JPS6118559B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a pregnane steroid 17α-ester compound, and more specifically, it converts a pregnane steroid 17α,21-dihydroxy compound into a cyclic 17α,21-dialkylaminoalkylidene dioxy compound, which can be easily cleaved and The present invention relates to a method for selectively producing a pregnane steroid 17α-ester compound. Pregnane steroid 17α-ester is
It is an adrenal corticosteroid agent that is important as a pharmaceutical with anti-inflammatory effects, etc., and conventional methods have been used to directly acylate pregnane steroid 17α-hydroxy form, and pregnane steroid 17α, 21
- Methods using cyclic orthoesters are known. The direct acylation method uses a strong acid such as trifluoroacetic anhydride or para-toluenesulfonic acid as a catalyst, and uses an aliphatic carboxylic acid anhydride or aliphatic carboxylic acid halide as an acylating agent to esterify the 17α-hydroxy form of a pregnane steroid. However, unnecessary by-products or destruction of the steroid ring itself is often observed. In order to prevent this, if the reaction is carried out at a low temperature of about room temperature, it will take a very long time, and therefore, if the amount of strong acid is increased, by-products will be produced and decomposition will easily occur. In this direct 17α-acylation method, an alkaline catalyst such as calcium carbonate is used, and an aliphatic carboxylic acid anhydride is used as the acylating agent at the corresponding 17α-position.
- There are a few methods known to obtain ester compounds, but the reaction time is extremely long, and if it has a keto group, it will be enolized, and if a large amount of catalyst is used to speed up the reaction, by-products will also be produced. ,
Furthermore, acylating agents having sterically large functional groups, such as phenyl groups, have the disadvantage of resisting the reaction and making it difficult to form esters. Furthermore, such direct acylation at the 17α-position requires that the acylation at the 21-position and
Since it is necessary to protect the 11-position hydroxyl group and remove the protecting group after acylating the 17α-position, the number of steps increases, the actual yield of the target product decreases, and the industrial This is a very disadvantageous method. As an alternative to the direct 17α-acylation method, which has various drawbacks, a pregnane steroid 17α,21-dihydroxy compound is prepared in dimethylformamide in the presence of an acid catalyst to form an orthoester (e.g. methyl orthoacetate, methylorthopropionate, methylorthobenzoate, etc.)
In this method, a 21-cyclic orthoester is obtained, and this intermediate is treated with an acid to produce the desired pregnane steroid 17α-ester. However, in this case, unless a strong acid catalyst is used, the 17α,21-cyclic orthoester is not produced, and the corresponding 21-ester is produced as a by-product when the 17α,21-cyclic orthoester is cleaved. For this reason, it is necessary to adjust the pH, but even this cannot completely prevent the by-product of the 21-ester, and it is a time-consuming method to obtain a pure 17-ester. Particularly in the synthesis of pregnane steroids such as 17α-benzoate, large functional groups sterically resist the formation of the intermediate orthoester, resulting in low yields. The present inventors discovered that pregnane steroid 17α
- As a result of examining industrially advantageous methods for producing esters by eliminating the drawbacks of the conventional methods described above, we found that they are more convenient than the method via the 17α,21-cyclic orthoester, which is still considered the most advantageous method. reaction conditions,
We have invented a method that is advantageous in terms of the yield of the target product and is more industrially advantageous. The present invention will be explained below. The present invention is based on the partial structural formula () A 17α,21-dihydroxy-pregnane steroid with the general formula () (In the formula, R represents a hydrogen atom, a lower alkyl group, or a phenyl group, R ¹ represents a lower alkyl group or a group that combines with each other to form a heterocycle with adjacent nitrogen atoms, and R ² represents a lower alkyl group. ) is reacted with an amide acetal represented by the partial structural formula (). (In the formula, R and R ¹ have the same meanings as above.) A 17α,21-cyclic dialkylaminoalkylidene dioxy-pregnane steroid [hereinafter abbreviated as compound ()] was obtained and Cleaved downward, partial structural formula () This is a method for selectively producing a pregnane steroid 17α-ester having the formula (wherein R has the same meaning as above). The amide acetal which is a reagent in the present invention is N,N-dialkylformamide dialkyl acetal, N,N-dialkylalkylamide dialkyl acetal or N,N-dialkylbenzamide dialkyl acetal, and N,N-dialkylformamide dialkyl acetal. For example, N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, N,N-
dimethylformamide dipropylacetal,
N,N-dimethylformamide di-n-butyl acetal, N,N-dimethylformamide di-
tert-butyl acetal, etc., and N,N-dialkylalkylamide dialkyl acetal is, for example, N,N-methylacetamide, dimethylacetal, N,N-diethylacetamide.
