JPS6357438B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides steroidal carboxylic acid lactones, particularly those of the formula (In this formula, R ₁ is an α-acylthio group, and R ₂
is a hydrogen atom) 3-oxo-17α-pregnane-4 represented by
-Ene-21,17-Carboxylic acid lactone production method. The above-mentioned acylthio groups are especially lower acylthio groups, mainly acertylthio groups.

These compounds are known aldosterone antagonists, such as spironolactone [formula ()]
It is a compound in which R ₁ is an acetylthio group, and is sold under the trade name Aldactone A].

Many methods have been proposed in literature and patent specifications for producing the compound of formula (). For example, in J.Am.Chem.Soc., 79, 4808 and U.S. Patent No. 2705712, R ₁ in formula () and
A method for preparing a compound in which R ₂ and R 2 both represent a 6,7-C·C bond is described. This manufacturing method can be carried out as follows (method A).

Corresponding compounds in which R is an acylthio group, especially an acetylthio group, are prepared by reacting a compound of the above formula () with a thiocarboxylic acid, especially a thioacetic acid, for example by the method described in German Patent No. 1 121 610. .

The above-mentioned method for preparing 4,6-diene compounds of formula () should now be considered obsolete due to insufficient yields. The improved method is described in U.S. Patent No.
No. 3738983 and No. 3270008, and is carried out in the following steps (method B).

Further, German Patent Application No. 2237143 describes a method for producing spironolactone according to the following steps (method C).

A variant of this method is described in DE 22 48 834 (Method D) and a further variant in DE 22 48 835 (Method E).

Furthermore, other variants are described in DE 22 51 476 A1. According to this, 3-oxo- which corresponds to the compound of the above formula ()
Starting from a 4,6-diene derivative and adding thioacetic acid to it, the corresponding 3-oxo-7α obtained
-acetylthio-4-ene derivative (this is 17β-
Hydroxy-17α-propionaldehyde (with the acetal side chain intact) is oxidized to spironolactone in an acidic solution. 6, while retaining the substituent at the 17-position in this raw material.
The above patent specification states that it is surprising that thioacetic acid is added to the 7-double bond. The reason is that thioacetic acid in an acidic medium is naturally expected to bring about cyclization as follows.

However, as a result of reexamining this method experimentally,
The above-mentioned 17β-hydroxy-17α- used as a raw material
3- with propionaldehyde acetal side chain
It was found that no oxo-4,6-diene was observed and that it could not be produced even by the method described in DE 2251476 mentioned above. Namely, the above-mentioned German Patent Publications No. 2237143 and No.
3-oxo-4-ene with 17β-hydroxy-17α-propionaldehyde acetal side chain obtained by the method described in German Patent Publication No. 2248834 (cited on page 4 of German Patent Publication No. 251476) was dehydrated with chloranil (carried out by the method described in US Pat. No. 3,137,690, which is also cited in DE 2,251,476, page 4 and experimental example, page 12), but the corresponding 4,6-
No diene was produced, but 4,6-diene, a cyclic derivative produced according to the above process diagram, was produced. In this case, an ether group derived from the alcohol used as a solvent may be present in place of the acetylthio group. Therefore, the method described in DE 2251476 cannot be carried out.

All of the above-mentioned methods for preparing carboxylic acid lactones of formula () are unsatisfactory from the point of view of operating technology. The originally published method A requires reactions that are not well suited for implementation, such as a prolonged carbon dioxide treatment in the second stage and a catalytic hydrogen treatment in the third stage. Furthermore, the yield is extremely low.

In method B, due to work-up operations, the yield is approximately 20% with respect to the dehydro-shrimp androsterone used.
Weight%. Note that this dehydro-epi-androsterone is used as a raw material for producing 17α-ethynyl-androst-5-ene-3β-,17β-diol described in the first step of the process.

For processes (C) to (E), the yields according to the experimental examples of the patent range from 10 to 23% with respect to the dehydro-epi-androsterone used.

The present inventors have found a method for preparing the compound of formula () which has a higher yield than hitherto and which is simpler and more suitable from the point of view of the operating technique than hitherto and which is more reproducible.

The method of the present invention provides 3β,17-dihydroxy-17α-
The acetal of pregnane-5-ene-21-aldehyde is treated with a brominating agent suitable for the bromination of the double bond in a basic to neutral medium, and the 5,6-dibromo compound thus obtained is treated with a basic to neutral medium. After oxidation with a hexavalent chromium compound under neutral conditions to eliminate hydrogen bromide from the product obtained, and after pretreatment of the product thus obtained with a thiocarboxylic acid corresponding to the 7α-acylthio group. , treatment with a hexavalent chromium compound in an acidic solution.

Addition of bromine to the 5,6-double bond of the above-mentioned raw material can be carried out using a brominating agent that can generally add bromine to a double bond. In this case, the reaction is carried out in a basic to neutral medium. This addition reaction can therefore be carried out in a manner known per se, for example by reacting a halogenated hydrocarbon such as an inert solvent such as ethylene chloride or chloroform in a di-lower alkyl-lower alkanoic acid amide such as dimethylformamide. , if desired in the presence of a buffer such as an organic or inorganic base, using bromine or an organic nitrogen base such as pyridine or its C-methyl analogue such as picoline or especially collidine. This can be done using bromine among organic aromatic bases. Bromine forms intermediately with these nitrogenous bases perbromide or perbromide of the hydrohalide salt of this base, for example perbromide of the hydrobromide salt. Such perbromides can also be advantageously used in the bromination reaction according to the invention. In particular, pyridine hydrobromide perbromide is used. In addition, it is advantageous to use bromine in an amount slightly in excess of the theoretical amount required for bromination of the double bond.

In addition to the perbromides of the above-mentioned nitrogen bases or other bases, it is also advantageous to use bromine addition products of ethers, such as cyclic ethers, such as in particular dioxane. In this case as well, the third
It is advantageous to add an aromatic base.

These perbromides or bromine adducts are dissolved in inert organic solvents, such as the solvents mentioned above, as well as ethers, hydrocarbons, alcohols, especially lower aliphatic mono- or dihydric alcohols, such as methanol,
React in ethanol, n-butanol or ethylene glycol.

In addition to the above-mentioned bromine compounds, other bromine addition complexes such as the bromine addition complex of tetramethylammonium bromide can also be used.

Furthermore, it is very advantageous to use pyridine hydrobromide perbromide, which is prepared in a pyridine solution at room temperature, low temperature or high temperature, e.g.
The reaction is carried out at +100°C, preferably between 0 and 20°C.

The 5,6-dibromo addition product thus obtained was
Oxidation with valent chromium compounds such as chromium trioxide or chromic acid should be carried out in a basic to neutral medium. If desired, in this oxidation reaction,
Either the base used in the above bromination reaction, such as pyridine, is added in a sufficient amount so as not to exceed the neutralization point too much, or the bromination reaction mixture obtained in the previous step is mixed with the pyridine chromate solution. Advantageously, this reaction operation is carried out at a temperature of about -10 DEG to +30 DEG C.

Hydrogen bromide can be removed from the chromic acid oxidation reaction product thus obtained by a method known per se. Inorganic basic agents such as lithium salts, especially lithium halides, primarily lithium bromide, and basic salts of alkali metals or alkaline earth metals, such as lithium, sodium, calcium or magnesium carbonates or in the presence of basic carbonates, Use below. In this process, preferably a lower alkyl derivative such as a dialkylamide of a lower aliphatic carboxylic acid, especially dimethylformamide, is used as a solvent at a temperature of from 0 to about 180°C, preferably from 80 to 150°C. For this hydrogen bromide elimination reaction, it is also possible to use aromatic nitrogen-containing bases such as those mentioned above, especially pyridine or collidine.

When hydrogen bromide is eliminated in this way, a 4,6-dien-3-one derivative having a 17α-propionic aldehyde-acetal side chain is produced as a reaction product.

In the second case, a thioalkanoic acid is added to the 4,6-diene derivative obtained by elimination of hydrogen bromide by a method known per se, that is, R ₁ and R ₂ in formula () are Furthermore, it is added by known methods to compounds exhibiting 6,7-C.C bonds and treated with a hexavalent chromium compound in an acidic solution as shown below and then or simultaneously with this addition. be.

