JPS632280B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing steroid aldehydes. Specifically, intermediates for the production of progesterone (progesterone), adrenal corticosteroids (hydrocortisone, cortisone, prednisolone, prednisone, etc.), namely 22.23-bisnorcholar 4-en-3-one-22-al and 22. 23-bisnorcholar 1,4-diene-3-
The present invention relates to a method for producing ON-22-R.

In recent years, 22-hydroxy-22,23-bisnorcholar-4-en-3-one and 22-hydroxy-
It has been found that 22,23-bisnorcholar 1,4-dien-3-one can be produced in larger quantities and at lower cost by microorganisms belonging to the genus Mycobacterium than sterols such as cholesterol or sitosterol. (For example, Japanese Patent Application Laid-Open No. 54-67094,
-67095 publication, West German patent publication No. 2571560) On the other hand, 22・23-bisnorcholar 4-en-3-
It is a well-known fact that on-22-al is an important intermediate in the production of progesterone (progesterone), and since brogesterone is an intermediate in the production of hydrocortisone, it is also an intermediate in the production of adrenocortical hormone. (See, e.g., LF Fieser and M. Fieser, “Steroids,” p. 675 (1959) USA) Therefore, 22-hydroxy-22,23-bisnorcholar-4-ene-3- The preparation of 22,23-bisnorcholar 4-en-3-one-22-al from 1 is of great industrial importance.

Furthermore, pregnar 1,4-diene-3,20-dione is available from the Journal of Organic Chemistry.
(J.Org.Chem.), vol. 33, p. 3294 (1968) 17α-hydroxy-
Pregner can be induced into 1,4-diene-3,20-dione, and then a hydroxyl group is introduced at the 11β position by a fermentation method, and a hydroxyl group is introduced at the 21st position by the method described in Japanese Patent Publication No. 50-8080 to produce prednisolone. can be guided to Therefore 22-hydroxy-22・23-
From bisnorcholar 1,4-dien-3-one
22,23-Bisnorcholar 1,4-dien-3-one-22-al And the production of pregner 1,4-diene-3,20-dione is also of great industrial importance.

Conventionally, as a method for obtaining aldehydes from alcohols, a method of oxidizing with a chromium trioxide-pyridine complex is generally known. For example, Tetrahedron Letters,
3363 pages (1968), British National and Journal of Organic Chemistry (J.Org.
Chem.), vol. 26, p. 4814 (1961) and the same American journal, vol. 35, p. 4000 (1970), it was reported that the corresponding aldehyde could be obtained from aliphatic alcohol in a yield of over 90%. ing. but,
60 in the case of 22-hydroxy-22,23-bisnorcholar 4-en-3-one, 22-hydroxy-22,23-bisnorcholar 1,4-dien-3-one
The corresponding aldehyde is formed only in ~70% yield. Furthermore, due to the toxicity of chromium compounds, disposal costs are high, and this method cannot be said to be advantageous as an industrial production method.

On the other hand, in recent years, EJ Corey has
It has been reported that dimethylsulfonium ion, which is obtained by reacting dimethylsulfide with an oxidizing agent such as chlorine or N-chlorosuccinimide, oxidizes alcohol to aldehyde with good selectivity. Journal of American Chemical Society (J.
Am.Chem.Soc.) Volume 94, Page 7586 (1972) United States, Reference.

The present inventors have determined that 22-hydroxy-22·23-bisnorcholar-4-en-3-one, 22·23-bisnorcholar-4-en-3-one-22-al,
22-Hydroxy-22,23-bisnorcholar 1,4
-dien-3-one to 22-hydroxy-22・23
-bisnorcholar 1,4-dien-3-one-22
- Researched the industrial method for producing 22-hydroxy-22,23-bisnorcholar-4-ene-3 using the above-mentioned dimethylsulfonium ion.
-one and 22-hydroxy-22,23-bisnorcholar 1,4-dien-3-one, and by making improvements thereto, the corresponding aldehyde could be obtained in high yield, completing the present invention.