Dimethyl acetal (new compound), piperidine acetamide dimethyl acetal (new compound), etc. N,N-dialkylbenzamide dialkyl acetal is, for example, N,N-
Dimethylbenzamide is dimethyl acetal. These reagents, for example, N,N-dimethylformamide and dialkyl acetal, are commercially available, but the others were synthesized. At that time, the known synthesis method was improved, for example, N,
N-Dimethylacetamide Dimethylacetal and Dimethylbenzamide Dimethylacetal can be prepared by heating the corresponding N,N-dimethylacetamide and N,N-dimethylbenzamide with dimethyl sulfuric acid and then reacting them with sodium methoxide in methanol. However, when the reactions were actually carried out, the yields were low. Therefore, when this reaction was carried out by suspending sodium methoxide in ether, the desired acetal was obtained in high yield. Examples of this improvement will be described below in addition to the method for synthesizing the novel compound described above. 17α,21-dihydroxy used in the present invention
Pregnane steroids are 9-, 11-, and 16-
Any steroid having an optional substituent (e.g., hydroxyl group, ketone group, halogen group, methyl group, etc.) at the 17α, 21- The dihydroxy form is a good example. In the reaction of the present invention, 1 to 1.5 moles of amide acetal are usually used per mole of steroid, and in this case, dimethylformamide, dioxane, 1,
Preferably, the reaction is carried out in an organic solvent such as 1,1-trichloroethane or chloroform. The reaction conditions for the method of the present invention may be mild, and the steroid and amide acetal may be mixed in the above solvent at a temperature of 80 to
Heat at 100℃ for 10-30 minutes or at room temperature for 24-48 minutes.
The reaction is completed by standing for a period of time, and the reaction mixture is purified by neutral or basic alumina column chromatography to obtain the compound (). All of the compounds () obtained in this reaction are new compounds, and their structures were confirmed by elemental analysis and various spectral analyses. This reaction does not require the use of a catalyst, and in this respect is also superior to the method for synthesizing the 17α,21-cyclic orthoester described above. Next, a method for producing pregnane steroid 17α-ester by acid cleavage of compound () will be explained. In other words, the compound () is a lower alcohol such as methanol, dioxane, acetone,
The reaction can be initiated by dissolving the compound in a polar solvent such as dimethylformamide or dimethyl sulfoxide and adding a small amount of oxalic acid to make it weakly acidic, or by dissolving the compound () in acetic acid and leaving it at room temperature for 1 to 3 hours. Complete. Next, the solvent is distilled off and the resulting residue is subjected to recrystallization or column chromatography to obtain pregnane steroids.
17α-ester is obtained. Instead of oxalic acid, acetic acid, phosphoric acid, citric acid, or their respective buffers can also be used. Pregnane steroid obtained by the present invention 17
Examples of α-esters include hydrocortisone 17-formate, hydrocortisone 17-acetate, hydrocortisone 17-propionate,
Hydrocortisone 17-benzoate, cortisone 17-formate, cortisone 17-acetate, cortisone 17-propionate, cortisone 17-benzoate, prednisolone 17-formate, prednisolone 17-acetate, prednisolone 17-propionate, prednisolone 17-benzoate, prednisone 17-formate, Prednisone 17-acetate, Prednisone 17-propionate, Prednisone
17-benzoate, beta-methasone 17-formate, beta-methasone 17-acetate, beta-methasone 17-propionate, beta-methasone 17-benzoate, etc., and are clinically important corticosteroids or their raw material intermediates. . Next, in order to clarify the advantages of the present invention, hydrocortisone made from hydrocortisone 17
- In the synthesis of benzoates, the method of the present invention (A
) and 17α, 21−, which is conventionally considered the best
A comparison was made with a method via a cyclic orthoester (referred to as method B). This reaction is shown by the following reaction formula. In addition, a table comparing the reaction conditions and yields in Step 1 and Step 2 of Method A and Method B is shown below.

