JPH0357919B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula () It relates to a 12α-substituted pregna-1,4-diene-3,20-dione represented by In the above general formula (), R is a hydrogen atom,
Represents R ¹ CO group or R ² SO ₂ group. Here, R ¹ is a hydrogen atom; methyl group, chloromethyl group, ethyl group, 2
- optionally substituted alkyl groups such as chloroethyl, propyl, hexyl, octyl; or phenyl, o-, m- or p-tolyl, o-, m- or p-nitrophenyl, o -, m- or p-chlorophenyl group,
o-, m- or p-promphenyl group, α-
or an optionally substituted aryl group such as a β-naphthyl group. R ² represents an alkyl group such as a methyl group, ethyl group, butyl group, or octyl group. 12α-substituted pregna-1,4-diene-3,20 represented by the general formula () provided by the present invention
-dione is 12α-hydroxypregna-1,4
- It is a new compound that has not been described in known literature and can be derived from dien-3-one-20-carbaldehyde, and can be a synthetic intermediate for corticoids such as prednisone and prednisolone, which have excellent anti-inflammatory effects. . Traditionally, prednisone has been manufactured by using deoxycholic acid as the starting material and going through more than 20 steps [Co-authored by L.F. Fieser and M. Fieser; Steroids (published by Reinhold, Inc.;
(1959), pp. 634-647] is known.
This method uses expensive reagents and requires a long process, so it is not necessarily suitable for industrial implementation. Some of the present inventors have discovered that a bacterium belonging to the genus Alcaligenes produces 12α-hydroxypregna-1,4-dien-3-one-20-carbaldehyde using deoxycholic acid and/or its yen as a substrate. 12α-Hydroxypregna-1,4-dien-3-one-20-
We have discovered a method for producing carbaldehyde with high selectivity and high yield. One object of the present invention is to develop novel 12α-carbaldehyde derivable from 12α-hydroxypregna-1,4-dien-3-one-20-carbaldehyde
The present invention provides 5-substituted pregna-1,4-diene-3,20-diones. Another object of the present invention is to provide a novel 12α-substituted pregna-1,4-diene-3,20-dione that is useful as an intermediate for the synthesis of various corticoids. Still another object of the present invention is to develop a novel compound as an excellent synthetic intermediate for prednisone and prednisolone.
12α-substituted pregna-1,4-diene-3,20-
It is to provide Zeon. The 12α-substituted pregna-1,4-dien-3,20-dione represented by the general formula () can be converted into 12α-hydroxypregna-1,4-dien-3-one-20-carbaldehyde by the following method. derived from. [In the formula, R ¹ and R ² have the same meanings as in the general formula (). ] That is, 12α-hydroxypregna-1,4
-dien-3-one-20-carbaldehyde and the general formula () R ¹ COOH ... () [wherein R ¹ has the same meaning as in the general formula (). ] or a reactive derivative thereof, such as an acid halide, an acid anhydride, etc., by a conventional method to produce 12α-acyloxypregna-1,4- represented by the general formula ().
Dien-3-one-20-carbaldehyde is obtained. 12α-hydroxybregna-1,4-dien-3-one, which is cited as a typical reaction example.
The reaction between 20-carbaldehyde and the chloride of the carboxylic acid represented by the general formula () is carried out in the presence of a tertiary amine such as triethylamine or pyridine. This reaction is preferably carried out in a solvent, and methylene chloride, chloroform, or a mixed solvent of these and benzene, toluene, ethyl acetate, etc. is preferably used as the solvent. This reaction is usually carried out at room temperature, but if necessary, it can be carried out with heating up to about 60°C. After the reaction, the reaction mixture is washed with dilute hydrochloric acid, sodium bicarbonate, water, etc., and then dried, and then the low boiling point substances are distilled off to obtain 12α-acyloxypregna-1,4- represented by the general formula (). A crude product of dien-3-one-20-carbaldehyde is obtained. This crude product can be used as it is in the next reaction. By reacting 12α-acyloxypregna-1,4-dien-3-one-20-carbaldehyde represented by the general formula () with a secondary amine such as piperidine, pyrrolidine, or morpholine, the general formula () The enamine shown is produced. The secondary amine is 12α-acyloxypregna-1,4-dien-3-one- represented by the general formula ().