The addition reaction of the thiocarboxylic acid to the 4,6-diene derivative is carried out in the above sense by a method known per se, for example by treating the steroid without a solvent with an excess of the thiocarboxylic acid at the time of heating. I can do it. However, when this 4,6-steroid diene is dissolved in a polar solvent, especially an alcohol, mainly a lower alkanol having 1 to 7 carbon atoms,
Add water if desired to obtain approximately 1.5 to 1.5 thiocarboxylic acids.
Higher yields are achieved when reacting with 3.5 mol. The highest yields are achieved when reacting in the absence of water at ~120° C., for example the boiling point of the abovementioned alcohols such as methanol, ethanol, propanol, isopropanol, butanol or pentanol. Most preferably, the temperature is between 50 and 100°C. By this method the desired 7α-acylthio derivatives are obtained in very high yields without significant formation of its 7β-isomer. The thiocarboxylic acids used are in particular lower thioalkanoic acids having 1 to 7 C atoms, such as thioacetic acid, thiopropionic acid or thiovaleric acid.

The acetal used as raw material can be any aliphatic, cycloaliphatic, araliphatic or alicyclic aliphatic alcohol, mainly lower alkanols with 1 to 7 C atoms or lower alkanes with 1 to 7 C atoms. It is derived from diol. Especially 3β,
Ethylene glycol acetal of 17β-dihydroxy-17α-pregnane-5-ene-21-albitedo is used as a raw material.

The 7α-acylthio derivative obtained is treated with a hexavalent chromium compound in an acidic solution, in particular a mineral acid solution. During such treatment, the aldehyde-acetal group is simultaneously deacetalized, followed by cyclization of the propionaldehyde side chain with the 17β-hydroxy group to obtain the cyclic hemyacetal and its oxidation to obtain the corresponding lactone group. occurs. The oxidation is carried out in an acidic solution, in particular in hydrochloric acid or one of the phosphoric acids, or in a lower carboxylic acid such as an alkanecarboxylic acid having 1 to 7 carbon atoms, such as formic acid, acetic acid or propionic acid or one of butyric acid or valeric acid. or with chromium trioxide in a mixture of these acids, with or without further addition of water. Oxidation can also be carried out in organic solvents such as ketones or ethers, such as acetone, dioxane or tetrahydrofuran.
It can also be carried out with or without the addition of water.

If the cyclic hemyacetal is first obtained, it is advantageous to pre-treat it with one of the fried acids before oxidation and then carry out the oxidation in a second step under the conditions just mentioned.

Next, the method of the present invention can be explained using the following process diagram using the production of spironolactone as an example. This process diagram also shows the yield relative to the theoretical yield based on the raw material ('). As can be seen, the total yield of spironolactone' with respect to raw material (') is 47% of theory.

For comparison with conventional methods, such as those described in the above-mentioned German patent application, the preparation of (') from dehydro-epi-androsterone, i.e. dehydro-epi-androsterone is converted into chloropropionaldehyde in the presence of lithium. - must include the preparation of (') adopted in those patent specifications by reacting with an acetal, for example ethylene acetal. The process proceeds with a yield of approximately 60% of theory. If the total yield is converted to % by weight with respect to dehydro-epi-androsterone, then in the preparation of spironolactone according to the process of the invention, as for example in Examples 2 and 7 below, the yield is about 41% by weight. In contrast, as mentioned above, the yields according to methods (C) to (E) above are approximately 10-23% of spironolactone with respect to dehydro-epi-androsterone.
Weight%.

Therefore, insofar as compound (') is prepared from dehydro-epi-androsterone by addition of chloropropionaldehyde-ethylene acetal in the presence of Li, and in this case the new method described below, which is If a special embodiment of the inventive process is employed (which is included within the scope of the invention), the inventive process can give the desired end product in even higher yields. That is,
The inventor has discovered that when dehydro-epi-androsterone is reacted with chloropropionaldehyde acetal in the presence of lithium, if this reaction is followed by steam treatment of the reaction product by methods known per se, a large amount of It was discovered that dehydro-epi-androstetron could be recovered. Dehydro-epi-androsterone and reaction products such as 17α-(3′-ethylenedioxy-propyl)-
Androst-5-ene-3β,17-diols are easily separated from each other from components that do not evaporate in water vapor by conventional purification procedures such as chromatography (e.g. aluminum oxide) and/or crystallization. be able to. The improvements of the present invention with respect to obtaining starting materials, as also explained in Example 5 hereinafter, reduce the yield of, for example, spironolactone as a result of the recovery of the starting material, for example as a result of the recovery of dehydro-epi-androsterone. of the reacted dehydro-ep-androstene.
Can be increased to 50% by weight.