【table】

[Table] As described above, the production method of the present invention has the same number of steps as the method using 17α,21-cyclic orthoester, but has more advantageous reaction conditions and a better yield. I understand. That is, the method of the present invention can be said to be an industrially advantageous method. Next, the present invention will be explained in more detail with reference to Examples. Example 1 N,N-dimethylacetamide Production of dimethylacetal 23.75g (0.27g) of N,N-dimethylacetamide
mol) and 33.65 g (0.26 mol) of dimethyl sulfate.
After heating at 90°C for 2 hours, the temperature was gradually lowered to room temperature. Add this reaction solution to 6.2g of metallic sodium
100 ml of an ether suspension of sodium methylate (white powder) prepared from (0.27 mol) and methanol
It was added dropwise at 0°C. After the dropwise addition, the mixture was stirred for 1 hour while gradually raising the temperature to room temperature, the precipitated crystals were removed, and the liquid was distilled under normal pressure to obtain the desired product. Yield 9.20g Yield 28% bp108-109℃ Example 2 N,N-dimethylbenzamide Production of dimethyl acetal 10g (0.07 mol) of N,N-dimethylbenzamide and 8.5g (0.06 mol) of dimethyl sulfate were heated at 90℃.
After heating for 4 hours, the temperature was gradually lowered to room temperature. This reaction solution was added dropwise at 0° C. to 50 ml of an ether suspension of sodium methylate (white powder) prepared from 1.6 g (0.7 mol) of sodium metal and methanol. After the dropwise addition, the mixture was stirred for 1 hour while gradually raising the temperature to room temperature, the precipitated crystals were removed, and the liquid was distilled under reduced pressure to obtain the desired product. Yield 3.4g Yield 25% bp 120-125℃ (20mm
Hg) Example 3 Production of N,N-dimethylpropylamide dimethyl acetal 47.0g (0.47g) of N,N-dimethylpropylamide
mol) and 60 g (0.47 mol) of dimethyl sulfate to 100
After heating at ℃ for 3 hours, the temperature was gradually lowered to room temperature. Add this reaction solution to 11.0g of metallic sodium.
(0.47 mol) and methanol were added dropwise to 150 ml of an ether suspension of sodium methylate at 0°C. After the dropwise addition, the mixture was stirred for 1 hour while gradually raising the temperature to room temperature, the precipitated crystals were removed, and the liquid was distilled under reduced pressure to obtain the desired product. Yield 3.0g Yield 4.7% bp 40-50℃ (90mm
Hg) Example 4 N,N-diethylacetamide Production of dimethyl acetal 25.0 g (0.22 mol) of N,N-diethylacetamide and 28 g (0.22 mol) of dimethyl sulfuric acid were mixed at 90 to 90 g (0.22 mol).
After heating at 100°C for 4 hours, the temperature was gradually lowered to room temperature. Add this reaction solution to 6.0g of metallic sodium.
(0.26 mol) was added dropwise to an ether suspension of sodium methylate prepared from methanol at 0°C. After the dropwise addition, the mixture was stirred for 1 hour while gradually raising the temperature to room temperature, the precipitated crystals were removed, and the liquid was distilled under normal pressure to obtain the desired product. Yield 2.8g Yield 7.9% bp 135-140°C Example 5 Production of piperidyl acetamide dimethyl acetal 25 g (0.179 mol) of 1-acetylpiperidine and 25 g (0.195 mol) of dimethyl sulfate were mixed at 110°C.
After heating for an hour, the temperature was gradually lowered to room temperature.
Add this reaction solution to 4.5 g (0.196 mol) of metallic sodium.
The mixture was added dropwise to 100 ml of an ether suspension of sodium methylate prepared from methanol at 0°C. After the dropwise addition, the mixture was stirred for 1 hour while gradually raising the temperature to room temperature, the precipitated crystals were removed, and the liquid was distilled under reduced pressure to obtain the desired product. Yield 9.8g Yield 28.8% bp 97℃ (33mm
Hg) Example 6 17α,21-dimethylaminomethylenedioxy-
Production of 4-pregnen-11β-ol-3,20-dione (1) 1.0 g (2.8 mmol) of hydrocortisone was suspended in 100 ml of well-dried chloroform.