It is used in an equimolar to twice the molar amount of 20-carbaldehyde. Water produced as a by-product during the reaction is removed from the reaction system under heating under reflux using a solvent that is azeotropic with water, such as benzene or toluene. Although this reaction does not particularly require a catalyst, it can also be carried out in the presence of a catalyst such as p-toluenesulfonic acid. After the reaction,
By distilling off low-boiling substances from the reaction mixture under reduced pressure, a crude enamine product represented by the general formula () is obtained. This crude product can be used as it is in the next reaction. Note that the enamine represented by the general formula () is first converted into 12α-hydroxypregna-1,4-diene-
3-one-20-carbaldehyde and a secondary amine were combined with the above 12α-acyloxypregna-1,
The reaction is carried out in the same manner as in the reaction of 4-dien-3-one-20-carbaldehyde and a secondary amine, and then the obtained enamine is reacted with a carboxylic acid represented by the general formula () or a reactive derivative thereof, preferably Reaction in the same manner as in the reaction between the acid anhydride, the above 12α-hydroxypregna-1,4-dien-3-one-20-carbaldehyde, and the carboxylic acid represented by the general formula () or its reactive derivative. It can also be obtained by letting 12α-
Acyloxypregna-1,4-diene-3,20
- Diones can be obtained. Note that the oxidation reaction using chromic anhydride is usually carried out in a pyridine solvent. In this case, a mixture of chromic anhydride and pyridine is gradually added to a pyridine solution in which the enamine represented by the general formula () is dissolved, or the enamine represented by the general formula () is added to the mixture of chromic anhydride and pyridine. The reaction is carried out by gradually adding a pyridine solution in which . This oxidation reaction is carried out under ice cooling or at room temperature. After the reaction, the reaction mixture is diluted with benzene, toluene, etc., solids are removed by filtration, diluted hydrochloric acid is added to the filtrate, then extracted with benzene, toluene, etc., and low-boiling substances are distilled from the extract. By removing, a crude product of 12α-acyloxypregna-1,4-diene-3,20-dione represented by the general formula (-a) is obtained. This crude product is purified by silica gel column chromatography or recrystallization as necessary to obtain highly pure 12α-acyloxypregna-1,4-diene represented by the general formula (-a). -3,20-dione can be obtained. By subjecting the 12α-acyloxypregna-1,4-diene-3,20-dione represented by the general formula (-a) to a conventional hydrolysis reaction, the formula (
-12α-hydroxypregna shown by b)
1,4-diene-3,20-dione is obtained. For example, this hydrolysis reaction is carried out in a solvent such as methanol or ethanol in the presence of potassium hydroxide, sodium hydroxide, etc. at room temperature to the reflux temperature of the solvent. After the reaction, the reaction mixture was concentrated under reduced pressure, then diluted with benzene, toluene, etc.
After washing with water, dilute hydrochloric acid, etc., and drying, by distilling off the lower boiling point substances, the formula (-
12α-hydroxypregna-1 shown in b),
A crude product of 4-diene-3,20-dione is obtained. This crude product can be purified, for example, by recrystallization from ethyl acetate. 12α-hydroxypregna-1,4-diene-
By subjecting 3,20-dione to a conventional sulfonation reaction, a sulfonate represented by general formula (-c) can be obtained. For example, this sulfonation reaction
-Diene-3,20-dione is dissolved in pyridine, picoline, or a mixed solvent of these and benzene, toluene, etc., and this solution is mixed with the general formula () R ² SO ₂ Cl [wherein R ² is the general formula ()] has the same meaning as in. ] The sulfonic acid chloride represented by
Equimolar to 1,4-diene-3,20-dione
Add twice the molar amount and bring to room temperature or about 80 ml as needed.
The test is carried out under conditions of temperature up to ℃. After the reaction, the reaction mixture is poured into diluted hydrochloric acid, etc., extracted with benzene, etc., the extract is washed with diluted hydrochloric acid, sodium bicarbonate, water, etc., dried, and the low boiling point substances are distilled off to obtain the general formula. A crude product of the sulfonate represented by (-c) is obtained. A highly purified sulfonate represented by the general formula (-c) can be obtained by recrystallizing this crude product from, for example, ethyl acetate. 12α-substituted pregnar represented by general formula ()
12α-hydroxypregna-1,4-diene, a raw material for the synthesis of 1,4-diene-3,20-dione
3-one-20-carbaldehyde is also a new compound that has not been described in the known literature. It can be obtained by culturing aldehyde-producing bacteria belonging to the genus Alcaligenes in a medium containing deoxycholic acid and/or its salt. The above bacteria belonging to the genus Alcaligenes include Alcaligenes faecalis D4020−K15
(Alcaligenes faecalis D4020-K15) strain (Feikoken Article No. 204). This strain is Alcaligenes fuecalis D4020 obtained from Tuyongzhong.
(Alcaligenes faecalis D4020) strain (Feikoken Joyori No. 182) was subjected to mutation treatment. The following table lists the mycological properties of Alcaligenes faecalis D4020 strain and Alcaligenes faecalis D4020-K15 strain.

【table】

[Table] Based on the mycological properties shown in the table above, Alcaligenes faecalis D4020 strain and Alcaligenes faecalis D4020-K15 strain were identified. Alcaligenes fuecalis strain D4020 is a bacillus, has periflagella,
Microscopic findings such as negative Gram staining, positive oxidase and catalase reactions, aerobic status, O-F
Based on the physiological properties such as oxidative test results, it was identified as a bacterium belonging to the genus Alcaligenes based on the Verges Manual of Determinative Bacteriology, 7th edition and 8th edition. . Furthermore, Alcaligenes fuecalis strain D4020 was identified as a bacterium belonging to the Alcaligenes faecalis species because it does not liquefy gelatin, does not change milk other than becoming alkaline, and does not undergo denitrification reactions. Furthermore, it is generally believed that mutant strains belong to the same species as their parent strains, and it was concluded that the Alcaligenes fuecalis strain D4020-K15 belongs to the Alcaligenes fuecalis species. In the method for producing 12α-hydroxypregna-1,4-dien-3-one-20-carbaldehyde using the above microorganism, deoxycholic acid and/or a salt thereof is used as a substrate. Specific examples of the salts of deoxycholic acid include salts of deoxycholic acid with alkali metals such as sodium and potassium, and salts with alkaline earth metals such as calcium and magnesium. The concentration of deoxycholic acid and/or its salt may normally be in the range of about 1 to 200 g/h, but the yield of 12α-hydroxypregna-1,4-dien-3-one-20-carbaldehyde produced and the culture From economical viewpoints such as conditions and operability, the amount is preferably in the range of about 20 to 50 g/. The culture method is basically the same as that used for aerobic culture of general microorganisms, but usually a shaking culture method using a liquid medium or an aerated agitation culture method is used.
The medium contains 12α-hydroxypregnane-1,4 using the above deoxycholic acid and/or its salt as a substrate.
-Dien-3-one-20-carbaldehyde-producing bacteria belonging to the genus Alcaligenes may contain a nutrient source that can be assimilated and utilized. As a carbon source, deoxycholic acid and/or its salt may be used as a single carbon source, or deoxycholic acid and/or its salt may be combined with glucose, glycerin,
Peptone, meat extract, yeast extract, etc. may be used in combination. Examples of nitrogen sources include ammonium sulfate, ammonium chloride, ammonium phosphate,
Inorganic nitrogen sources such as ammonium nitrate, sodium nitrate, potassium nitrate, or organic nitrogen sources such as polypeptone, peptone, meat extract, etc. are used. In addition, inorganic salts such as dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and magnesium sulfate are added. There is no particular culture condition, but it is usually 25-35℃.
Perform shaking culture or aeration stirring culture for 10 hours to 7 days. 12α-Hydroxypregna-1,4-dien-3-one- accumulated in the culture medium in this way
20-carbaldehyde has significantly lower solubility in water than the substrate deoxycholic acid or its salt, and usually precipitates in the culture solution.
In order to separate and collect this 12α-hydroxypregna-1,4-dien-3-one-20-carbaldehyde, the precipitated 12α-hydroxypregna-1,4-dien-3-one-20- The precipitated 12α-hydroxy precipitate can be removed by separating the carbaldehyde from the culture medium containing the floating bacteria by decantation, or by centrifuging at a rotation speed that does not allow the floating bacteria to precipitate. Guna
After precipitating 1,4-dien-3-one-20-carbaldehyde, 12α-hydroxypregna-1,4-diene-
A method is used to separate 3-one-20-carbaldehyde. Obtained by separating and removing bacterial cells and other insoluble components contained in a culture solution from which precipitated 12α-hydroxypregna-1,4-dien-3-one-20-carbaldehyde has been removed by filtration or centrifugation. After making the culture filtrate or supernatant alkaline by adding an alkali such as sodium hydroxide, potassium hydroxide, or calcium hydroxide to the culture filtrate or supernatant, the above-mentioned aldehyde is dissolved and phase-separated from water. By performing an extraction operation using an organic solvent, such as ethyl acetate, chloroform, or a mixture of chloroform and methanol, collecting the obtained extract and distilling off the solvent from it,
12α-hydroxypregna-1,4-dien-3-one-20-carbaldehyde dissolved in the culture solution can be recovered. This extraction operation using an organic solvent can be performed not only on the culture filtrate or supernatant, but also on the culture solution itself. The precipitate or extract obtained by the above method contains, in addition to 12α-hydroxypregna-1,4-dien-3-one-20-carbaldehyde, the remaining substrate deoxycholic acid and/or its salts. Contains almost no by-products, and can easily produce high-purity 12α by recrystallization from an aqueous methanol solution, for example.
-Hydroxypregna-1,4-dien-3-one-20-carbaldehyde can be obtained. The general formula (-c) provided by the present invention
The sulfonate represented by is induced into the known compound pregna-1,4,11(12)-triene-3,20-dione by subjecting it to a desulfonic acid reaction. This desulfonic acid reaction is usually
It is carried out in the presence of reaction aids (compounds capable of scavenging sulfonic acids) such as potassium acetate, lithium base, collidine, potassium t-butoxide. The amount of reaction aid used is according to the general formula (-c)
The amount is equimolar to 20 times the molar amount of the sulfonate represented by. This reaction is preferably carried out in a solvent such as hesamethylphosphorotriamide or N,N-dimethylformamide, and is usually carried out at a temperature of about 80 to 140°C.
This is done by heating to a temperature of . Also provided by the present invention is represented by the general formula (-a)
12α-acyloxypregna-1,4-diene-
Pregnare-1,4,11 can also be obtained by subjecting 3,20-dione to a decarboxylic acid reaction under heating.
(12)-triene-3,20-dione can be obtained. Pregna-1,4 11(12)-triene-
For example, 3,20-dione can be derived into prednisone and then prednisolone by a conventional method as shown in the following reaction formula. The present invention will be specifically explained below using Examples and Reference Examples. Reference example 1 Method for obtaining Alcaligenes faecalis D4020-K15 strain Medium 1 (composition: deoxycholic acid 0.5%, sodium hydroxide 0.05%, hepton 0.5%, yeast extract
Alcaligenes fuecalis grown on slants of 0.5% sodium chloride, 0.5% sodium chloride and 1.5% agar)
Culture medium 2 (composition: 2% deoxycholic acid, 0.2% sodium hydroxide, 0.2% ammonium nitrate, 2% phosphoric acid, prepared in advance in a test tube)
Potassium hydrogen 0.1%, dipotassium hydrogen phosphate 0.6%,
The cells were inoculated into 10 ml of 0.02% magnesium sulfate heptahydrate and 0.02% yeast extract, and cultured with shaking at 30°C for 8 to 10 hours. Medium 3 (composition: deoxycholic acid 0.5%,
Sodium hydroxide 0.05%, glucose 01%, ammonium nitrate 0.2%, potassium dihydrogen phosphate 0.1%,
Dipotassium hydrogen phosphate 0.6%, magnesium sulfate
0.02% heptahydrate and 0.02% yeast extract) and cultured at 30°C for 10 to 15 hours. Next, the bacterial cells in the logarithmic growth phase were collected by aseptic filtration using a 0.45μ membrane filter, washed with 20ml of 0.1M phosphate buffer (PH: 7.0), and then suspended in 25ml of the same buffer. . Mutation treatment was carried out by adding N-methyl-N'-nitro-N-nitrosoguanidine to the mixture at a final concentration of 20 μg/ml and shaking at 30° C. for 10 to 15 minutes. The mutant-treated bacterial cells were collected by filtration using a 0.45μ membrane filter, washed with 20ml of 0.1M phosphate buffer (PH: 7.0), and then suspended in 20ml of the same buffer. The obtained bacterial suspension was diluted with sterile physiological saline and added to medium 4.
(Composition: Deoxycholic acid 0.5%, sodium hydroxide 0.05%, ammonium nitrate 0.2%, potassium dihydrogen phosphate 0.1%, dipotassium hydrogen phosphate 0.6%, magnesium sulfate heptahydrate 0.02%, yeast extract 0.02
% and agar 1.5%) on an agar plate so that 500 to 1000 colonies appear, and then incubated at 30°C.
The cells were cultured for 3 to 4 days. After isolating the tiny colonies among the colonies that appeared on the slant of medium 1,
Culture medium 5 (composition: deoxycholic acid 0.2%, sodium hydroxide
0.02%, glucose 0.1%, ammonium nitrate 0.2
%, potassium dihydrogen phosphate 0.1%, dipotassium hydrogen phosphate 0.6%, magnesium sulfate heptahydrate 0.02%
and yeast extract 0.02%) and inoculated at 30℃.
It was cultured with shaking for 24 hours. The products in each culture solution obtained were assayed by thin layer chromatography, and 12α-hydroxypregna-1,4-dien-3-one-20-carbaldehyde was selectively detected under the above culture conditions. Find one strain that has accumulated,
This is Alcaligenes fuecalis D4020−K15
It was named. Reference example 2 12α-hydroxypregna-1,4-diene-
Fermentative production of 3-one-20-carbaledehyde Alcaligenes faecalis D4020-K15 strain (Feikokenjo No. 204) was cultured by the following method.
Deoxycholic acid 1.0g, glucose 0.1g, ammonium nitrate 0.2g, potassium dihydrogen phosphate 0.12g,
Dipotassium hydrogen phosphate 0.61g, magnesium sulfate.
Add tap water to 0.02g of heptahydrate, 0.02g of yeast extract, and 0.1g of sodium hydroxide to make a volume of 100ml.
(PH: 8.4) and used as a medium. This medium was placed in a 500 ml Sakaguchi flask and steam sterilized at 120°C for 15 minutes. Inoculum grown in advance in a test tube shaker for one day in the same medium as above.