That is, the gist of the present invention is the general formula () (In the formula, the dotted line between the 1st and 2nd positions of ring A represents a single bond or a double bond. The same applies to the following formulas.) It is oxidized by contacting with dimethylsulfonium ion in a mixed solvent consisting of a solvent selected from ether and an aromatic hydrocarbon, and the general formula () The present invention relates to a method for producing a steroid aldehyde, which is characterized by producing a steroid aldehyde represented by:

The method of the present invention will be described below.

Dimethylsulfonium ions can be prepared in aromatic hydrocarbon solvents such as benzene, toluene, xylene, and the like. That is, the above aromatic hydrocarbon solution of dimethyl sulfide is added to an aromatic hydrocarbon solution in which N-chlorosuccinimide or chlorine gas is dissolved. At this time, dimethyl sulfide is N-
1.2 for chlorosuccinimide or chlorine
Add up to 2.0 times the amount, preferably 1.3 to 1.7 times the amount. The reaction temperature is 10°C to -10°C, preferably 5° to -5°C.

22-Hydroxy-22,23-biscolor-4-en-3-one or 22-hydroxy-22,23-bisnorcholar-1,4-dien-3-one (hereinafter referred to as
A solution of 22-hydroxysteroids (both of which are collectively referred to as 22-hydroxysteroids) is added. Reaction temperature is −10° to −30°
°C, preferably -15° to -25°C. The amount of 22-hydroxysteroid is preferably 1.0 to 0.1 times the molar amount of N-chlorosuccinimide or chlorine.
It is 0.8 to 0.5 times the mole. Of particular importance here is 22
- a solvent that dissolves hydroxysteroids;
Particularly preferred are halogenated hydrocarbons such as dichloromethanechloroform and cyclic ethers such as tetrahydrofuran and dioxane. Of course,
Both may be used together. In other solvents, such as aromatic hydrocarbons such as toluene and benzene, only about 0.3% of 22-hydroxysteroids are dissolved, making it difficult to obtain a sufficient conversion rate of 22-hydroxysteroids.

When a halogenated hydrocarbon or cyclic ether is used as the solvent for dissolving 22-hydroxysteroid, the reaction solvent is a mixed solvent of an aromatic hydrocarbon solvent and a halogenated hydrocarbon or cyclic ether. It was found that the composition of this mixed solvent had a significant effect on the reaction results. When the proportion of aromatic hydrocarbons is high, the solubility of 22-hydroxysteroid decreases, so there is a risk that 22-hydroxysteroid will precipitate. On the other hand, when the proportion of highly polar solvents such as halogenated hydrocarbons and cyclic ethers, which have a large dissolving power for 22-hydroxysteroids, is high, the A large amount of methyl ethers is produced as a by-product, significantly reducing the yield of the desired steroid aldehyde. In order to obtain steroid aldehyde in good yield, the composition of aromatic hydrocarbons, halogenated hydrocarbons and cyclic ether should be 1:1 to 4:1, especially
The ratio is preferably 1.5:1 to 2.5:1 (volume ratio).

The present invention will be explained in more detail in the following Examples, but the present invention is not limited to the following Examples unless the gist thereof is exceeded.

Example 1 8.0 g of N-chlorosuccinimide is dissolved in 150 ml of toluene and cooled to 0°C. On the other hand, a solution of 6 ml of dimethyl sulfide dissolved in 50 ml of toluene,
Add dropwise to the above N-chlorosuccinimide solution over 15 minutes. After stirring for 1 hour at 0°C, cool to -22°C.

A solution of 6.0 g of 22-hydroxy-22.23-bisnorcholar 1.4-dien-3-one dissolved in 100 ml of dichloromethane was added dropwise to this over 1 hour. Continue stirring for 2.0 hours after the addition is complete. After adding a solution of 6 g of triethylamine dissolved in 5 ml of toluene, the mixture was heated to room temperature. ether 200ml
Add 1% aqueous hydrochloric acid solution, stir, and separate the liquid. Repeat the same operation until the separated aqueous layer becomes acidic, then wash the organic layer with water.