1 ml of N,N-dimethylformamide dimethyl acetal was added, and the mixture was reacted at room temperature for 3 hours with stirring. When the reaction solution became pale yellow and transparent, the solvent was distilled off under reduced pressure and subjected to neutral alumina column chromatography, and a pale yellow oil was isolated from the chloroform eluate. Yield: 250 mg Yield: 20.4% A portion of this was recrystallized from a mixture of n-hexane and acetone to obtain colorless needle crystals. mp 249-251℃ IRν ^CHCl _3nax cm ^-1 : 1650, 1620 NMR (C ₅ D ₅ N) δ: 1.35 (3H, s), 1.57
(3H, s), 2.90 (6H, s), 4.45 (1H, m),
4.80 (2H.s), 5.80 (1H, s) (2) Dissolve 1.0g (2.8 mmol) of hydrocortisone in 20ml of well-dried dioxane and add N,N
- Dimethylformamide Add 0.35 g (2.9 mmol) of dimethyl acetal (bp 103°C),
The temperature was raised to 80° C. while stirring, the methanol produced was distilled off, and the reaction was continued for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the chloroform effluent was subjected to alumina column chromatography.
The desired product was obtained by recrystallization from a hexane-acetone mixture. Yield: 0.2g Yield: 13% (3) In (1) above, N,N-dimethylformamide and N,N-dimethylacetal were used instead of dimethylacetal.
Using dimethylformamide diethyl acetal (bp 135°C), the mixture was reacted at room temperature for 3 hours and treated in the same manner to obtain the desired product. Yield: 0.16g Yield: 12% (4) In (1) above, N,N-dimethylformamide and N,N-dimethylacetal were used instead of dimethylacetal.
Using dimethylformamide di-n-butyl acetal (bp 88-90°C/10mmHg), reaction was carried out at room temperature for 1 hour, and the desired product was obtained by the same treatment. Yield: 0.04g Yield: 2.6% (5) In (1) above, N,N-dimethylformamide instead of dimethylacetal
Using dimethylformamide di-tert-butyl acetal (bp 75-77°C/25mmHg), reaction was carried out at room temperature for 1 hour, and the desired product was obtained by the same treatment. Yield 0.03g Yield 2.0% Example 7 Production of hydrocortisone 17-formate 17α,21-dimethylaminomethylenedioxy-
4-Pregnen-11β-ol-3,20-dione
Dissolve 100 mg (0.237 mmol) in 100 ml of methanol and drop 2 to 3 drops of saturated oxalic acid aqueous solution (pH 5 to
6) After stirring the reaction solution for 1 hour at room temperature, the solvent was distilled off, and the target product was isolated by preparative thin layer silica gel chromatography. Recrystallization from an acetone-n-hexane mixture gave colorless fine needle-like crystals. Yield 40mg Yield 43.3% mp177-183℃ Example 8 17α,21-dimethylaminomethylenedioxy-
Production of 4-pregnene-3,11,20-trione Dissolve 0.3 g (0.83 mmol) of cortisone in 3 ml of well-dried dimethylformamide and add N,N
-dimethylformamide dimethyl acetal
0.3 ml was added and stirred at room temperature for 3 hours. When the reaction solution became pale yellow and transparent, the solvent was distilled off under reduced pressure and subjected to alumina column chromatography to obtain a pale yellow oil from the chloroform eluate. Yield 34mg Yield 9.7% NMR (CDCl ₃ ) δ: 0.63 (3H, s), 1.37
(3H, s), 2.10 (6H, s), 3.70 (2H, s),
5.60 (1H, s) Example 9 Production of cortisone 17-formate 17α,21-dimethylaminomethylenedioxy-
Dissolve 100 mg of 4-pregnene-3,11,20-trione in 20 ml of methanol, add acetate buffer (PH5~
Add 5 ml of 6) and leave at room temperature for 3 hours. After the reaction is complete, methanol is distilled off, 100 ml of water is added, and the mixture is extracted with chloroform. The extract was washed with water, dried over Glauber's salt, the solvent was distilled off, isolated and purified by preparative thin-layer silica gel chromatography, and recrystallized from a mixture of n-hexane and acetone to obtain colorless needles. Obtained crystals. Yield 40mg Yield 45% mp 217-224℃ Example 10 17α,21-dimethylaminomethylenedioxy-
1,4-pregnadiene-11β-ol-3,
20-Production of dione Dissolve 0.3 g (0.83 mmol) of prednisolone in 2 ml of well-dried dimethylformamide.