Add 10 ml to the above 500 ml melt Sakaguchi flask and add 30
The cells were cultured with shaking at ℃ for 2 days. After culturing, the culture solution was collected, and a mixture consisting of precipitates and bacterial cells produced during the culture was separated from the culture solution supernatant using a centrifuge. 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 ml of ethyl acetate. on the other hand,
A 1N aqueous sodium hydroxide solution was added to the culture supernatant to adjust the pH of this solution to 9, and then the solution was extracted with 200 ml of ethyl acetate. A mixture of this extract and the extract obtained above was dried over anhydrous sodium sulfate, and 12α-hydroxypregna-1,4-diene-3- On-20-
700 mg of carbaldehyde was obtained. The obtained 12α-hydroxypregna-1,4-
Take a portion of dien-3-one-20-carbaldehyde, add methanol to it to make a 1% solution, and add 25μ of this solution to Microbondapak C-18.
The mixture was injected into a fast liquid chromatograph (HLC-GPC-224 model, manufactured by Waters, USA) equipped with a column. As a mobile phase, a mixed solution of water/methanol in a volume ratio of 25/75 adjusted to pH 4.0 was flowed at a flow rate of 1 ml/min, and detection was performed using a refractive index method. The area ratio of each peak in the obtained liquid chromatograph was measured using an integrator (Shimadzu Chromato Pack C-
R1A), and from this area ratio, the above 12α-hydroxypregna-1,4-dien-3-one-20
-The purity of carbaldehyde was determined to be 96%.
It was hot. 12α-hydroxy pregnane obtained above
1,4-dien-3-one-20-carbaldehyde was confirmed by the following method. Melting point: 194-201℃ Mass spectrum m/Z: 342 [M] ⁺ 324 [M-H ₂ O] ⁺ 309 [M-H ₂ O-CH ₃ ] ⁺ 3-keto from m/Z = 121 and 122 -1,4
-The presence of diene was confirmed. NMR spectrum (90MHz) δ ^DMSO-d6 _HMS : 0.71 (3H, s) 18-CH ₃ 1.09 (3H, d) 21-CH ₃ 1.17 (3H, s) 19-CH ₃ 3.83 (1H, t, J = 3Hz ) 12α-H 4.33 (1H, d) 12α-OH 5.95 (1H, s) 4-H 3.83 (1H, d, J = 10Hz) 2-H 7.08 (1H, d, J = 10Hz) 1-H 9.56 ( 1H, s) 22-CHO Example 1 12α-acetoxypregna-1,4-diene-
Synthesis of 3,20-dione 12α-hydroxypregna-1,4-diene-
Dissolve 32.2 g of 3-one-20-carbaldehyde in 300 ml of methylene chloride, and add acetyl chloride to this solution.
23.6 g and 27.7 g of pyridine were added, and the mixture was stirred at room temperature for 5 hours. Add 300ml of methylene chloride to the resulting reaction solution.
After adding this solution, the solution was washed successively with diluted hydrochloric acid and water, and dried over anhydrous magnesium sulfate. By distilling off low boiling point substances from this solution under reduced pressure,
A candy-like crude product of 12α-aketoxypregna-1,4-dien-3-one-20-carbaldehyde was obtained. This crude product was dissolved in 300 ml of benzene, 21.3 g of piperidine was added to this solution, and the mixture was heated under reflux for 3 hours while distilling off water produced below the benzene azeotropic point. By distilling off low boiling point substances from the obtained reaction solution under reduced pressure, a candy-like 12α-acetoxy-22-(N-piperidyl)-bisnor-1,
A crude product of 4,20(22)-cholatrien-3-one was obtained. Dissolve this crude product in 180 ml of pyridine,
Add 20.0 g of chromic anhydride and 250 ml of pyridine to this solution.
The mixture was gradually added to the mixture at room temperature, and the mixture was stirred as it was for 1 hour. Benzene 1 was added to the reaction solution, solid matter was removed from this solution by filtration, then diluted hydrochloric acid was added to the filtrate to perform sufficient benzene extraction, and the benzene layer was washed successively with diluted hydrochloric acid and water. From this solution, low-boiling substances were distilled off under reduced pressure,
The resulting residue was subjected to preparative liquid chromatography [Prep LC/System 500, manufactured by Waters, USA.
Prep PAK ^TM 500/SILICA column, using a mixed solvent of isopropyl alcohol/n-hexane = 20/80 (volume)] to produce 12α-acetoxy pregnathic acid having the following physical properties.
9.1g of 1,4-diene-3,20-dione crystals
Obtained. Melting point: 175-176℃ NMR spectrum (90MHz) δ ^CDCl3 _HMS : 0.76, 1.20, 2.0, 2.06 (each s, each 3H); 5.10-5.22 (m, 1H); 6.07 (bs, 1H); 6.18, 6.20 ( each d, 1H); 6.93 (d, 1H) Example 2 12α-Hydroxypregna-1,4-diene-
Synthesis of 3,20-dione Dissolve 2.2 g of sodium hydroxide in 80 ml of methanol, and add 12α-acetoxy pregnathic acid to this solution.
Add 7.4 g of 1,4-diene-3,20-dione,
Stirred at room temperature for 10 hours. Methanol was distilled off from the resulting reaction solution under reduced pressure, and the reaction solution was concentrated to about 1/10. 150 ml of benzene was added to this reaction solution, and this solution was washed successively with water, diluted hydrochloric acid, and water, and dried over anhydrous magnesium sulfate. By distilling off low-boiling substances from this solution under reduced pressure and recrystallizing the obtained residue from ethyl acetate, a product having the following physical properties was obtained.
12α-hydroxypregna-1,4-diene-
5.4 g of 3,20-dione was obtained. The purity of this product was determined by gas chromatography analysis.
It was 90%. Melting point: 185-186℃ NMR spectrum (90MHz) δ ^CDCl3 _HMS : 0.69, 1.17, 2.14 (each s, each 3H); 4.04-4.16 (m, 1H); 6.06 (bs, 1H); 6.16, 6.18 (each d , 1H); 7.03 (d, 1H) Example 3 Synthesis of 12α-mesyloxypregna-1,4-diene-3,20-dione 12α-hydroxypregna-1,4-diene-
Dissolve 3.3g of 3,20-dione in 17ml of pyridine,
3.4 g of methanesulfonic acid chloride was added to this solution, and the mixture was stirred at room temperature for 8 hours. The resulting reaction solution was poured into 300 ml of diluted hydrochloric acid and extracted three times with 300 ml of benzene. The extract was washed successively 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, 3.8 g of a crude product of 12α-mesyloxypregna-1,4-diene-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℃ NMR spectrum (90MHz) δ ^CDCl3 _HMS : 0.82, 1.18, 2.10, 2.96 (each s, each 3H); 5.04-5.16 (m, 1H); 6.05 (bs, 1H); 6.19, 6.21 ( each d, 1H); 6.95 (d, 1H) Examples 4 to 8 Example 1 except that propionyl chloride, n-butyryl chloride, benzoyl chloride, p-chlorobenzoyl chloride or chloroacetyl chloride is used instead of acetyl chloride. By reacting in the same way and then separating and purifying, the corresponding 12α
-Propionyloxypregna-1,4-diene-3,20-dione, 12α-(n-butyryloxy)
Pregna-1,4-diene-3,20-1-dione, 12α-benzoyloxypregna-1,4-
Diene-3,20-dione, 12α-(p-chlorobenzoyloxy)pregna-1,4-diene-
3,20-dione and 12α-(chloroacetoxy)
Pregna-1,4-diene-3,20-dione was obtained. The physical properties of these products are shown below. 12α-propionyloxypregna-1,4-
Diene-3,20-dione Melting point: 172-173℃ NMR spectrum (90MHz) δ ^CDCl3 _HMS : 0.75, 2.00 (each s, each 3H); 1.10, 1.20 (t, s, 6H); 5.10-5.22 (m, 1H); 6.07 (bs, 1H); 6.18, 6.20 (each d, 1H); 6.93 (d, 1H) 12α-(n-butyryloxy)pregna-1,
4-Diene-3,20-1-dione Melting point: 143-144℃ NMR spectrum (90MHz) δ ^CDCl3 _HMS : 0.75, 1.18, 1.99 (each s, each 3H); 0.88 (t, 3H); 5.10-5.22 ( m, 1H); 6.07 (bs, 1H); 6.17, 6.19 (each d, 1H) 6.92 (d, 1H) 12α-benzoyloxypregna-1,4-diene-3,20-dione NMR spectrum (90MHz) δ ^CDCl3 _HMS : 0.84, 1.21, 1.97 (each s, each 3H); 5.38-5.50 (m, 1H); 6.03-6.22 (m, 2H); 6.90 (d, 1H); 7.32-7.71 (m, 3H) ; 7.92-8.17 (m, 2H) 12α-(p-chlorobenzoyloxy)pregna-1,4-diene-3,20-dione NMR spectrum (90MHz) δ ^CDCl3 _HMS : 0.84, 1.20, 1.97 (each s, each 3H); 5.37-5.48 (m, 1H); 6.02-6.21 (m, 2H); 6.89 (d, 1H); 7.41 (d, 2H); 7.92 (d, 2H) 12α-(chloroacetoxy)pregna-1 ,4
-Diene-3,20-dione FD Mass spectrum (m/Z): 405 [M+1] ⁺ Example 9 Synthesis of 12α-(n-butylsulfonyloxy)pregna-1,4-diene-3,20-dione Implementation The reaction was carried out in the same manner as in Example 3 except that n-butylsulfonic acid chloride was used instead of methanesulfonic acid chloride, and then separation and purification was performed to produce 12α-(n-butylsulfonyloxy).
Pregna-1,4-diene-3,2-dione was obtained. This product was confirmed by the following FD Mass spectrum. FD Mass spectrum (m/Z): 449 [M+1] ⁺ 311 [M+1-CH ₃ (CH ₂ ) ₃ SO ₃ H] ⁺ Reference example 3 Pregna-1,4,11(12)-Toluene-3,20
-Synthesis of dione 3.0 g of 12α-mesyloxypregna-1,4-diene-3,20-dione was dissolved in 60 ml of hexamethylphosphortriamide, 7.2 g of potassium acetate was added to this solution, and the mixture was heated at a temperature of 120°C. Stirred for 5 hours.
300 ml of diluted hydrochloric acid water was added to the resulting reaction solution, and the mixture was extracted three times with 200 ml of benzene. The extract was washed successively with diluted hydrochloric acid and water, and dried over anhydrous magnesium sulfate. Low-boiling substances were distilled off from this extract under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluent: acetone to n-hexane volume ratio: 46
By recrystallizing this from ethyl acetate, pregna-1,4,11(12)-triene-3, having the following physical properties was obtained.
1.6 g of 20-dione crystals were obtained. Melting point: 167-169℃ NMR spectrum (90MHz) δ ^CDCl3 _HMS : 0.74, 1.17, 2.15 (each s, each 3H); 5.66 (d, 1H); 6.07-6.40 (m, 3H); 7.12 (d, 1H)

Claims (1)

[Claims] 1. General formula (In the formula, R represents a hydrogen atom, an R ¹ CO group, or an R ² SO ₂ group, where R ¹ represents a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl group, R ² represents an alkyl group.) 12α-substituted pregna-1,4-diene-3,20-dione. 2 General formula (In the formula, R ¹ represents a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl group.) 12α-acyloxypregna-1,4 represented by
12α-substituted pregna-1,4-diene-3,20-dione according to claim 1, which is -diene-3,20-dione. 3 12α-substituted pregna-1,4-diene-3 according to claim 1, which is 12α-hydroxypregna-1,4-diene-3,20-dione;
20-Zion. 4 General formula (In the formula, ^R2 represents an alkyl group.) 12α-substituted pregna-1,4-diene-3,20-dione according to claim 1, which is a sulfonate represented by the following formula.