After drying the organic layer with a desiccant, the organic solvent was removed by distillation to obtain 6.54 g of white crystals. Analysis of this crystal by liquid chromatography revealed that it contained 80.1% of 22,23-bisnorcholar 1,4-dien-3-one-22-al. Yield: 90.3 mol% Example 2 22-Hydroxy 22.23 was prepared in the same manner as in Example 1.
- bisnorcholar 4-en-3-one to 22 and 23
-bisnorcholar 4-en-3-one-22-al is obtained with a yield of 92.3 mol%.

Example 3 The same operation as in Example 1 was carried out, except that 22-
When 6.0 g of hydroxy-22,23-bisnorcholar 1,4-dien-3-one is dissolved in 200 ml of dichloromethane and the ratio of toluene and dichloromethane in the reaction solvent is 1:1, 22,23-bisnorcholar 1, The yield of 4-dien-3-one-22-al was 81.0 mol%.

Example 4 The same operation as in Example 1 was carried out, except that 6.0 g of 22-hydroxy-22,23-bisnorcholar 1,4-dien-3-one was dissolved in 1000 ml of toluene and carried out in a toluene solvent. 22・23 in case
-Bisnorcholar 1,4-dien-3-one-22
-R has a yield of 57.7 mol%. At this time, 39.0% of unreacted 22-hydroxy-22.23-bisnorcholar 1.4-dien-3-one remains.

Example 5 8.0 g of N-chlorosuccinimide is dissolved in 150 ml of dichloromethane and cooled to 0°C. On the other hand, a solution was prepared by dissolving 6 ml of dimethyl sulfide in 50 ml of dichloromethane, and this was added to the N-chlorosuccinimide solution. Stir at 0°C for 1 hour.

After cooling to -22°C, 22-
A solution of 6.0 g of hydroxy-22,23-bisnorcholar 1,4-dien-3-one dissolved in 100 ml of dichloromethane is prepared and reacted at -22°C.

22,23-bisnorcholar 1,4-diene-3-
74.7 mol% of on-22-al is obtained.

Reference Example 1 Add 1.8 g of chromium trioxide to a mixture of 3.0 ml of pyridine and 45 ml of dichloromethane. Stir for 30 minutes at 20°C.

After cooling to 4 DEG C., 1.0 g of 22-hydroxy-22.23-bisnorcholar 1.4-dien-3-one was dissolved in 10 ml of dichloromethane and added dropwise to the chromium trioxide solution. Stir at 20°C for 2 hours.

Ether is added to the reaction mixture and insoluble materials are filtered off. The ether layer is washed with water and then concentrated.
Obtain 0.81 g of crystals.

This crystal contained 83.4% of 22.23-bisnorcholar 1.4-dien-3-one-22-al. Yield 68.4 mol% Reference example 2 22,23-bisnorcholar 1,4-diene-3-
On-22-R 0.5g, cupric acetate 8.0mg, 2.
Dissolve 7.0 mg of 2'-dipyridyl in 5.0 ml of dimethylformamide. After adding 0.17 g of triethylenediamine, air was blown at 40°C.

After stirring for 19 hours while blowing air, the reaction mixture was extracted with chloroform. The chloroform layer is washed with a 1% aqueous hydrochloric acid solution and then with water. After drying with a desiccant, the solvent is evaporated to give 0.46 g of white crystals. When this crystal was analyzed by liquid chromatography, it was found that 87.4% of pregnar 1,4-diene-
It can be seen that it contains 3.20-dione. Yield 83.8 mol%

Claims (1)

[Claims] 1 General formula () (In the formula, the dotted line between the 1st and 2nd positions of ring A represents a single bond or a double bond. The same applies to the following formulas.) It is oxidized by contacting with dimethylsulfonium ion in a mixed solvent consisting of a solvent selected from ethers and an aromatic hydrocarbon to form the general formula () A method for producing a steroid aldehyde, the method comprising producing a steroid aldehyde represented by: