl-dimethylsilyloxy)-7α-(1-hydroxyethyl)-1α, 2α; 15β, 16β-dimethylene-4-androstene [(17β-1′)-Sugiro 2′] Berch? Starting from LoFlan 1.57g 7
α-acetyl-1α, 2α; 15β, 16β-dimethylene-3-oxo-17α-zoregun-4-ene-21,
252 da of 17-cal lactone is obtained. Melting point 195
．． 5°0 (from dichloromethane/diisozolopyl ether), [α), = +190° (in chloroform), Uv
:'! 23o = 12500 (in methanol) Example 50 A1 Under the conditions of Example 45A 3.5'-bis(tert-butyl-dimethylsilyloxy)-1α, 2α; 15β,
16β-dimethylene-4-androstene [(17β-
1')-Spiro-2']Berch V-furan-7α-Calgaldehyde 3.5'- by reacting 1.5 g with 6 rnl of 1.6 mol of butyl lithium in hexane. Bis(tert-butyl-dimethylsilyloxy)-7α-(1-hydroxypentyl)-1α,2
1.64 g of α;15β,16β-dimethylene-4-androstene [(17β-1′)-spiro-2′] Perch furan is obtained.

B, 3.5'-bis(tert-butyl-dimethylsilyloxy)-7α-(1-hydroxyethyl)-1α,
2α; 15β, 16β-Dimethylene-4-androstene [(17β-1′)-spiro-2] Perch furan 1.64 g was prepared under the conditions of Example 45B as 1α, 2α: 15β,
16β-dimethylene-6-oxo-7α-(1-oxohentyl)-17α-zoregun-4-ene-21.17
- Convert to carbolactone 249 Da. Melting point 236.9
°C (from dichloromethane/diisopropyl ether).

[α19=+154° (in Chloropho/I/lb),”
■: '239 = 12300 (in methanol) Example 51 A3 Under the conditions described in Example 45A, 6,5'-bis(tar
t-butyl-dimethylsilyloxy)-1α, 2α; 1
5α, 16α-dimethylene-4-an1ki Rosten [(
17β-1′)-spiro-2]perhydrofuran-7α
-carbaldehyde 750 m9 to 6,5'-bis(
tθrt-butyl-dimethylsilyloxy)-7α-(
1-hydroxyethyl)-1α, 2α; 15α, 16α
-dimethylene-4-androstene ((17β-1')
- Sugiro 2'] Verhydrofuran 630 da is obtained.

B, 3.5'-bix (tθrt-butyl-dimethylsilyloxy)-7α-(1-hydroxyethyl)-1α
, 2α; 15α, 16α-dimethylene-4-androstene [(17β-1′)-spiro-2]berhydrofuran 6301v”ff 7α-acetyl-1α, 2α; 15α, 16α-dimethylene under the conditions of Example 45B. -3-oxo-17α-zoregn-4-en-21.17-cal is converted to lactone 249Ln9. UV: 8239=1
2000 (in methanol) Example 52 7α-acetyl-15β, 16β-methylene-6-oxo-17α-deregun-4-ene-21,17-calzelactone 2051V' suspended in 2rnl of methanol? Potassium hydroxide 28 da in 0.5 d of Shusase water and 16 da at room temperature
Stir for 1 hour at 60° C. and concentrate in vacuo.

The resulting oil is dissolved in a small amount of ethanol and precipitated with diethyl ether. 7α-acetyl-17β-
Hydroxy-15β, 16β-methylene-6-oxo-
120 da of 17α-zoregun-4-dyne-21-carboxylic acid potassium salt is obtained.

Claims (1)

