JPS59157100A - 12alpha-substituted pregna-1,4-diene-3,20-dione - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R is H, R<1>CO (R<1> is H, alkyl which may be substituted, aryl which may be substituted), R<2>SO2 (R<2> is alkyl)]. EXAMPLE:12alpha-Hydroxypregna-1,4-diene-3,20-dione. USE:Synthetic intermediate of corticoid, an antiinflammatory. PREPARATION:12alpha-Hydroxypregna-1,4-diene-3-one-20-carbaldehyde of formula IIis acylated with a carboxylic acid of formula: R<1>COOH or its reactive derivative to give 12alpha-acyloxypregna-1,4-diene-3-one-20-carbaldehyde of formula III. The product is allowed to react with a secondary amine such as piperidine to form an enamine of formula IV, which is oxidized with ozone to give a compound of formula I where R is R<1>CO.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 12α-directly converted pregna-1,4-diene-3 represented by the general formula (1,)
, 20-dione.

In the above general formula (1), R represents a hydrogen atom, an RCO group or an RS02 group. Here, R1 is a hydrogen atom; an optionally substituted alkyl group such as a methyl group, a chloromethyl group, an ethyl group, a 2-chloroethyl group, a glopyl group, a hexyl group, an octyl group; or a phenyl group% o-lm
- or p-tolyl group, 0-lm-or L<Up-nitrophenyl group, Os m H or Bp-chlorophenyl group, o-, m- or p-bromphenyl group, α-
or an optionally substituted aryl group such as a β-su7ter group. R2 represents an alkyl group such as a methyl group, ethyl group, butyl group, or octyl group.

The general formula (12α-
substituted pregna-1,4-diene-3,20-dione d,
It is a novel compound that has not been described in known literature and is capable of inducing 12α-hydroquine pregnathyl-1,4.9 It is an intermediate in the synthesis of corticoids, such as prednisone and undredninolone, which have excellent anti-inflammatory effects. It can become a body.

Traditionally, prednisone has been prepared using deoxycholic acid as a starting material and a 20-step process. fj34~
However, this method is not suitable for industrial centers because the millet used is expensive and the process is time consuming.

Some of the present inventors have reported that 12α-hydroxypregnane-1 is based on deoxycholic acid and/or its derivatives.
, 4-die/-3-one-20-carbaldehyde by culturing bacteria belonging to alkaline earth metals in a medium containing thioxycholic acid and/or its salts. 1,4-diene-3-
We have discovered a method for producing 1-20-carbaldehyde with high selectivity and high yield.

One object of the present invention is to provide a new 12α-conversion gunner 1,4-dien-3-one-3,20 which can be derived from 12α-hydroxy 7′regner 1,4-dien-3-one-20-carphaldehyde. - Providing dione.

Another object of the present invention is to provide a novel 12α-substituted phlebnar-1 useful as a synthetic intermediate for various corticoids.
, 4-diene-3,20-dione.

Still another object of the present invention is to provide a novel 12α-substituted pregnar 1,4-diene-3,20-dione as an excellent intermediate for the synthesis of prednisone and glednisolone.

12α-substituted pregna represented by general formula (1) = 1.4
-Diene-3,20-dione can be prepared by the following method.12
α-Hydroquine Regner 1,4-dien-3-one-
Derived from 20-carbaldehyde (% formula %) ([In the formula, Hl and R2 have the same meanings as in Iga formula (1).] That is, 12α-hydroquine pregna-1,4-diene-3-or 20-E Rubalbucht general formula (■) R"coOH124,-01) [wherein ni has the same meaning as in general formula (I)] Carboxylic acid or its reactive visiting conductor, such as acid halide, 12α-acyloquine Regner 1,4-dien-3-off-20-carbaltehyde represented by the general formula (i, l) is obtained by reacting with acid anhydride m etc. by a conventional method.