0.3 ml of N,N-dimethylformamide dimethyl acetal was added, and the mixture was heated and stirred at 100°C to react for 30 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was subjected to neutral alumina column chromatography to obtain the target product as a pale yellow oil from the chloroform eluate. Yield 40mg Yield 11.6% NMR (CDCl ₃ ) δ: 1.32 (3H, s), 1.52
(3H, s), 2.04 (6H, s) Example 11 Production of prednisolone 17-formmate 17α,21-dimethylaminomethylenedioxy-
1,4-pregnadiene-11β-ol-3,20
−40 mg (0.095 mmol) of dione in 20 methanol
ml, dropwise added 2 to 3 drops of a saturated oxalic acid aqueous solution (PH 5 to 6), stirred the reaction solution at room temperature for 1 hour, distilled off the solvent, and produced the product using preparative thin-layer silica gel chromatography. The substance was isolated. Recrystallization from a mixture of n-hexane and acetone gave the desired product as colorless needle-like crystals. Yield 15mg Yield 41% mp 244-245℃ Example 12 17α,21-dimethylaminomethylenedioxy-
Preparation of 9α-fluoro-16β-methylene-1,4-pregnadiene-11β-ol-3,20-dione 0.2 g (0.51 mmol) of betamethasone was dissolved in 2 ml of well-dried dimethylformamide.
0.2 ml of N,N-dimethylformamide dimethylacetal was added, and the mixture was heated and stirred at 100°C to react for 30 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was subjected to neutral alumina column chromatography to obtain the target product as a pale yellow oil from the chloroform outflow. Yield 36 mg Yield 15.6% NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 8
Hz), 1.24 (3H, s), 1.55 (3H, s), 2.04
(6H,s) Example 13 Production of betamethasone 17-formate 17α,21-dimethylaminomethylenedioxy-
9α-fluoro-16β-methyl-1,4-pregnadiene-11β-ol-3,20-dione 100mg
Dissolve in 20 ml of methanol and add acetate buffer (PH5~
Add 5 ml of 6), leave at room temperature for 3 hours, distill off the methanol, extract with chloroform, wash the extracted solution with water, dry the sodium sulfate, remove the solvent, and perform preparative thin-layer silica gel column chromatography. The target product was isolated and purified, and recrystallized from a mixture of n-hexane and acetone to obtain colorless needle crystals. Yield 55mg Yield 60% mp 238-247℃ Example 14 17α,21-(1′-dimethylamino)ethylidenedioxy-4-pregnen-11β-ol-
Production of 3,20-dione 3.0 g (8.2 mmol) of hydrocortisone was dissolved in 3 ml of dimethylformamide, 1.0 g (8.4 mmol) of N,N-dimethylamide dimethyl acetal was added, and the mixture was heated and stirred at 100°C for 10 minutes. After the reaction was completed, the solvent was distilled off, and the product was subjected to basic alumina column chromatography to isolate the desired product as a pale yellow oil from the chloroform outflow. Yield: 3.0g Yield: 84% A portion of this was recrystallized from a mixture of n-hexane and acetone to obtain pale yellow fine needle-shaped crystals. mp244-245℃ NMR ( _CDCl3 ) δ: 1.20 (3H, s), 1.40
(3H, s), 2.10 (3H, s), 3.07 (6H, s) Example 15 17α,21-(1′-piperidino)ethylidenedioxy-4-pregnen-11β-ol-3,20
-Production of dione 1.0 g (2.8 mmol) of hydrocortisone was dissolved in 3 ml of dimethylformamide, 0.5 g (2.9 mmol) of piperidyl acetamide dimethyl acetal was added, and the mixture was heated and stirred at 100° C. for 60 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was subjected to alumina column chromatography to obtain the target product as a pale yellow oil from the chloroform outflow. Yield 0.2g Yield 15.2% NMR (CDCl ₃ ) δ: 1.32 (3H, s), 1.57
(3H, s), 1.62 (3H, s), 5.62 (1H, s) Example 16 Production of hydrocortisone 17-acetate 17α,21-(1′-dimethylamino)ethylidenedioxy-4-pregnen-11β-ol -3,
0.3 g of 20-dione was dissolved in 10 ml of methanol, 2 to 3 drops of a saturated aqueous oxalic acid solution was added, and the mixture was left at room temperature for 2 hours. After the reaction, the solvent was distilled off, the desired product was isolated by preparative thin layer silica gel chromatography, and recrystallized from n-hexane-acetone to obtain colorless columnar crystals. Yield 0.11g Yield 40% mp 227-232℃ Example 17 Production of 17α,21-(1′-dimethylamino)ethylidenedioxy-4-pregnadiene-11β-ol-3,20-dione Prezonisolone 0.3g (0.83 mmol) and N,
N-dimethylacetamide 0.1 g (0.84 mmol) of dimethyl acetal (bp 106-110°C) was heated and stirred in 2 ml of dimethylformamide at 100°C for 30 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure.