A particular advantage of the process according to the invention is that in the reaction step of the starting materials with the brominating agent, their oxidation step and dehydrobromination step, 4,6-diene-3
It is also the case that the -one intermediate products are formed as unitary compounds that can be easily purified, for example by simple crystallization. On the other hand, 4,6- by formula ()
The above method (C) via the diene-3-one step
In (E), it is difficult to obtain a pure composition of the above structure, since the product is always a mixture of alkoxy compounds that are epimers at the 21a-carbon atom. As a result, the final step purification, for example the purification of spironolactone, is extremely tedious and complex compared to other matters. In contrast, in the final step of the process according to the invention, a product of said quality is obtained. The final step is usually a simple purification, such as crystallization, to obtain a completely pure product.

Furthermore, the method of the present invention has fewer operational steps and is less technical than the aforementioned method (B), that is, the method described in U.S. Pat. It has the advantage of being simple.

The present invention allows starting from the compound obtained at any intermediate step to carry out the remaining process steps, or to carry out the process step or to interrupt the process at any stage, or to produce the raw materials in situ in the reaction. It also concerns the implementation format that allows moreover,
The present invention involves reacting dehydro-epi-androsterone with chloropropionaldehyde acetal in the presence of lithium to produce the raw material and after this reaction, pre-steaming the reaction mixture before unreacted dehydro-epi-androsterone. - also relates to the above-mentioned special embodiment, which consists in recovering androsterone.

Next, the present invention will be explained in more detail with reference to Examples.

Example 1 Dissolve 20g of dehydro-epi-androsterone in 500ml of anhydrous tetrahydrofuran. Add 5.2 g of lithium wire cut into small pieces to this. β-Chloropropionaldehyde-ethylene acetal 38 was then cooled to 0 °C in an ice bath and dissolved in 50 ml of anhydrous tetrahydrofuran while stirring under _N2 gas.
g solution is added dropwise over 15 minutes. At this time, strongly cool (using an ice/salt mixture) so that the reaction temperature does not rise above 10°C. This is stirred for a further 2.5 hours at 0° C. and overnight at room temperature (done under nitrogen gas). Next, excess lithium pieces are separated and the reaction solution is poured into ice water. This is extracted with acetic acid ester and washed with a saturated aqueous solution of NaCl until neutral. The organic phase was dried with Na ₂ SO ₄ and evaporated, the precipitated crude product was combined with 300 g of activity neutral Al ₂ O ₃
Filter. In this case, unreacted reactants and non-steroidal impurities are pre-eluted using a 1:1 mixture 3 of petroleum ether and toluene.
Next, using CH ₂ Cl ₂ as the eluent, 17α-(3′-ethylenedioxy-propyl)-androst-5
19.9 g of -ene-3β,17β-diol is obtained.
It melts at 181-182°C after crystallization from an acetone-petroleum ether mixture. Yield 16.4g
(60.6% of theory). IR: 3600, 3450 cm ^-1 (CH ₂ Cl ₂ ).
NMR: 0.87, s, CH ₃ (18); 1.02, s, CH ₃
(19);3.50,m,CH(3);3.92,m,-
OCH ₂ CH ₂ O―; 4.91, t, J=4, CH(3′);
5.34, m, CH(6) ( _CDCl3 ).

Example 2 17α-(3'-ethylenedioxy-propyl)-
Androst-5-ene-3β,17β-diol 6
g is mixed with 5.4 g of solid pyridine hydrobromide perbromide in 60 ml of pyridine at 0°C.
Stir for 3 hours at 0°C under non-aqueous conditions. One hour after the start of the reaction, CrO ₃ dissolved in 6 ml of H ₂ O was added.
Add 4.5 g dropwise to 45 ml of ice-cooled pyridine while stirring, adjusting the dropping speed so that the temperature inside the flask does not rise above 10°C. The pyridine chromate solution thus produced is stirred at 0° C. until the bromination reaction, which proceeds in parallel, is completed. This pyridine chromate solution is then poured into the bromination reaction solution and stirred for an additional 3 hours at 0°C and overnight at room temperature. A large amount of this
Dilute with CHCl ₃ and wash 4 times with a saturated aqueous solution of NaCl, 10 times with water and again 4 times with a saturated aqueous solution of NaCl.
The organic phase is dried with Na ₂ SO ₄ and evaporated to dryness in vacuo.