As a typical reaction example, the reaction between 12α-hydroquine pregna-1,4-dien-3-one-20-carbaldehyde and the chloride of the carboxylic acid represented by the general formula (11,) is carried out using triethylamine. , in the presence of a tertiary amine such as pyridine. This reaction is preferably carried out in a bath medium such as methylene chloride, chloroform, or these and benzene, toluene, ethyl acetate.
Which mixed bath medium is preferably used. Against this! Step 6 is usually carried out at room temperature, but it can also be carried out under heating up to about 60°C, depending on the safety. After the reaction, the reaction mixture is washed with diluted hydrochloric acid, heavy distilled water, water, etc., dried, and then the low boiling point substances are distilled off to obtain the 12α-acyl ocypleg represented by the general formula (ill). A crude product of 4-dien-3-one-20-carbaldehyde is obtained. This crude product can be used as it is in the next reaction.

12α-acyloxybrebner represented by the general formula (U)
An enamine represented by the general formula (Jl) is produced by reacting 1,4-dien-3-one-20-carbaldehyde with a secondary amine such as piperidine, pyrrolidine, or morpholine. The secondary amine has the general formula (III)
12α-acyloquine Regner 1,4-diene-3-, f 7-20-carbaldehyde represented by δ is used in equimolar to 2-fold molar amounts. The water generated during the reaction is removed from the V-6 system under heating and reflux using water such as benzene, toluene, etc. and the sound of a large refrigerant. Although this reaction does not particularly require a catalyst, it can also be carried out in the presence of a catalyst such as *P-toluenesulfone. After the reaction, one Bosu point product is distilled off from the reaction mixture under reduced pressure to obtain a crude enamine product represented by the general formula (J). This crude product? It can be used for the next reaction.

In addition, the enamine represented by the general formula (■) is first 12α
-Hydroxypregna-1,4-dien-3-one-2
0-carbaldehyde and a secondary amine in the above 12
A co-worker showed that the reaction between α-acyloxypregna-1,4-dinin-3-one-20-carbaldehyde and a secondary amine was carried out, and the resulting enakun was expressed by the general formula (formerly a carbonic acid or a reactive fatty acid thereof, preferably an acid anhydride, the above-mentioned 12α-hydroxypregna-1,4-dien-3-off-20-carbaldehyde, and a carboxyl group represented by the general formula C■). They can also be obtained by reaction with acids or other reactive fatty conductors.

12α represented by the general formula (I-a) can be obtained by oxidizing the enamine represented by the general formula C1V) with ozone oxidation or using chromic anhydride, pyridinium chlorochromate, thorium, etc. -Acyloxyl Wagner-
It is possible to obtain 1,4-diene-3,20-dione. The oxidation reaction using chromic anhydride is carried out in a pyridine bath medium. For this combination, a mixture of chromic anhydride and pyridine is gradually added to a pyridine solution in which an enamine represented by general formula (1v) is dissolved, or a mixture of chromic anhydride and pyridine is added to a mixture of chromic anhydride and pyridine represented by general formula (IV). The reaction is carried out by gradually adding a pyridine solution in which the enamine is dissolved. This oxidation reaction is carried out under ice cooling or at room temperature. After anti-KEi, the reaction mixture was diluted with benzene,
After diluting with toluene, etc., and removing solid matter by filtration, add Kigaki Enyui to the 4th solution, and then add benzene,
By extracting with toluene etc. and distilling off the boiling point wJ from the extract, 12α-anluokine-regner 1,4-diene-3,20-dione of general formula (I-a) is obtained. of crude product is obtained.

This crude product is sheathed by silica cage/L column chromatography or sheathed by the mother crystal method, depending on the requirements, to obtain a highly pure product of the general formula (1-a).
α-acyloxypregna-1,4-dinine-3,20
- You can get Zeon.

By subjecting 12α-acyloxypregna-1,4-diene-3,20-dione represented by general formula (1-a) to a normal hydrolysis reaction, 12α-hydroxypropylene/gunar 1,4-diene-3,
20-dione is obtained. For example, this hydrolysis reaction is carried out in a medium such as methanol or ethanol in the presence of water-converted potassium, sodium hydroxide, etc., at very low to moderate temperatures. After the reaction, the reaction mixture was concentrated under reduced pressure, diluted with benzene, toluene, etc., washed with water and 1 liter of dilute salt water, and dried. 12α denoted by (1-b)
A crude product of -hydroxypregna-1,4-diene-3,20-dione is obtained. This crude product can be made into silk by crystallizing it from, for example, ethyl vinegar.

