JPS6353998B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an acyloxysteroid and a method for producing the same, and more particularly to a 17β-ethynyl-17α-acyloxysteroid useful as a new intermediate for producing adrenocortical hormones such as hydrocortisone and prednisolone, and a method for producing the same. Recently, androst-4-4 has been produced using microorganisms such as Mycobacterium in large quantities and at low cost, rather than sterols such as cholesterol or sitosterol.
ene-3,17-dione, androsta-1,4-
Diene-3,17-dione began to be produced, and various steroid drugs such as estrone, testosterone, and spironolactone began to be produced from these raw materials. On the other hand, adrenal corticosteroids (corticoids), which account for the majority of steroid medicines, are still derived from progesterone from stigmasterol and diosgenin.
It is produced by a long process using 16-dehydropregnenolone as an intermediate raw material or bile acids as raw material. The present inventors have discovered the above-mentioned androst-4-ene, which has recently become available in large quantities and at low cost.
Produced not only from 3,17-dione and androst-1,4-diene-3,17-dione, but also from 9α-hydroxyandrost-4-ene-3,17-dione, which has also recently been produced by fermentation. We have begun research to develop a more economical method for producing corticoids using androsta-4,9 ⁽¹¹⁾ -diene-3,17-dione, which is produced by the present invention, as a raw material. As a result, we discovered a novel 17β, represented by the general formula (), which is extremely advantageous for producing corticoids from these raw materials.
-Ethynyl-17α-acyloxysteroids could be produced. (In the formula, the dotted line represents a single bond or a double bond, and X represents an acyloxy group.) The present invention will be explained in detail below. The compounds represented by the general formula () include 17β-ethynyl-17α-hydroxyandrost-4-en-3-one, 17β-ethynyl-17α-hydroxyandrost-1,4-dien-3-one,
17β-ethynyl-17α-hydroxyandrost-4,9 ⁽¹¹⁾ -dien-3-one, 17β-ethynyl-17α-hydroxyandrost-1,4,9 ⁽¹¹⁾
These are esters of -trien-3-one etc. and carboxylic acids such as acetic acid, propionic acid and benzoic acid, and these can be easily converted into corticoids by the reaction route shown in the following formula.

[Table] 17β-ethynyl-17α represented by general formula ()
-Acyloxysteroids are produced by the reaction route shown below and are represented by the general formula ().
It is produced by reacting 17β-ethynyl-17α-hydroxysteroids with carboxylic acid anhydrides or acid halides. (In the formula, the dotted line represents a single bond or a double bond.) The first method is 17β shown in the general formula ().
-Ethynyl-17α-hydroxysteroid can be reacted with a carboxylic acid anhydride such as acetic anhydride in an aromatic amine such as pyridine. In this case, the acid anhydride should be used in an amount equal to or more than 5 times the molar amount of the steroid, preferably 5 times or more. The reaction temperature is
The temperature is 80-150°C, preferably 100-135°C. The second method can be carried out by using a carboxylic acid such as acetic acid as a solvent and allowing a carboxylic acid anhydride to act on the steroid represented by the general formula (). In this case, p-toluenesulfonic acid, trifluoroacetic acid, sulfuric acid, phosphoric acid, zinc chloride, iron chloride,
Acidic compounds such as Lewis acids or Lewis acids are used as catalysts. The reaction temperature is usually 0 to 50°C. The third method involves adding a steroid represented by the general formula () to a commonly used solvent such as benzene, toluene, carbon tetrachloride, dichloroethane, etc., and adding a carboxylic acid anhydride such as acetic anhydride to dimethylaminopyridine or the like. This can be carried out using pyridines as a catalyst. The amount of dimethylaminopyridine used as a catalyst is 1 to 50% by mole based on the steroid, preferably 5% by mole based on the steroid.
~10 mol%. The acid anhydride is required in an amount equal to or more than the same molar amount as the steroid, preferably at least 5 times the molar amount.
The reaction temperature is 5-150°C, preferably 20-100°C. In this case, it is necessary to neutralize the produced carboxylic acids by adding a basic substance such as triethylamine, trimethylamine, or benzylamine that is more basic than the pyridine such as dimethylaminopyridine used as a catalyst. The fourth method can be carried out by reacting a steroid represented by the general formula () with an acid halide of a carboxylic acid such as acetyl chloride in a basic solvent such as pyridine. The acid halide is required in a molar amount 1 to 10 times that of the steroid. The reaction temperature is 0~
The temperature is 150°C, preferably 30-100°C. The present invention will be explained in more detail with reference to Examples below. Example 1 12.0 g of 17β-ethynyl-17α-hydroxyandrosta-1,4-dien-3-one and pyridine
Add 50 ml and 50 ml of acetic anhydride and heat at 120°C for 30 hours. The reaction mixture was poured into ice water and the separated tar-like substance was extracted with dichloromethane. The organic layer is washed with a 5% aqueous hydrochloric acid solution and then with a 5% aqueous sodium bicarbonate solution. The separated organic layer is dried over anhydrous sodium sulfate and then concentrated. Concentrate is alumina
A column packed with 250 g of the solution was charged and eluted with 500 ml of a benzene-ethyl acetate (9:1) mixed solvent.
12.3 g of crystals are obtained. Octane-tetrahydrofuran (20:1), heptane-ethanol (5:1), octane-tetrahydrofuran (30:
Recrystallization from 7) yields 8.1 g of 17β-ethyl-17α-acetoxyandrosta-1,4-dien-3-one. Melting point 171.8-172.6℃ (heating rate 1℃/min) NMR spectrum (CDCl ₃ ) δppm 1.00 (S, 3H), 1.26 (S, 3H), 2.02 (S,
3H), 2.56 (S, 1H), 6.04 (S, 1H), 6.15 (q,
1H), 6.98 (d, 1H) Example 2 2.0 g of 17β-ethynyl-17α-hydroxyandrosta-1,4-dien-3-one and acetic anhydride
Add 2.0ml, triethylamine 2.0ml, dimethylaminopyridine 0.114g, and toluene 5.0ml to 80-90℃.
Heat for 11 hours. After cooling, the product is extracted with dichloromethane according to the procedure of Example 1. The extract is analyzed by liquid chromatography. 17β-ethyl-17α-acetoxyandrosta-1,4-dien-3-one is obtained with a yield of 96.7 mol%. Example 3 10.0 g of acetic acid in 2.0 g of 17β-ethynyl-17α-hydroxyandrosta-1,4-dien-3-one
ml, acetic anhydride, 4.0 ml, and zinc chloride, 0.4 g, and stirred at room temperature for 25 hours. The product is extracted with dichloromethane in a similar manner to Example 1. The extract is analyzed by liquid chromatography. 17β-ethynyl-
77.2 mol % of 17α-acetoxyandrosta-1,4-dien-3-one is obtained.

Claims (1)

[Claims] 1 General formula () (In the formula, the dotted line represents a single bond or a double bond, and X represents an acyloxy group.) A 17β-ethynyl-17α-acyloxysteroid. 2 General formula () (In the formula, the dotted line represents a single bond or a double bond.) A 17β-ethynyl-17α-hydroxysteroid represented by the formula is reacted with a carboxylic acid anhydride or an acid halide to obtain the general formula (). (In the formula, the dotted line represents a single bond or a double bond, and X represents an acyloxy group.)