The crude oxidation product thus precipitated is repeatedly dissolved in toluene and evaporated in vacuum in order to azeotropically remove residual pyridine. Dissolve this in 108 ml of anhydrous dimethylformamide, add 10.8 g each of LiBr and Li ₂ CO ₃ and heat to 100 °C for 15 minutes while stirring in N ₂ gas.
and leave at this temperature for a further 1 hour and 15 minutes. After that, let it cool and dilute with acetate,
Wash 10 times with water and once with saturated saline. organic phase
Dry with Na ₂ SO ₄ , evaporate in vacuo and filter the evaporation residue through 100 g of neutral Al ₂ O ₃ (activity). First, non-polar impurities are eluted with 500 ml of toluene. Next, what was eluted with acetate was 17β-
Hydroxy-17α-(3'-ethylenedioxy-propyl)-androster-4,6-diene-3-
Consisting of 4.56g of onion. It melts at 132°C after one recrystallization from an acetone/petroleum ether mixture. The yield after recrystallization was 4.44 g (theoretical 74.7
%).

IR: 3570, 3450, 1655 ^{, 1620, 1582cm -1}
_{( CH2Cl2} ). UV: 287 (19700) ( _{C2H5OH solution} ).
NMR: 0.95, s, CH ₃ (18); 1.10, s, CH ₃
(19); Approximately 3.95, m, ―OCH ₂ CH ₂ O―; 4.89, t,
J=4, CH(3′); 5.65, s, CH(4); 6.08, s
(2H), CH(6) + CH(7) (CDCl ₃ ). [α] _D = −6° (1.04, CHCl ₃ ).

Example 3 Dissolve 5 g of 17β-hydroxy-17α-(3'-ethylenedioxy-propyl)-androster-4,6-dien-3-one in 50 ml of methanol at room temperature. Add 7.5 ml of water and 2.5 ml of thioacetic acid to this and stir at room temperature for 3 hours. Add this to _2N of NaHCO3
Pour into an ice-cold aqueous solution of water, extract with acetic acid ester and wash with a saturated aqueous solution of NaCl until neutral. Drying (Na ₂ SO ₄ ) and evaporation in vacuo yields 7α-acetylthio-17β-hydroxy-
5.86 g of 17α-(3'-ethylenedioxy-propyl-androst-4-en-3-one is obtained. [IR: 3450 (wide), 1685, 1670, 1620 cm ^-1
_{( CH2Cl2} ). NMR: 0.92, s, CH ₃ (18); 1.22,
s, CH ₃ (19): 2.33, s, SCOCH ₃ ; 3.94, m,
CH(7)＋―OCH ₂ CH ₂ O―; 4.91, t, J=4,
CH(3′); 5.68, bs, CH(4)(CDCl ₃ )]. Process this as is. 5.86 g of this crude product are dissolved in 200 ml of acetone and cooled to 0°C. To this, 10 ml of 8N CrO ₃ solution in 8N H ₂ SO ₄ is added dropwise with stirring so that the temperature does not exceed 10°C. Then stir at room temperature for 45 minutes. Furthermore, 5 ml of the above CrO ₃ solution was added dropwise at room temperature, and the mixture was further stirred at room temperature for 1 hour. Add 10 ml of methanol to this, stir for another 10 minutes, and then dilute with acetate. The acetate ester phase was washed three times each with saturated aqueous solutions of sodium acetate and common salt, Na ₂ SO ₄
and evaporate in vacuo until dry. 5.5 g of a crystalline crude product are thus obtained. After crystallizing these from methanol at -10℃, the compound melting point
Spironolactone (7α) with 135℃ and 202℃
-Acetylthio-3-oxo-17α-pregnane-4-ene-21,17-carboractone) 2.75g
(51% of theory based on the product of Example 3) is obtained. IR: 1770, 1670~1700 (wide width), 1620cm ^-1
_{( CH2Cl2} ). UV: 240 (19400) ( _{C2H5OH solution} ),
NMR; 0.97, s, CH ₃ (18); 1.20, s, CH ₃
(19); 2.31, s, SCOCH ₃ ; 2.84, 8 signals, J _6.6 = 15, J _6.7 = 4, J _4.6 = 2, CH (6β);
3.97, m, CH(7); 5.68, d, J=2, CH(4)
( _CDCl3 ).