12α-hydroxypregna-1,4-diene-3,2
By passing 0-dione into the sulfonation reaction of n, a sulfonate represented by the general formula (1-C) is obtained. For example, this sulfonation reaction can be carried out by dissolving 12.alpha.-hydroxygnuar 1.4 and in this solution a compound of general formula CV) R2SO2.alpha., where R has the same meaning as in general formula (1). ] Add 1 to 2 moles of the sulfone-depleted chloride shown above to the 12α-hydroxygregner 1,4-diene-3,2°-dione to a temperature of about 80°C depending on the temperature or necessity. It is carried out under heating up to. After the reaction, the reaction mixture was placed in a diluted salt container, and the solution was extracted with benzene, etc., and the extracted residue was washed with cloth salted water, X-carbonated water, water, etc., and after drying, it was washed with a low boiling point like milk. By distilling off the product, a crude product of sulfonate represented by general formula (1-c) is obtained.

A highly pure sulfonate represented by the general formula (1-C) can be obtained by crystallizing this crude product from, for example, ethyl acetate.

12α-direct pregnathoner 1,4 represented by general formula (1)
-12α- which is a raw material for the synthesis of diene-3,20-dione
Hydroxypregna-1,4-dien-3-one-20
- Carbaldehyde is also a new compound that has not been described in known literature, and 12α-hydroxypregna-1,4-dien-3-one-20-carbaldehyde is produced using deoxycholic acid and/or its salt as a substrate. It can be obtained by culturing alkaline earth metals in a medium containing deoxycholic acid and/or Shichi no Weir.

Bacteria belonging to the above alkaline earth metals include Alca faecalis L) 4020- and 15 (Alca faecalis L).
ligenes faecalis L) 4020- to 15)-stock (Imitation Koken Article No. 204). This piece is made of Alcaligenes faecali D4020, which was taken from the soil.
s D 4020) strain (Nikokoken Jokyo No. 182) is a variant strain obtained by mutation treatment.

The characteristics of the 15 strains of Alcaligenes faecalis I) 40201 strain and Alcaligenes faecalis D4020- are listed in the following table.

Based on the chemical properties shown in the above table, one strain of Alcaligenes faecalis D4020m and Alcaligenes faecalis L)4020-K15i was determined.

Alcaligenes faecalis strain D4020 has microscopic findings such as being rod-colored, having periflagella, being negative in Durham staining, and positive in both oxidase and catalase reactions. It must be temperamental, and the lees of the 〇-F' test are oxidative (Oxida).
purge aids manual on titer: native
Based on the 7th and 8th editions of Bacteriology, it is said that the #I value corresponds to alkaline earth metals, fCo, and Alcaligenes faecalis D 4020-11 strain does not standardize Ceratene, and milk is alkaline. It was identified as #1 bacterium belonging to the alkaline Dice-like Faecalis ridge because there was no change other than the following and there was no denitrification reaction. In addition, mutant strains are generally considered to belong to the same species as their host, Alcaligenes faecalis D.
The 4020-15 strain was determined to be a bacterium belonging to the alkaline earth metal 7th grade chalice building.

In the first method for producing 12α-hydroxypregna-1,4-dien-3-one-20-carbaldehyde using the above-mentioned microorganism, thioxycholic acid and/or a salt thereof is used as a substrate. Examples of deoxycholic salts include thioxycholic acid.l) Salts of alkali metals such as rum and potassium, or salts of alkaline earth metals such as calcium and red sea bream and shim. The degree of harshness of thioxycholic acid and/or its salt is usually about 1 to 2.
It may be within the range of 009/43, but from the economic point of view, such as the situation of 12α-hydroquine brebnar-1,4-dien-3-one-20-carbaldehyde to be produced, culture conditions, and operability, approximately A range of 2 to 50 I/min is preferred. The culture method is basically the same as that used for aerobic culture of general microorganisms, but usually a shaking culture method using an adult culture medium or an aerated agitation culture method is used.