The residue was subjected to alumina column chromatography to obtain the target product as a pale yellow oil from the chloroform outflow. Yield 60mg Yield 17.2% NMR (CDCl ₃ ) δ: 1.20 (3H, g), 1.36
(3H, s), 1.60 (3H, s), 2.15 (6H, s) Example 18 Production of prednisolone 17-acetate 17α,21-(1′-dimethylamino)ethylidenedioxy-1,4-pregnadiene-11β -Dissolve 50 mg of ol-3,20-dione in 10 ml of methanol, add 1 to 2 drops of oxalic acid saturated solution, leave to stand at room temperature for 2 hours, distill off the solvent, and perform preparative thin-layer silica gel chromatography. The product was isolated and recrystallized from a mixture of n-hexane and acetone to obtain colorless needles. Yield 28mg Yield 67% mp 240-242℃ Example 19 Production of 17α,21-(1'-dimethylamino)ethylidenedioxy-4-pregnene-3,11,20-trione Cortisone 0.3g (0.83 mmol) and N, N-
Dimethylacetamide Dimethylacetal 0.1
g (0.84 mmol) was heated and stirred at 100° C. for 30 minutes in 2 ml of dimethylformamide. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was subjected to alumina column chromatography to obtain the target product as a pale yellow oil from the chloroform outflow. Yield 0.1g Yield 28.7% NMR (CDCl ₃ ) δ: 0.65 (3H, s), 1.40
(3H, s), 1.60 (3H, s), 2.05 (3H, s),
3.35 (2H, s) Example 20 Production of cortisone 17-acetate Dissolve 0.1 g of 17α,21-(1′-dimethylamino)ethylidenedioxy-4-pregnene-3,11,20-trione in 10 ml of methanol, Add 2 to 3 drops of a saturated aqueous oxalic acid solution, leave to stand at room temperature for 2 hours, then evaporate the solvent, isolate the target product by preparative thin layer silica gel chromatography, and recrystallize from an acetone-n-hexane mixture to obtain a colorless product. Needle crystals were obtained. Yield 30mg Yield 33% mp 194-198℃ Example 21 17α,21-dimethylaminobenzylidenedioxy-4-pregnen-11β-ol-3,20-
Production of dione Hydrocortisone 2.0g (5.5 mmol) and N,
N-dimethylbenzamide dimethyl acetal (bp 65-68℃/5mmHg) 1.1g (5.6 mmol)
The mixture was heated and stirred in 2 ml of dimethylformamide at 80°C for 10 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, the residue was subjected to alumina column chromatography, and the chloroform effluent was recrystallized from a mixture of n-hexane and acetone to obtain pale yellow needle crystals. Yield 1.85g Yield 68% mp 160-163℃ IRν ^KBr _nax cm ^-1 : 1710, 1665, 1610 NMR (C ₅ D ₅ N) δ: 1.25 (3H, s), 1,50
(3H, s), 2.05 (6H, s), 4.30 (1H, m),
4.80 (2H, s), 5.75 (1H, s), 7.40 (5H,
m) Example 22 Production of hydrocortisone 17-benzoate Dissolve 0.1 g (0.2 mmol) of 17α,21-dimethylaminobenzylidenedioxy-4-pregnen-11β-ol-3,20-dione in 100 ml of methanol, and dissolve saturated oxalic acid aqueous solution 2 ~3 drops were added and left at room temperature for 2 hours. The solvent was distilled off under reduced pressure, the residue was separated by preparative thin layer chromatography, and the desired product was recrystallized from n-hexane-acetone to obtain colorless needles. Yield 40mg Yield 42% mp 227-231℃ Example 23 17α,21-dimethylaminobenzylidenedioxy-1,4-pregnadiene-11β-ol-
Production of 3,20-dione Prednisolone 1g (2.8 mmol) and N,N
-dimethylbenzamide dimethyl acetal
0.5 g (2.8 mmol) was heated and stirred in 2 ml of dimethylformamide at 100° C. for 30 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was subjected to alumina column chromatography to obtain the target product as a pale yellow oil from the chloroform outflow. Yield 0.85g Yield 60% NMR (CDCl ₃ ) δ: 0.90 (3H, s), 1.30