Example 4 Dissolve 1.80 g of 17β-hydroxy-17α-(3'-ethylenedioxy-propyl)-androster-4,6-dien-3-one in 5.1 ml of boiling methanol. To this boiling solution 1 ml of thioacetic acid is added dropwise over 5 minutes and boiled for a further 30 minutes. Cool this and
Dilute with acetate and wash with an aqueous solution of NaHCO ₃ and then with an aqueous solution of NaCl until neutral point. The organic phase is dried with Na ₂ SO ₄ and then evaporated in vacuo. 2.09 g of crude product are thus obtained. This is dissolved in 80 ml of acetone and at 0° C. 4 ml of a solution of 8NCrO ₃ in 8N sulfuric acid is added with stirring. Stir this at room temperature for 1 hour, and then
Add 2 ml of CrO ₃ solution and stir for an additional hour.
It was then taken up in acetic acid ester, washed three times each with saturated aqueous solutions of sodium acetate and NaCl,
Dry with Na ₂ SO ₄ and evaporate to dryness in vacuo. 1.87 g of spironolactone are thus obtained. One recrystallization from a CH ₂ Cl ₂ -methanol mixture gives 1.25 g of pure compound. (Physical data are the same as described in Example 3).

Example 5 Dissolve 20g of dehydro-epi-androsterone in 500ml of anhydrous tetrahydrofuran. Add 5.2 g of lithium wire cut into small pieces to this. β-Chloropropionaldehyde-ethylene acetal 38 was then cooled to 0 °C in an ice bath and dissolved in 50 ml of anhydrous tetrahydrofuran while stirring under _N2 gas.
g solution is added dropwise over 15 minutes. At this time, strongly cool (using an ice/salt mixture) so that the reaction temperature does not rise above 10°C. This is stirred for a further 2.5 hours at 0° C. and overnight at room temperature (done under nitrogen gas). The excess lithium pieces are then separated and poured into ice water and the excess reactants and decomposition products are removed by steam distillation. The residue that is not steam distilled is extracted with methylene chloride. The methylene chloride phase was washed with a saturated aqueous solution of NaCl until neutral;
Dry with Na ₂ SO ₄ and evaporate in vacuo. The crude product precipitated in this way was treated with neutral Al ₂ O ₃ of activity.
Filter over 600g. First, four sections were eluted with one portion of methylene chloride. The column is then eluted in six sections (all 1) with a 4:1 mixture of methylene chloride and acetic acid ester. Evaporation of the third section yields 3.2 g of unreacted crude dehydro-epi-androsterone, which is recrystallized from an acetone-petroleum ether mixture to recover 2.65 g of pure material. From sections 4 to 10, 20.1 g of 17α-(3-ethylenedioxy-propyl)-androst-5-ene-3β,17β-diol was produced. It melts at 181-182°C after crystallization from a methylene chloride/petroleum ether mixture. Yield is 17 g (74% of theory considering recovered material).

Claims (1)