The medium uses the above deoxycholic acid and/or its salt as a substrate and 12&-hydroxypregna-1,4-diene-
3-one-20-carbaldehyde is suitable for producing alkaline earth metals since it has a poor nutritional source that can be assimilated. As the carbon source, deoxycholic acid and/or its salt may be used as the sole carbon source, or glucose, glycerin, peptone, meat extract, vinegar extract, etc. may be used in combination with deoxycholic acid and/or its salt. good. As the fc nitrogen source, for example, an inorganic nitrogen source such as ammonium sulfate, ammonium chloride, ammonium phosphate, ammonium nitrate, sodium nitrate, potassium nitrate, or an organic nitrogen source such as polypeptone, begtone, meat extract, etc. is used. In addition, there is no special feature in the zero culture conditions in which inorganic salts such as dipotassium hydrogen phosphate, potassium dihydrate phosphate, and magnesium sulfate are added.
Shaking culture or aerated agitation culture is performed at 25 to 35°C for 10 hours to 7 days.

12α-Hydroxypregna-1,4-dien-3-one-20-carbaldehyde accumulated in the culture medium in this way has a lower solubility in water than the substrate deoxycholic acid or 7-salt. It is extremely small and usually precipitates in the culture medium.

This 12α-hydroxypregna-1,4-diene-3
To separate and collect -one-20-carbaldehyde,
Separate precipitated 12α-hydrogen 1,4-dien-3-one-20-carbaldehyde floating microbial cells from the suspicious culture solution, or Centrifugation is carried out at a rotational speed such that the solid does not disintegrate, and the precipitated 12α-hydroxyprefnar-1,4-dien-3-one-20-alfaltehyde is precipitated, followed by decantation as described above. 12α-hydroxypregna-1,4-diene-3
A method is adopted in which the precipitated
1,4-dien-3-one-20-carbaldehyde has been removed, and bacterial cells and other insoluble components contained in the culture solution are separated and removed by filtration or centrifugation, and the culture filtrate or supernatant is served. After making the culture filtrate or supernatant alkaline by adding an alkali such as water-sensitized sodium, karylem hydroxide, or calunium hydroxide, an organic solvent that dissolves the aldehyde and phase-separates from water, such as ethyl acetate, is used. ,
The 12α-hydroxybrebnar-1 dissolved in the culture solution is extracted by performing an extraction operation using chloroform or a mixture of chloroform and methanol, collecting the obtained extract, and distilling off the solvent. ,4-diene-
The solution is to recover 3-one-20-carbaldehyde. This extraction operation using an organic hot medium can be performed not only on the culture filtrate or supernatant, but also on the culture medium itself. The precipitate or extract obtained by the above method contains 12α-hydroquine brebner-1,4-diene-3.
In addition to -one-20-carbaldehyde, it contains almost no residual substrate thioxycholic acid and/or its salts and by-products, and can easily be recrystallized from a methanol aqueous solution for example with high Nl and 12α-hydroxy Pregna
1,4-dien-3-one-20-carbaldehyde can be obtained.

The sulfonate represented by the general formula (1-c) provided by the present invention is a known compound Brebner-1,4,11(
12) -) Derived from Tzene-3,20-dione.

This desulfonic acid reaction is usually carried out in the presence of a reaction aid (a compound capable of scavenging sulfonic acid) such as potassium acetate, lithium chloride, collidine, and botanical t-butoxide. The general formula (1-
The amount is equivalent to 20 times the molar amount of the sulfonate shown in c). This reaction is preferably carried out in a solvent such as hexamethylphosphoramide, N,N-dimethylformamide, etc., and is usually carried out by heating to a temperature of about 80 to 140°C. Furthermore, the present invention provides that the 12α-acyloxypregna-1,4-diene-3,20-dione represented by the general formula (1-a) can be subjected to a decarboxylation reaction under heating. However, Pregna-1,4,11 (12,1-triene-3,20-dione can be used. Pregna-1,411 (12)
-) Ciprednisone, or even glednisolone, can be derived from ciprednisone or glednisolone by a conventional method, for example, as shown in the following reaction formula.

The present invention will be specifically explained below using examples and reference examples.

Reference Example 1 Medium 1 (composition: theoxycholic acid 0.5%, sodium hydroxide 0.05%, peptone 0.5%, yeast extract 0.
Alcaligenes faecalis D40 grown on slants of 5% sodium chloride, 0.5% sodium chloride and 1.5% agar).
A loopful of 20 bacterial strains was prepared in a test tube in advance in medium 2.
(Composition: 2% deoxycholic acid, 0.0% sodium hydroxide.
2%, ammonium nitrate 0.2m, phosphorus dihydrogen potassium 0.1%, hydrogen phosphate dipotassium 0.6%, magnesium sulfate/'ll water 111m 0.02%, and yeast extract 0
．． 02%) and 8-101#j at 30℃.
The cells were incubated with intermittent shaking. Culture medium 3 (composition: thioxycol & 0.5%
, sodium hydroxide 0.05%, glucose 0.1%,
Ammonium nitrate 0.2%, Karylem dihydrogen phosphate 0.1
%, Phosphate hydrogen dipotassium 0.6%, Magnesium sulfate.
Heptahydrate 0.02% and yeast x Ki', < 0.02
%) and cultured at 30°C for 10-15 hours. Next, the bacterial cells in the logarithmic growth phase were collected by sterile filtration using a 0.45μ membrane filter, and
x ■ Phosphate buffer a (1)) i: 7.0 ) 20rt
After washing with rl, the cells were turbid with 25 dKi of the same buffer. Add N-methyl=N to this so that the final degree is 20μ9/lri.
'-nitro N-tetronguanidine was added, 30
Mutations were carried out by shaking for 10-15 minutes at <RTIgt;C. The mutant-treated bacterial cells were collected by filtration with a 0.45 μ membrane filter, washed with 2 ow of 0.1 M phosphate buffer (pH 47,0), and then washed with 2 ow of the same buffer.
1. The obtained bacterial suspension was diluted with sterile physiological saline and mixed into medium 4 (composition).

Deoxycholic acid 0.5%, sodium hydroxide 0.05
H, ammonium nitrate 0.2%, phosphorus dihydrogen potassium 0
．． 1%, dipotassium hydrogen phosphate 0.6%, magnesium sulfate heptahydrate 0.02%, yeast extract 0.02% and agar 1.5%). After applying it so that it appears, it is heated to 30°C.
Cultured for ~4 days. After separating the microcolonies that appeared on the slant of medium 1, the platinum loop was prepared in advance in a test tube in medium 5 (composition: 0 deoxycholic acid).
．． 2%, sodium hydroxide 0.02%, crucose 0.
1%, ammonium nitrate 0.2%, potassium dihydrogen phosphate 0.1%, dipotassium hydrogen phosphate 0.6%, magnesium sulfate heptahydrate 0.02 t and yeast extract 0.02 t)
The cells were inoculated on 10 days of the culture, and cultured with shaking at 30°C for 24 hours. The products in each culture solution obtained were examined by thin-layer talomadography, and 12α-hydroxypregna-1,4-dien-3-one-20-
We found a strain B that selectively accumulates carbaldehyde and used it as Alcaligenes faecalis D4020.
It was named 15.

Reference Example 2 Alkaliguis faecalis D4020- was cultured with 15@strain (Feikokenjo Kyori No. 204) by the following method. Deoquincholic acid i, oi,! Lucose 0.1g1 Ammonium nitrate 0.2g, Potassium phosphate dihydrate 0.12
．． 9, Dipotassium hydrogen phosphate o, 6iL'4A * Magosium heptahydrolyte 0.02 II, Yeast extract 0.0
Add tap water to 29 and 0.1 g of sodium hydroxide to make a volume of 100 m1 (pfi: 8-4) Kn
MS cholera kmt. This medium was placed in a 5001 volume Sakaro flask and steam sterilized at 120°C for 15 minutes. 10 d of seeds were grown in advance in a test tube shaker in the same medium as above for 1 day, and added to the above 5001 Yosaka Lough flask, and cultured with shaking at 30°C for 2 days. ○ After culturing, this culture solution was collected. A mixture of precipitates and bacterial cells produced during culture was separated from the culture supernatant using a centrifugal separator.

The pH of this solution was adjusted to 9 by adding 1N aqueous sodium hydroxide solution to this mixture, and then this solution was extracted with 200 ttl of ether acetate. On the other hand, a 1N aqueous sodium hydroxide solution was added to the culture supernatant, and after the solution was adjusted to 9V3, the solution was extracted with 200d of ethyl acetate. A mixed solution of this extract and the extract obtained above was dried over anhydrous sodium sulfate, and ethyl acetate was distilled off using a rotary evaporator.
-one-20-carpaldehyde was obtained.

Take a portion of the obtained 12α-hydroxypregna-1,4-dinin-3-one-20-carbaldehyde9, add methanol to it to make a 1% solution, and add 25μ of this solution.
High performance liquid chromatography equipped with a Microbondapak C-18 column (manufactured by Waters, USA, HL
C-GPC-244 type). pH as mobile phase
A mixed solution of water/methanol with a volume ratio of '25/75 adjusted to 4.0 was flowed at a flow rate of 1 to 7 minutes, and detection was performed using a refractive index method. The area ratio of each peak in the obtained liquid chromatograph was determined using a fraction meter (Takagura Chromato Pack c-glA, manufactured by Takagura Seisakusho), and from this area ratio, the above 12α-hydroxypregna-1,4-diene was determined. -3-one-20-
The purity of carbaldehyde was determined to be 96.

, 12α-hydroxypregna-1,4 obtained above
-Dien-3-one-20-carbaldehyde was identified by the following method.

Melting point = 194-201°C Mass spectrum/l/rn/Z: 342 (M)”
.

324 [M-)i20]"3091:M-H2O-CHa]" Ma/kom/Z=121 and 122 3-keto 1,4
-The presence of diene was confirmed.

NMR smoothness (90MHz) δDMSO-ds
.