(3H, s), 2.04 (6H, s), 4.15 (3H, m),
5.95 (1H, s), 7.35 (5H, m) Example 24 Production of prednisolone 17-benzoate 17α,21-dimethylaminobenzylidenedioxy-4-pregnadiene-11β-ol-3,20
- 0.8 g (1.63 mmol) of dione in 100 g of methanol
ml, drop 2 to 3 drops of saturated oxalic acid aqueous solution,
After standing at room temperature for 2 hours, the solvent was distilled off under reduced pressure, the target product was isolated by preparative thin layer chromatography, and recrystallized from n-hexane-acetone to obtain colorless needles. . Yield 200mg Yield 26.3% mp 270-273℃ Example 25 Production of 17α,21-dimethylaminobenzylidenedioxy-1,4-pregnadiene-9α-fluoro-11β-ol-16β-methyl-3,20-dione betamethazone 1.0g (2.6 mmol) and N,N
-dimethylbenzamide dimethyl acetal
0.6 g (3.1 mmol) was heated and stirred in 2 ml of dimethylformamide at 100° C. for 30 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was subjected to alumina column chromatography to obtain the target product as a pale yellow oil. Yield 0.5g Yield 36.6% NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 8
Hz), 1.22 (3H, s), 1.55 (3H, s), 2.05
(6H, s), 7.10-7.70 (5H, m) Example 26 Production of betamethasone 17-benzoate 17α,21-dimethylaminobenzylidenedioxy-1,4-pregnadiene-9α-fluoro-
11β-ol-16β-methyl-3,20-dione
Dissolve 0.1 g in 20 ml of methanol, add 2 to 3 drops of a saturated aqueous oxalic acid solution (PH 5 to 6), and leave it at room temperature for 2 hours. The solvent is distilled off under reduced pressure and subjected to preparative thin layer chromatography. The desired product was isolated and recrystallized from a mixture of n-hexane and acetone to obtain colorless flaky crystals. Yield 30mg Yield 35% mp 225-231℃ Example 27 Production of 17α,21-dimethylaminobenzylidenedioxy-4-pregnene-3,11,20-trione Cortisone 1.0g (2.8 mmol) and dimethylbenzamide Dimethyl acetal 0.6 g (3.0 mmol) in 2 ml of dimethylformamide.
The mixture was heated and stirred at 100°C for 30 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was subjected to alumina column chromatography to obtain the target product as a yellow oil. Yield 600mg Yield 54.5% NMR (CDCl ₃ ) δ: 0.63 (3H, s), 1.37
(3H, s), 2.05 (6H, s), 7.10~7.60 (5H,
m) Example 28 Production of cortisone 17-benzoate 17α,21-dimethylaminobenzylidenedioxy-4-pregnene-3,11,20-trione 0.2
Dissolve g (0.4 mmol) in 30 ml of methanol,
Drop 2-3 drops of saturated oxalic acid aqueous solution (PH5-6),
After standing at room temperature for 2 hours, the solvent was distilled off under reduced pressure, the target product was isolated by preparative thin layer chromatography, and recrystallized from an acetone-n-hexane mixture to obtain colorless needle crystals. Ta. Yield 70mg Yield 41.0% mp 227-230℃.

Claims (1)

[Claims] 1. Partial structural formula A 17α,21-dihydroxy-pregnane steroredo with the general formula (In the formula, R represents a hydrogen atom, a lower alkyl group, or a phenyl group, R ¹ represents a lower alkyl group or a group that combines with each other to form a heterocycle with adjacent nitrogen atoms, and R ² represents a lower alkyl group. ) is reacted with an amide acetal represented by the partial structural formula (In the formula, R and R ¹ have the same meanings as above.) A 17α,21-cyclic dialkylaminoalkylidene dioxy-pregnane steroid is obtained, and this is cleaved in the presence of an acid. substructure formula A method for producing a pregnane steroid 17α-ester having the formula (wherein R has the same meaning as above).