[Claims] 1. General formula ■: [In the formula ↓? R7 is a group SR'(R' is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may be substituted with a linear or branched hydroxy group or an acyloxy group); or the group 000R" or OOR"(R" is an alkyl group having 1 to 4 carbon atoms) and -oxo-17α-predan-4-ene-21,17
- Carbolactone. The compound according to claim 1, which is 2.7α-mercapto-1α, 2α-methylene-3-oxo-17α-predan-4-ene-21,1 fucarboractone. 3, 7α-ethylthio-1α,2α-methylene-6-
The compound according to claim 1, which is oxo-17α-zoregun-4-ene-21.17-carbolactone. 4.7α-Mercapto-1α, 2α; 15β. The compound according to claim 1, which is 16β-dimethylene-3-oxo-1phα-pregn-4-ene-21,17-carbolactone. 5.7α-methylthio-15β,16β-methicine-3
-oxy-1ph α-pregn-4-ene-21,17-
The compound according to claim 1, which is a carbolactone. 6.7α-methylthio-15β, 16β-methylene-3
-oxo-1ph α-pregna-1°4-zoene ~21.
The compound according to claim 1, which is a 17-carboractone. Z 7α-(2-hydroxyethylthio)-15β, 1
6β-methylene-6-oxo-17α-zoregun-4-
The compound according to claim 1, which is en-21.17-carzalactone. 8.7α-(2-hydroxypropylthio)-15β,
16β-methylene-6-oxo-1ph α-pregun-4
The compound according to claim 1, which is -ene-21,17-carboractone. 9.7α-Methylthio-1α, 2α; 15β. The compound according to claim 1, which is 16β-dimethylene-3-oxo-17α-pregn-4-ene-21,,17-carpora(6) chthon. 10,7α-ethylthio-1α,2α:15β. The compound according to claim 1, which is 16β-dimethylene-3-oxo-1phα-pregn-4-ene-21,17-carbolactone. 11,7α-methylthio-1α,2α; 15α. The compound according to claim 1, which is 16α-dimethylene-6-oxo-17α-zoregun-4-ene-21,17-carbolactone. 12,7α-methoxycarbonyl-15α,16α-methylene-3-oxo-1ph α-zoregun-4-ene-2
The compound according to claim 1, which is a 1,17-carboractone. 13.7α-ethoxycarbonyl-1α,2α-methylene-6-oxo-1phα-zolegne-4-ene-21,
The compound according to claim 1, which is a 17-carboractone. (4) 14.7α-methoxycarbonyl-1α, 2α; 15β
, 16β-dimethylene-3-oxo-1phα-pregn-4-ene-21,17-carbolactone. 15.7α-ethoxycarbonyl-1α, 2α; 15β
, 16β-dimethylene-3-oxo-1phα-zoregn-4-ene-21,17-carboractone. 16.7α-isosorobyloxycarbonyl-1α,2
α; 15β, 16β-dimethylene-3-oxo-1 α
-Pregn-4-ene-21,17-carboractone. 17,7α-methoxycarbonyl-1α,2α; 15α
, 16α-dimethylene-3-oxo-1phα-zoregn-4-ene-21,17-carbolactone. 18, 7α-acetyl-15β, 16β-methylene-3
-oxo-1ph α-zoregun-4-ene-21,17-
The compound according to claim 1, which is a carbolactone. 197α-acetyl-1α, 2α; 15β. The compound according to claim 1, which is 16β-dimethylene-3-mexo-17α-pregn-4-ene-21,17-carbolactone. 20, General formula I: [In the formula, '6 represents an o-o single bond or an a-o double bond or represents a group, R7 represents a group SR'(R' is a hydrogen atom),
In the method for producing 7α-M-converted 3-oxo-17α-predan-4-ene-21,17-carboractone of 1 ≧ Σ or L ni, the corresponding general formula I
7α-substituted 3-thioester of 1: Wasu], and optionally introduces a Δ′-double double bond, and optionally esterifies a free hydroxy group.
Method for producing oxo-17α-zoregun-4-ene-21.17-carboractone. 21, General formula I: (7) [In the formula, 2- represents a 0-0 single bond or a-c double bond, or a group b. R7 is a group SR'(R' is a linear or branched represents an alkyl group which may be tm-substituted with a branched hydroxy group, and "+16 represents a 0-0 single bond or a group) Σ or 1
．． -, -5] of 7α-substituted 3-oxo-17α
In the method for producing -predan-4-ene-21,17-carbolactone, a d6-unsaturated compound of the general formula 1: 7α-substituted 6-oxo-17α-zoregun-4-, which is characterized by the addition of a thioalcoholne (representing a compound), optionally introducing a Δl-double bond, and optionally esterifying a free hydroxy group.
En-21.17-Production method of carbolactone. 22, General formula ■: [In the formula, σ represents an O-0 single bond or a C-0 double bond, or represents a group b, and R7 is a group 000f (f is an alkyl group having 1 to 4 carbon atoms) (is), and or) (represents 2)
7α-substituted 6-oxo-1-phα-delegun-4-ene-21,17-carboxyl compound (!-In the method for producing 7α-carboxyl compound of general formula ■varnish)’Jh Y Ol-04
-conversion into an alkyl ester and optionally introducing a Δ1-double bond and optionally esterifying free hydroxy groups? 7α-substituted 3-oxo-1 as a percentage
7α-zoregun-4-ene-21.17-Carbolactone production method. 23. General formula I: [in the formula, represents an O-0 single bond or a 0-0 double bond, or represents a group R7 is a group oof (m' is an alkyl group having 1 to 4 carbon atoms ), and A: represents an O-a single bond, or a group) S or 11. In the method for producing a 7α-substituted 6-oxo-17α-zoregun-4-ene-21,17-carbolactone of formula V: [formula nakadu and )■ is the above-mentioned one? Representation, 2 and 2
' represents a silyl group] 7α-formyl compound '6-metal organic compound '-X (in the formula, ν' represents the above, and X represents a lithium or magnesium halide 9
The resulting 7α-(1-hydroxyalkyl)-compound of the general formula (1) is treated with an acidic oxidizing agent to eliminate the siliny ether and oxidize the hydroxy group, and optionally A process for producing 7α-substituted 3-oxy-1phα-pregn-4-2-21.17-carbolactone, characterized by introducing a Δl-double bond and optionally esterifying a free bitroxy group. 24, General formula ■: [In the formula, σ represents an a-O single bond or a 0-〇 double bond, or a group, R7 is a group SR'(R' is a hydrogen atom or a linear or branched an alkyl group having 1 to 6 carbon atoms which may be substituted by a branched hydroxy group or an acyloxy group) or a group coof or 00zo/(f is an alkyl group having 1 to 4 carbon atoms); ), and i5 represents an a-O single bond, or a group \ or j,
A pharmaceutical preparation having anti-aldosterone activity containing a 7α-substituted 6-oxo-17α-predan-4-ene-21,1-fucarboractone.