) IMS' 0.71 (3Js) 18-CkLg 1.09 (3M, cQ21-CHs l, 17 (3M, a) 19-CIEL33.83 (I
n, z, J = 3Mz) 12β-H4,33 (IH, d)
12α-0H 5,95 (in, S) 4-J-r 6.08 (IH, d, J=10Hz) 2-H7,08 (
I H+ d + J = 10 Hz) 1-H9,
56(1)1,5)22-CHO Example 1 342 g of 12α-hydroxys V gunar 1,4-dien-3-one-20-carbaldehyde was added to 3 g of methylene chloride.
Dissolve 00ml of water in the bath and add acenal chloride 23.6F to this solution.
and 27.7 f of pyridine were added, and the mixture was stirred at room temperature for 5 hours. After adding 300 mJ of methylene chloride to the resulting reaction solution, this solution was first washed with diluted hydrochloric acid and water, and dried over anhydrous magnesium chloride. By distilling off low-boiling substances from this bath liquid under reduced pressure, the traceability of the p1 candy-like 12α-acetoxypregnathic acid-1,4-dien-3-one-20-alpaldehyde was achieved. Nko. This crude product was fed to a Sanzen 300 bath, and this bath solution was poured into a 2J tube.
, 3y>, and the water produced in the presence of benzene was heated and reduced for 3 hours to obtain 7c0. The resulting reaction solution was heated under ship pressure to obtain a candy-like 12α.
A crude product of -acetoquine-22-(biveridyl)bistrue-i, 4.20(22)-cholatrien-3-one was obtained. This crude product was bathed in 180 mJVC of pyridine, and this solution was mixed with chromic anhydride 20.02 and pyridine 2.
After gradually adding the mixture with 50% of the mixture at room temperature, the mixture was stirred as it was for 1 hour. Be/cene 1 was added to the reaction solution, solids were removed from this solution by filtration, diluted hydrochloric acid was added to the filtrate, benzene was extracted optically, and benzene t* was washed sequentially with diluted hydrochloric acid and water. . Low-boiling substances were distilled off from this solution under reduced pressure, and the resulting residue was subjected to a preparative liquid chromatograph 1-[Waters Corporation H1PrepLC/
System 500. Prep PAK”500/
12α-acetoxypregna-1,4-diene having the following physical properties was purified using a SI LI CA column using a mixed solvent of isopropyl alcohol/n-hexane = 20/80 (volume). -3,
Obtained 9.12 crystals of 20-dione 0 Melting point = 175-176°C CDα3°NMR spectrum (9QMHz) δMMS '0.7
6, 1.20.2.0.2.06 (each s,
each 3H) ;5.10~5.22 (m, L
H); 6.07 (bs, In); 6.18.
6.20(each d, li(,) ;6.93(
d, IH) Example 2 2.22 potassium hydroxide was dissolved in 8 Q ml of methanol, 7.4 v of 12α-acetoxypregna-1,4-diene-3,20-dione was added to this solution, and the solution was heated to 10 Stir for hours. The resulting reaction solution was distilled off with methanol (!) under reduced pressure, and the reaction solution was concentrated to about 1/10. The reaction solution was treated with benzene for 1 s, and the solution was diluted with water, diluted hydrochloric acid, and water. The solution was washed successively and dried over anhydrous magnesium sulfate. Low-boiling substances were distilled off from this solution under reduced pressure.
When the obtained residue was recrystallized from ethyl acetate, 12α-hydroxy pregnathyl chloride having the following physical properties was obtained.
5.42 of 1,4-diene-3,20-dione was obtained. The purity of this product was determined by gas chromatography analysis, and it was found to be 90%.
S' 0.69.1.17.2.14 (each s, ea
ch 3H) ;4.04-4.16(m, If(,
): 6.06 (bs, lJ; 6.16. ti,
1g (eacll d, IH); 7.03(d)1)
1,1 Example 3 12α-hydroxypregna-1,4-diene-3,2
Dissolve 3.32 ml of 0-dione in 7 ml of dione, and add 3.41 ml of methanesulfonic acid chloride to this solution.
was added and stirred at room temperature for 8 hours. Pour the resulting reaction solution into 300 ml of 300 ml of benzene and add 300 ml of benzene.
Extracted twice. The extract was first washed with diluted hydrochloric acid, sodium bicarbonate, and water, and dried over anhydrous magnesium sulfate. By distilling off low-boiling substances from this extract under reduced pressure, 12α-
A crude product of 3,8F mesyloxopregna-1,4-diene to 3,20-dione was obtained.

The physical properties of the crude product obtained by recrystallizing it from ethyl acetate are shown below. "Melting point, 185-186 °C NMR spectrum (90 MfiJ δCDα3:MS O, 82,1,18,2,10,2,96 (each
s, each 3H); 5.04-5.1 also (m,
1iL); 6.05 (bs, IH) 6.19.6.2
1 (each d, LH); 6.95 (d, IJ Examples 4 to 8 In Example 1, propionyl chloride, n-butyryl chloride, benzoyl chloride, p-chlorobenzoyl chloride or chloroacetyl chloride was used instead of acetyl chloride. The reaction was carried out in the same manner except that 12α-(n-
butyryloxy)pregna-1,4-diene-3,20
-dione, 12α-penzoyl ookine pregna-1,4
-diene-3,20-dione, 12α-(p-chlorobenzoyluoquine)pregna-1,4-diene-3,2o
-dione and 12α~ (chloracetquine) pregna-
1,4-cy,r-3,2o-dione was obtained. The physical properties of these products are shown below.