[Claims] Primary formula: (In the formula, R ₁ is an α-acylthio group and R ₂ is a hydrogen atom.) A method for producing a compound represented by 3β,
The acetal of 17-dihydroxy-17α-pregnane-5-ene-21-aldehyde is treated with a brominating agent suitable for the addition of bromine to the double bond in a basic to neutral medium to give the 5,6- A dibromo compound is oxidized with a hexavalent chromium compound under basic to neutral conditions, and the resulting product is pretreated with a thiocarboxylic acid corresponding to a 7α-acylthio group, and then the hexavalent chromium compound is oxidized in an acidic solution. said method comprising treating with. 2. The method according to claim 1 for producing a compound having a group derived from a lower thioalkadic acid having 1 to 7 carbon atoms as the acylthio group R ₁ . 3. The method according to claim 1 for producing a compound having an acetylthio group as the acylthio group R ₁ . 4. The method according to any one of claims 1 to 3, wherein an acetal derived from a lower aliphatic alkanol having 1 to 7 carbon atoms is used as a raw material. 5. The method according to any one of claims 1 to 3, wherein an acetal derived from a lower alkanediol having 1 to 7 carbon atoms is used as a raw material. 6 As a raw material, 3β,17β-dihydroxy-17α
The method according to any one of claims 1 to 3, wherein ethylene glycol acetal of pregnane-5-ene-21-aldehyde is used. 7. The method according to any of claims 1 to 6, wherein bromine is used as the brominating agent in an aromatic tertiary nitrogen base. 8. The method according to any one of claims 1 to 6, wherein a perbrominated product of an aromatic tertiary nitrogen base or a hydrohalide thereof, or a bromine addition product of an ether is used as the brominating agent. 9 Chlorinated lower aliphatic hydrocarbons, ethers, ketones, di-lower alkyl-lower alkanoic acid amides, if desired in the presence of a buffer such as an organic or inorganic base or a tertiary organic aromatic base. 9. The method according to claim 8, wherein the bromination is carried out in 10. A process according to any of claims 1 to 9, in which pyridine hydrobromide perbromide is used in pyridine. 11. The method according to any one of claims 1 to 10, wherein the reaction is carried out at low temperature or room temperature. 12. The method according to claim 10 or 11, wherein the bromination is carried out at 0 to +20°C. 13. A process according to any of claims 1 to 12, wherein the 5,6-dipromo addition product is oxidized with chromium trioxide or with chromic acid in an aromatic tertiary nitrogen base. 14. The method according to claim 13, wherein the oxidation is carried out in the base used in the bromination. 15. A method according to claim 13 or 14, wherein the oxidation is carried out at a temperature of -10 to about +30°C. 16. The method according to claim 14 or 15, wherein pyridine is used as the base. 17 Claims 1 to 1 in which hydrogen bromide is removed by treating the chromic acid oxidation product with an inorganic basic agent
The method described in any of Section 5. 18. The method according to claim 17, wherein lithium halide is used in the presence of a basic salt of an alkali metal or alkaline earth metal. 19. The method according to claim 18, wherein lithium bromide is used in the presence of lithium carbonate. 20 Claim 18, which eliminates hydrogen bromide in dialkylamide of lower aliphatic carboxylic acid
The method according to item 19. 21. The method according to claim 20, which uses dimethylformamide. 22. The method according to any one of claims 19 to 21, wherein the reaction is carried out at 80 to 150°C. 23. The method according to any one of claims 1 to 15, wherein hydrogen bromide is eliminated using a nitrogen-containing aromatic base. 24 Formula () in which R ₁ is an acylthio group and R ₂ is a hydrogen atom from compounds in which R ₁ and R ₂ in formula () both represent a 6,7-C・C bond
By known methods for producing compounds of
24. The method according to any one of claims 1 to 23, wherein a 4,6-dien-3-one derivative having a 17α-propionalbitedo-acetal side chain is treated with a thiocarboxylic acid. 25. The process of claim 24, comprising treatment with about 1.5 to 3.5 moles of thiocarboxylic acid in a lower alkanol having 1 to 7 carbon atoms at 0 to 120°C. 26. The method according to claim 24, which is operated in absolute alcohol at 50-100°C. 27. The method according to any one of claims 24 to 26, wherein the reaction is carried out with a lower thiocarboxylic acid having 1 to 7 carbon atoms. 28 Claim 2 to be reacted with thioacetic acid
The method described in Section 7. 29. The method according to any one of claims 24 to 28, wherein the compound obtained by the method according to any one of claims 24 to 28 is treated with a compound of hexavalent chromium in a mineral acid solution. 30. The method of claim 29, wherein the oxidation is carried out using hexavalent chromium in a sulfuric acid solution, with or without the addition of acetone. 31. Any one of claims 24 to 28, wherein the oxidation of the compound obtained by any of the methods 24 to 28 above is carried out with chromium trioxide in a lower carboxylic acid having 1 to 7 carbon atoms. Method described.