Melting point: 172-173℃ NMR, :<　Pek) Lu (90MHz) δCDα°.

HM, S' tJ, 75.2. QO(each s, each 3
B) ;1.1(J, 1.20(t, s, 6)i)
;5.10-5.22 (m, LH) ;6.07
(bs, IH); 6.18.6.20 (each
d, LM, ); 6.93 (d, LH) Melting point: 14
3-144°C NMR subekhk(90M)lz)l;CDα3・fi
gs ゛0.75.1.18.1.99 (each s, ea
ch 3H); 0.88 (t+3h); 5
．． 10~5.22 (my I H)'+6.07(
ba, IH) ;6.17.6.19 (each
d, IH); 6゜92 (a, 1m) NMR SHE') /l/ (901VIHz)δ
CDα3゜HMS' 0.84. 1.21. ],,97(each s
, each 3H); 5.38-5.50 (m, L
H): 6.03 to 6.22 (m, 2 to 6.90 (d, 1
fi); 7.32-7.71 (m, 7.92-8 for 3H
．． 17 (m, 2H) NMR spectrum (90 MI
H2) δCDQ'a゛HMS' 0.84. 1.20. 1.97 (each s,
each 3H); 5.37-5.48 (m, 1)
1); 6.02~6.21 (m, 2f-1)
; 6.89 (d, IH); 7.41 (d, 7.9 on 2
2 (d, 2H) FD MaSS Spect/'(m/Z): 405(M
+1:)"311[:M+1-αCH2C02H]'"
Example 9 n instead of methanesulfonic acid chloride in Example 3
12α-(n
-butylsulfonyloxy)pregna-1,4-diene-3,2o-dione was obtained.

This product was analyzed by the following FD MasB spectrum.

B″D Mass y, vector (m/Z): 44
9 [M+1]" 311 [M+1-CHa(CH2)3SOaH)" Reference Example 3 Pregna-1,4,11(1,2)-Toluene-3,2
Synthesis of 0-dione 12α-menloxy pregner 14-diene-3,2
0-Geo 73. O? f Hexamethylphosphortriamide was dissolved in 60 g of fresh water, 7.22 g of acetic acid was added to the solution, and the mixture was stirred at a temperature of 120° C. for 5 hours. Add 300 g of dilute salt water to the obtained reaction number, and add 200 g of benzene.
Extract 3 times with /ko. Add the extract to dilute hydrochloric acid water 1. It was washed with water and dried over anhydrous 7 um sulfate. From this extract, the products that were obtained by distillation were distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluent: acetone and
- Pregnane 1,4,11 having the following physical properties was purified by a mixed solution of hexane with a volume ratio of 4:6, and then crystallized from +'4 M ethyl acetate.
(12) -Triene-3,20-dione crystal 1,
I got 62.

Melting point = 167-169°C CDQ! a.

NMR spectrum (9Q R4Hz) δHMs'0.
74.1.17.2.15 (each s, each
3H); 5.66(d, 1)L); 6.0?・-6
, 40 (m, 3H); 7.12 (d, 1l-1) License applicant Rira Co., Ltd. Representative patent attorney Ken Honda

Claims (1)

[Claims] 1. General formula (wherein R represents a hydrogen atom, R"CO group, or R2SO2 group, where 'kC1 is a hydrogen atom, an optionally substituted alkyl group, or a substituted 12 represents a good aryl group and R2 represents an alkyl group)
α-substituted pregna-1,4-diene-3,20-dione. 2. 12α-acyloquine Regner 1,4-diene-3 represented by the general formula (wherein Hl represents a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl group) , 20-dione 12α-substituted Brebner-1,4-diene-3,20 according to claim 8 (1)
-Geo/. 3,12α-hydroxy7Gregner 1,4-diene-3
, 20-dione as set forth in claim 1.
αi-substituted pregna-1,4-diene-3,20-dione. 4. 12α-substituted pregna-1,4-diene-3,20-dione according to claim 1, which is a sulfonate represented by the general formula (wherein B2 represents an alkyl group).